Faculty Bibliography

BACKGROUND:Magnetic resonance imaging (MRI)-targeted prostate biopsy has become an increasingly common method of diagnosing prostate cancer. A previous study from our institution demonstrated that the biopsy global Grade Group (gGG, aggregate GG of all positive cores) and highest Grade Group (hGG in any core) both show substantial concordance with the Grade Group at radical prostatectomy (RPGG) while the discordance predominantly consists of upgrading in gGG and downgrading in hGG. We performed a larger cohort study focused on biopsy cases in which gGG and hGG differ, to determine their relative concordance with RPGG. METHODS:We conducted a retrospective review of radical prostatectomy specimens with prior MRI-targeted biopsies from our institution between 2016 and 2020. Separate gGG and hGG were assigned to each MRI-targeted lesion. Targeted lesions with different gGG versus hGG were segregated from those with identical gGG and hGG. The concordance of biopsy GG with RPGG was evaluated using κ coefficient analysis. RESULTS:Of the 489 lesions with MRI-targeted biopsies, 82 (17%) differed in gGG versus hGG. The gGG of 46 (56%), 33 (40%), and 3 (4%) lesions were unchanged, upgraded, and downgraded at radical prostatectomy, respectively (κ= 0.302, weighted κ = 0.334). The hGG of 24 (29%), 9 (11%), and 49 (60%) lesions were unchanged, upgraded, and downgraded at radical prostatectomy, respectively (κ = 0.040, weighted κ = 0.198). When stratified by the biopsy GG, gGG showed the highest concordance in GG2 (61%) and GG3 (54%) lesions. The hGG resulted in substantial downgrading (60%) with less optimal concordance regardless of the biopsy GG. Neither the prebiopsy prostate specific antigen level nor the PI-RADS score was predictive of upgrading of gGG. CONCLUSIONS:When gGG and hGG differ, gGG method more accurately predicts the RPGG than hGG, particularly in GG2 and GG3 lesions which comprised the majority of targeted lesions.

OBJECTIVE:Our purpose was to critically evaluate time dependent sexual function following primary partial gland cryo-ablation (PGCA) stratified according to baseline erectile function. METHODS:Between March 2017 and March 2022, all men undergoing primary PGCA by two surgeons were enrolled in an IRB approved outcomes registry. All subjects with PIRADS 2-5 lesion concordant with unilateral GGG 1-3 disease, no gross extra-prostatic extension on mpMRI, GGG >1 contralateral to the ROI, or distal apical disease on mpMRI were enrolled. Patients completed the Sexual Health Inventory for Men (SHIM) scale at baseline, 6, and 24 months. Men were stratified by baseline erectile function. Men with SHIM Score < 8 were excluded. Ability to sustain erection (aka "potency") was defined as a score of 3 or greater on question 2 of the SHIM index. Median SHIM scores and the proportion of men reporting "potency" at baseline, 6, and 24 months was recorded with comparisons between each timepoint. A univariate analysis was used to determine if clinical factors were associated with loss of "potency" at 24 months. RESULTS:106 men met the inclusion criteria. There was a statistically significant decrease in the mean SHIM scores for the entire cohort between baseline to 6 months and baseline to 24 months. SHIM scores increased significantly for the total cohort between 6 and 24 months. "Potency" was preserved in 70% at 24 months. CONCLUSIONS:Those patients most likely to exhibit a decrease in sexual function have moderate ED at baseline. Only baseline ED was shown to predict preservation of "potency".

Introduction: We aimed to determine cancer detection rates following early repeat multiparametric magnetic resonance imaging (mpMRI) and biopsy of Prostate Imaging-Reporting and Data System (PI-RADS), v2.1 4 and 5 regions of interest (ROI) exhibiting no clinically significant prostate cancer (csPCa) on prior biopsy and to identify predictors for these missed csPCa. Methods: Between January 2019 and August 2020, 36 men with 38 PI-RADS 4 or 5 ROI with no evidence of csPCa (defined as Gleason grade group [GGG] >1) on prior MRI fusion target biopsy (MRFTB) + systematic biopsy (SB) were invited to participate in the present prospective study. All men underwent repeat mpMRI and persistent PI-RADS >2 ROI were advised to undergo repeat MRFTB+SB. Cancer detection rates of any and csPCa were determined. Relative risk was calculated to analyze association of baseline variables with the finding of csPCa on repeat biopsy. Results: Of the 38 initial PI-RADS 4 and 5 ROI, on followup mpMRI, 14 were downgraded to PI-RADS 1/2 and, per protocol, did not undergo repeat biopsy and; eight (33%), 12 (50%), and four (17%) were PI-RADS 3, 4, and 5 respectively. Of these 24 persistently suspicious mpMRI ROI, 20 (83%) underwent repeat biopsy and six (30%), six (30%), and eight (40%) were benign, GGG 1, and GGG >1, respectively. Only prostate-specific antigen ≥10 ng/mL was a predictor for missed csPCa. Conclusions: Our prospective study supports a recommendation for early repeat mpMRI of all PI-RADS 4 or 5 ROI exhibiting no csPCa, with repeat MRFTB + SB of persistent PI-RADS >2 ROI .

PURPOSE/OBJECTIVE:F-Fluciclovine) PET/MRI informs the decision to perform an early repeat biopsy of PI-RADS 4/5 region of interest (ROI) exhibiting no clinically significant prostate cancer (csPCa) on initial biopsy. METHODS:This prospective study enrolled men with at least one PI-RADS 4/5 ROI on multi-parametric MRI and no csPCa on prior biopsy defined as Gleason grade group (GGG) > 1. All men underwent an Axumin PET/MRI and only-persistent PI-RADS > 2 ROI were advised to undergo a repeat biopsy. A PET cancer suspicion score (PETCSS) was internally developed to stratify PET avid lesions according to their suspicion of harboring csPCa. The sensitivity, specificity, positive (PPV) and negative predictive value (NPV) of the PETCSS for predicting csPCa were assessed. Relative risk was calculated to analyze the association of baseline variables with csPCa on repeat biopsy. RESULTS:Thirty-eight ROI on 36 enrolled men were analyzed. Fourteen (36.8%) were downgraded to PI-RADS 1/2 and were not subjected to repeat biopsy. Thirteen (92.9%) of these downgraded scans also exhibited low-risk PETCSS. Overall, 18/22 (81.2%) subjects underwent a repeat per protocol biopsy. Of the 20 ROI subjected to repeat biopsy, eight (40%) were found to harbour csPCa. The sensitivity, specificity, PPV and NPV of the PETCSS were 50, 50, 40, and 60%, respectively. No predictor of csPCa was found in the risk analysis. CONCLUSION/CONCLUSIONS:Our pilot study showed that both MRI and PET sequences have limited performance for identifying those persistently suspicious PI-RADS 4/5 ROI that are found to harbor csPCa on repeat biopsy.

BACKGROUND:Focal Therapy (FT) for Prostate Cancer (PCa) is promising. However, long-term oncological results are awaited and there is no consensus on follow-up strategies. Molecular biomarkers (MB) may be useful in selecting, treating and following up men undergoing FT, though there is limited evidence in this field to guide practice. We aimed to conduct a consensus meeting, endorsed by the Focal Therapy Society, amongst a large group of experts, to understand the potential utility of MB in FT for localised PCa. MATERIALS AND METHODS/METHODS:A 38-item questionnaire was built following a literature search. The authors then performed three rounds of a Delphi Consensus using DelphiManager, using the GRADE grid scoring system, followed by a face-to-face expert meeting. Three areas of interest were identified and covered concerning MB for FT, i) the current/present role; ii) the potential/future role; iii) the recommended features for future studies. Consensus was defined using a 70% agreement threshold. RESULTS:Of 95 invited experts, 42 (44.2%) completed the three Delphi rounds. Twenty-four items reached a consensus and they were then approved at the meeting involving (n=15) experts. Fourteen items reached a consensus on uncertainty, or they did not reach a consensus. They were re-discussed, resulting in a consensus (n=3), a consensus on a partial agreement (n=1), and a consensus on uncertainty (n=10). A final list of statements were derived from the approved and discussed items, with the addition of three generated statements, to provide guidance regarding MB in the context of FT for localised PCa. Research efforts in this field should be considered a priority. CONCLUSIONS:The present study detailed an initial consensus on the use of MB in FT for PCa. This is until evidence becomes available on the subject.

Purpose/UNASSIGNED:The goal of partial gland ablation (PGA) is to eradicate focal lesions of clinically significant prostate cancer (csPCa) with minimal adverse impact on functional outcomes. The primary objective of this study is to characterize the performance of 18F-Fluciclovine PET imaging for detection of prostate cancer following PGA. Materials and Methods/UNASSIGNED:Subjects 2 years following primary partial gland cryoablation (PPGCA) were invited to participate in an IRB-approved study providing they met the following inclusion criteria: a single reported mpMRI region of interest (ROI) concordant with biopsy Gleason Grade Group (GGG) < 4, no gross extra-prostatic extension on mpMRI, and no GGG > 1 or GGG 1 with a core length > 6 mm on contralateral systematic biopsy. 18F-Fluciclovine PET MRI imaging of the prostate was performed followed by in and out-of-field biopsies. Results/UNASSIGNED:Twenty-seven men who met eligibility criteria participated in the prospective study. In-field and out-of-field csPCa recurrence rate was 7.4% and 22.2%, respectively. The sensitivity and positive predictive value of mpMRI and PET imaging did not reach performance to reliably inform who should undergo prostate biopsy. Conclusion/UNASSIGNED:At 2 years following PPGCA, the rate of in-field csPCa was exceedingly low indicating a limited role for imaging to inform in-field biopsy decisions. The csPCa detection rate of out-of-field recurrence was 22% which provides an opportunity for imaging to inform out-of-field biopsy decisions. Based on our findings, 18F-Fluciclovine PET MRI cannot be used to inform who should undergo out-of-field prostate biopsy at 2 years following PPGCA.

INTRODUCTION/BACKGROUND:Given the increasing interest in partial gland cryo-ablation as a treatment modality and the lack of data surrounding urinary and sexual outcomes after the procedure, the goal of this analysis was to assess functional outcomes following partial gland cryo-ablation (PGCA) stratified according to baseline severity of lower urinary tract symptoms (LUTS) and erectile function (EF). A secondary goal was to also determine if there were any clinical factors associated with significant change in LUTS and EF. MATERIALS AND METHODS/METHODS:Since 3/2017, all men undergoing primary PGCA were offered enrollment into an IRB-approved prospective outcomes registry. Men were given International Prostate Symptom Score (IPSS) and Sexual Health Inventory for Men (SHIM) surveys prior to and 6 months post treatment. Differences in IPSS and SHIM scores are described, and factors associated with clinically significant change were assessed using univariate and multivariate analysis. RESULTS:A total of 100 men completed 6 month follow up. The mean IPSS for the overall cohort decreased 2.1 units (p > 0.05). The mean changes in IPSS for men with baseline mild, moderate, and severe LUTS were 0.9 (p = 0.06), -4.2 (p = 0.001), and -11.1(p = 0.001) units, respectively. The mean changes in the SHIM score for all men were - 5.1 units (p = 0.001). The mean changes in SHIM score for baseline none, mild/mild-to-moderate, moderate-severe ED were -7.6 (p = 0.001), -6.5 (p = 0.001) and -1.1 units (p = 0.27), respectively. No variables of interest were significantly associated with changes in IPSS or SHIM scores. CONCLUSION/CONCLUSIONS:Stratifying functional outcomes according to baseline IPSS and SHIM is imperative to assess the true impact of PGCA on functional outcomes.

Purpose/UNASSIGNED:Whole gland cryoablation is a guideline-approved definitive treatment for localized prostate cancer, and is being explored for partial gland ablation. However, there is limited data regarding management of cryoablation failures. Stereotactic body radiation therapy (SBRT) is a well-established method of primary treatment for prostate cancer. Here we review salvage SBRT after cryoablation failures. Methods and Materials/UNASSIGNED:A large database of patients treated with definitive SBRT was interrogated to identify those who underwent primary cryoablation. All patients were determined to have progressive disease based on a rising prostate specific antigen and/or postcryoablation biopsy. All patients were treated with SBRT over 5 treatment fractions using a robotic radiosurgical platform. Baseline cryoablation characteristics and pre- and posttreatment Expanded Prostate Cancer Index Composite questionnaires were analyzed. Acute and late toxicity was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Cancer outcomes after salvage SBRT were stratified by disease and treatment characteristics. Results/UNASSIGNED:A total of 51 patients were identified who underwent cryoablation followed by salvage SBRT. The majority (47%) were found to have intermediate-risk disease at the time of SBRT salvage and most commonly were treated with 3500 cGy in 5 fractions to the prostate and seminal vesicles. Only 1 grade 3+ toxicity was identified. Patient-reported quality of life metrics after SBRT salvage followed prior patterns observed in the de novo SBRT setting. With a median follow-up of 40 months, 76% of the cohort demonstrated disease control. Median time to prostate cancer recurrence was 57.5 months, and recurrence was predominantly seen in patients with underlying high-risk disease. Conclusions/UNASSIGNED:This is the largest cohort of patients treated with any radiation therapy salvage after cryoablation and the first institution to report SBRT as a modality of salvage. Salvage SBRT after cryoablation results in low rates of high-grade toxicity, acceptable changes in patient-reported quality of life, and durable rates of long-term oncologic control.

Pyruvate kinase M2 (PKM2) has been shown to promote tumorigenesis by facilitating the Warburg effect and enhancing the activities of oncoproteins. However, this paradigm has recently been challenged by studies in which the absence of PKM2 failed to inhibit and instead accelerated tumorigenesis in mouse models. These results seem inconsistent with the fact that most human tumors overexpress PKM2. To further elucidate the role of PKM2 in tumorigenesis, we investigated the effect of PKM2 knockout in oncogenic HRAS-driven urothelial carcinoma. While PKM2 ablation in mouse urothelial cells did not affect tumor initiation, it impaired the growth and maintenance of HRAS-driven tumors. Chemical inhibition of PKM2 recapitulated these effects. Both conditions substantially reduced complex formation of PKM2 with STAT3, their nuclear translocation, and HIF1α- and VEGF-related angiogenesis. The reduction in nuclear STAT3 in the absence of PKM2 also correlated with decreased autophagy and increased apoptosis. Time-controlled, inducible PKM2 overexpression in simple urothelial hyperplasia did not trigger tumorigenesis, while overexpression of PKM2, but not PKM1, in nodular urothelial hyperplasia with angiogenesis strongly accelerated tumorigenesis. Finally, in human patients, PKM2 was overexpressed in low-grade non-muscle invasive and high-grade muscle-invasive bladder cancer. Based on these data, PKM2 is not required for tumor initiation but is essential for tumor growth and maintenance by enhancing angiogenesis and metabolic addiction. The PKM2-STAT3-HIF1α/VEGF signaling axis may play a critical role in bladder cancer and may serve as an actionable therapeutic target.