External validation of the Memorial Sloan Kettering Cancer Center preoperative nomogram predicting lymph node invasion in a cohort of high-grade prostate cancer patients.

BACKGROUND: Commonly used preoperative nomograms predicting clinical and pathological outcomes in prostate cancer (PCa) patients have not been yet validated in high-grade only PCa patients. Our objective is to perform an external validation of the Memorial Sloan Kettering Cancer Center (MSKCC) preoperative nomogram as a predictor of lymph node invasion (LNI) in a cohort of high-grade PCa patients. METHODS: We included patients with high-grade PCa (Gleason ≥8) treated at our institution between 2011 and 2020 with radical prostatectomy and pelvic lymph node dissection without receiving neoadjuvant or adjuvant therapy. The area under the curve (AUC) of the receiver operator characteristic (ROC) was used to quantify the accuracy of the model to predict LNI. A calibration plot was used to evaluate the model's precision, and a decision curve analysis was computed to evaluate the net benefit associated with its use. This study was approved by our institution's ethics board. RESULTS: A total of 242 patients with a median age of 66 (60-71) years were included. LNI was observed in 70 (29%) patients with a mean of 16 (median = 15; range = 2-42) resected nodes. The MSKCC nomogram discriminative accuracy, as evaluated by the AUC-ROC was 79.0% (CI: [0.727-0.853]). CONCLUSION: The MSKCC preoperative nomogram is a good predictor of LNI and a useful tool associated with net clinical benefit in this patient population.

Mass spectrometry redefines optimal testosterone thresholds in prostate cancer patients undergoing androgen deprivation therapy.

BACKGROUND: Androgen deprivation therapy (ADT) is the standard of care for prostate cancer treatment. Studies suggest that patients with testosterone levels below 0.7 nM have a longer time to castration resistance. Using the most accurate testosterone measurement method, namely mass spectrometry (MS), we sought to determine if a lower testosterone level under ADT could be associated with longer time to castration resistance. METHODS: This retrospective study included 138 prostate cancer patients undergoing noncurative continuous ADT for which we had access to testosterone measurements assessed by MS. For 108 samples, paired immunoassays (IA) testosterone measurement was available. Primary outcome was time to castration-resistant prostate cancer (CRPC). The Contal and O'Quigley method was used to determine the optimal testosterone castration cut-off point considering the outcome and time-to-event variables. Relationship between testosterone levels assessed either by IA or MS and time to CRPC was evaluated using Cox regression. RESULTS: Mean testosterone level was 0.370 nM by IA and 0.275 nM as assessed by MS. The optimal testosterone cut-off point identified to predict time to CRPC was of 0.705 nM for IA and of 0.270 nM for MS. While no significant difference for time to CRPC was found between patients showing IA testosterone level ≥0.705 nM versus <0.705 nM (hazard ratio [HR]: 1.579; 95% confidence interval [CI]: 0.908-2.745), patients with MS testosterone ≥0.270 nM had an increased risk of progression to CRPC compared to MS testosterone <0.270 nM in univariate (HR: 1.717; 95% CI: 1.160-2.541) and multivariate analysis (HR: 1.662; 95% CI: 1.043-2.648). CONCLUSIONS: The higher sensitivity of MS testosterone measurement methods allows the identification of a lower castration threshold and leads to early identification of patients more likely to progress to CRPC. These patients would likely benefit from treatment intensification by androgen receptor axis-targeted therapies to delay disease progression.

Estimated glomerular filtration rate from the renal hypothermia trial: clinical implications.

OBJECTIVE: To assess if estimated glomerular filtration rate (eGFR) can replace measured GFR (mGFR) in partial nephrectomy (PN) trials, using data from a randomised clinical trial. PATIENTS AND METHODS: We conducted a post hoc analysis of the renal hypothermia trial. Patients underwent mGFR with diethylenetriaminepentaacetic acid (DTPA) plasma clearance preoperatively and 1 year after PN. The eGFR was calculated using the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equations incorporating age and sex, with and without race: 2009 eGFRcr(ASR) and 2009 eGFRcr(AS), and the 2021 equation that only incorporates age and sex: 2021 eGFRcr(AS). Performance was evaluated by determining the median bias, precision (interquartile range [IQR] of median bias), and accuracy (percentage of eGFR within 30% of mGFR). RESULTS: Overall, 183 patients were included. Pre- and postoperative median bias and precision were similar between the 2009 eGFRcr(ASR) (-0.2 mL/min/1.73 m2 , 95% confidence interval [CI] -2.2 to 1.7, IQR 18.8; and -2.9, 95% CI -5.1 to -1.5, IQR 15, respectively) and 2009 eGFRcr(AS) (-0.3 mL/min/1.73 m2 , 95% CI -2.4 to 1.5, IQR 18.8; and -3.0, 95% CI -5.7 to -1.7, IQR 15.0, respectively). Bias and precision were worse for the 2021 eGFRcr(AS) (-8.8 mL/min/1.73 m2 , 95% CI -10.9 to -6.3, IQR 24.7; and -12.0, 95% CI -15.8 to -8.9, IQR 23.5, respectively). Similarly, pre- and postoperative accuracy was >90% for the 2009 eGFRcr(ASR) and 2009 eGFRcr(AS) equations. Accuracy was 78.6% preoperatively and 66.5% postoperatively for 2021 eGFRcr(AS). CONCLUSION: The 2009 eGFRcr(AS) can accurately estimate GFR in PN trials and could be used instead of mGFR to reduce cost and patient burden.

Proximity-dependent Mapping of the Androgen Receptor Identifies Kruppel-like Factor 4 as a Functional Partner.

Prostate cancer (PCa) is the most frequently diagnosed cancer in men and the third cause of cancer mortality. PCa initiation and growth are driven by the androgen receptor (AR). The AR is activated by androgens such as testosterone and controls prostatic cell proliferation and survival. Here, we report an AR signaling network generated using BioID proximity labeling proteomics in androgen-dependent LAPC4 cells. We identified 31 AR-associated proteins in nonstimulated cells. Strikingly, the AR signaling network increased to 182 and 200 proteins, upon 24 h or 72 h of androgenic stimulation, respectively, for a total of 267 nonredundant AR-associated candidates. Among the latter group, we identified 213 proteins that were not previously reported in databases. Many of these new AR-associated proteins are involved in DNA metabolism, RNA processing, and RNA polymerase II transcription. Moreover, we identified 44 transcription factors, including the Kru¨ppel-like factor 4 (KLF4), which were found interacting in androgen-stimulated cells. Interestingly, KLF4 repressed the well-characterized AR-dependent transcription of the KLK3 (PSA) gene; AR and KLF4 also colocalized genome-wide. Taken together, our data report an expanded high-confidence proximity network for AR, which will be instrumental to further dissect the molecular mechanisms underlying androgen signaling in PCa cells.

Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma.

BACKGROUND: The combination of pembrolizumab and axitinib showed antitumor activity in a phase 1b trial involving patients with previously untreated advanced renal-cell carcinoma. Whether pembrolizumab plus axitinib would result in better outcomes than sunitinib in such patients was unclear. METHODS: In an open-label, phase 3 trial, we randomly assigned 861 patients with previously untreated advanced clear-cell renal-cell carcinoma to receive pembrolizumab (200 mg) intravenously once every 3 weeks plus axitinib (5 mg) orally twice daily (432 patients) or sunitinib (50 mg) orally once daily for the first 4 weeks of each 6-week cycle (429 patients). The primary end points were overall survival and progression-free survival in the intention-to-treat population. The key secondary end point was the objective response rate. All reported results are from the protocol-specified first interim analysis. RESULTS: After a median follow-up of 12.8 months, the estimated percentage of patients who were alive at 12 months was 89.9% in the pembrolizumab-axitinib group and 78.3% in the sunitinib group (hazard ratio for death, 0.53; 95% confidence interval [CI], 0.38 to 0.74; P<0.0001). Median progression-free survival was 15.1 months in the pembrolizumab-axitinib group and 11.1 months in the sunitinib group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.57 to 0.84; P<0.001). The objective response rate was 59.3% (95% CI, 54.5 to 63.9) in the pembrolizumab-axitinib group and 35.7% (95% CI, 31.1 to 40.4) in the sunitinib group (P<0.001). The benefit of pembrolizumab plus axitinib was observed across the International Metastatic Renal Cell Carcinoma Database Consortium risk groups (i.e., favorable, intermediate, and poor risk) and regardless of programmed death ligand 1 expression. Grade 3 or higher adverse events of any cause occurred in 75.8% of patients in the pembrolizumab-axitinib group and in 70.6% in the sunitinib group. CONCLUSIONS: Among patients with previously untreated advanced renal-cell carcinoma, treatment with pembrolizumab plus axitinib resulted in significantly longer overall survival and progression-free survival, as well as a higher objective response rate, than treatment with sunitinib. (Funded by Merck Sharp & Dohme; KEYNOTE-426 ClinicalTrials.gov number, NCT02853331.).

Extensive Alteration of Androgen Precursor Levels After Castration in Prostate Cancer Patients and Their Association With Active Androgen Level.

PURPOSE: Dihydrotestosterone and testosterone are thought to be major contributors of prostate cancer progression and resistance. We studied the modulation of 15 circulating steroids by castration and their association with dihydrotestosterone and testosterone levels. MATERIALS METHODS: A total of 116 serum samples were collected from 99 prostate cancer patients and categorized as eugonadal, castration-sensitive prostate cancer, castration-resistant prostate cancer, or castration-resistant prostate cancer under abiraterone acetate. Serum levels of 15 steroids were measured using mass spectrometry and compared between groups using analysis of variance. Intrapatient association of steroid levels and the androgens testosterone and dihydrotestosterone were assessed using Pearson correlation and linear regression. RESULTS: Testosterone, dihydrotestosterone, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone-sulfate, androsterone, androstenediol, estrone, estrone-sulfate, estradiol, and androsterone/3α-diol-3/3α-diol-17-glucuronide levels were significantly decreased in castration-sensitive prostate cancer (castrated) compared to eugonadal patients. Testosterone levels were strongly associated with multiple steroids under eugonadal conditions, whereas they were weakly affected by precursor steroids in castrated patients. By contrast, dihydrotestosterone levels under androgen deprivation therapy were associated with testosterone and the backdoor pathway metabolite androsterone. In castration-resistant prostate cancer patients, levels of androstenedione were significantly associated with testosterone level, while testosterone was the only steroid associated with dihydrotestosterone levels. CONCLUSIONS: Androgen deprivation therapy significantly reduces the levels of 13 circulating steroids. Upon androgen deprivation therapy initiation, the backdoor pathway metabolite androsterone are strongly associated with dihydrotestosterone levels. Under castration-resistant prostate cancer conditions, androstenedione was significantly associated with testosterone levels, suggesting the presence of tumor-related circulating androgens in these patients. These results provide further rationale to intensify treatments with androgen receptor axis signaling pathway inhibitors in patients with prostate cancer.

A Comparison of Percutaneous Ablation Therapy to Partial Nephrectomy for cT1a Renal Cancers: Results from the Canadian Kidney Cancer Information System.

PURPOSE: Percutaneous ablation therapy (AT) and partial nephrectomy (PN) are successful management strategies for T1a renal cancer. Our objective was to compare AT to PN with respect to recurrence-free survival (RFS) and overall survival (OS). MATERIALS AND METHODS: Patients post-PN or -AT for cT1aN0M0 renal cancer from 2011 to 2021 were identified from the national Canadian Kidney Cancer information system. Inverse probability of treatment weighting (IPTW) using propensity score (PS) was used. The primary outcomes, RFS and OS, were compared using Kaplan-Meier log-rank test analyses and Cox proportional hazard regression models. RESULTS: A total of 275 patients underwent AT and 2,001 underwent PN, with a median followup of 2.0 years (IQR 0.6-4.1). Covariates were well balanced between the AT and PN cohorts following PS matching. Two-year RFS following IPTW PS analysis for patients undergoing AT and PN was 88.1% and 97.4% (p <0.0001), respectively, while 2-year OS was 97.4% and 99.0% (p=0.7), respectively. Five-year RFS following IPTW PS analysis for patients undergoing AT and PN was 86.0% and 95.1%, respectively (p=0.003), while 5-year OS was 94.2% and 95.1%, respectively (p=0.9). Following IPTW PS analysis, treatment modality (PN vs AT) was a predictor of disease recurrence (HR 0.36, p=0.003) but not for OS (HR 0.96, p=0.9). CONCLUSIONS: With short followup, PN offers better RFS than AT, although no significant difference in OS was detected following PS adjustments. Both modalities can be offered to appropriately selected patients while we await prospective randomized data.

The Triple-Tracer strategy against Metastatic PrOstate cancer (3TMPO) study protocol.

OBJECTIVE: To determine the prevalence of intra-patient inter-metastatic heterogeneity based on positron emission tomography (PET)/computed tomography (CT) in patients with metastatic castration-resistant prostate cancer (mCRPC) and to determine the prevalence of neuroendocrine disease in these patients and their eligibility for radioligand therapies (RLTs). PATIENTS AND METHODS: This multicentre observational prospective clinical study will include 100 patients with mCRPC from five Canadian academic centres. Patients with radiological or biochemical progression and harbouring at least three metastases by conventional imaging will be accrued. Intra-patient inter-metastatic heterogeneity will be determined with triple-tracer imaging using fluorine-18 fluorodeoxyglucose (18 F-FDG), gallium-68-(68 Ga)-prostate-specific membrane antigen (PSMA)-617 and 68 Ga-DOTATATE, which are a glucose analogue, a PSMA receptor ligand and a somatostatin receptor ligand, respectively. The 68 Ga-PSMA-617 and 18 F-FDG PET/CT scans will be performed first. If at least one PSMA-negative/FDG-positive lesion is observed, an additional PET/CT scan with 68 Ga-DOTATATE will be performed. The tracer uptake of individual lesions will be assessed for each PET tracer and patients with lesions presenting discordant uptake profiles will be considered as having inter-metastatic heterogeneous disease and may be offered a biopsy. EXPECTED RESULTS: The proposed triple-tracer approach will allow whole-body mCRPC characterisation, investigating the inter-metastatic heterogeneity in order to better understand the phenotypic plasticity of prostate cancer, including the neuroendocrine transdifferentiation that occurs during mCRPC progression. Based on 68 Ga-PSMA-617 or 68 Ga-DOTATATE PET positivity, the potential eligibility of patients for PSMA and DOTATATE-based RLT will be assessed. Non-invasive whole-body determination of mCRPC heterogeneity and transdifferentiation is highly innovative and might establish the basis for new therapeutic strategies. Comparison of molecular imaging findings with biopsies will also link metastasis biology to radiomic features. CONCLUSION: This study will add novel, biologically relevant dimensions to molecular imaging: the non-invasive detection of inter-metastatic heterogeneity and transdifferentiation to neuroendocrine prostate cancer by using a multi-tracer PET/CT strategy to further personalise the care of patients with mCRPC.

Glucuronidated Metabolites of Bisphenols A and S Alter the Properties of Normal Urothelial and Bladder Cancer Cells.

Bisphenol A (BPA) and bisphenol S (BPS) are synthetic chemicals used to produce plastics which can be released in food and water. Once ingested, BPA and BPS are metabolized by the liver, mainly as glucuronidated metabolites, and are excreted through urine. Since urine can be stored for many hours, the bladder is chronically exposed to BP metabolites, and studies have shown that these metabolites can remain active in the organism. Therefore, the effect of physiological concentrations of glucuronidated BPs was evaluated on the bioenergetics (glycolysis and mitochondrial respiration), migration and proliferation of normal urothelial cells, and non-invasive and invasive bladder cancer cells. The results demonstrated that an exposure of 72 h to glucuronidated BPA or BPS decreased the bioenergetics and activity of normal urothelial cells, while increasing these parameters for bladder cancer cells. These findings suggest that BP metabolites are not as inactive as initially believed, and their ubiquitous presence in the urine could promote bladder cancer progression.

Interpreting Testosterone and Concomitant Prostate Specific Antigen Values during Androgen Deprivation Therapy for Recurrent Prostate Cancer.

PURPOSE: Measurement of testosterone levels during androgen deprivation therapy (ADT) is broadly recommended, but how therapy should be altered in response to testosterone values during ADT remains controversial. Our objective was therefore to evaluate the relation between testosterone and concomitant prostate specific antigen (PSA) levels during ADT on clinical outcomes. MATERIALS AND METHODS: Patients from the continuous androgen deprivation arm of the PR.7 trial of intermittent ADT for biochemically recurrent prostate cancer following radiotherapy were included. Statistical analyses evaluated the prognostic importance of testosterone levels during ADT relative to concomitant PSA levels. We similarly evaluated whether the number of testosterone breakthroughs >1.7 nmol/l predicted the time to castrate-resistant prostate cancer (CRPC), cancer specific survival (CSS) or overall survival (OS) with Kaplan-Meier and Cox regression analyses. RESULTS: Overall, the prognostic importance of testosterone on outcomes was eclipsed by the prognostic value of concomitant PSA values. The occurrence of testosterone values >0.7 nmol/l in the first year of therapy was associated with subsequent rises >1.7 nmol/l, but the number of testosterone breakthroughs per patient had no relationship to the risk of CRPC, CSS or OS. A time-dependent adjusted analysis indicated as expected that PSA values were prognostic, but there was no association of relative cumulative testosterone exposure with outcomes. CONCLUSIONS: In this large-scale trial with long followup, breakthrough testosterone was unrelated to time to CRPC, CSS or OS. Castrate testosterone values during ADT for recurrent prostate cancer provides prognostic information that must be considered alongside the time since ADT initiation and concomitant PSA values.

A Phase 2/3 Prospective Multicenter Study of the Diagnostic Accuracy of Prostate Specific Membrane Antigen PET/CT with 18F-DCFPyL in Prostate Cancer Patients (OSPREY).

PURPOSE: Prostate specific membrane antigen-targeted positron emission tomography/computerized tomography has the potential to improve the detection and localization of prostate cancer. OSPREY was a prospective trial designed to determine the diagnostic performance of 18F-DCFPyL-positron emission tomography/computerized tomography for detecting sites of metastatic prostate cancer. MATERIALS AND METHODS: Two patient populations underwent 18F-DCFPyL-positron emission tomography/computerized tomography. Cohort A enrolled men with high-risk prostate cancer undergoing radical prostatectomy with pelvic lymphadenectomy. Cohort B enrolled patients with suspected recurrent/metastatic prostate cancer on conventional imaging. Three blinded central readers evaluated the 18F-DCFPyL-positron emission tomography/computerized tomography. Diagnostic performance of 18F-DCFPyL-positron emission tomography/computerized tomography was based on imaging results compared to histopathology. In cohort A, detection of pelvic nodal disease (with specificity and sensitivity as co-primary end points) and of extrapelvic metastases were evaluated. In cohort B, sensitivity and positive predictive value for prostate cancer within biopsied lesions were evaluated. RESULTS: A total of 385 patients were enrolled. In cohort A (252 evaluable patients), 18F-DCFPyL-positron emission tomography/computerized tomography had median specificity of 97.9% (95% CI: 94.5%-99.4%) and median sensitivity of 40.3% (28.1%-52.5%, not meeting prespecified end point) among 3 readers for pelvic nodal involvement; median positive predictive value and negative predictive value were 86.7% (69.7%-95.3%) and 83.2% (78.2%-88.1%), respectively. In cohort B (93 evaluable patients, median prostate specific antigen 11.3 ng/ml), median sensitivity and positive predictive value for extraprostatic lesions were 95.8% (87.8%-99.0%) and 81.9% (73.7%-90.2%), respectively. CONCLUSIONS: The primary end point for specificity was met while the primary end point for sensitivity was not. The high positive predictive value observed in both cohorts indicates that 18F-DCFPyL-positive lesions are likely to represent disease, supporting the potential utility of 18F-DCFPyL-positron emission tomography/computerized tomography to stage men with high-risk prostate cancer for nodal or distant metastases, and reliably detect sites of disease in men with suspected metastatic prostate cancer.

Hypothermia During Partial Nephrectomy for Patients with Renal Tumors: A Randomized Controlled Trial.

PURPOSE: Surgeons induce renal hypothermia during partial nephrectomy to preserve kidney function, without strong evidence of benefit. This trial examined the effectiveness and safety of renal hypothermia during partial nephrectomy. MATERIALS AND METHODS: We conducted a parallel randomized controlled trial of hypothermia versus no hypothermia (control group) during partial nephrectomy at 6 academic hospitals. Eligible patients had a planned open partial nephrectomy for the treatment of a renal tumor. During surgery, after clamping the renal hilum, patients were randomized to the intervention or control arm in a 1:1 ratio using permuted blocks of variable lengths (2 and 4), stratified by institution, using a computer-based program. Surgeons and study coordinators were masked to treatment allocation until the renal hilum was clamped. Overall glomerular filtration rates were determined before, and 1-year after, surgery. The primary outcome was measured glomerular filtration rate (mGFR) assessed by the plasma clearance of 99mTc-DTPA. The trial (NCT01529658) was designed with 90% power to detect a minimal clinically important difference in mGFR of 10 ml/minute/1.73 m2 at a 5% significance level. RESULTS: Of the 184 patients randomized, hypothermia and control patients had similar baseline mean mGFR (87.1 vs 81.0 ml/minute/1.73 m2). One hundred and sixty-one (79 hypothermia, 82 control) were alive with primary outcome data 1 year after surgery. The change in mGFR 1 year after surgery was -6.6 ml/minute/1.73 m2 in the hypothermia group and -7.8 ml/minute/1.73 m2 in the control group (mean difference 1.2 ml/minute/1.73 m2, 95% CI -3.3 to 5.6). Operated-kidney change in mGFR was similar between groups (-5.8 vs -6.3 ml/minute/1.73 m2; mean difference 0.5 ml/minute/1.73 m2, 95% CI -2.9 to 3.8). No clinically significant difference in the mGFR was observed when patients were stratified by pre-planned subgroups. Renal hypothermia did not impact the secondary outcomes of surgical complications and patient reported quality of life. CONCLUSIONS: Renal hypothermia during partial nephrectomy does not preserve kidney function in patients with normal or mildly impaired renal function.

Impact of Time to Surgery and Surgical Delay on Oncologic Outcomes for Renal Cell Carcinoma.

PURPOSE: The time between radiographic identification of a renal tumor and surgery can be concerning for patients and clinicians due to fears of tumor progression while awaiting treatment. This study aimed to evaluate the association between surgical wait time and oncologic outcomes for patients with renal cell carcinoma. MATERIALS AND METHODS: The Canadian Kidney Cancer Information System is a multi-institutional prospective cohort initiated in January 2011. Patients with clinical stage T1b or greater renal cell carcinoma diagnosed between January 2011 and December 2019 were included in this analysis. Outcomes of interest were pathological up staging, cancer recurrence, cancer specific survival and overall survival. Time to recurrence and death were estimated using Kaplan-Meier estimates and associations were determined using Cox proportional hazards models. RESULTS: A total of 1,769 patients satisfied the study criteria. Median wait times were 54 days (IQR 29-86) for the overall cohort and 81 days (IQR 49-127) for cT1b tumors (1,166 patients), 45 days (IQR 27-71) for cT2 tumors (672 cases) and 35 days (IQR 18-61) for cT3/4 tumors (563). Adjusting for comorbidity, tumor size, grade, histological subtype, margin status and pathological stage, there was no association between prolonged wait time and cancer recurrence or death. CONCLUSIONS: In the context of current surgeon triaging practices surgical wait times up to 24 weeks were not associated with adverse oncologic outcomes after 2 years of followup.

Achieving the "trifecta" with open versus minimally invasive partial nephrectomy.

INTRODUCTION: The "trifecta" is a summary measure of outcome after partial nephrectomy (PN) that encompasses three parameters: negative surgical margin, ≤ 10% decrease in post-operative estimated glomerular filtration rate (eGFR) and absence of urological complications. We assessed trifecta rates in patients undergoing open (OPN), laparoscopic (LPN), and robotic PN (RPN) for a clinical T1 renal mass (≤ 7 cm). METHODS: Clinical and pathologic parameters were extracted from the prospectively maintained Canadian Kidney Cancer Information System for patients treated between January 2011 and October 2018. Comparisons between groups were made using Kruskal-Wallis test for continuous variables and Chi-squared independence test for categorical variables. Multivariable analysis was performed to identify predictors of each component of the trifecta and the trifecta itself. RESULTS: Of 1708 total patients, 746 underwent OPN, 678 LPN, and 284 RPN for a T1 renal mass. A 'trifecta' was achieved in 53% OPN, 52% LPN and 47% RPN (p = 0.194). On multivariable analysis, OPN and LPN were associated with less frequent post-operative decline in eGFR and more frequent trifecta when compared to RPN, but there was no difference between OPN and LPN. OPN also predicted a higher rate of negative margins compared to RPN but not LPN. CONCLUSION: After correction for confounding variables, OPN and LPN were more likely than RPN to achieve the trifecta, which appeared to be due primarily to loss of renal function. No difference was observed between OPN and LPN. Analyses were limited by the lack of nephrometry score.

TGFß Signaling in the Tumor Microenvironment.

Transforming growth factor beta (TGFß) is a pleiotropic growth factor. Under normal physiological conditions, TGFß maintains homeostasis in mammalian tissues by restraining the growth of cells and stimulating apoptosis. However, the role of TGFß signaling in the carcinogenesis is complex. TGFß acts as a tumor suppressor in the early stages of disease and as a tumor promoter in its later stages where cancer cells have been relieved from TGFß growth controls. Overproduction of TGFß by cancer cells lead to a local fibrotic and immune-suppressive microenvironment that fosters tumor growth and correlates with invasive and metastatic behavior of the cancer cells. Here, we present an overview of the complex biology of the TGFß family, and we discuss the roles of TGFß signaling in carcinogenesis and how this knowledge is being leveraged to develop TGFß inhibition therapies against the tumor.

Identification of Abundant and Functional dodecaRNAs (doRNAs) Derived from Ribosomal RNA.

Using a modified RNA-sequencing (RNA-seq) approach, we discovered a new family of unusually short RNAs mapping to ribosomal RNA 5.8S, which we named dodecaRNAs (doRNAs), according to the number of core nucleotides (12 nt) their members contain. Using a new quantitative detection method that we developed, we confirmed our RNA-seq data and determined that the minimal core doRNA sequence and its 13-nt variant C-doRNA (doRNA with a 5' Cytosine) are the two most abundant doRNAs, which, together, may outnumber microRNAs. The C-doRNA/doRNA ratio is stable within species but differed between species. doRNA and C-doRNA are mainly cytoplasmic and interact with heterogeneous nuclear ribonucleoproteins (hnRNP) A0, A1 and A2B1, but not Argonaute 2. Reporter gene activity assays suggest that C-doRNA may function as a regulator of Annexin II receptor (AXIIR) expression. doRNAs are differentially expressed in prostate cancer cells/tissues and may control cell migration. These findings suggest that unusually short RNAs may be more abundant and important than previously thought.

Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial.

BACKGROUND: The first interim analysis of the KEYNOTE-426 study showed superior efficacy of pembrolizumab plus axitinib over sunitinib monotherapy in treatment-naive, advanced renal cell carcinoma. The exploratory analysis with extended follow-up reported here aims to assess long-term efficacy and safety of pembrolizumab plus axitinib versus sunitinib monotherapy in patients with advanced renal cell carcinoma. METHODS: In the ongoing, randomised, open-label, phase 3 KEYNOTE-426 study, adults (≥18 years old) with treatment-naive, advanced renal cell carcinoma with clear cell histology were enrolled in 129 sites (hospitals and cancer centres) across 16 countries. Patients were randomly assigned (1:1) to receive 200 mg pembrolizumab intravenously every 3 weeks for up to 35 cycles plus 5 mg axitinib orally twice daily or 50 mg sunitinib monotherapy orally once daily for 4 weeks per 6-week cycle. Randomisation was done using an interactive voice response system or integrated web response system, and was stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk status and geographical region. Primary endpoints were overall survival and progression-free survival in the intention-to-treat population. Since the primary endpoints were met at the first interim analysis, updated data are reported with nominal p values. This study is registered with ClinicalTrials.gov, NCT02853331. FINDINGS: Between Oct 24, 2016, and Jan 24, 2018, 861 patients were randomly assigned to receive pembrolizumab plus axitinib (n=432) or sunitinib monotherapy (n=429). With a median follow-up of 30·6 months (IQR 27·2-34·2), continued clinical benefit was observed with pembrolizumab plus axitinib over sunitinib in terms of overall survival (median not reached with pembrolizumab and axitinib vs 35·7 months [95% CI 33·3-not reached] with sunitinib); hazard ratio [HR] 0·68 [95% CI 0·55-0·85], p=0·0003) and progression-free survival (median 15·4 months [12·7-18·9] vs 11·1 months [9·1-12·5]; 0·71 [0·60-0·84], p<0·0001). The most frequent (≥10% patients in either group) treatment-related grade 3 or worse adverse events were hypertension (95 [22%] of 429 patients in the pembrolizumab plus axitinib group vs 84 [20%] of 425 patients in the sunitinib group), alanine aminotransferase increase (54 [13%] vs 11 [3%]), and diarrhoea (46 [11%] vs 23 [5%]). No new treatment-related deaths were reported since the first interim analysis. INTERPRETATION: With extended study follow-up, results from KEYNOTE-426 show that pembrolizumab plus axitinib continues to have superior clinical outcomes over sunitinib. These results continue to support the first-line treatment with pembrolizumab plus axitinib as the standard of care of advanced renal cell carcinoma. FUNDING: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.

Testosterone Breakthrough Rates during Androgen Deprivation Therapy for Castration Sensitive Prostate Cancer.

PURPOSE: Androgen deprivation therapy is an established therapy for castration sensitive prostate cancer and recent studies have observed that patients whose testosterone levels are suppressed below 0.7 nmol/l have improved outcomes. Testosterone breakthrough, or a rise in testosterone above a target threshold after the first month of androgen deprivation therapy, is generally associated with treatment deficiency. The purpose of this review is to summarize breakthrough rate data and explore the relationship to clinical outcomes in patients with castration sensitive prostate cancer receiving androgen deprivation therapy. MATERIALS AND METHODS: Our systematic search identified 45 studies with a total of 52 cohorts representing 6,047 total patients reporting testosterone breakthrough rates or derivative measures above the thresholds of 1.7 nmol/l (51 cohorts, 6,015 patients) or 0.7 nmol/l (15 cohorts, 2,495 patients). RESULTS: Significantly higher weighted mean breakthrough rates were seen for the 0.7 nmol/l threshold compared to 1.7 nmol/l (41.3% vs 6.9%, p <0.0001). A significant association between breakthrough rates and worse clinical outcomes overall was not found, although when larger trials (sample size greater than 100) and higher event rates (greater than 50%) were considered for the lowest threshold, significant associations between breakthrough rates and clinical outcomes were observed. Clinical factors such as administration and monitoring frequency, type of testosterone assay and type of androgen deprivation therapy did not significantly affect breakthrough rates, although nonvalidated assays were associated with a large degree of variability. CONCLUSIONS: Results from our analysis indicate that testosterone breakthroughs likely result in worse clinical outcomes and should be avoided. Moreover, there is a need to standardize assessment of testosterone levels both clinically and in the research context to better inform treatment decisions and improve the reliability and comparability of results across studies.

Extragonadal Steroids Contribute Significantly to Androgen Receptor Activity and Development of Castration Resistance in Recurrent Prostate Cancer after Primary Therapy.

PURPOSE: Beyond testosterone, several steroids contribute to the activation of the androgen receptor pathway, but their relative contributions to the activation of the androgen receptor signaling axis in patients with castrated prostate cancer remain unknown. MATERIALS AND METHODS: Serum levels of 9 steroids were measured by mass spectrometry from continuously castrated patients of the PR.7 study (219) and from the PCA24 cohort (116). For each steroid standard curves for dose dependent prostate specific antigen promoter activation were built in castration sensitive (LAPC4) and resistant (VCaP) prostate cancer models. Standard curves were used to determine the androgen receptor activation potency for each steroid measurement from patients in these trials. RESULTS: In LAPC4 and VCaP cells testosterone, dihydrotestosterone and androstenedione induced androgen receptor transcriptional activity, while dehydroepiandrosterone, 5alpha-androstan-3beta,17beta-diol, androstenediol and androsterone stimulated androgen receptor only in VCaP cells. Extragonadal steroids were responsible for 34% (LAPC4) and 88% (VCaP) of the serum total androgen receptor transcriptional activity found in castrated cases. The total androgen receptor transcriptional activity secondary to testosterone, dihydrotestosterone and androstenedione was associated with time to castration resistance in patients from the PR.7 study (HR 2.17, 95% CI 1.12-4.23, p=0.02) in multivariate analysis using the castration sensitive model (LAPC4). Androgen receptor transcriptional activity of extragonadal androstenedione was the only steroid statistically associated with time to castration resistance in univariate analysis (HR 1.89, 95% CI 1.04-3.44, p=0.036). CONCLUSIONS: Extragonadal steroids contribute significantly to the androgen receptor axis activation at castration levels of testosterone in recurrent nonmetastatic prostate cancer and these sustain the development of castration resistance after primary local treatment.

Glucuronidation of Abiraterone and Its Pharmacologically Active Metabolites by UGT1A4, Influence of Polymorphic Variants and Their Potential as Inhibitors of Steroid Glucuronidation.

Abiraterone (Abi) acetate (AA) is a prodrug of Abi, a CYP17A1 inhibitor used to treat patients with advanced prostate cancer. Abi is a selective steroidal inhibitor that blocks the biosynthesis of androgens. It undergoes extensive biotransformation by steroid pathways, leading to the formation of pharmacologically active Δ4-Abi (D4A) and 5α-Abi. This study aimed to characterize the glucuronidation pathway of Abi and its two active metabolites. We show that Abi, its metabolites, and another steroidal inhibitor galeterone (Gal) undergo secondary metabolism to form glucuronides (G) in human liver microsomes with minor formation by intestine and kidney microsomal preparations. The potential clinical relevance of this pathway is supported by the detection by liquid chromatography-tandem mass spectrometry of Abi-G, D4A-G, and 5α-Abi-G in patients under AA therapy. A screening of UGT enzymes reveals that UGT1A4 is the main enzyme involved. This is supported by inhibition experiments using a selective UGT1A4 inhibitor hecogenin. A number of common and rare nonsynonymous variants significantly abrogate the UGT1A4-mediated formation of Abi-G, D4A-G, and 5α-Abi-G in vitro. We also identify Gal, Abi, and its metabolites as highly potent inhibitors of steroid inactivation by the UGT pathway with submicromolar inhibitor constant values. They reduce the glucuronidation of both the adrenal precursors and potent androgens in human liver, prostate cancer cells, and by recombinant UGTs involved in their inactivation. In conclusion, tested CYP17A1 inhibitors are metabolized through UGT1A4, and germline variations affecting this metabolic pathway may also influence drug metabolism. SIGNIFICANCE STATEMENT: The antiandrogen abiraterone (Abi) is a selective steroidal inhibitor of the cytochrome P450 17α-hydroxy/17,20-lyase, an enzyme involved in the biosynthesis of androgens. Abi is metabolized to pharmacologically active metabolites by steroidogenic enzymes. We demonstrate that Abi and its metabolites are glucuronidated in the liver and that their glucuronide derivatives are detected at variable levels in circulation of treated prostate cancer patients. UDP-glucuronosyltransferase (UGT)1A4 is the primary enzyme involved, and nonsynonymous germline variations affect this metabolic pathway in vitro, suggesting a potential influence of drug metabolism and action in patients. Their inhibitory effect on drug and steroid glucuronidation raises the possibility that these pharmacological compounds might affect the UGT-associated drug-metabolizing system and pre-receptor control of androgen metabolism in patients.