Androgen Receptor-Mediated Nuclear Transport of NRDP1 in Prostate Cancer Cells Is Associated with Worse Patient Outcomes

To our knowledge, our group is the first to demonstrate that NRDP1 is located in the nucleus as well as the cytoplasm of CaP cells. Subcellular fractionation, immunohistochemistry, and immunofluorescence analysis combined with confocal microscopy were used to validate this finding. Subcellular fractionation followed by western blot analysis revealed a strong association between AR and NRDP1 localization when AR expression and/or cellular localization was manipulated via treatment with R1881, AR-specific siRNA, or enzalutamide. Transfection of LNCaP with various NRDP1 and AR constructs followed by immunoprecipitation confirmed binding of NRDP1 to AR is possible and determined that binding requires the hinge region of AR. Co-transfection with NRDP1 constructs and HA-ubiquitin followed by subcellular fractionation confirmed that nuclear NRDP1 retains its ubiquitin ligase activity. We also show that increased nuclear NRDP1 is associated with PSA recurrence in CaP patients (n = 162, odds ratio; 1.238, p = 0.007) and that higher levels of nuclear NRDP1 are found in castration resistant cell lines (CWR22Rv1 and PC3) compared to androgen sensitive cell lines (LNCaP and MDA-PCa-3B). The combined data indicate that NRDP1 plays a role in mediating CaP progression and supports further investigation of both the mechanism by which nuclear transport occurs and the identification of specific nuclear targets.

Choosing a treatment method for post-catheterization pseudoaneurysms guided by the late to early velocity index

Ultrasound-guided thrombin injection (UGTI) is often the first-line treatment for iatrogenic post-catheterization pseudoaneurysms (psA). There are also first reports of the use of biologically derived tissue glues (TG) instead of sole thrombin especially when UGTI was unsuccessful or in case of psA recurrence. Previously, we have established that a late to early velocity index (LEVI) < 0.2 could be a predictor of an increased risk of psA recurrence after standard UGTI. In this paper, we report our first experiences when the choice of the first-line treatment method was based on LEVI assessment. From May 2017 till January 2020 we included 36 patients with psA. Of them, 10 had LEVI < 0.2 and they underwent ultrasound-guided tissue glue injection (UGTGI) with biological TG and 26 had LEVI > 0.2 and they underwent UGTI. The injection set containing human thrombin and fibrinogen was used for UGTGI. Bovine thrombin was used for UGTI. The success rate was 100% and no psA recurrence was detected during a 2-week follow-up. It was significantly better when compared to the expected recurrence rates based on our previous 14 years of experience (0% vs. 13%, p = 0.01). All complications (10% in the UGTGI group and 15% in the UGTI group) were mild and transient and included clinical symptoms of paresthesia, numbness, tingling, or pain. Their rates were comparable to the rates we previously reported. No significant differences in other characteristics were observed. The approach to choose the first-line treatment method for iatrogenic psA based on LEVI is encouraging. It may increase the success rate and avoid unnecessary repetition of the procedure, without increasing complication rate while keeping costs of the procedure reasonable.

Radiation Therapy After Radical Prostatectomy: What Has Changed Over Time?

The role and timing of radiotherapy (RT) in prostate cancer (PCa) patients treated with radical prostatectomy (RP) remains controversial. While recent trials support the oncological safety of early salvage RT (SRT) compared to adjuvant RT (ART) in selected patients, previous randomized studies demonstrated that ART might improve recurrence-free survival in patients at high risk for local recurrence based on adverse pathology. Although ART might improve survival, this approach is characterized by a risk of overtreatment in up to 40% of cases. SRT is defined as the administration of RT to the prostatic bed and to the surrounding tissues in the patient with PSA recurrence after surgery but no evidence of distant metastatic disease. The delivery of salvage therapies exclusively in men who experience biochemical recurrence (BCR) has the potential advantage of reducing the risk of side effects without theoretically compromising outcomes. However, how to select patients at risk of progression who are more likely to benefit from a more aggressive treatment after RP, the exact timing of RT after RP, and the use of hormone therapy and its duration at the time of RT are still open issues. Moreover, what the role of novel imaging techniques and genomic classifiers are in identifying the most optimal post-operative management of PCa patients treated with RP is yet to be clarified. This narrative review summarizes most relevant published data to guide a multidisciplinary team in selecting appropriate candidates for post-prostatectomy radiation therapy.

A Selective Androgen Receptor Modulator (OPK-88004) in Prostate Cancer Survivors: A Randomized Trial

Background Androgen deficiency is common among prostate cancer survivors, but many guidelines consider history of prostate cancer a contraindication for testosterone replacement. We determined the safety and efficacy of a selective androgen receptor modulator (OPK-88004) in symptomatic, testosterone-deficient men who had undergone radical prostatectomy for low grade, organ-confined prostate cancer. Methods In this placebo-controlled, randomized, double-blind trial, 114 men, &gt;19 years, who had undergone radical prostatectomy for low grade, organ-localized prostate cancer, undetectable PSA (&lt;0.1 ng/mL) for &gt;2 years after radical prostatectomy and testosterone deficiency were randomized in stages to placebo or 1, 5 or 15 mg OPK-88004 daily for 12-weeks. Outcomes included PSA recurrence, sexual activity, sexual desire, erectile function, body composition, muscle strength and physical function measures, mood, fatigue and bone markers. Results Participants were on average 67.5-years and had severe sexual dysfunction (mean erectile function and sexual desire domain scores 7.3, and 14.6, respectively). No participant experienced PSA recurrence or erythrocytosis. OPK-88004 was associated with a dose-related increase in whole body (P&lt;0.001) and appendicular (P&lt;0.001) lean mass and a significantly greater decrease in percent body fat (p&lt;0.001) and serum alkaline phosphatase (p&lt;0.001) than placebo. Changes in sexual activity, sexual desire, erectile function, mood, fatigue, physical performance, and bone markers did not differ among groups (p=0.73). Conclusions Administration of OPK-8804 was safe and not associated with PSA recurrence in androgen-deficient men who had undergone radical prostatectomy for organ-confined prostate cancer. OPK-88004 increased lean body mass and decreased fat mass, but did not improve sexual symptoms or physical performance.

Interim analysis of STARTAR: A phase II salvage trial of androgen receptor (AR) inhibition with androgen deprivation therapy (ADT) and apalutamide with radiation therapy (RT) followed by docetaxel in men with PSA recurrent prostate cancer (PC) after radical prostatectomy (RP).

90 Background: ADT with salvage RT improves survival for men with PSA recurrence after RP. Current standard duration of ADT for high risk PSA recurrence is up to 2 years with RT; therefore shortening but intensifying systemic therapy may improve outcomes. The STREAM trial showed 6 mo of enzalutamide added to ADT/RT had a 3-year progression free survival (PFS) of 53% in high risk patients including lymph node (LN) positive. Given that docetaxel improves survival in men with mHSPC, we evaluated the combination of salvage RT, ADT/apalutamide and docetaxel in this setting. Methods: STARTAR is a multicenter phase 2 trial for salvage treatment of PSA recurrent PC following RP conducted within the US Dept. of Defense Prostate Cancer Clinical Trials Consortium (DOD PCCTC). Key inclusion criteria included PC with Gleason 7 with T3/positive margin/1-4 positive LNs or Gleason 8-10 disease and PSA relapse within 4 years of RP (min PSA 0.2 ng/mL to max PSA 4 ng/mL). Men with up to 4 positive resected LNs were eligible. Men started ADT with apalutamide, continued with RT (66-74 Gy to the prostate bed +/- pelvic LNs over 6-8 weeks), and finally completed docetaxel 75mg/m2 IV q3 weeks for 6 cycles. Men were treated with ADT and apalutamide for approximately 9 months. The primary endpoint was PSA PFS at 36 months. This interim analysis evaluated secondary endpoints of 1-year PSA recurrence, testosterone recovery, and safety of this treatment sequence. Results: From 3/2018 to 12/2019, 39 men were enrolled at Duke, Wake Forest, Cornell, and the GU Research Network. With a data cutoff in 9/2020, median follow up from enrollment was 14 months. Baseline patient characteristics included Gleason 4+3 = 7 in 54% and Gleason 8-10 in 46%, and 23% LN positive; median PSA at the time of enrollment was 0.58 ng/mL (range 0.21-3.40) and the median time from RP to enrollment was 7 mo (range 2-98). At 1 year, there have been no progression events with 38% (12/31) of men with post-treatment testosterone recovery into normal range (recovery time median 10 mos [1-17 mos]). Common adverse events (AEs) of any-grade at least possibly related to the regimen were 98% hot flashes, 88% fatigue, 77% alopecia, 57% dysgeusia, and 53% rash (28% grade 1; 15% grade 2, 10% grade 3), with neutropenia as the most common grade 3/4 AE (27/39 men, 70%) with two grade 3 febrile neutropenia. Conclusions: In this first phase 2 trial of ADT, apalutamide, radiation, and 6 cycles docetaxel in the salvage setting for high risk PSA recurrence, short term outcomes are excellent with no recurrences at 12 months of follow-up. This salvage treatment was well tolerated in the majority of men with the exception of a high rate of drug rashes and neutropenia related to the course of treatment, in line with known safety profiles of the study agents. Clinical trial information: NCT03311555.

A new approach to the treatment of post-catheterization pseudoaneurysms by ultrasound-guided tissue glue injection or ultrasound-guided thrombin injection depending on a late to early velocity index

Background Ultrasound-guided thrombin injection (UGTI) is often the first-line treatment for iatrogenic post-catheterization pseudoaneurysms (psA). There are reports of the use of biologically-derived tissue glues (TG) instead of sole thrombin especially when UGTI was unsuccessful or in case of psA recurrence. TG are more potent procoagulants and may increase the procedure success rates at the cost of higher risk of complications in case too much substance escape into the patient's circulation during the procedure. TG are also more expensive than thrombin so they are often reserved for selected patients. We have previously identified a late to early velocity index (LEVI) &lt;0.2 as a predictor of an increased risk of psA recurrence after standard UGTI. In the current paper we report our first experiences when the choice of the first-line treatment method was based on LEVI. Methods From May 2017 till January 2020 we included 36 patients with psA. Of them, 10 had LEVI &lt;0.2 and they underwent ultrasound-guided tissue glue injection (UGTGI) and 26 had LEVI &gt;0.2 and underwent UGTI. The injection set (containing human thrombin and fibrinogen) was used for UGTGI. Bovine thrombin was used for UGTI. Results The success rate was 100% and no psA recurrence was detected during 2-week follow-up. It was significantly better when compared to the expected recurrence rates based on our previous 15 years of experience (0% vs. 13%, p=0.02). All complications were mild and transient and included clinical symptoms of paraesthesia, numbness, tingling, or pain. Their rates were comparable to the rates we previously reported. No significant differences in other characteristics were observed. Conclusion The approach to choose the first-line treatment method for iatrogenic psA based on LEVI is encouraging. Two examples of LEVI calculations Funding Acknowledgement Type of funding source: None

Impact of overall survival (OS) as a function of facility caseload on feasibility of referral of radical prostatectomy (RP) to higher volume facilities.

363 Background: We recently reported a significant all-cause mortality (ACM) risk reduction associated with higher annual caseload for RP (PMID 31398279). Four volume groups (VG) were defined as VG1: <50th, VG2: 50th-74th, VG3: 75th-89th and VG4: top 10 percentile of caseload. The adjusted OS difference between VG1 and VG4 at 90th percentile survivorship reached 13.2 months, HR 1.30 (p<0.0001). Here we explore this economics of referral to VG4. Methods: Using a Markov model, we designed 4 scenarios (Sc) where 100,000 RPs were performed. In Sc 1 all RPs were performed at VG1; in Sc 2, 3 & 4, all RPs were performed at VG2, 3 &4 respectively. Subjects were followed for up to 20 years after RP. Survival and costs of care for each Sc were recorded. Probabilities of PSA recurrence (PSAR), development of metastatic disease (Met), cancer specific mortality (CSM) and ACM were adjusted for each VG according to the published HRs. Savings resulting from fewer recurrences, avoidance of salvage radiation therapy (SRT) and management of fewer Met were calculated. Standard discounting at 3% were applied to costs and benefits. Survival benefit and costs savings associated with making referrals from VG1, VG2, or VG3 centers to VG4 center were calculated. Using a willingness to pay (WTP) of $50K per life years gained (LYG), the maximum referral costs (MRC) were calculated. Results: Referral from a VG1 to a VG4 center was associated with highest OS benefit of 720 LYG at 20 years of follow up per 1000 referrals (PKR). Within a WTP of $50K, MRC of up to $37K was cost effective- Table. Conclusions: Given the survival benefit associated with performing RP at facility with high annual caseload, significant resources could be allocated to making a referral possible while still remaining within cost effectiveness boundaries.[Table: see text]