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Background: Racial disparities exist in prostate cancer (PCa) care and outcomes. Ultrasound-guided biopsy may miss a significant portion of clinically significant PCa while magnetic resonance imaging (MRI) improves its detection. This study aims to investigate demographic and SES factors influencing MRI utilization for PCa detection., Methods: SEER-Medicare data were used to assess use of pre-diagnostic MRI in 90,908 patients diagnosed with primary PCa (2012-2019). Modified Poisson regression models adjusted for socioeconomic factors such as income, education, Medicare buy-in and dual eligibility were used to examine factors associated with MRI use. All statistical tests were two-sided., Results: Pre-diagnostic MRI utilization increased substantially between 2012 (3.8%) and 2019 (32.6%). The disparity in utilization between non-Hispanic Black and non-Hispanic White patients decreased by more than half from 43% (RR = 0.57, 95%CI = 0.48-0.67) in 2012 to 20% (RR = 0.80, 95%CI = 0.74-0.86) in 2019. Rural residents were 35% less likely (RR = 0.65, 95%CI = 0.61-0.69) to undergo MRI, while those in the Central US (vs West) were 49% less likely (RR = 0.49, 95%CI = 0.48-0.51). No significant disparities in MRI use were identified between ages ≥75 and 64-75. SES factors associated with MRI were income, education, Medicare buy-in and dual eligibility., Conclusions: This study revealed increased MRI utilization over time including among those 75 and older. Racial disparities decreased, while wide urban/rural disparities remained. Targeted public health interventions should focus on geographical factors, as "urban/rural designations" and "US region" were associated with the most prominent disparities. Future research should explore pathways contributing to these disparities, using a multidisciplinary approach, including geographical studies, to help eliminate healthcare inequities., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Competing Interests: Disclosure: M.B. is a coinventor on a patent application (WO2018013849A1) for cross-circulation as a platform for extracorporeal organ recovery, regeneration, and maintenance. W.K.W., R.U., and M.B. are co-inventors on a patent application for an alternate configuration of cross-circulation for the same purpose. The other authors have no conflicts of interest to report.

Importance: Olaparib is a poly(adenosine diphosphate-ribose) polymerase inhibitor that provides benefit in combination with hormonal therapies in patients with metastatic prostate cancer who harbor homologous recombination repair (HRR) alterations. Its efficacy in the absence of androgen deprivation therapy has not been tested., Objective: To determine the activity of olaparib monotherapy among patients with high-risk biochemically recurrent (BCR) prostate cancer after radical prostatectomy., Design, Setting, and Participants: This phase 2, single-arm nonrandomized controlled trial enrolled genetically unselected patients across 4 sites in the US from May 2017 to November 2022. Eligible patients had BCR disease following radical prostatectomy, a prostate-specific antigen (PSA) doubling time of 6 months or shorter, an absolute PSA value of 1.0 ng/mL or higher, and a testosterone level of 150 ng/dL or higher., Intervention: Treatment was with olaparib, 300 mg, by mouth twice daily until doubling of the baseline PSA, clinical or radiographic progression, or unacceptable toxic effects., Main Outcome and Measure: The primary end point was a confirmed 50% or higher decline in PSA from baseline (PSA50). Key secondary end points were outcomes by HRR alteration status, as well as safety and tolerability., Results: Of the 51 male patients enrolled (mean [SD] age, 63.8 [6.8] years), 13 participants (26%) had a PSA50 response, all within the HRR-positive group (13 of 27 participants [48%]). All 11 participants with BRCA2 alterations experienced a PSA50 response. Common adverse events were fatigue in 32 participants (63%), nausea in 28 (55%), and leukopenia in 22 (43%), and were consistent with known adverse effects of olaparib., Conclusions and Relevance: In this nonrandomized controlled trial, olaparib monotherapy led to high and durable PSA50 response rates in patients with BRCA2 alterations. Olaparib warrants further study as a treatment strategy for some patients with BCR prostate cancer but does not have sufficient activity in those without HRR alterations and should not be considered for those patients., Trial Registration: ClinicalTrials.gov Identifier: NCT03047135.

It is known that small extracellular vesicles (sEVs) are released from cancer cells and contribute to cancer progression via crosstalk with recipient cells. We have previously reported that sEVs expressing the αVβ3 integrin, a protein upregulated in aggressive neuroendocrine prostate cancer (NEPrCa), contribute to neuroendocrine differentiation (NED) in recipient cells. Here, we examine the impact of αVβ3 expression on sEV protein content, density and function. sEVs used in this study were isolated by iodixanol density gradients and characterized by nanoparticle tracking analysis, immunoblotting and single vesicle analysis. Our proteomic profile of sEVs containing αVβ3 shows downregulation of typical effectors involved in apoptosis and necrosis and an upregulation of tumour cell survival factors compared to control sEVs. We also show that the expression of αVβ3 in sEVs causes a distinct reposition of EV markers (Alix, CD81, CD9) to a low-density sEV subpopulation. This low-density reposition is independent of extracellular matrix (ECM) protein interactions with sEVs. This sEV subset contains αVβ3 and an αVβ3 downstream effector, NgR2, a novel marker for NEPrCa. We show that sEVs containing αVβ3 are loaded with higher amounts of NgR2 as compared to sEVs that do not express αVβ3. Mechanistically, we demonstrate that sEVs containing NgR2 do not affect the sEV marker profile, but when injected in vivo intratumorally, they promote tumour growth and induce NED. We show that sEVs expressing NgR2 increase the activation of focal adhesion kinase (FAK), a known promoter of cancer cell proliferation, in recipient cells. We also show that NgR2 mimics the effect of sEVs containing αVβ3 since it displays increased growth of NgR2 transfectants in vivo, as compared to control cells. Overall, our results describe the changes that occur in cargo, density and functions of cancer cell-derived sEVs containing the αVβ3 integrin and its effector, NgR2, without affecting the sEV tetraspanin profiles., (© 2024 The Author(s). Journal of Extracellular Vesicles published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.)

High-dose intravenous vitamin C (HDIVC) administered to produce pharmacologic concentrations shows promise in preclinical models and small clinical trials, but larger prospective randomized trials are lacking. We evaluated the clinical benefit of combining HDIVC with docetaxel in patients with progressive metastatic castration-resistant prostate cancer (mCRPC). In this double-blind, placebo-controlled phase II trial, 47 patients were randomized 2:1 to receive docetaxel (75 mg/m2 i.v.) with either HDIVC (1 g/kg) or placebo. Coprimary endpoints were PSA50 response and adverse event rates. Secondary endpoints included overall survival, radiographic progression-free survival, and quality of life measured using the Functional Assessment of Cancer Therapy-Prostate instrument. Correlative analyses included pharmacokinetics and oxidative stress markers. Eighty-nine percent of patients previously had three or more lines of therapy. The PSA50 response rate was 41% in the HDIVC group and 33% in the placebo group (P = 0.44), with comparable adverse event rates in both groups. There were no significant differences in Functional Assessment of Cancer Therapy-Prostate scores. The median radiographic progression-free survival was not significantly different between the HDIVC and placebo groups, with durations of 10.1 and 10.0 months (HR, 1.35; 95% confidence interval, 0.66-2.75; P = 0.40), respectively. The median overall survival was 15.2 months in the HDIVC group and 29.5 months in the placebo group (HR, 1.98; 95% confidence interval, 0.85-4.58; P = 0.11). HDIVC did not decrease F2-isoprostanes, indicators of oxidative stress. The study was suspended after prespecified interim analysis indicated futility in achieving primary endpoints. In this patient population, combining HDIVC with docetaxel did not improve PSA response, toxicity, or other clinical outcomes compared with docetaxel alone. Findings do not support the routine use of HDIVC in mCRPC treatment outside of clinical trials., Significance: This is the first randomized, placebo-controlled, double-blind trial to evaluate HDIVC in cancer treatment. The addition of HDIVC to docetaxel in patients with mCRPC does not improve PSA response, toxicity, or other clinical outcomes compared with docetaxel alone. The routine use of HDIVC in mCRPC treatment is not supported outside of clinical trials., (©2024 The Authors; Published by the American Association for Cancer Research.)

Bevacizumab-induced hypertension poses a therapeutic challenge and identifying biomarkers for hypertension can enhance therapy safety. Lower plasma levels of VEGF-A, angiopoietin-2, and rs6770663 in KCNAB1 were previously associated with increased risk of bevacizumab-induced hypertension. This study investigated whether these factors independently contribute to grade 2-3 bevacizumab-induced hypertension risk in 277 cancer patients (CALGB/Alliance 90401). Multivariable analyses assessed the independent association of each factor and hypertension. Likelihood ratio test (LRT) evaluated the explanatory significance of combining protein levels and rs6770663 in predicting hypertension. Boostrap was employed to assess the mediation effect of protein levels on the rs6770663 association with hypertension. Lower protein levels and rs6770663 were independently associated with increased hypertension risk. Adding rs6770663 to protein levels improved the prediction of hypertension (LRT p = 0.0002), with no mediation effect observed. Protein levels of VEGF-A, angiopoietin-2 and rs6770663 in KCNAB1 are independent risk factors and, when combined, may improve prediction of bevacizumab-induced hypertension. ClinicalTrials.gov Identifier: NCT00110214., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Nematodes are the most abundant and diverse metazoans on Earth, and are known to significantly affect ecosystem functioning. A better understanding of their biology and ecology, including potential adaptations to diverse habitats and lifestyles, is key to understanding their response to global change scenarios. Mitochondrial genomes offer high species level characterization, low cost of sequencing, and an ease of data handling that can provide insights into nematode evolutionary pressures., Results: Generally, nematode mitochondrial genomes exhibited similar structural characteristics (e.g., gene size and GC content), but displayed remarkable variability around these general patterns. Compositional strand biases showed strong codon position specific G skews and relationships with nematode life traits (especially parasitic feeding habits) equal to or greater than with predicted phylogeny. On average, nematode mitochondrial genomes showed low non-synonymous substitution rates, but also high clade specific deviations from these means. Despite the presence of significant mutational saturation, non-synonymous (dN) and synonymous (dS) substitution rates could still be significantly explained by feeding habit and/or habitat. Low ratios of dN:dS rates, particularly associated with the parasitic lifestyles, suggested the presence of strong purifying selection., Conclusions: Nematode mitochondrial genomes demonstrated a capacity to accumulate diversity in composition, structure, and content while still maintaining functional genes. Moreover, they demonstrated a capacity for rapid evolutionary change pointing to a potential interaction between multi-level selection pressures and rapid evolution. In conclusion, this study helps establish a background for our understanding of the potential evolutionary pressures shaping nematode mitochondrial genomes, while outlining likely routes of future inquiry., (© 2024. The Author(s).)

Introduction: Prostate cancer (PCa) is the most common non-cutaneous tumor among American men. Androgen receptor signaling inhibitors such as abiraterone and enzalutamide have been approved for similar disease states among patients with advanced PCa. Existing data suggest using steroids is associated with an increased risk of infection. Because abiraterone is usually prescribed with prednisone, we sought to compare the risk of septicemia in patients using abiraterone vs. enzalutamide., Materials and Methods: We utilized the SEER-Medicare-linked data and used negative binomial regression models to compare the changes in the rates of septicemia-related hospitalizations six months pre- and post-abiraterone and enzalutamide initiation., Results: We found that the incidence of septicemia-related hospitalizations increased 2.77 fold within six months of initiating abiraterone (incidence rate ratio [IRR]: 2.77, 95% confidence interval [CI]: 2.17-3.53) 1.97 fold within six months of starting enzalutamide (IRR: 1.97, 95% CI: 1.43-2.72). However, the difference in the changes did not reach statistical significance (interaction IRR: 0.71, 95% CI: 0.48-1.06)., Discussion: The findings suggest that both abiraterone and enzalutamide are associated with an increased risk of septicemia-related hospitalizations. However, the difference in the increase of septicemia risk following the two treatments did not reach statistical significance. Further studies are warranted to understand the mechanisms at play., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Identification of emerging molecular biomarkers on circulating tumor cells (CTCs) represents an attractive feature of liquid biopsy that facilitates precision and tailored medicine in the management of metastatic castration-resistant prostate cancer (mCRPC). Prostein is an androgen-regulated transmembrane protein with high prostate specificity. Prostein-positive circulating tumor cell (CTC) was recently suggested to have diagnostic potential; however, no study has been conducted to evaluate its prognostic value in mCRPC., Methods: CTCs from mCRPC patients were enumerated using the CellSearch System. Prostein-positive CTCs were identified by immunostaining results. The relationships between prostein expression on CTCs and PSA response rate, PSA progression-free survival (PSA-PFS), radiographic progression-free survival (PFS), and overall survival (OS) were tested by Fisher's exact test or evaluated using Kaplan-Meier and multivariate Cox analyses., Results: Prostein-positive CTCs were identified in 31 of 87 baseline samples from mCRPC patients and 16 of 51 samples collected at the first follow-up visit. PSA response rates were significantly lower in baseline prostein-positive patients (0%, 0/31) than in prostein-negative patients (19.6%, 11/56) (p = 0.007). The 31 prostein-positive patients had significantly shorter PSA-PFS (p < 0.001), radiographic PFS (p < 0.001), and OS (p = 0.018), compared to the 56 prostein-negative patients at baseline. The association with PSA-PFS maintained its significance (p = 0.028) in multivariate analyses. Analyzing prostein expression at the first follow-up as well as the conversion of prostein expression from baseline to follow-up samples not only confirmed the association with PSA-PFS, but also demonstrated prognostic significance with OS., Conclusion: Our study provides the first evidence to support the potential of prostein expression on CTCs to serve as a novel prognostic marker in mCRPC patients. Future large-scale prospective studies are needed to validate our findings., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

The objective of this study was to discover clinical and pharmacogenetic factors associated with bevacizumab-related gastrointestinal hemorrhage in Cancer and Leukemia Group B (Alliance) 90401. Patients with metastatic castration-resistant prostate cancer received docetaxel and prednisone ± bevacizumab. Patients were genotyped using Illumina HumanHap610-Quad and assessed using cause-specific risk for association between single nucleotide polymorphisms (SNPs) and gastrointestinal hemorrhage. In 1008 patients, grade 2 or higher gastrointestinal hemorrhage occurred in 9.5% and 3.8% of bevacizumab (n = 503) and placebo (n = 505) treated patients, respectively. Bevacizumab (P < 0.001) and age (P = 0.002) were associated with gastrointestinal hemorrhage. In 616 genetically estimated Europeans (n = 314 bevacizumab and n = 302 placebo treated patients), grade 2 or higher gastrointestinal hemorrhage occurred in 9.6% and 2.0% of patients, respectively. One SNP (rs1478947; HR 6.26; 95% CI 3.19-12.28; P = 9.40 × 10 -8 ) surpassed Bonferroni-corrected significance. Grade 2 or higher gastrointestinal hemorrhage rate was 33.3% and 6.2% in bevacizumab-treated patients with the AA/AG and GG genotypes, versus 2.9% and 1.9% in the placebo arm, respectively. Prospective validation of these findings and functional analyses are needed to better understand the genetic contribution to treatment-related gastrointestinal hemorrhage., (© 2024. The Author(s).)

Purpose: Germline genetic testing (GT) is important for prostate cancer (PCA) management, clinical trial eligibility, and hereditary cancer risk. However, GT is underutilized and there is a shortage of genetic counselors. To address these gaps, a patient-driven, pretest genetic education webtool was designed and studied compared with traditional genetic counseling (GC) to inform strategies for expanding access to genetic services., Methods: Technology-enhanced acceleration of germline evaluation for therapy (TARGET) was a multicenter, noninferiority, randomized trial (ClinicalTrials.gov identifier: NCT04447703) comparing a nine-module patient-driven genetic education webtool versus pretest GC. Participants completed surveys measuring decisional conflict, satisfaction, and attitudes toward GT at baseline, after pretest education/counseling, and after GT result disclosure. The primary end point was noninferiority in reducing decisional conflict between webtool and GC using the validated Decisional Conflict Scale. Mixed-effects regression modeling was used to compare decisional conflict between groups. Participants opting for GT received a 51-gene panel, with results delivered to participants and their providers., Results: The analytic data set includes primary outcome data from 315 participants (GC [n = 162] and webtool [n = 153]). Mean difference in decisional conflict score changes between groups was -0.04 (one-sided 95% CI, -∞ to 2.54; P = .01), suggesting the patient-driven webtool was noninferior to GC. Overall, 145 (89.5%) GC and 120 (78.4%) in the webtool arm underwent GT, with pathogenic variants in 15.8% (8.7% in PCA genes). Satisfaction did not differ significantly between arms; knowledge of cancer genetics was higher but attitudes toward GT were less favorable in the webtool arm., Conclusion: The results of the TARGET study support the use of patient-driven digital webtools for expanding access to pretest genetic education for PCA GT. Further studies to optimize patient experience and evaluate them in diverse patient populations are warranted.

Objectives: Combined heart-liver transplantation (CHLT) is becoming increasingly frequent as a maturing population of patients with Fontan-palliated congenital heart disease develop advanced liver fibrosis or cirrhosis. The authors present their experience with CHLT for congenital and noncongenital indications, and identify characteristics associated with poor outcomes that may guide intervention in high-risk patients., Design: This was a single-center retrospective cohort study., Setting: This study was conducted at Vanderbilt University Medical Center in Nashville, Tennessee., Participants: The study included 16 consecutive adult recipients of CHLT at the authors' institution between April 2017 and February 2022., Interventions: Eleven patients underwent transplantation for Fontan indications, and 5 were transplanted for non-Fontan indications., Measurements and Main Results: Compared with non-Fontan patients, Fontan recipients had longer cardiopulmonary bypass duration (199 v 119 minutes, p =m0.002), operative times (786 v 599 minutes, p = 0.01), and larger blood product transfusions (15.4 v 6.3 L, p = 0.18). Six of 16 patients required extracorporeal membrane oxygenation (ECMO), of whom 4 were Fontan patients who subsequently died. Patients who required ECMO had lower 5-hour lactate clearance (0.0 v 3.5 mmol/L, p = 0.001), higher number of vasoactive infusions, lower pulmonary artery pulsatility indices (0.58 v 1.77, p = 0.03), and higher peak inspiratory pressures (28.0 v 18.5 mmHg, p = 0.01) after liver reperfusion., Conclusions: Combined heart-liver transplantation in patients with Fontan-associated end-organ disease is particularly challenging and associated with higher recipient morbidity compared with non-Fontan-related CHLT. Early hemodynamic intervention for signs of ventricular dysfunction may improve outcomes in this growing high-risk population., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier Inc.)

Background: CALGB 90401 (Alliance) was a phase III trial of 1050 patients with metastatic castration-resistant prostate cancer (mCRPC) comparing docetaxel, prednisone, bevacizumab (DP+B) versus DP alone. While this trial did not show an improvement in overall survival (OS), there were improved intermediate outcomes suggesting that subsets of men may derive benefit from this combination. The purpose of this analysis was to identify prognostic and predictive biomarkers associated with OS and progression-free survival (PFS) benefit from DP+B., Methods: Baseline EDTA plasma samples from 650 consenting patients were analyzed for 24 biomarkers. The proportional hazards model was utilized to test for the prognostic and predictive importance of the biomarkers for OS. The statistically significant biomarkers of OS were further investigated for prognostic and predictive importance for other secondary outcomes., Results: 15 markers [ICAM-1, VEGF-R3, TIMP-1, TSP-2, Ang-2, Her-3, Osteopontin (OPN), PlGF, VCAM-1, HGF, VEGF, Chromogranin A, IL-6, VEGF-R1, BMP-9] were prognostic of OS, while 9 markers (ICAM-1, VEGF-R3, Her-3, TIMP-1, Ang-2, OPN, PlGF, HGF, and VEGF) were also prognostic of PFS. All markers were statistically significant in univariate analyses after adjustment for multiplicity (FDR < 0.1). In multivariable analyses of OS adjusting for risk score, seven markers had FDR < 0.1, including ICAM-1, VEGF-R3, TIMP-1, Ang-2, VEGF, TSP-2 and HGF. In unadjusted analysis, OPN was predictive of PFS improvement with DP+B, in both univariate and multivariable analysis. However, none of the biomarkers tested were predictive of clinical outcomes after adjusting for multiple comparisons., Conclusions: Multiple biomarkers were identified in CALGB 90401 as prognostic of clinical outcomes but not predictive of OS. While OPN may have promise as a potential biomarker for anti-angiogenic therapies, further mechanistic and clinical studies are needed to determine the underlying biology and potential clinical application., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Xaluritamig (AMG 509) is a six-transmembrane epithelial antigen of the prostate 1 (STEAP1)-targeted T-cell engager designed to facilitate lysis of STEAP1-expressing cancer cells, such as those in advanced prostate cancer. This first-in-human study reports monotherapy dose exploration for patients with metastatic castration-resistant prostate cancer (mCRPC), primarily taxane pretreated. Ninety-seven patients received ≥1 intravenous dose ranging from 0.001 to 2.0 mg weekly or every 2 weeks. MTD was identified as 1.5 mg i.v. weekly via a 3-step dose. The most common treatment-related adverse events were cytokine release syndrome (CRS; 72%), fatigue (45%), and myalgia (34%). CRS occurred primarily during cycle 1 and improved with premedication and step dosing. Prostate-specific antigen (PSA) and RECIST responses across cohorts were encouraging [49% PSA50; 24% objective response rate (ORR)], with greater frequency at target doses ≥0.75 mg (59% PSA50; 41% ORR). Xaluritamig is a novel immunotherapy for prostate cancer that has shown encouraging results supporting further development., Significance: Xaluritamig demonstrated encouraging responses (PSA and RECIST) compared with historical established treatments for patients with late-line mCRPC. This study provides proof of concept for T-cell engagers as a potential treatment for prostate cancer, validates STEAP1 as a target, and supports further clinical investigation of xaluritamig in prostate cancer. See related commentary by Hage Chehade et al., p. 20. See related article by Nolan-Stevaux et al., p. 90. This article is featured in Selected Articles from This Issue, p. 5., (©2023 The Authors; Published by the American Association for Cancer Research.)

Signaling rewiring allows tumors to survive therapy. Here we show that the decrease of the master regulator microphthalmia transcription factor (MITF) in lethal prostate cancer unleashes eukaryotic initiation factor 3B (eIF3B)-dependent translation reprogramming of key mRNAs conferring resistance to androgen deprivation therapy (ADT) and promoting immune evasion. Mechanistically, MITF represses through direct promoter binding eIF3B, which in turn regulates the translation of specific mRNAs. Genome-wide eIF3B enhanced cross-linking immunoprecipitation sequencing (eCLIP-seq) showed specialized binding to a UC-rich motif present in subsets of 5' untranslated regions. Indeed, translation of the androgen receptor and major histocompatibility complex I (MHC-I) through this motif is sensitive to eIF3B amount. Notably, pharmacologic targeting of eIF3B-dependent translation in preclinical models sensitizes prostate cancer to ADT and anti-PD-1 therapy. These findings uncover a hidden connection between transcriptional and translational rewiring promoting therapy-refractory lethal prostate cancer and provide a druggable mechanism that may transcend into effective combined therapeutic strategies., Significance: Our study shows that specialized eIF3B-dependent translation of specific mRNAs released upon downregulation of the master transcription factor MITF confers castration resistance and immune evasion in lethal prostate cancer. Pharmacologic targeting of this mechanism delays castration resistance and increases immune-checkpoint efficacy. This article is featured in Selected Articles from This Issue, p. 2489., (©2023 The Authors; Published by the American Association for Cancer Research.)

Highly aggressive, metastatic, neuroendocrine prostate cancer, which typically develops from prostate cancer cells acquiring resistance to androgen deprivation therapy, is associated with limited treatment options and hence poor prognosis. We have previously demonstrated that the αVβ3 integrin is over-expressed in neuroendocrine prostate cancer. We now show that LM609, a monoclonal antibody that specifically targets the human αVβ3 integrin, hinders the growth of neuroendocrine prostate cancer patient-derived xenografts in vivo. Our group has recently identified a novel αVβ3 integrin binding partner, NgR2, responsible for regulating the expression of neuroendocrine markers and for inducing neuroendocrine differentiation in prostate cancer cells. Through in vitro functional assays, we here demonstrate that NgR2 is crucial in promoting cell adhesion to αVβ3 ligands. Moreover, we describe for the first time co-fractionation of αVβ3 integrin and NgR2 in small extracellular vesicles derived from metastatic prostate cancer patients' plasma. These prostate cancer patient-derived small extracellular vesicles have a functional impact on human monocytes, increasing their adhesion to fibronectin. The monocytes incubated with small extracellular vesicles do not show an associated change in conventional polarization marker expression and appear to be in an early stage that may be defined as "adhesion competent". Overall, these findings allow us to better understand integrin-directed signaling and cell-cell communication during cancer progression. Furthermore, our results pave the way for new diagnostic and therapeutic perspectives for patients affected by neuroendocrine prostate cancer., Competing Interests: Declaration of Competing Interest FQ is an employee/contractor at Janssen Pharmaceutical. EC is a consultant of Dotquant and received funding under institutional SRA from Janssen Research, Bayer Pharmaceuticals, Forma Therapeutics, Foghorn, Kronos Bios, Genentech, Astra Zeneca, and MacroGenics. No potential conflict of interest was reported by the other authors., (Copyright © 2023. Published by Elsevier B.V.)

Background and Aims: The scarcity of suitable donor livers highlights a continuing need for innovation to recover organs with reversible injuries in liver transplantation., Approach and Results: Explanted human donor livers (n = 5) declined for transplantation were supported using xenogeneic cross-circulation of whole blood between livers and xeno-support swine. Livers and swine were assessed over 24 hours of xeno-support. Livers maintained normal global appearance, uniform perfusion, and preservation of histologic and subcellular architecture. Oxygen consumption increased by 75% ( p = 0.16). Lactate clearance increased from -0.4 ± 15.5% to 31.4 ± 19.0% ( p = 0.02). Blinded histopathologic assessment demonstrated improved injury scores at 24 hours compared with 12 hours. Vascular integrity and vasoconstrictive function were preserved. Bile volume and cholangiocellular viability markers improved for all livers. Biliary structural integrity was maintained., Conclusions: Xenogeneic cross-circulation provided multisystem physiological regulation of ex vivo human livers that enabled functional rehabilitation, histopathologic recovery, and improvement of viability markers. We envision xenogeneic cross-circulation as a complementary technique to other organ-preservation technologies in the recovery of marginal donor livers or as a research tool in the development of advanced bioengineering and pharmacologic strategies for organ recovery and rehabilitation., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Prostate cancer (PCa) is the most common cancer in men in the US and androgen deprivation therapy (ADT) is the most frequently used systemic therapy for PCa. Data suggest that ADT is associated with an increased risk of new-onset diabetes mellitus (NODM) and cardiovascular complications. As the incidence and mortality of PCa are highest among the African American (AA) population, it is important to evaluate the difference in the incidence of NODM and ischemic heart disease (IHD) between AA men compared to Caucasian men., Methods: This is a retrospective cohort study utilizing the TriNetX database to assess NODM and IHD risk, risk difference, and risk ratio (RR) after recent ADT initiation in an AA cohort and a Caucasian cohort of patients with PCa. Propensity score matching (PSM) was performed by age, BMI, and confounding comorbidities., Results: After matching, the cohort included 1159 AA patients and 843 Caucasian patients with NODM after ADT initiation. The IHD cohort included 1269 AA patients and 1248 Caucasian patients. The risk of incidence of NODM is higher among AA men at 11.6% risk compared to Caucasian men at 7.4%. The risk difference is 4.1% (95% CI = 3.4, 4.9) p = 0.000. The RR is 1.56 (95% CI = 1.43, 1.70). In contrast, risk difference and risk ratio of IHD was not significant between AA and Caucasian groups., Conclusion: ADT exposure increases the risk of NODM in men with PCa, especially among AA men compared with Caucasian men. Men receiving ADT should be monitored routinely for signs and symptoms of metabolic syndrome and diabetes. Targeted close monitoring of AA men on ADT would be critical to prevent and treat metabolic complications with potential of reducing disparities in PCa morbidity., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Right ventricular failure (RVF) is a major cause of mortality in pulmonary hypertension (PH). Mechanical circulatory support holds promise for patients with medically refractory PH, but there are no clinical devices for long-term right ventricular (RV) support. Investigations into optimal device parameters and circuit configurations for PH-induced RVF (PH-RVF) are needed., Methods: Eleven sheep underwent previously published chronic PH model. We then evaluated a low-profile, ventricular assist device (VAD)-quality pump combined with a novel low-resistance membrane oxygenator (Pulmonary Assist Device, PAD) under one of four central cannulation strategies: right atrium-to-left atrium (RA-LA, N = 3), RA-to-pulmonary artery (RA-PA, N=3), pumpless pulmonary artery-to-left atrium (PA-LA, N = 2), and RA-to-ascending aorta (RA-Ao, N = 3). Acute-on-chronic RVF (AoC RVF) was induced, and mechanical support was provided for up to 6 hours at blood flow rates of 1 to 3 liter/min. Circuit parameters, physiologic, hemodynamic, and echocardiography data were collected., Results: The RA-LA configuration achieved blood flow of 3 liter/min. Meanwhile, RA-PA and RA-Ao faced challenges maintaining 3 liter/min of flow due to higher circuit afterload. Pumpless PA-LA was flow-limited due to anatomical limitations inherent to this animal model. RA-LA and RA-Ao demonstrated serial RV unloading with increasing circuit flow, while RA-PA did not. RA-LA also improved left ventricular (LV) and septal geometry by echocardiographic assessment and had the lowest inotropic dependence., Conclusion: RA-LA and RA-Ao configurations unload the RV, while RA-LA also lowers pump speed and inotropic requirements, and improves LV mechanics. RA-PA provide inferior support for PH-RVF, while an alternate animal model is needed to evaluate PA-LA., Competing Interests: Disclosure statement Drs. David Skoog, Keith Cook, and Mathew Bacchetta are partners in Advanced Respiratory Technologies, LLC. Pumps used in the study were donated to us by CardioDyme Inc., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Prostate cancer is the most common cancer among men and the second leading cause of cancer-related deaths in men in the United States. The treatment paradigm for prostate cancer has evolved with the emergence of a variety of novel therapies which have improved survival; however, treatment-related toxicities are abundant and durable responses remain rare. Immune checkpoint inhibitors have shown modest activity in a small subset of patients with prostate cancer and have not had an impact on most men with advanced disease. The discovery of prostate-specific membrane antigen (PSMA) and the understanding of its specificity to prostate cancer has identified it as an ideal tumor-associated antigen and has revived the enthusiasm for immunotherapeutics in prostate cancer. T-cell immunotherapy in the form of bispecific T-cell engagers (BiTEs) and chimeric antigen receptor (CAR) T-cell therapy have shown exceptional success in treating various hematologic malignancies, and are now being tested in patients with prostate cancer with drug design centered on various target ligands including not just PSMA, but others as well including six-transmembrane epithelial antigen of the prostate 1 (STEAP1) and prostate stem cell antigen (PSCA). This summative review will focus on the data surrounding PSMA-targeting T-cell therapies. Early clinical studies with both classes of T-cell redirecting therapies have demonstrated antitumor activity; however, there are multiple challenges with this class of agents, including dose-limiting toxicity, 'on-target, off-tumor' immune-related toxicity, and difficulty in maintaining sustained immune responses within a complex and overtly immunosuppressive tumor microenvironment. Reflecting on experiences from recent trials has been key toward understanding mechanisms of immune escape and limitations in developing these drugs in prostate cancer. Newer generation BiTE and CAR T-cell constructs, either alone or as part of combination therapy, are currently under investigation with modifications in drug design to overcome these barriers. Ongoing innovation in drug development will likely foster successful implementation of T-cell immunotherapy bringing transformational change to the treatment of prostate cancer., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2023.)

Introduction: To report the impact of our 25-year multidisciplinary care delivery model experience on patients with muscle invasive bladder cancer treated at our National Cancer Institute (NCI)-designated Sidney Kimmel Cancer Center at Jefferson University. To our knowledge, our multidisciplinary genitourinary cancer clinic (MDC) is the longest continuously operating center of its kind at an NCI Cancer Center in the United States., Materials and Methods: We selected a recent group of patients with cT2-4 N0-1 M0 bladder cancer seen in the Sidney Kimmel Cancer Center Genitourinary Oncology MDC from January 2016 to September 2019. These patients were identified retrospectively. SEER-18 (Surveillance, Epidemiology, and End Results) database, November 2019 submission was queried to obtain patients with similarly staged disease diagnosed between 2015 and 2017. Completion rates of radical cystectomy, use of neoadjuvant therapies, and survival outcomes were compared between the two cohorts., Results: Ninety-one patients from the MDC form this time period were identified; 65.9% underwent radical cystectomy and 71.8% received neoadjuvant therapy in the form of chemotherapy, immune checkpoint inhibition or a combination of the two - higher than reported national trends for neoadjuvant therapies. Progression of disease was seen in 24.2% of patients. A total of 8675 patients met inclusion criteria in the SEER database. Rates of radical cystectomy were significantly higher in MCD patients when compared to SEER derived data (65.9% vs. 37.7%, p =< 0.001). MCD patients had significantly better cancer-specific survival (mean 20.4 vs. 18.3 months p = 0.028, median survival not reached)., Conclusion: Our long term experience caring for patients with genitourinary malignancies such as bladder cancer in a uniform multidisciplinary team results in a high utilization of neoadjuvant therapies. When compared to a contemporary SEER-derived cohort, multidisciplinary patients were more likely to undergo radical cystectomy and had longer cancer-specific survival.

Purpose: We have previously developed and externally validated a prognostic model of overall survival (OS) in men with metastatic, castration-resistant prostate cancer (mCRPC) treated with docetaxel. We sought to externally validate this model in a broader group of men with docetaxel-naïve mCRPC and in specific subgroups (White, Black, Asian patients, different age groups, and specific treatments) and to classify patients into validated two and three prognostic risk groupings on the basis of the model., Methods: Data from 8,083 docetaxel-naïve mCRPC men randomly assigned on seven phase III trials were used to validate the prognostic model of OS. We assessed the predictive performance of the model by computing the time-dependent area under the receiver operating characteristic curve (tAUC) and validated the two-risk (low and high) and three-risk prognostic groups (low, intermediate, and high)., Results: The tAUC was 0.74 (95% CI, 0.73 to 0.75), and when adjusting for the first-line androgen receptor (AR) inhibitor trial status, the tAUC was 0.75 (95% CI, 0.74 to 0.76). Similar results were observed by the different racial, age, and treatment subgroups. In patients enrolled on first-line AR inhibitor trials, the median OS (months) in the low-, intermediate-, and high-prognostic risk groups were 43.3 (95% CI, 40.7 to 45.8), 27.7 (95% CI, 25.8 to 31.3), and 15.4 (95% CI, 14.0 to 17.9), respectively. Compared with the low-risk prognostic group, the hazard ratios for the high- and intermediate-risk groups were 4.3 (95% CI, 3.6 to 5.1; P < .0001) and 1.9 (95% CI, 1.7 to 2.1; P < .0001)., Conclusion: This prognostic model for OS in docetaxel-naïve men with mCRPC has been validated using data from seven trials and yields similar results overall and across race, age, and different treatment classes. The prognostic risk groups are robust and can be used to identify groups of patients for enrichment designs and for stratification in randomized clinical trials.

Androgen deprivation therapy is the cornerstone of prostate cancer therapy. Recent studies have revealed an association between androgen deprivation therapy and cardiovascular adverse effects such as myocardial infarction and stroke. This review summarizes the available research on the cardiovascular risk of men using androgen deprivation therapy. We also discuss racial disparities surrounding both prostate cancer and cardiovascular disease, emphasizing the importance of biological/molecular and socioeconomic factors in assessing baseline risk in patients beginning androgen ablation. Based on the literature, we provide recommendations for monitoring patients who are at high risk for a cardiovascular adverse event while being treated on androgen deprivation therapy. This review aims to present the current research on androgen deprivation therapy and cardiovascular toxicity with an emphasis on racial disparities and provides a framework for clinicians to decrease the cardiovascular morbidity in men that are being treated with hormone therapy.

Congestive hepatopathy is becoming increasingly recognized among Fontan-palliated patients. Elevated central venous pressure is thought to drive the pathologic progression, characterized by sinusoidal dilatation, congestion, and fibrosis. A clinically relevant large animal model for congestive hepatopathy would provide a valuable platform for researching novel biomarkers, treatment, and prevention. Here, we report on a titratable, sheep pulmonary artery banding model for this disease application. Pulmonary artery banding was achieved by progressively inflating the implanted pulmonary artery cuff. Right ventricular catheter was implanted to draw venous blood samples and measure pressure. The pulmonary artery cuff pressure served as a surrogate for the intensity of pulmonary artery banding and was measured weekly. After about 9 wk, animals were euthanized, and the liver was harvested for histopathological assessment. Nine animal subjects received pulmonary artery banding for 64 ± 8 days. Four of the nine subjects exhibited moderate to severe liver injury, and three of those four exhibited bridging fibrosis. Increasing pulmonary artery cuff pressure significantly correlated with declining mixed venous oxygen saturation ( P = 3.29 × 10 -5 ), and higher congestive hepatic fibrosis score ( P = 0.0238), suggesting that pulmonary artery banding strategy can be titrated to achieve right-sided congestion and liver fibrosis. Blood analyses demonstrated an increase in plasma bile acids, aspartate aminotransferase, and γ-glutamyltransferase among subjects with moderate to severe injury, further corroborating liver tissue findings. Our large animal pulmonary artery banding model recapitulates congestive hepatopathy and provides a basis to bridge the current gaps in scientific and clinical understanding about the disease. NEW & NOTEWORTHY We present here a large animal platform for congestive hepatopathy, a disease growing in clinical prevalence due to the increasing number of Fontan-palliated patients. Further data are needed to develop a better clinical management strategy for this poorly characterized patient population. Previous reports of animal models to study this disease have mostly been in small animals with limited fidelity. We show that congestive hepatopathy can be replicated in a chronic, progressive pulmonary artery banding model in sheep. We also show that the banding strategy can be controlled to titrate the level of liver injury. To date, we do not know of any other large animal model that can achieve this level of control over disease phenotype and clinical relevance.

Over the past decade, immunotherapy has demonstrated an impressive improvement in treatment outcomes for multiple cancers. Following the landmark approvals for use of immune checkpoint inhibitors, new challenges emerged in various clinical settings. Not all tumor types harbor immunogenic characteristics capable of triggering responses. Similarly, many tumors' immune microenvironment allows them to become evasive, leading to resistance and, thus, limiting the durability of responses. To overcome this limitation, new T-cell redirecting strategies such as bispecific T-cell engager (BiTE) have become attractive and promising immunotherapies. Our review provides a comprehensive perspective of the current evidence of BiTE therapies in solid tumors. Considering that immunotherapy has shown modest results in advanced prostate cancer to date, we review the biologic rationale and promising results of BiTE therapy in this clinical setting and discuss potential tumor-associated antigens that may be integrated into BiTE construct designs. Our review also aims to evaluate the advances of BiTE therapies in prostate cancer, illustrate the major obstacles and underlying limitations, and discuss directions for future research.

Metastatic prostate cancer (PCa) inevitably acquires resistance to standard therapy preceding lethality. Here, we unveil a chromosomal instability (CIN) tolerance mechanism as a therapeutic vulnerability of therapy-refractory lethal PCa. Through genomic and transcriptomic analysis of patient datasets, we find that castration and chemotherapy-resistant tumors display the highest CIN and mitotic kinase levels. Functional genomics screening coupled with quantitative phosphoproteomics identify MASTL kinase as a survival vulnerability specific of chemotherapy-resistant PCa cells. Mechanistically, MASTL upregulation is driven by transcriptional rewiring mechanisms involving the non-canonical transcription factors androgen receptor splice variant 7 and E2F7 in a circuitry that restrains deleterious CIN and prevents cell death selectively in metastatic therapy-resistant PCa cells. Notably, MASTL pharmacological inhibition re-sensitizes tumors to standard therapy and improves survival of pre-clinical models. These results uncover a targetable mechanism promoting high CIN adaptation and survival of lethal PCa., Competing Interests: Declaration of interests The authors declare no competing financial interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Patient participation in clinical trials is influenced by demographic and other individual level characteristics. However, there is less research on the role of geography and neighborhood-level factors on clinical trial participation. This study identifies the demographic, clinical, geographic, and neighborhood predictors of consenting to a clinical trial among cancer patients at a large, urban, NCI-designated cancer center in the Mid-Atlantic region., Methods: We used demographic and clinical data from patients diagnosed with cancer between 2015 and 2017. We geocoded patient addresses and calculated driving distance to the cancer center. Additionally, we linked patient data to neighborhood-level educational attainment, social capital and cancer prevalence. Finally, we used generalized linear mixed-effects conditional logistic regression to identify individual and neighborhood-level predictors of consenting to a clinical trial., Results: Patients with higher odds of consenting to trials were: Non-Hispanic White, aged 50-69, diagnosed with breast, GI, head/neck, hematologic, or certain solid tumor cancers, those with cancers at regional stage, never/former tobacco users, and those with the highest neighborhood social capital index. Patients who lived further from the cancer center had higher odds of consenting to a trial. With every 1-km increase in residential distance, there was a 4% increase in the odds that patients would consent to a trial. Neither of the additional neighborhood-level variables predicted consenting to a clinical trial., Conclusions: This study identifies important demographic, patient-level, and geographic factors associated with consenting to cancer clinical trials, and lays the groundwork for future research exploring the role of neighborhood-level factors in clinical trial participation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To identify the safety of niraparib, a PARP inhibitor, in combination with Radium-223 for the treatment of metastatic castrate-resistant prostate cancer (mCRPC) in men without known BRCA mutations., Patients and Methods: Men with progressive mCPRC following ≥1 line of androgen receptor (AR)-targeted therapy and bone metastases but no documented BRCA-1 or BRCA-2 alterations or bulky visceral disease were included. Niraparib dose was escalated in combination with standard dosing of Radium-223 using a time-to-event continual reassessment method. The highest dose level with a DLT probability <20% was defined as MTD. Secondary endpoints included PSA change and progression-free survival. Exploratory analyses included assessing DNA mutations found in ctDNA as well as gene expression changes assessed in whole blood samples., Results: Thirty patients were treated with niraparib and radium-223: 13 patients received 100 mg, 12 received 200 mg, and 5 patients received 300 mg of niraparib. There were six DLT events: two (13%) for neutropenia, two (13%) for thrombocytopenia, whereas fatigue and nausea each occurred once (3%). Anemia (2/13%) and neutropenia (2/13%) were the most common grade 3 adverse events. For patients with prior chemotherapy exposure, the MTD was 100 mg, whereas the MTD for chemotherapy naïve patients was 200 mg. Whole blood gene expression of PAX5 and CD19 was higher in responders and ARG-1, IL2R, and FLT3 expression was higher in nonresponders., Conclusions: Combining niraparib with Radium-223 in patients with mCRPC was safe; however, further studies incorporating biomarkers will better elucidate the role of combinations of PARP inhibitors with DNA damaging and other agents., (©2022 American Association for Cancer Research.)

We report the case of a 61-year-old male with metastatic prostate cancer who presented with urinary retention secondary to subdermal penile and corpora cavernosa metastases with neuroendocrine transformation of his metastatic hormone sensitive prostate cancer. We highlight the presentation, diagnosis, and management of this rare condition.

Androgen deprivation therapies aimed to target prostate cancer (PrCa) are only partially successful given the occurrence of neuroendocrine PrCa (NEPrCa), a highly aggressive and highly metastatic form of PrCa, for which there is no effective therapeutic approach. Our group has demonstrated that while absent in prostate adenocarcinoma, the αVβ3 integrin expression is increased during PrCa progression toward NEPrCa. Here, we show a novel pathway activated by αVβ3 that promotes NE differentiation (NED). This novel pathway requires the expression of a GPI-linked surface molecule, NgR2, also known as Nogo-66 receptor homolog 1. We show here that NgR2 is upregulated by αVβ3, to which it associates; we also show that it promotes NED and anchorage-independent growth, as well as a motile phenotype of PrCa cells. Given our observations that high levels of αVβ3 and, as shown here, of NgR2 are detected in human and mouse NEPrCa, our findings appear to be highly relevant to this aggressive and metastatic subtype of PrCa. This study is novel because NgR2 role has only minimally been investigated in cancer and has instead predominantly been analyzed in neurons. These data thus pave new avenues toward a comprehensive mechanistic understanding of integrin-directed signaling during PrCa progression toward a NE phenotype., (© 2022. The Author(s).)

Background: Emerging evidence suggests that a subset of Black men with National Comprehensive Cancer Network (NCCN) low-risk prostate cancer (PCa) may harbor high volume and genomically aggressive disease. However, limited, and ambiguous research exist to evaluate the risk of extreme Gleason reclassification in Black men with low-risk PCa., Methods: This retrospective cohort study included 45,674 low-risk PCa patients who underwent prostatectomy and were not on active surveillance, from National Cancer Database (NCDB). A propensity score matched-pair design was employed, and the final cohort was limited to 1:1 matched 12,340 patients. Gleason score reclassification was used as primary endpoint. As such, any migration to pathologic Gleason score ≥7(3 + 4) was identified as overall, whereas migration to ≥7(4 + 3) was defined as extreme reclassification. A conditional Poisson regression model was used to estimate the risk of reclassification. Whereas spline model was used to estimate the impact of increasing time to treatment as a non-linear function on Gleason reclassification between race group., Results: Upon matching there were no differences in the baseline characteristics between race groups. In a matched cohort, higher proportion of low-risk Black men (6.6%) reported extreme reclassification to pathologic Gleason score than White men (5.0%), p < 0.001. In a conditional Poisson regression model adjusted for time to treatment, the risk of overall (RR = 1.09, 95% CI, 1.05-1.13, p < 0.001) and extreme (RR = 1.30, 95% CI, 1.12-1.50, p = 0.004) reclassification was significantly higher in Black men as compared to their White counterpart. In spline model, the probability of Gleason reclassification in Black men was elevated with increasing time to treatment, especially after 180 days (53% vs. 43% between Black and White men)., Conclusion: Risk of Gleason score reclassification is disparately elevated in Black men with low-risk PCa. Furthermore, time to treatment can non-linearly impact Gleason reclassification in Black men., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Progress in the management of rare diseases, including rare cancers, is dependent upon clinical trials; however, as many as 32% of rare-disease trials go uncompleted or unpublished due to insufficient accrual. Monitoring practices may differ between institutions. We sought to survey the regulatory standards for various trial types among major U.S. cancer centers. A 10-question survey was designed using Qualtrics assessment software. The survey was sent via email to an internal server of member institutions of the Association of American Cancer Institutes (AACI). Of 103 AACI centers, 31% completed the survey ( n = 32). Respondents differed in their definitions of a rare disease, minimum expectations for rare tumor studies, and frequency of accrual monitoring by their institutional Protocol Review and Monitoring Committee. Seventy-three percent of respondents did not close trials based on low accrual. Strategies to optimize accrual included investigator incentives for high accrual and penalties for low accrual in 37% and 13% of respondents, respectively.

Introduction: Abiraterone acetate and enzalutamide are commonly employed in prostate cancer therapy in an interchangeable manner. These drugs are highly efficacious in androgen antagonism to improve patient outcomes, but they also carry noteworthy risk of adverse effects. Common toxicities vary amongst the two drugs and may have differential interactions with patient co-morbidities, but these patterns are unclear as co-morbidities typically serve as exclusion criteria in clinical trials. Hence, there is no existing guidance on how clinicians may tailor treatment based on patient-specific factors. Analysis of differential patient outcomes between these two drugs can inform future systematic reviews, new clinical studies, and clinical decision making., Method and Analysis: The framework for this methodology was informed by the Joanna Briggs Institute methodology for scoping reviews. Title and abstract screening will be performed by two independent researchers to create an initial study inventory. This will be followed by full-text screening for study inclusion. Population-based studies describing patient outcomes, common toxicities, and associations with patient co-morbidities following abiraterone or enzalutamide therapy will be included. After data is extracted, it will be summarized for presentation., Ethics and Dissemination: The findings of this scoping review will be published in a peer-reviewed journal. The results will be used to inform future studies on patient-specific factors informing treatment choice between abiraterone and enzalutamide for castration-resistant prostate cancer. All data are from published openly accessible sources, and therefore, no ethical clearance is necessary. The protocol is also registered at https://doi.org/10.6084/m9.figshare.19149227., Competing Interests: The authors have declared that no competing interests exist.

Six-Transmembrane Epithelial Antigen of the Prostate 1-4 (STEAP1-4) compose a family of metalloproteinases involved in iron and copper homeostasis and other cellular processes. Thus far, five homologs are known: STEAP1, STEAP1B, STEAP2, STEAP3, and STEAP4. In prostate cancer, STEAP1, STEAP2, and STEAP4 are overexpressed, while STEAP3 expression is downregulated. Although the metalloreductase activities of STEAP1-4 are well documented, their other biological functions are not. Furthermore, the properties and expression levels of STEAP heterotrimers, homotrimers, heterodimers, and homodimers are not well understood. Nevertheless, studies over the last few decades have provided sufficient impetus to investigate STEAP1-4 as potential biomarkers and therapeutic targets for prostate cancer. In particular, STEAP1 is the target of many emerging immunotherapies. Herein, we give an overview of the structure, physiology, and pathophysiology of STEAP1-4 to provide context for past and current efforts to translate STEAP1-4 into the clinic.

Abiraterone acetate (AA) and enzalutamide (ENZ) are commonly used for metastatic prostate cancer. It is unclear how their outcomes and toxicities vary with patient-specific factors because clinical trials typically exclude patients with significant comorbidities. This study aims to fill this knowledge gap and facilitate informed treatment decision making. A registered protocol utilizing PRISMA scoping review methodology was utilized to identify real-world studies. Of 433 non-duplicated publications, 23 were selected by three independent reviewers. ENZ offered a faster and more frequent biochemical response (30-50% vs. 70-75%), slowed progression (HR 0.66; 95% CI 0.50-0.88), and improved overall survival versus AA. ENZ was associated with more fatigue and neurological adverse effects. Conversely, AA increased risk of cardiovascular- (HR 1.82; 95% CI 1.09-3.05) and heart failure-related (HR 2.88; 95% CI 1.09-7.63) hospitalizations. Ultimately, AA was associated with increased length of hospital stay, emergency department visits, and hospitalizations (HR 1.26; 95% CI 1.04-1.53). Accordingly, total costs were higher for AA, although pharmacy costs alone were higher for ENZ. Existing data suggest that AA and ENZ have important differences in outcomes including toxicities, response, disease progression, and survival. Additionally, adherence, healthcare utilization, and costs differ. Further investigation is warranted to inform treatment decisions which optimize patient outcomes.

Refractory hypoxemia despite the use of extracorporeal membrane oxygenation (ECMO) for coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome remains a challenging problem. A single ECMO circuit may not provide adequate physiologic support in the setting of an elevated cardiac output, physiologic demand, and impaired gas exchange. In select patients with refractory hypoxemia, addition of a second ECMO circuit in parallel can improve oxygenation, facilitate lung protective ventilation, awakening, and physical rehabilitation. We report the largest case series to date of patients receiving ECMO circuits in parallel and the first to report this approach in COVID-19., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2022.)

Background: Germline testing has an increasingly important role in prostate cancer care. However, a relative shortage of genetic counselors necessitates alternate strategies for delivery of pre-test education for germline testing. This study, funded by the Prostate Cancer Foundation, seeks to address the need for novel methods of delivery of pre-test germline education beyond traditional germline counseling to facilitate informed patient decision-making for germline testing., Methods: This is a two-armed randomized controlled trial (RCT) with a target enrollment of 173 participants with prostate cancer per study arm (total anticipated n = 346). Patients who meet criteria for germline testing based on tumor features, family history or Ashkenazi Jewish ancestry are being recruited from 5 US sites including academic, private practice and Veterans healthcare settings. Consenting participants are randomized to the interactive pretest webtool or germline counseling with assessment of key patient-reported outcomes involved in informed decision-making for germline testing., Results: Participants complete surveys at baseline, after pretest education/counseling, and following disclosure of germline results. The primary outcome of the study is decisional conflict for germline testing. Secondary outcomes include genetic knowledge, satisfaction, uptake of germline testing, and understanding of results., Conclusion: Our hypothesis is that the web-based genetic education tool is non-inferior to traditional genetic counseling regarding key patient-reported outcomes involved in informed decision-making for germline testing. If proven, the results would support deploying the webtool across various practice settings to facilitate pre-test genetic education for individuals with prostate cancer and developing collaborative care strategies with genetic counseling., Clinicaltrials: gov Identifier: NCT04447703., (Copyright © 2022 Elsevier Inc. All rights reserved.)

In the expanding precision medicine landscape, along with improvements in and the availability of testing, the use of genetics in the evaluation and treatment of patients has increased significantly. Multiple urologic cancers in different organ systems associated with an inherited gene mutation have been described. As these mutations can impact screening and treatment decisions for patients and their families, it is important for providers to be familiar with the current guidelines for germline testing. Here we summarize the current guidelines regarding germline testing for patients with suspected urologic tumor syndromes. PATIENT SUMMARY: Several cancers of the genitourinary tract can be associated with inherited genetic mutations. Knowledge of when to test for these mutations has implications for both treatment and screening of patients and their family members at risk of genitourinary cancers., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: As prostate-specific membrane antigen (PSMA) positron emission tomography (PET) becomes increasingly available in the United States, the greater sensitivity of the technology in comparison to conventional imaging poses challenges for clinical trials. The NCI Clinical Imaging Steering Committee (CISC) PSMA PET Working Group was convened to coordinate the identification of these challenges in various clinical scenarios and to develop consensus recommendations on how best to integrate PSMA PET into ongoing and upcoming National Clinical Trials Network (NCTN) trials., Methods: NCI CISC and NCI Genitourinary Steering Committee members and leadership nominated clinicians, biostatisticians, patient advocates, and other imaging experts for inclusion in the PSMA PET Working Group. From April to July 2021, the working group met independently and in conjunction with the CISC to frame challenges, including stage migration, response assessment, trial logistics, and statistical challenges, and to discuss proposed solutions. An anonymous, open-ended survey was distributed to members to collect feedback on challenges faced. Representatives from each NCTN group were invited to present an overview of affected trials. From these discussions, the consensus document was developed and circulated for the inclusion of multiple rounds of feedback from both the Working Group and CISC., Results: The current consensus document outlines the key challenges for clinical prostate cancer trials resulting from the increasing availability of PSMA PET. We discuss implications for patient selection and definition of end points and provide guidance and potential solutions for different clinical scenarios, particularly with regard to best practices in defining eligibility criteria and outcome measures., Recommendations: This article provides guidance regarding clinical trial design and conduct, and the interpretation of trial results., Competing Interests: Thomas A. HopeStock and Other Ownership Interests: RayzeBioHonoraria: GE HealthcareConsulting or Advisory Role: Ipsen, Curium Pharma, Blue Earth DiagnosticsResearch Funding: Philipps Healthcare, GE Healthcare, Advanced Accelerator Applications, Clovis OncologyTravel, Accommodations, Expenses: GE Healthcare William K. KellyHonoraria: Janssen OncologyConsulting or Advisory Role: Merck Sharp & DohmeResearch Funding: Sanofi, Novartis, Janssen Oncology, Bayer, Exelixis, Seattle Genetics, Endocyte, Amgen, BioClin Therapeutics, Sarah Cannon Research Institute, RocheTravel, Accommodations, Expenses: Janssen Oncology, Merck Sharp & Dohme Jeff M. MichalskiStock and Other Ownership Interests: ViewRay (I)Consulting or Advisory Role: Mevion Medical Systems, Boston Scientific, Merck Sharp & Dohme, Blue Earth DiagnosticsResearch Funding: Merck Sharp & Dohme (Inst)Travel, Accommodations, Expenses: Boston Scientific, Merck Sharp & DohmeOpen Payment Link: https://openpaymentsdata.cms.gov/physician/221723 Seth P. LernerStock and Other Ownership Interests: C2i genomicsHonoraria: Annenberg Center for Health Sciences, at Eisenhower (ACHS), UroToday, Grand Rounds in Urology, Ology Medical Education, Clinical Care OptionsConsulting or Advisory Role: Vaxiion, Urogen Pharma, Verity Pharmaceuticals, Roche/Genentech, Ferring, Merck Sharp & Dohme, FerGene, Pfizer/EMD Serono, C2i genomics, Aura Biosciences, AstraZenecaResearch Funding: Endo Pharmaceuticals, FKD Therapies, Viventia Biotech, Roche/Genentech, Japan BCG Laboratory, Urogen Pharma, Vaxiion, QED TherapeuticsPatents, Royalties, Other Intellectual Property: TCGA expression subtype single patient classifierOther Relationship: UpToDate, Bladder Cancer Journal Daniel W. LinConsulting or Advisory Role: Astellas Pharma, Lantheus Medical Imaging, AstraZenecaResearch Funding: GenomeDx (Inst), MDxHealth (Inst), Magforce (Inst) Evan Y. YuConsulting or Advisory Role: Janssen, Bayer, Merck, Clovis Oncology, Advanced Accelerator Applications, ExelixisResearch Funding: Dendreon (Inst), Merck (Inst), Seattle Genetics (Inst), Daiichi Sankyo (Inst), Taiho Pharmaceutical (Inst), Blue Earth Diagnostics (Inst), Bayer (Inst), Lantheus Medical Imaging (Inst) Ronald C. ChenConsulting or Advisory Role: Medivation/Astellas, Accuray, Bayer, Blue Earth Diagnostics, AbbVie, Myovant Sciences, Genentech, PfizerResearch Funding: Accuray Gillian C. BeachEmployment: Emmes Company, LLCNo other potential conflicts of interest were reported.

Purpose: DNA-dependent protein kinase catalytic subunit (DNA-PKcs, herein referred as DNA-PK) is a multifunctional kinase of high cancer relevance. DNA-PK is deregulated in multiple tumor types, including prostate cancer, and is associated with poor outcomes. DNA-PK was previously nominated as a therapeutic target and DNA-PK inhibitors are currently undergoing clinical investigation. Although DNA-PK is well studied in DNA repair and transcriptional regulation, much remains to be understood about the way by which DNA-PK drives aggressive disease phenotypes., Experimental Design: Here, unbiased proteomic and metabolomic approaches in clinically relevant tumor models uncovered a novel role of DNA-PK in metabolic regulation of cancer progression. DNA-PK regulation of metabolism was interrogated using pharmacologic and genetic perturbation using in vitro cell models, in vivo xenografts, and ex vivo in patient-derived explants (PDE)., Results: Key findings reveal: (i) the first-in-field DNA-PK protein interactome; (ii) numerous DNA-PK novel partners involved in glycolysis; (iii) DNA-PK interacts with, phosphorylates (in vitro), and increases the enzymatic activity of glycolytic enzymes ALDOA and PKM2; (iv) DNA-PK drives synthesis of glucose-derived pyruvate and lactate; (v) DNA-PK regulates glycolysis in vitro, in vivo, and ex vivo; and (vi) combination of DNA-PK inhibitor with glycolytic inhibitor 2-deoxyglucose leads to additive anti-proliferative effects in aggressive disease., Conclusions: Findings herein unveil novel DNA-PK partners, substrates, and function in prostate cancer. DNA-PK impacts glycolysis through direct interaction with glycolytic enzymes and modulation of enzymatic activity. These events support energy production that may contribute to generation and/or maintenance of DNA-PK-mediated aggressive disease phenotypes., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: Prostate cancer (PCA) germline testing (GT) is now standard-of-care for men with advanced PCA. Thousands of men may consider GT due to clinical and family history (FH) features. Identifying and consenting men for GT can be complex. Here we identified barriers and facilitators of GT across a spectrum of providers which informed the development of Helix - an educational and clinical/FH collection tool to facilitate GT in practice., Materials and Methods: A 12-question survey assessing knowledge of genetics PCA risk and FH was administered December 2017 to March 2018 in the Philadelphia area and at the Mid-Atlantic AUA meeting (March 2018). Responses were analyzed using descriptive statistics. Semi-structured interviews were conducted with medical oncologists, radiation oncologists, and urologists across practice settings from March-October 2020 as part of a larger study based on the Tailored Implementation in Chronic Diseases framework. Helix was then developed followed by user testing., Results: Fifty-six providers (50% urologists) responded to the survey. Multiple FH and genetic knowledge gaps were identified: only 66% collected maternal FH and 43% correctly identified BRCA2 and association to aggressive PCA. Genetic counseling gaps included low rates of discussing genetic discrimination laws (45%). Provider interviews (n = 14) identified barriers to FH intake including access to details and time needed. In user testing (n = 10), providers found Helix helpful for FH collection. All providers found Helix easy to use, suggesting expanded clinical use., Conclusion: Helix addressed multiple GT knowledge and practice gaps across a spectrum of providers. This tool will become publicly available soon to facilitate PCA GT in clinical practice., (Copyright © 2021. Published by Elsevier Inc.)