Forging the Association for Clinical and Translational Science (ACTS)

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91162/1/j.1752-8062.2012.00404.x.pd

Erythropoietin supports the survival of prostate cancer, but not growth and bone metastasis

Erythropoietin (Epo) is used in clinical settings to enhance hematopoietic function and to improve the quality of life for patients undergoing chemotherapy by reducing fatigue and the need for transfusions. However, several meta‐analyses have revealed that Epo treatments are associated with an increased risk of mortality in cancer patients. In this study, we examined the role of Epo in prostate cancer (PCa) progression, using in vitro cell culture systems and in vivo bone metastatic assays. We found that Epo did not stimulate the proliferation of PCa cell lines, but did protect PCa cells from apoptosis. In animal models of PCa metastasis, no evidence was found to support the hypothesis that Epo enhances metastasis. Together, these findings suggest that Epo may be useful for treating severe anemia in PCa patients without increasing metastatic risk. J. Cell. Biochem. 114: 2471–2478, 2013. © 2013 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/100159/1/jcb24592.pd

GREB1 is a novel androgen-regulated gene required for prostate cancer growth

BACKGROUND Gene regulated in breast cancer 1 (GREB1) is a novel estrogen-regulated gene shown to play a pivotal role in hormone-stimulated breast cancer growth. GREB1 is expressed in the prostate and its putative promoter contains potential androgen receptor (AR) response elements. METHODS We investigated the effects of androgens on GREB1 expression and its role in androgen-dependent prostate cancer growth. RESULTS Real-time PCR demonstrated high level GREB1 expression in benign prostatic hypertrophy (BPH), localized prostate cancer (L-PCa), and hormone refractory prostate cancer (HR-PCa). Androgen treatment of AR-positive prostate cancer cells induced dose-dependent GREB1 expression, which was blocked by anti-androgens. AR binding to the GREB1 promoter was confirmed by chromatin immunoprecipitation (ChIP) assays. Suppression of GREB1 by RNA interference blocked androgen-stimulated LNCaP cell proliferation. CONCLUSIONS GREB1 is expressed in proliferating prostatic tissue and prostate cancer, is regulated by androgens, and suppression of GREB1 blocks androgen-induced growth suggesting GREB1 may be critically involved in prostate cancer proliferation. Prostate © 2006 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/49275/1/20403_fta.pd

A Phase 3 Trial of 2 Years of Androgen Suppression and Radiation Therapy With or Without Adjuvant Chemotherapy for High-Risk Prostate Cancer: Final Results of Radiation Therapy Oncology Group Phase 3 Randomized Trial NRG Oncology RTOG 9902.

PURPOSE: Long-term (LT) androgen suppression (AS) with radiation therapy (RT) is a standard treatment of high-risk, localized prostate cancer (PCa). Radiation Therapy Oncology Group 9902 was a randomized trial testing the hypothesis that adjuvant combination chemotherapy (CT) with paclitaxel, estramustine, and oral etoposide plus LT AS plus RT would improve overall survival (OS). METHODS AND MATERIALS: Patients with high-risk PCa (prostate-specific antigen 20-100 ng/mL and Gleason score [GS] ≥ 7 or clinical stage ≥ T2 and GS ≥ 8) were randomized to RT and AS (AS + RT) alone or with adjuvant CT (AS + RT + CT). CT was given as four 21-day cycles, delivered beginning 28 days after 70.2 Gy of RT. AS was given as luteinizing hormone-releasing hormone for 24 months, beginning 2 months before RT plus an oral antiandrogen for 4 months before and during RT. The study was designed based on a 6% improvement in OS from 79% to 85% at 5 years, with 90% power and a 2-sided alpha of 0.05. RESULTS: A total of 397 patients (380 eligible) were randomized. The patients had high-risk PCa, 68% with GS 8 to 10 and 34% T3 to T4 tumors, and median prostate-specific antigen of 22.6 ng/mL. The median follow-up period was 9.2 years. The trial closed early because of excess thromboembolic toxicity in the CT arm. The 10-year results for all randomized patients revealed no significant difference between the AS + RT and AS + RT + CT arms in OS (65% vs 63%; P=.81), biochemical failure (58% vs 54%; P=.82), local progression (11% vs 7%; P=.09), distant metastases (16% vs 14%; P=.42), or disease-free survival (22% vs 26%; P=.61). CONCLUSIONS: NRG Oncology RTOG 9902 showed no significant differences in OS, biochemical failure, local progression, distant metastases, or disease-free survival with the addition of adjuvant CT to LT AS + RT. The trial results provide valuable data regarding the natural history of high-risk PCa treated with LT AS + RT and have implications for the feasibility of clinical trial accrual and tolerability using CT for PCa

Test-retest repeatability of organ uptake on PSMA‐targeted 18F‐DCFPyL PET/CT in patients with prostate cancer

Objectives We evaluated 18F-DCFPyL test–retest repeatability of uptake in normal organs. Methods Twenty-two prostate cancer (PC) patients underwent two 18F-DCFPyL PET scans within 7 days within a prospective clinical trial (NCT03793543). In both PET scans, uptake in normal organs (kidneys, spleen, liver, and salivary and lacrimal glands) was quantified. Repeatability was determined by using within-subject coefficient of variation (wCOV), with lower values indicating improved repeatability. Results For SUVmean, repeatability was high for kidneys, spleen, liver, and parotid glands (wCOV, range: 9.0%–14.3%) and lower for lacrimal (23.9%) and submandibular glands (12.4%). For SUVmax, however, the lacrimal (14.4%) and submandibular glands (6.9%) achieved higher repeatability, while for large organs (kidneys, liver, spleen, and parotid glands), repeatability was low (range: 14.1%–45.2%). Conclusion We found acceptable repeatability of uptake on 18F-DCFPyL PET for normal organs, in particular for SUVmean in the liver or parotid glands. This may have implications for both PSMA-targeted imaging and treatment, as patient selection for radioligand therapy and standardized frameworks for scan interpretation (PROMISE, E-PSMA) rely on uptake in those reference organs

Comparison of Evaluations for Heart Transplant Before Durable Left Ventricular Assist Device and Subsequent Receipt of Transplant at Transplant vs Nontransplant Centers

IMPORTANCE: In 2020, the Centers for Medicare & Medicaid Services revised its national coverage determination, removing the requirement to obtain review from a Medicare-approved heart transplant center to implant a durable left ventricular assist device (LVAD) for bridge-to-transplant (BTT) intent at an LVAD-only center. The association between center-level transplant availability and access to heart transplant, the gold-standard therapy for advanced heart failure (HF), is unknown. OBJECTIVE: To investigate the association of center transplant availability with LVAD implant strategies and subsequent heart transplant following LVAD implant before the Centers for Medicare & Medicaid Services policy change. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study of the Society of Thoracic Surgeons Intermacs multicenter US registry database was conducted from April 1, 2012, to June 30, 2020. The population included patients with HF receiving a primary durable LVAD. EXPOSURES: LVAD center transplant availability (LVAD/transplant vs LVAD only). MAIN OUTCOMES AND MEASURES: The primary outcomes were implant strategy as BTT and subsequent transplant by 2 years. Covariates that might affect listing strategy and outcomes were included (eg, patient demographic characteristics, comorbidities) in multivariable models. Parameters for BTT listing were estimated using logistic regression with center-level random effects and for receipt of a transplant using a Cox proportional hazards regression model with death as a competing event. RESULTS: The sample included 22 221 LVAD recipients with a median age of 59.0 (IQR, 50.0-67.0) years, of whom 17 420 (78.4%) were male and 3156 (14.2%) received implants at LVAD-only centers. Receiving an LVAD at an LVAD/transplant center was associated with a 79% increased adjusted odds of BTT LVAD designation (odds ratio, 1.79; 95% CI, 1.35-2.38; P \u3c .001). The 2-year transplant rate following LVAD implant was 25.6% at LVAD/transplant centers and 11.9% at LVAD-only centers. There was an associated 33% increased rate of transplant at LVAD/transplant centers compared with LVAD-only centers (adjusted hazard ratio, 1.33; 95% CI, 1.17-1.51) with a similar hazard for death at 2 years (adjusted hazard ratio, 0.99; 95% CI, 0.90-1.08). CONCLUSIONS AND RELEVANCE: Receiving an LVAD at an LVAD-transplant center was associated with increased odds of BTT intent at implant and subsequent transplant receipt for patients at 2 years. The findings of this study suggest that Centers for Medicare & Medicaid Services policy change may have the unintended consequence of further increasing inequities in access to transplant among patients at LVAD-only centers

Effect of Point-Spread Function Reconstruction for Indeterminate PSMA-RADS-3A Lesions on PSMA-Targeted PET Imaging of Men with Prostate Cancer

Purpose: Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is emerging as an important modality for imaging patients with prostate cancer (PCa). As with any imaging modality, indeterminate findings will arise. The PSMA reporting and data system (PSMA-RADS) version 1.0 codifies indeterminate soft tissue findings with the PSMA-RADS-3A moniker. We investigated the role of point-spread function (PSF) reconstructions on categorization of PSMA-RADS-3A lesions. Methods: This was a post hoc analysis of an institutional review board approved prospective trial. Around 60 min after the administration of 333 MBq (9 mCi) of PSMA-targeted 18F-DCFPyL, patients underwent PET/computed tomography (CT) acquisitions from the mid-thighs to the skull vertex. The PET data were reconstructed with and without PSF. Scans were categorized according to PSMA-RADS version 1.0, and all PSMA-RADS-3A lesions on non-PSF images were re-evaluated to determine if any could be re-categorized as PSMA-RADS-4. The maximum standardized uptake values (SUVs) of the lesions, mean SUVs of blood pool, and the ratios of those values were determined. Results: A total of 171 PSMA-RADS-3A lesions were identified in 30 patients for whom both PSF reconstructions and cross-sectional imaging follow-up were available. A total of 13/171 (7.6%) were re-categorized as PSMA-RADS-4 lesions with PSF reconstructions. A total of 112/171 (65.5%) were found on follow-up to be true positive for PCa, with all 13 of the re-categorized lesions being true positive on follow-up. The lesions that were re-categorized trended towards having higher SUVmax-lesion and SUVmax-lesion/SUVmean-blood-pool metrics, although these relationships were not statistically significant. Conclusions: The use of PSF reconstructions for 18F-DCFPyL PET can allow the appropriate re-categorization of a small number of indeterminate PSMA-RADS-3A soft tissue lesions as more definitive PSMA-RADS-4 lesions. The routine use of PSF reconstructions for PSMA-targeted PET may be of value at those sites that utilize this technolog

Neuropilin-2 regulates androgen-receptor transcriptional activity in advanced prostate cancer

Aberrant transcriptional activity of androgen receptor (AR) is one of the dominant mechanisms for developing of castration-resistant prostate cancer (CRPC). Analyzing AR-transcriptional complex related to CRPC is therefore important towards understanding the mechanism of therapy-resistance. While studying its mechanism, we observed that a transmembrane protein called neuropilin-2 (NRP2) plays a contributory role in forming a novel AR-transcriptional complex containing nuclear pore proteins. Using immunogold electron microscopy, high-resolution confocal microscopy, chromatin immunoprecipitation, proteomics, and other biochemical techniques, we delineated the molecular mechanism of how a specific splice variant of NRP2 becomes sumoylated upon ligand stimulation and translocates to the inner nuclear membrane. This splice variant of NRP2 then stabilizes the complex between AR and nuclear pore proteins to promote CRPC specific gene expression. Both full-length and splice variants of AR have been identified in this specific transcriptional complex. In vitro cell line-based assays indicated that depletion of NRP2 not only destabilizes the AR-nuclear pore protein interaction but also inhibits the transcriptional activities of AR. Using an in vivo bone metastasis model, we showed that the inhibition of NRP2 led to the sensitization of CRPC cells toward established anti-AR therapies such as enzalutamide. Overall, our finding emphasize the importance of combinatorial inhibition of NRP2 and AR as an effective therapeutic strategy against treatment refractory prostate cancer

Lack of repeatability of radiomic features derived from PET scans: results from a 18F‐DCFPyL test–retest cohort

Objectives PET-based radiomic metrics are increasingly utilized as predictive image biomarkers. However, the repeatability of radiomic features on PET has not been assessed in a test–retest setting. The prostate-specific membrane antigen-targeted compound 18F-DCFPyL is a high-affinity, high-contrast PET agent that we utilized in a test-retest cohort of men with metastatic prostate cancer (PC). Methods Data of 21 patients enrolled in a prospective clinical trial with histologically proven PC underwent two 18F-DCFPyL PET scans within 7 days, using identical acquisition and reconstruction parameters. Sites of disease were segmented and a set of 29 different radiomic parameters were assessed on both scans. We determined repeatability of quantification by using Pearson's correlations, within-subject coefficient of variation (wCOV), and Bland–Altman analysis. Results In total, 230 lesions (177 bone, 38 lymph nodes, 15 others) were assessed on both scans. For all investigated radiomic features, a broad range of inter-scan correlation was found (r, 0.07–0.95), with acceptable reproducibility for entropy and homogeneity (wCOV, 16.0% and 12.7%, respectively). On Bland–Altman analysis, no systematic increase or decrease between the scans was observed for either parameter (±1.96 SD: 1.07/−1.30, 0.23/−0.18, respectively). The remaining 27 tested radiomic metrics, however, achieved unacceptable high wCOV (≥21.7%). Conclusion Many common radiomic features derived from a test–retest PET study had poor repeatability. Only Entropy and homogeneity achieved good repeatability, supporting the notion that those image biomarkers may be incorporated in future clinical trials. Those radiomic features based on high frequency aspects of images appear to lack the repeatability on PET to justify further study

High SUVs have more robust repeatability in patients with metastatic prostate cancer: results from a prospective test-retest cohort imaged with 18F-DCFPyL

OBJECTIVES: In patients with prostate cancer (PC) receiving prostate-specific membrane antigen- (PSMA-) targeted radioligand therapy (RLT), higher baseline standardized uptake values (SUVs) are linked to improved outcome. Thus, readers deciding on RLT must have certainty on the repeatability of PSMA uptake metrics. As such, we aimed to evaluate the test-retest repeatability of lesion uptake in a large cohort of patients imaged with (18)F-DCFPyL. METHODS: In this prospective, IRB-approved trial (NCT03793543), 21 patients with history of histologically proven PC underwent two (18)F-DCFPyL PET/CTs within 7 days (mean 3.7, range 1 to 7 days). Lesions in the bone, lymph nodes (LN), and other organs were manually segmented on both scans, and uptake parameters were assessed (maximum (SUV(max)) and mean (SUV(mean)) SUVs), PSMA-tumor volume (PSMA-TV), and total lesion PSMA (TL-PSMA, defined as PSMA − TV × SUV(mean))). Repeatability was determined using Pearson's correlations, within-subject coefficient of variation (wCOV), and Bland-Altman analysis. RESULTS: In total, 230 pairs of lesions (177 bone, 38 LN, and 15 other) were delineated, demonstrating a wide range of SUV(max) (1.5–80.5) and SUV(mean) (1.4–24.8). Including all sites of suspected disease, SUVs had a strong interscan correlation (R(2) ≥ 0.99), with high repeatability for SUV(mean) and SUV(max) (wCOV, 7.3% and 12.1%, respectively). High SUVs showed significantly improved wCOV relative to lower SUVs (P < 0.0001), indicating that high SUVs are more repeatable, relative to the magnitude of the underlying SUV. Repeatability for PSMA-TV and TL-PSMA, however, was low (wCOV ≥ 23.5%). Across all metrics for LN and bone lesions, interscan correlation was again strong (R(2) ≥ 0.98). Moreover, LN-based SUV(mean) also achieved the best wCOV (3.8%), which was significantly reduced when compared to osseous lesions (7.8%, P < 0.0001). This was also noted for SUV(max) (wCOV, LN 8.8% vs. bone 12.0%, P < 0.03). On a compartment-based level, wCOVs for volumetric features were ≥22.8%, demonstrating no significant differences between LN and bone lesions (PSMA-TV, P =0.63; TL-PSMA, P =0.9). Findings on an entire tumor burden level were also corroborated in a hottest lesion analysis investigating the SUV(max) of the most intense lesion per patient (R(2), 0.99; wCOV, 11.2%). CONCLUSION: In this prospective test-retest setting, SUV parameters demonstrated high repeatability, in particular in LNs, while volumetric parameters demonstrated low repeatability. Further, the large number of lesions and wide distribution of SUVs included in this analysis allowed for the demonstration of a dependence of repeatability on SUV, with higher SUVs having more robust repeatability