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STRUCTURED ABSTRACTBackgroundPatients with localized prostate cancer have historically been assigned to clinical risk groups based on local disease extent, serum prostate specific antigen (PSA), and tumor grade. Clinical risk grouping is used to determine the intensity of treatment with external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT), yet a substantial proportion of patients with intermediate and high risk localized prostate cancer will develop biochemical recurrence (BCR) and require salvage therapy. Prospective identification of patients destined to experience BCR would allow treatment intensification or selection of alternative therapeutic strategies.MethodsTwenty-nine individuals with intermediate or high risk prostate cancer were prospectively recruited to a clinical trial designed to profile the molecular and imaging features of prostate cancer in patients undergoing EBRT and ADT. Whole transcriptome cDNA microarray and whole exome sequencing were performed on pretreatment targeted biopsy of prostate tumors (n=60). All patients underwent pretreatment and 6-month post EBRT multiparametric MRI (mpMRI), and were followed with serial PSA to assess presence or absence of BCR. Genes differentially expressed in the tumor of patients with and without BCR were investigated using pathways analysis tools and were similarly explored in alternative datasets. Differential gene expression and predicted pathway activation were evaluated in relation to tumor response on mpMRI and tumor genomic profile. A novel TGF-β gene signature was developed in the discovery dataset and applied to a validation dataset.FindingsBaseline MRI lesion volume andPTEN/TP53status in prostate tumor biopsies correlated with the activation state of TGF-β signaling measured using pathway analysis. All three measures correlated with the risk of BCR after definitive RT. A prostate cancer-specific TGF-β signature discriminated between patients that experienced BCR vs. those that did not. The signature retained prognostic utility in an independent cohort.InterpretationTGF-β activity is a dominant feature of intermediate-to-unfavorable risk prostate tumors prone to biochemical failure after EBRT with ADT. TGF-β activity may serve as a prognostic biomarker independent of existing risk factors and clinical decision-making criteria.FundingThis research was supported by the Prostate Cancer Foundation, the Department of Defense Congressionally Directed Medical Research Program, National Cancer Institute, and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

(A) LNCaP cells {plus minus} AD were treated with edelfosine (10 µM) and the cells were harvested after 3, 6 and 18 h time points. Cell lysates were examined by Western blotting for p-AKT and total AKT. (B) ARv7 expression in 22RV1 cells. Cells were cultured in 10 cm tissue culture dishes in CM or AD medium and then treated edelfosine (10 µM). Treated cells were harvested after 24 h, whole-cell lysates were extracted, and ARv7 expression was determined by Western immunoblotting. The same blot was re-probed for β-actin.

Supplementary Figures 1-3

Cells were harvested after 24 hours following treatment and caspase 3/7 assay was carried out. For ATF3 knockdown, VCaP were transfected with control siRNA or siATF3 (10 nM), followed by treatment with edelfosine (5 µM). Data shown represent the mean values ({plus minus} SEM) from three independent experiments. *p < 0.05, compared to control siRNA + edelfosine (one way ANOVA).

Androgen deprived LNCaP cells were co-transfected with 5 µg of ARE-luciferase reporter constructs, renilla luciferase and siATF3 (10 nM), followed by treatment with edelfosine (5 µM) and R1881 (5 nM). Cells were harvested and lysed after 24 hours following treatment and assayed for ARE reporter activity. Luciferase expression of each sample was measured using dual luciferase reporter gene assay system (Promega Corp., Madison, WI). The data represents the ratio between firefly/renilla luciferase activities. The mean values {plus minus} SEM of three independent experiments are shown. *p < 0.05, compared to group with R1881 alone (one way ANOVA).

S1. VSV-hIFNβ treatment followed by RT caused S-phase cell cycle arrest of prostate cancer cells. S2. VSV treatment in combination with radiation therapy increases the GFP or Luciferase expression in vitro and in vivo. S3. C57BL/6 CD8 Re-challenge study with VSV-mIFNβ+RT followed by CD8 depletion.

VCaP cells were grown for 24 h in complete (A) or AD (B) medium. Cells were treated with edelfosine (1, 2.5, 5, 10 and 20 µM) with control groups receiving PBS (0.01 M) vehicle (S1A) VCaP and (S1B) VCaP + AD. Cells were monitored and cell proliferation was measured in real time by RTCA cell proliferation assay and the average cell index was shown for 72 h. Each data point is represented by its means (n = 3) {plus minus} SD.

Supplementary Figure legends for Figures S1-S5.

BACKGROUND Salvage radiotherapy (SRT) is an established treatment for men with biochemical recurrence following radical prostatectomy (RP). There are several risk factors associated with adverse outcomes; however, the value of postoperative prostate-specific antigen (PSA) kinetics is less clear in the ultrasensitive PSA era. OBJECTIVE To characterize the impact of PSA kinetics on outcomes following SRT and generate nomograms to aid in identifying patients with an increased risk of adverse clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS A multi-institutional analysis was conducted of 1005 patients with prostate cancer treated with SRT after RP, with a median follow-up of 5 years. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Variables examined include immediate postoperative PSA, postoperative PSA doubling time (DT), and pre-SRT PSA, in addition to previously identified predictive factors. Multivariable survival analyses were completed using Fine-Gray competing risk regression. Rates of biochemical failure (BF), distant metastasis (DM), and prostate cancer-specific mortality (PCSM) were estimated by the cumulative incidence method. Nomograms were generated from multivariable competing risk regression with bootstrap cross-validation. RESULTS AND LIMITATIONS Factors associated with BF after SRT include PSA DT

Background. Historically, intraductal carcinoma of the prostate (IDC-P) was postulated to be a retrograde spread of high-grade invasive prostate cancer. There is evidence that IDC-P can primarily originate in the prostatic ducts. The retrograde genesis has never been experimentally or clinically confirmed before. Methods. Biopsy proven intermediate or high-risk prostate cancer was orthotopically grafted in the prostate of severe combined immunodeficiency gamma mice. Cancer growth was monitored by serum PSA levels. The animals were sacrificed and grafted areas were histological examined. Results. Twenty-one of 23 mice survived and demonstrated rising serum PSA. In 10 of 21 animals, human prostate cancer was identified orthotopically. Except for one case where the human biopsy showed a Grade Group 2 prostate cancer and mouse graft was Grade Group 5, other 9 specimens showed comparable grades. One of the specimens demonstrated a cribriform invasive prostate cancer and adjacent IDC-P. Conclusion. These experimental data offer some evidence that invasive prostate cancer can demonstrate a retrograde spread in the prostatic ducts as IDC-P. Its ability to primarily arise in the ducts has been demonstrated in other studies. However, the issue which remains unresolved is in its most common presentation of IDC-P intermixed with high-grade invasive cancer if it is the former or the latter which came first. Possibly resolving this dilemma will shed some light on the existing controversies if IDC-P should or should not be graded when invasive cancer is present.

Purpose: We previously reported that protein kinase A type I (PKARIα) overexpression was predictive of outcome in prostate cancer patients treated with radiotherapy (RT) ± short-term androgen deprivation (STAD) on Radiation Therapy Oncology Group (RTOG) protocol 86-10. Here, we attempt to verify our prior findings and test the hypothesis that the relationship of the length of AD to patient outcome is affected by PKARIα overexpression.Experimental Design: There were 313 cases in the RTOG 92-02 study cohort with available tissue and suitable staining by immunohistochemistry. Median follow-up was 10.1 years. The intensity of PKARIα staining intensity was quantified manually and by image analysis. Multivariate analyses were done for overall mortality using Cox proportional hazards models and for local failure, biochemical failure, distant metastasis, and cause-specific mortality using Fine and Gray's regression models.Results: The expression levels of PKARIα, determined by manual and image analysis, were strongly correlated (P < 0.0001). In the multivariate analyses, manual-quantified and image analysis–quantified PKARIα staining intensities were independent predictors of distant metastasis (P < 0.01), local failure (P < 0.05), and biochemical failure (P ≤ 0.01). Furthermore, the benefit of long-term AD over STAD was much less when PKARIα expression was high.Conclusions: PKARIα overexpression has been shown in two RTOG trials to be associated with an increased risk of failure after AD + RT. In this series of contemporary high-risk patients, PKARIα overexpression was associated with diminished response to LTAD + RT relative to STAD + RT, suggesting that such patients would be ideal for a PKARIα knockdown strategy. (Clin Cancer Res 2009;15(17):5478–84)

Supplementary Data from The Importance of Protein Kinase A in Prostate Cancer: Relationship to Patient Outcome in Radiation Therapy Oncology Group Trial 92-02

In this study, molecular interactions of prostate-specific membrane antigen (PSMA) with five chemically distinct urea-based boron-containing inhibitors have been investigated at the atomic level using molecular docking and molecular dynamics simulations. The PSMA–inhibitor complexations have been analyzed by comparing their binding modes, secondary structures, root-mean-square deviations, noncovalent interactions, principal components, and binding free energies. PSMA is a cell surface glycoprotein upregulated in cancerous cells and can be targeted by boron-labeled inhibitors for boron neutron capture therapy (BNCT). The effective BNCT requires the selective boron delivery to the tumor area and highly specific PSMA-mediated cellular uptake by tumor. Thus, a potent inhibitor must exhibit both high binding affinity and high boron density. The computational results suggest that the chemical nature of inhibitors affects the binding mode and their association with PSMA is primarily dominated by hydrogen bonding, salt bridge, electrostatic, and π–π interactions. The binding free energies (−28.0, −15.2, −43.9, −23.2, and −38.2 kcal/mol) calculated using λ-dynamics for all inhibitors (In1–5) predict preferential binding that is in accordance with experimental data. Among all inhibitors, In5 was found to be the best candidate for BNCT. The binding of this inhibitor to PSMA preserved its overall secondary structure. These results provide computational insights into the coordination flexibility of PSMA and its interaction with various inhibitors. They can be used for the design and synthesis of efficient BNCT agents with improved drug selectivity and high boron percentage.

We aimed to identify subgroups of Hispanic/Latino (H/L) cancer survivors with distinct health behavior patterns and their associated sociodemographic, medical, and psychosocial characteristics.Baseline data were used from a randomized clinical trial evaluating the efficacy of an enhanced patient navigation intervention in H/L cancer survivors. Participants (n = 278) completed the Lifestyle Behavior Scale and validated questionnaires on health-related quality of life (HRQOL), supportive care needs, distress, and satisfaction with cancer care. Latent class analysis was used to determine the latent classes and associated characteristics.Three latent classes emerged: class 1 (survivors who increased health behaviors [e.g., exercising and eating healthy] since diagnosis); class 2 (no changes in health behaviors since diagnosis); and class 3 (a "mixed class," with a higher or lower engagement across various health behaviors since diagnosis). Participants in class 1 were significantly more educated and less likely to be foreign born. Participants in class 2 were significantly older and more likely to have prostate cancer. H/L cancer survivors in class 3 had a significantly lower income, were less educated, and reported greater unmet supportive care needs, more distress, and poorer HRQOL.Survivors who report engaging in health behaviors less frequently since diagnosis may be experiencing psychosocial challenges and health disparities.Hispanic/Latino cancer survivors may benefit from screening for social determinants of health and mental health needs, prompt referral to supportive care services, community resources, and public services, and participating in culturally informed psychosocial interventions to address their unique needs.

The kidneys are radiosensitive and dose-limiting organs for radiotherapy (RT) targeting abdominal and paraspinal tumors. Excessive radiation doses to the kidneys ultimately lead to radiation nephropathy. Our prior work unmasked a novel role for the lipid-modifying enzyme, sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b), in regulating the response of renal podocytes to radiation injury. In this study, we investigated the role of SMPDL3b in DNA double-strand breaks (DSBs) repair in vitro and in vivo. We assessed the kinetics of DSBs recognition and repair along with the ATM pathway and nuclear sphingolipid metabolism in wild-type (WT) and SMPDL3b overexpressing (OE) human podocytes. We also assessed the extent of DNA damage repair in SMPDL3b knock-down (KD) human podocytes, and C57BL6 WT and podocyte-specific SMPDL3b-knock out (KO) mice after radiation injury. We found that SMPDL3b overexpression enhanced DSBs recognition and repair through modulating ATM nuclear shuttling. OE podocytes were protected against radiation-induced apoptosis by increasing the phosphorylation of p53 at serine 15 and attenuating subsequent caspase-3 cleavage. SMPDL3b overexpression prevented radiation-induced alterations in nuclear ceramide-1-phosphate (C1P) and ceramide levels. Interestingly, exogenous C1P pretreatment radiosensitized OE podocytes by delaying ATM nuclear foci formation and DSBs repair. On the other hand, SMPDL3b knock-down, in vitro and in vivo, induced a significant delay in DSBs repair. Additionally, increased activation of apoptosis was induced in podocytes of SMPDL3b-KO mice compared to WT mice at 24 h post-irradiation. Together, our results unravel a novel role for SMPDL3b in radiation-induced DNA damage response. The current work suggests that SMPDL3b modulates nuclear sphingolipid metabolism, ATM nuclear shuttling, and DSBs repair.

We investigated the longitudinal changes in multiparametric MRI (mpMRI) (T2-weighted, Apparent Diffusion Coefficient (ADC), and Dynamic Contrast Enhanced (DCE-)MRI) of prostate cancer patients receiving Lattice Extreme Ablative Dose (LEAD) radiotherapy (RT) and the capability of their imaging features to predict RT outcome based on endpoint biopsies. Ninety-five mpMRI exams from 25 patients, acquired pre-RT and at 3-, 9-, and 24-months post-RT were analyzed. MRI/Ultrasound-fused biopsies were acquired pre- and at two-years post-RT (endpoint). Five regions of interest (ROIs) were analyzed: Gross tumor volume (GTV), normally-appearing tissue (NAT) and peritumoral volume in both peripheral (PZ) and transition (TZ) zones. Diffusion and perfusion radiomics features were extracted from mpMRI and compared before and after RT using two-tailed Student t-tests. Selected features at the four scan points and their differences (Δ radiomics) were used in multivariate logistic regression models to predict the endpoint biopsy positivity. Baseline ADC values were significantly different between GTV, NAT-PZ, and NAT-TZ (p-values < 0.005). Pharmaco-kinetic features changed significantly in the GTV at 3-month post-RT compared to baseline. Several radiomics features at baseline and three-months post-RT were significantly associated with endpoint biopsy positivity and were used to build models with high predictive power of this endpoint (AUC = 0.98 and 0.89, respectively). Our study characterized the RT-induced changes in perfusion and diffusion. Quantitative imaging features from mpMRI show promise as being predictive of endpoint biopsy positivity.

To determine if limiting the doses delivered to the penile bulb (PB) and corporal bodies (CB) with IMRT preserves erectile function compared to standard IMRT in men with prostate cancer.117 patients with low-intermediate risk, clinical T1a-T2c prostate adenocarcinoma were enrolled to a single-institution, prospective, single blind, phase III randomized trial. All received definitive IMRT to 74-80 Gy in 37-40 fractions and standard IMRT (s-IMRT) or erectile tissue sparing IMRT (ETS-IMRT), which placed additional planning constraints that limited the D90 to the PB and CB to ≤ 15 Gy and ≤ 7 Gy, respectively. Erectile potency was assessed with components of the International Index of Erectile Function (IIEF) and PDE5 medication records.62 patients received ETS-IMRT and 54 received s-IMRT; 1 patient did not receive radiation therapy. Prior to treatment, all patients reported erectile potency. No patients received androgen deprivation therapy. In the intention-to-treat analysis, treatment arms did not differ in potency preservation at 24 months (37.1% ETS-IMRT vs 31.5% s-IMRT, p=0.53). Of 85 evaluable patients with IIEF and PDE5 medication follow-up, erectile potency was seen in 47.9% of patients in the ETS-IMRT arm and 46.0% of patients in the s-IMRT arm (p=0.86). PDE5 inhibitors were initiated in 41.7% of ETS-IMRT patients and 35.1% of s-IMRT patients (p=0.54). Among all patients enrolled, there was no difference in freedom from biochemical failure between those treated with ETS-IMRT and s-IMRT (5-yr 91.8% vs 90.7%, respectively, p=0.77) with a median follow-up of 7.4 years. There were no differences in acute or late GI or GU toxicity. An unplanned per-protocol analysis demonstrated no differences in potency preservation or secondary endpoints between patients who exceeded erectile tissue-sparing constraints and those who met constraints, though power was limited by attrition and unplanned dosimetric crossover.Erectile tissue sparing IMRT that strictly limits dose to the penile bulb and corporal bodies is safe and feasible. Use of this planning technique did not show an effect on potency preservation outcomes at 2 years, though power to detect a difference was limited.

Genomic prognostic signatures are used on prostate biopsy tissue for cancer risk assessment, but tumor heterogeneity and multifocality may be an issue. We evaluated the variability in genomic risk assessment from different biopsy cores within the prostate using 3 prognostic signatures (Decipher, CCP, GPS).Men in this study came from 2 prospective prostate cancer trials of patients undergoing multiparametric magnetic resonance imaging and magnetic resonance imaging targeted biopsy with genomic profiling of positive biopsy cores. We explored the relationship among tumor grade, magnetic resonance imaging risk and genomic risk for each signature. We evaluated the variability in genomic risk assessment between different biopsy cores and assessed how often magnetic resonance imaging targeted biopsy or the current standard of care (profiling the core with the highest grade) resulted in the highest genomic risk level.In all, 224 positive biopsy cores from 78 men with prostate cancer were profiled. For each signature, higher biopsy grade (p0.001) and magnetic resonance imaging risk level (p0.001) were associated with higher genomic scores. Genomic scores from different biopsy cores varied with risk categories changing by 21% to 62% depending on which core or signature was used. Magnetic resonance imaging targeted biopsy and profiling the core with the highest grade resulted in the highest genomic risk level in 72% to 84% and 75% to 87% of cases, respectively, depending on the signature used.There is variation in genomic risk assessment from different biopsy cores regardless of the signature used. Magnetic resonance imaging directed biopsy or profiling the highest grade core resulted in the highest genomic risk level in most cases.

Histopathological classification in prostate cancer remains a challenge with high dependence on the expert practitioner. We develop a deep learning (DL) model to identify the most prominent Gleason pattern in a highly curated data cohort and validate it on an independent dataset. The histology images are partitioned in tiles (14,509) and are curated by an expert to identify individual glandular structures with assigned primary Gleason pattern grades. We use transfer learning and fine-tuning approaches to compare several deep neural network architectures that are trained on a corpus of camera images (ImageNet) and tuned with histology examples to be context appropriate for histopathological discrimination with small samples. In our study, the best DL network is able to discriminate cancer grade (GS3/4) from benign with an accuracy of 91%, F1-score of 0.91 and AUC 0.96 in a baseline test (52 patients), while the cancer grade discrimination of the GS3 from GS4 had an accuracy of 68% and AUC of 0.71 (40 patients).

Decipher is a genomic classifier (GC) prospectively validated post-prostatectomy. Herein, we validate the performance of the GC in pre-treatment biopsy samples within the context of three randomized phase III high-risk definitive radiotherapy trials.A pre-specified analysis plan (NRG-GU-TS006) was approved to obtain formalin-fixed paraffin-embedded tissue from biopsy specimens from the NRG biobank from patients enrolled on the NRG/RTOG 9202, 9413, and 9902 phase III randomized trials. After central review, the highest-grade tumors were profiled on clinical-grade whole-transcriptome arrays and GC scores were obtained. The primary objective was to validate the independent prognostic ability for the GC for distant metastases (DM), and secondary for prostate cancer-specific mortality (PCSM) and overall survival (OS) with Cox univariable (UVA) and multivariable analyses (MVA).GC scores were obtained on 385 samples, of which 265 passed microarray quality control (69%) and had a median follow-up of 11 years (interquartile range, 9, 13). In the pooled cohort, on UVA, the GC was shown to be a prognostic factor for DM (per 0.1 unit; sHR 1.29, 95%CI 1.18-1.41, p0.001), PCSM (sHR 1.28, 95%CI 1.16-1.41, p0.001), and OS (HR 1.16, 95%CI 1.08-1.22, p0.001). On MVA, the GC (per 0.1 unit) was independently associated with DM (sHR 1.22, 95%CI 1.09-1.36), PCSM (sHR 1.23, 95%CI 1.09-1.39), and OS (HR 1.12, 95%CI 1.05-1.20) after adjusting for age, PSA, Gleason score, cT-stage, trial, and randomized treatment arm. GC had similar prognostic ability in patients receiving short-term or long-term androgen-deprivation therapy (ADT) but the absolute improvement in outcome varied by GC risk.This is the first validation of a gene expression biomarker on pre-treatment prostate cancer biopsy samples from prospective randomized trials and demonstrates an independent association of GC score with DM, PCSM, and OS. High-risk prostate cancer is a heterogeneous disease state and GC can improve risk stratification to help personalize shared decision-making.

Purpose: To investigate the relationships between circulating tumor cells (CTCs), free circulating DNA (fcDNA) and biochemical response in prostate cancer patients treated primarily versus salvage radiotherapy (RT). Methods and Materials: Blood was collected prospectively from patients, enrolled in two institutional Phase II trials for primary and salvage RT. Three blood samples were collected at: (i) prior to treatment [RT or androgen deprivation therapy (ADT)], (ii) last week of RT, and (iii) three months post-RT. CTCs were quantified in 31 samples from 12 primary patients and 30 samples from 12 salvage patients; fcDNA were analyzed in 11 primary (28 samples) and 5 (9 samples) salvage patients. CTCs were visualized by immunofluorescence after microfilter capture and fcDNA was quantified using real-time Polymerase chain reaction (PCR). CTCs and fcDNA were correlated with early biochemical response by subdividing patients into early favorable and unfavorable response at 3 months after RT. Results: For those treated primarily, there was a direct correlation with CTC counts and prostate specific antigen (PSA) pre-RT that changed to a reciprocal relationship 3 months post-RT. CTCs increased significantly (p=0.03) at 3 months after primary RT in the biochemical favorable patients, while no significant association was observed for fcDNA. Correspondingly, post-RT fcDNA levels were inversely related to CTC counts. In salvage patients, the number of CTCs was related to pre-RT PSA, but it was not correlated to RT response. In post-RT series, a significant direct correlation was observed between CTCs and PSA. Conclusion: Our preliminary studies suggest that RT affects CTC counts, which are thus associated with prostate cancer biochemical response. A larger cohort with longer follow-up will be needed to establish the association with more recognized treatment endpoints.

X-ray fluorescence computed tomography (XFCT) as a molecular imaging modality can simultaneously identify the localization and quantify the concentration of high-atomic-number contrast agents such as gold nanoparticles (GNPs). Commonly used benchtop pencil-beam XFCT, consisting of a polychromatic x-ray source and a single-pixel spectrometer, suffers from long scanning time and high imaging dose. Sparse-view strategy benefits XFCT to reduce both scanning time and imaging dose. Nevertheless, its reconstruction undergoes ill-posedness induced by the compressive sampling. To preserve consistent imaging quality for sparse-view XFCT, we proposed an iterative Bayesian algorithm based on L1-norm constraint, wherein the L1-norm regularization is included in the one-step-late expectation maximization (OSL-EM) algorithm with regularization parameter determined based on L-curve criteria. The proposed algorithm was verified by imaging a 3-cm-diameter water phantom with 4 inserts containing GNP solutions with concentrations of 0.02, 0.04, 0.08, and 0.16 wt.%, on an in-house-developed dual-modality transmission CT and XFCT system. Different numbers (i.e. 36, 18, 9, and 6) of projection views were used for XFCT reconstruction, to evaluate the performance of various reconstruction algorithms. L1-regularized EM algorithm demonstrated the consistent robustness to suppress background artifacts and localize low-concentration GNPs (0.02 wt.%) with submillimeter accuracy, when the number of projection views reduces from 36 to 9. Moreover, our method’s potential for small tumor spare-view XFCT imaging was validated on a mouse surgically implanted with a 6-mm GNP target.

70 Background: Prostate cancer (PCa) patients undergoing radiation therapy (RT) need comfortably full bladders during RT to reduce toxicities. Awareness of this state is lacking, and poor compliance is common with standard of care written/verbal instructions, leading to wasted patient value (PV) and inefficient throughput (TE). Herein, we assessed the feasibility and acceptability of a digital behavioral intervention (DBI) to improve bladder filling compliance, methods for quantifying PV, IT, and behavioral biomarkers. Methods: We enrolled 18 non-metastatic PCa patients in a prospective, single-arm pilot study using a DBI. The DBI consists of a smart water bottle and companion app that tracks water consumption. Additionally, visual alerts (water bottle glow and phone notifications) remind the patient to empty his bladder and drink a personalized volume goal (VG) at a set time. The VG is based on simulation bladder volume and reminders are initially set 1.25 hours prior to scheduled RT. Patients were trained to adjust their VG and notification times to achieve comfortably full bladders. Primary endpoint was met if qualitative (QLC) and quantitative compliance (QNC) were both >80%. Other endpoints include acceptability assessed via Service User Technology Acceptability Questionnaire (SUTAQ), engagement (>80% of patients used the device > 50% of the time) and impact of DBI on PV and TE. For QLC, patients were asked if they prepared their bladders before daily RT. QNC was met if bladder volumes on daily CBCT were > 75% of the simulation’s volume. The SUTAQ was given pre- and post-DBI. PV and TE were measured by time spent in clinic and on the linear accelerator (linac), respectively. Biometric data was probed for insights on optimal drinking behaviors. Results: All endpoints were met. QLC was 100% on 375/398 (94.2%) of total treatments, while QNC was 88.9% on 341/398 (85.7%) total treatments. Patients were accepting of DBI with few privacy concerns (4.33/5.00), believe in benefits (4.00/5.00), high satisfaction (4.56/5.00) and high usability (4.24/5.00). Most patients, 15/18 (83.3%), used the DBI on >50% of treatments and met the engagement requirements. Patients with empty bladders (n=43) spent significantly more time (75.14 vs 50.59 minutes, p=0.007) in clinic than patients who came with full bladders (n=355). Similarly, these patients spent nearly twice as long on the linac (21.63 v 12.50 minutes, p

Background: Emerging data suggest that metastasis is a spectrum of disease burden rather than a binary state, and local therapies, such as radiation, might improve outcomes in oligometastasis. However, current definitions of oligometastasis are solely numerical. Objective: To characterize the somatic mutational landscape across the disease spectrum of metastatic castration-sensitive prostate cancer (mCSPC) to elucidate a biological definition of oligometastatic CSPC. Design, setting, and participants: This was a retrospective study of men with mCSPC who underwent clinical-grade sequencing of their tumors (269 primary tumor, 25 metastatic sites). Patients were classified as having biochemically recurrent (ie, micrometa-static), metachronous oligometastatic (5 lesions), or de novo metastatic (metastasis at diagnosis) disease. Outcome measurements and statistical analysis: We measured the frequency of driver mutations across metastatic classifications and the genomic associations with radiographic progression-free survival (rPFS) and time to castrate-resistant prostate cancer (CRPC). Results and limitations: The frequency of driver mutations in TP53 (p = 0.01), WNT (p = 0.08), and cell cycle (p = 0.04) genes increased across the mCSPC spectrum. TP53 mutation was associated with shorter rPFS (26.7 vs 48.6 mo; p = 0.002), and time to CRPC (95.6 vs 155.8 mo; p = 0.02) in men with oligometastasis, and identified men with polymetastasis with better rPFS (TP53 wild-type, 42.7 mo; TP53 mutated, 18.5 mo; p = 0.01). Mutations in TP53 (incidence rate ratio [IRR] 1.45; p = 0.004) and DNA double-strand break repair (IRR 1.61; p < 0.001) were associated with a higher number of metastases. Mutations in TP53 were also independently associated with shorter rPFS (hazard ratio [HR] 1.59; p = 0.03) and the development of CRPC (HR 1.71; p = 0.01) on multivariable analysis. This study was limited by its retrospective nature, sample size, and the use of commercially available sequencing platforms, resulting in a limited predefined set of genes examined. Conclusions: Somatic mutational profiles reveal a spectrum of metastatic biology that helps in redefining oligometastasis beyond a simple binary state of lesion enumeration. Patient summary: Oligometastatic prostate cancer is typically defined as less than three to five metastatic lesions and evidence suggests that using radiation or surgery to treat these sites improves clinical outcomes. As of now, treatment decisions for oligometastasis are solely defined according to the number of lesions. However, this study suggests that tumor mutational profiles can provide a biological definition of oligometastasis and complement currently used numerical definitions. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology.

Purpose To determine the long-term outcomes for prostate adenocarcinoma when escalating radiation dose from 70 Gy to 78 Gy. Methods and Materials Between 1993 and 1998, 301 patients with biopsy-proven clinical stage T1b-T3 prostate adenocarcinoma, any prostate-specific antigen level, and any Gleason score were randomized to 70 Gy in 35 fractions versus 78 Gy in 39 fractions of photon radiation therapy using a 4-field box technique without hormone deprivation therapy. The primary outcome was powered to detect a 15% difference in biochemical or clinical failure. Secondary outcomes included survival, prostate cancer mortality, biochemical failure, local failure, nodal failure, distant failure, and secondary malignancy rates. Results With a median follow-up of 14.3 years, the cumulative incidence of 15-year biochemical or clinical failure was 18.9% versus 12.0% in the 70 Gy versus 78 Gy arms, respectively (subhazard ratio [sHR], 0.61; 95% confidence interval [CI], 0.38-0.98; Fine-Gray P = .042). The 15-year cumulative incidence of distant metastasis was 3.4% versus 1.1%, respectively (sHR, 0.33; 95% CI, 0.13-0.82; Fine-Gray P = .018). The 15-year cumulative incidence of prostate cancer-specific mortality was 6.2% versus 3.2%, respectively, (sHR, 0.52; 95% CI, 0.27-0.98; Fine-Gray P = .045). There were no differences in overall survival (HR, 1.10; 95% CI, 0.84-1.45; log rank P = .469) or other-cause survival (sHR, 1.33; 95% CI, 0.99-1.79; Fine-Gray P = .061). Salvage therapy was more common in the 70 Gy arm, at 38.7% versus 21.9% in the 78 Gy arm (P = .002). There was a 2.3% secondary solid malignancy rate (1 bladder, 6 rectal) within the radiation treatment field, which was not significantly different between treatment arms. Conclusions Dose escalation by 8 Gy (78 Gy vs 70 Gy) provided a sustained improvement in biochemical and clinical failure, which translated into lower salvage rates and improved prostate cancer-specific mortality, but not overall survival. Long-term follow-up demonstrated a low incidence of potential solid tumor secondary malignancies.