Biochemical Recurrence Of Prostate Cancer Research Articles

PARGP1, a specific enhancer RNA associated with biochemical recurrence of prostate cancer

Background: Enhancer RNA (eRNA) is a non-coding RNA transcribed by enhancers and has a crucial role in controlling gene transcription. However, the potential functions of eRNA in prostate cancer (PCa) are still not fully understood. Methods: Clinical information and expression data of eRNAs and their target genes for PCa were downloaded from TCGA. Each eRNA in PCa samples was divided into high- and low-expression groups. The Kaplan–Meier method was used to identify the eRNAs significantly associated with the overall survival of PCa. Their correlations with age, prostate-specific antigen (PSA), and tumor stage were analyzed using Spearman coefficients. Finally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEEG) analyzes were used to predict the possible biological functions and pathways associated with eRNAs. Results: We identified 12 eRNAs associated with PCa survival, of which PARGP1 was the most clinically significant. It was associated with biochemical recurrence in PCa patients and was also a valuable complement to distinguish between PSA 0–4 ng/ml and 4–10 ng/ml. GO, and KEEG analysis showed that herpes simplex virus-1 infection was the most biologically significant enriched process. Conclusions: PARGP1 is associated with biochemical recurrence in prostate cancer and contributes to assessing the outcome.

The Association Between Statin Use and Outcomes in Patients Initiating Androgen Deprivation Therapy

BackgroundStudies have conflicting results regarding the association between statin use and biochemical recurrence for prostate cancer (PCa). A limited number of studies examining statins in advanced stages report positive results, with a few specifically examining statins and androgen deprivation therapy (ADT). ObjectiveTo perform a post hoc secondary analysis of a randomised controlled trial (RCT) of men initiating ADT to examine the association between statin use and outcomes. Design, setting, and participantsPatients with prostate-specific antigen (PSA) >3 ng/ml >1 yr following primary/salvage radiotherapy were enrolled in an RCT of intermittent androgen deprivation (IAD) versus continuous ADT (NCT00003653). Baseline and on-study statin use was modelled as a time-dependent covariate. Outcome measurements and statistical analysisThe primary endpoint was overall survival. Models were adjusted for age, time from radiotherapy to ADT, baseline PSA, and prior ADT. Results and limitationsOf 1364 patients, statin users (585; 43%) were younger (72.7 vs 73.8 yr, p = 0.001) and less likely to have PSA >15 ng/ml (20% vs 25%, p = 0.04). After a median follow-up of 6.9 yr, statin use was associated with reduced overall (hazard ratio [HR]: 0.64; 95% confidence interval [CI] 0.53–0.78, p < 0.001) and PCa-specific (HR: 0.65, 95% CI 0.48–0.87, p = 0.004) mortality. Statin users had 13% longer time to castration resistance, but this did not reach statistical significance (p = 0.15). As an exploratory endpoint, in the IAD arm, statin users had longer time off treatment (median: 0.85 vs 0.64 yr, p = 0.06). Limitations include potential for residual confounding between statin users and nonusers, and confounding by indication. ConclusionsIn men treated with ADT following primary or salvage radiotherapy, statin use was associated with improved overall and PCa-specific survival. In patients treated with IAD, statin use was associated with a trend towards longer time off treatment. A prospective trial of statins in men commencing ADT is warranted. Patient summaryWe found a favourable association between statin use and survival outcomes in patients initiating androgen deprivation therapy.

An Eight-CircRNA Assessment Model for Predicting Biochemical Recurrence in Prostate Cancer.

Prostate cancer (PCa) is a high morbidity malignancy in males, and biochemical recurrence (BCR) may appear after the surgery. Our study is designed to build up a risk score model using circular RNA sequencing data for PCa. The dataset is from the GEO database, using a cohort of 144 patients in Canada. We removed the low abundance circRNAs (FPKM < 1) and obtained 546 circRNAs for the next step. BCR-related circRNAs were selected by Logistic regression using the “survival” and “survminer” R package. Least absolute shrinkage and selector operation (LASSO) regression with 10-fold cross-validation and penalty was used to construct a risk score model by “glmnet” R software package. In total, eight circRNAs (including circ_30029, circ_117300, circ_176436, circ_112897, circ_112897, circ_178252, circ_115617, circ_14736, and circ_17720) were involved in our risk score model. Further, we employed differentially expressed mRNAs between high and low risk score groups. The following Gene Ontology (GO) analysis were visualized by Omicshare Online tools. As per the GO analysis results, tumor immune microenvironment related pathways are significantly enriched. “CIBERSORT” and “ESTIMATE” R package were used to detect tumor-infiltrating immune cells and compare the level of microenvironment scores between high and low risk score groups. What’s more, we verified two of eight circRNA’s (circ_14736 and circ_17720) circular characteristics and tested their biological function with qPCR and CCK8 in vitro. circ_14736 and circ_17720 were detected in exosomes of PCa patients’ plasma. This is the first bioinformatics study to establish a prognosis model for prostate cancer using circRNA. These circRNAs were associated with CD8+ T cell activities and may serve as a circRNA-based liquid biopsy panel for disease prognosis.

Extended Versus Limited Pelvic Lymph Node Dissection During Radical Prostatectomy for Intermediate- and High-risk Prostate Cancer: Early Oncological Outcomes from a Randomized Phase 3 Trial

BackgroundThe role of extended pelvic lymph node dissection (EPLND) in the surgical management of prostate cancer (PCa) patients remains controversial, mainly because of a lack of randomized controlled trials (RCTs). ObjectiveTo determine whether EPLND has better oncological outcomes than limited PLND (LPLND. Design, setting and participantsThis was a prospective, single-center phase 3 trial in patients with intermediate- or high-risk clinically localized PCa. InterventionRandomization (1:1) to LPLND (obturator nodes) or EPLND (obturator, external iliac, internal iliac, common iliac, and presacral nodes) bilaterally. Outcome measurements and statistical analysisThe primary endpoint was biochemical recurrence–free survival (BRFS). Secondary outcomes were metastasis-free survival (MFS), cancer-specific survival (CSS), and histopathological findings. The trial was designed to show a minimal 15% advantage in 5-yr BRFS by EPLND. Results and limitationsIn total, 300 patients were randomized from May 2012 to December 2016 (150 LPLND and 150 EPLND). The median BRFS was 61.4 mo in the LPLND group and not reached in the EPLND group (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.63–1.32; p = 0.6). Median MFS was not reached in either group (HR 0.57, 95% CI 0.17–1.8; p = 0.3). CSS data were not available because no patient died from PCa before the cutoff date. In exploratory subgroup analysis, patients with preoperative biopsy International Society of Urological Pathology (ISUP) grade groups 3–5 who were allocated to EPLND had better BRFS (HR 0.33, 95% CI 0.14–0.74, interaction p = 0.007). The short follow-up and surgeon heterogeneity are limitations to this study. ConclusionThis RCT confirms that EPLND provides better pathological staging, while differences in early oncological outcomes were not demonstrated. Our subgroup analysis suggests a potential BCRFS benefit in patients diagnosed with ISUP grade groups 3–5; however, these findings should be considered hypothesis-generating and further RCTs with larger cohorts and longer follow up are necessary to better define the role of EPLND during RP. Patient summaryIn this study, we investigated early outcomes in prostate cancer patients undergoing prostatectomy according to the anatomic extent of lymph node resection. We found that extended removal of lymph nodes did not reduce biochemical recurrence of prostate cancer in the expected range.

Matched-Pair Comparison of 68Ga-PSMA-11 and 18F-rhPSMA-7 PET/CT in Patients with Primary and Biochemical Recurrence of Prostate Cancer: Frequency of Non-Tumor-Related Uptake and Tumor Positivity.

Radiohybrid prostate-specific membrane antigen (rhPSMA) ligands are a new class of prostate cancer theranostic agents. 18F-rhPSMA-7 offers the advantages of 18F labeling and low urinary excretion compared with 68Ga-PSMA-11. Here, we compare the frequency of non-tumor-related uptake and tumor positivity with 68Ga-PSMA-11 and 18F-rhPSMA-7 in patients with primary or recurrent prostate cancer. Methods: This retrospective matched-pair comparison matched 160 18F-rhPSMA-7 with 160 68Ga-PSMA-11 PET/CT studies for primary staging (n = 33) and biochemical recurrence (n = 127) according to clinical characteristics. Two nuclear medicine physicians reviewed all scans, first identifying all PET-positive lesions and then differentiating lesions suggestive of prostate cancer from those that were benign, on the basis of known pitfalls and ancillary information from CT. For each region, the SUVmax of the lesion with the highest PSMA ligand uptake was noted. Tumor positivity rates were determined, and SUVmax was compared separately for each tracer. Results:18F-rhPSMA-7 and 68Ga-PSMA-11 PET revealed 566 and 289 PSMA ligand-positive lesions, respectively. Of these, 379 and 100 lesions, equaling 67.0% and 34.6%, respectively, of all PSMA-positive lesions, were considered benign. The distribution of their etiology was similar (42%, 24%, and 25% with 18F-rhPSMA-7 vs. 32%, 24%, and 38% with 68Ga-PSMA-11 for ganglia, bone, and unspecific lymph nodes, respectively). All primary tumors were positive with both agents (n = 33 each), whereas slightly more metastatic lesions were observed with 68Ga-PSMA-11 in both disease stages (113 for 18F-rhPSMA-7 and 124 for 68Ga-PSMA-11). The SUVmax of 18F-rhPSMA-7 and 68Ga-PSMA-11 did not differ (P > 0.05) in local recurrence or primary prostate cancer; however, the tumor-to-bladder ratio was significantly higher with 18F-rhPSMA-7 (4.9 ± 5.3 vs. 2.2 ± 3.7, P = 0.02, for local recurrence; 9.8 ± 9.7 vs. 2.3 ± 2.6, P < 0.001, for primary prostate cancer). Conclusion: The tumor positivity rate was consistently high for 68Ga-PSMA-11 and 18F-rhPSMA-7. Both tracers revealed a considerable number of areas of uptake that were reliably identified as benign by trained physicians making use of corresponding morphologic imaging and known PSMA pitfalls. These were more frequent with 18F-rhPSMA-7. However, the matched-pair comparison could have introduced a source of bias. Adequate reader training can allow physicians to differentiate benign uptake from disease and be able to benefit from the logistical and clinical advantages of 18F-rhPSMA-7.

Evaluating determinants of receipt of molecular imaging in biochemical recurrent prostate cancer.

BackgroundMolecular imaging with novel radiotracers is changing the treatment landscape in prostate cancer (PCa). Currently, standard of care includes either conventional and molecular imaging at time of biochemical recurrence (BCR). This study evaluated the determinants of and cost associated with utilization of molecular imaging for BCR PCa.MethodsThis is a retrospective observational cohort study among men with BCR PCa from June 2018 to May 2019. Multivariate logistic regression models were employed to analyze the primary outcome: receipt of molecular imaging (e.g. Fluciclovine PET and Prostate Specific Membrane Antigen PET) as part of diagnostic work‐up for BCR PCa. Multivariate linear regression models were used to analyze the secondary outcome: overall healthcare cost within a 1‐year time frame.ResultsThe study sample included 234 patients; 79.1% White, 2.1% Black, 8.5% Asian/Pacific Islander, and 10.3% Other. The majority were 55 years or older (97.9%) and publicly insured (74.8%). Analysis indicated a one‐unit reduction in PSA is associated with 1.3 times higher likelihood of receiving molecular imaging (p < 0.01). Analysis found that privately insured patients were associated with approximately $500,000 more in hospital reimbursement (p < 0.01) as compared to the publicly insured. Additionally, a one‐unit increase in PSA is associated with $6254 increase in hospital reimbursement or an increase in total payments by 2.1% (p < 0.05).ConclusionsHigher PSA was associated with lower likelihood for molecular imaging and higher cost in a one‐year time frame. Higher cost was also associated with private insurance, but there was no clear relationship between insurance type and imaging type.

Outcome After 68Ga-PSMA-11 versus Choline PET-Based Salvage Radiotherapy in Patients with Biochemical Recurrence of Prostate Cancer: A Matched-Pair Analysis.

The purpose of this analysis was primarily to analyze biochemical-recurrence free survival (BRFS) after positron emission tomography (PET)-guided salvage radiotherapy (sRT) in a large cohort, and to further compare BRFS after PSMA vs. choline PET/ computer tomography (CT)-based sRT. This retrospective analysis is based on 421 patients referred for PSMA or choline PET/CT after radical prostatectomy due to biochemically recurrent or persistent disease. BRFS (PSA: 0.2 ng/mL) was defined as the study endpoint. Cox regression analyses were performed to assess the impact of different clinical parameters on BRFS. Additionally, propensity score matching was performed to adjust patient cohorts (PSMA vs. choline PET/CT-based sRT). The median follow-up time was 30 months. BRFS at three years after sRT was 58%. In the multivariate analysis, only PSA before PET imaging and PSA before sRT were significantly associated with BRFS (p < 0.05). After propensity score matching, 272 patients were further analyzed; there was no significant difference in three-year BRFS between patients with PSMA PET-based vs. choline PET-based sRT (55% vs. 63%, p = 0.197). The present analysis confirmed the overall high BRFS rates after PET-based sRT and the strong prognostic effect of PSA level prior to sRT. PSMA PET-based sRT did not have superior BRFS rates when compared with choline PET-based sRT.

The value of 18F-PSMA-1007 PET/CT in identifying non-metastatic high-risk prostate cancer

BackgroundClinical management decisions on prostate cancer (PCa) are often based on a determination of risk. 68Ga-prostate-specific membrane antigen (PSMA)-11-positron emission tomography (PET)/computer tomography (CT) is an attractive modality to assess biochemical recurrence of PCa, detect metastatic disease and stage of primary PCa, making it a promising strategy for risk stratification. However, due to some limitation of 68Ga-PSMA-11 the development of alternative tracers is of high interest. In this study, we aimed to investigate the value of 18F-PSMA-1007 in identifying non-metastatic high-risk PCa.MethodsA total of 101 patients with primary non-metastatic PCa who underwent 18F-PSMA-1007 PET/CT were retrospectively analyzed. According to the European Association of Urology guidelines on PCa, patients were classified into intermediate-risk (IR) group or high-risk (HR) group. The maximum standardized uptake values (SUVmax) of the primary prostate tumor were measured on PET/CT images. The diagnostic performance of PET/CT for IR and HR PCa was calculated, and the relationship between the SUVmax of primary prostate tumor, prostate-specific antigen (PSA) level and Gleason score (GS) was analyzed.ResultsOf all 101 patients, 49 patients were classified into IR group and 52 patients were classified into HR group. There was a significant positive correlation between PSA level/GS and SUVmax (r = 0.561, r = 0.496, P < 0.001, respectively). Tumors with GS 6 and 7a showed significantly lower 18F-PSMA-1007 uptake compared to patients with GS 8 and 9 (P < 0.01). SUVmax in patients of HR was significantly higher than those of IR (median SUVmax: 16.85 vs 7.80; P < 0.001). In receiver operating characteristic curve analysis, the optimal cutoff value of the SUVmax for identifying high-risk PCa was set as 9.05 (area under the curve: 0.829; sensitivity: 90.4%; specificity: 65.3%).Conclusion18F-PSMA-1007 PET/CT showed the powerful diagnosis efficacy for high-risk PCa, which can be used as an objective imaging reference index for clinical reference.

Prostate cancer recurrence in patients with negative or equivocal conventional imaging: A role for 18F-fluciclovine-PET/CT in delineating sites of recurrence and identifying patients with oligometastatic disease

IntroductionDespite improvements in overall survival, biochemical recurrence of prostate cancer, characterized by rising prostate-specific antigen (PSA) levels after curative intent primary therapy, remains common. With the advent of highly sensitive molecular imaging, men with limited metastatic disease burden, or oligometastatic prostate cancer, are increasingly being identified. The LOCATE trial (NCT02680041) assessed the impact of positron emission tomography (PET) with 18F-fluciclovine on management of men with prostate cancer recurrence after curative intent primary therapy and negative/equivocal conventional imaging. Here, we use LOCATE data to characterize the sites of disease recurrence and explore the potential for 18F-fluciclovine-PET/CT to evaluate oligometastatic disease. MethodsEligible men (≥18 years; prior curative intent treatment of prostate cancer; recurrence based on rising PSA; negative/equivocal conventional imaging) underwent 18F-fluciclovine-PET/CT according to standard protocols. The primary outcome measure of the LOCATE trial was a revised management plan post-scan. We performed a secondary analysis of the LOCATE imaging data to characterize anatomical sites of disease recurrence and to explore the potential for 18F-fluciclovine-PET/CT to evaluate oligometastatic disease. Imaging results were stratified by baseline PSA levels and prior treatment(s) and the Fisher exact test used to analyze differences between groups. Oligometastatic disease was defined as 1–5 extraprostatic lesions (≤3 lesions in any single organ system) plus negative prostate/bed imaging (as a surrogate for primary tumor control). ResultsOf 213 enrolled patients, 164 (77%) had undergone prostatectomy as their initial treatment; their median PSA was 0.57ng/ml. For the 49 patients with an intact prostate, the median PSA was 5.5ng/ml. The overall 18F-fluciclovine-PET/CT detection rate was 57%. Detection rates were 84% in men with intact prostates and 49% in those who had undergone prostatectomy, with the difference being attributable to prostate/bed findings (71% vs. 18%, respectively). The detection rate in lymph nodes was 29% and in bone was 11%. In total, 53/213 (25%) had oligometastatic disease. Twenty (38%) oligometastatic patients had PSA ≤1.0 ng/ml. Forty-two (79%) experienced a change to their management plan following the scan, commonly to target a lesion identified by 18F-fluciclovine-PET/CT. The majority of management changes (74%) involved a new treatment modality; however, 10 patients (24%) experienced a modification of the existing plan for radiotherapy to incorporate a boost to an area guided by the 18F-fluciclovine-PET/CT results. ConclusionEven at low PSA levels, 18F-fluciclovine-PET/CT identified a diverse pattern of recurrence missed with conventional imaging. One-quarter of men had oligometastatic disease, raising the potential for 18F-fluciclovine-PET/CT to guide targeted treatment of oligometastases.

Impact of Matrix Metalloproteinase-11 Gene Polymorphisms on Biochemical Recurrence and Clinicopathological Characteristics of Prostate Cancer.

Prostate cancer is among the most common malignant tumors worldwide. Matrix metalloproteinase (MMP)-11 is involved in extracellular matrix degradation and remodeling and plays an essential role in cancer development and metastasis. This study investigated the association of MMP-11 polymorphisms with the clinicopathological characteristics and biochemical recurrence of prostate cancer. Five single-nucleotide polymorphisms (SNPs) of the MMP-11 were analyzed in 578 patients with prostate cancer through real-time polymerase chain reaction analysis. A prostate-specific antigen level of >10 ng/mL, Gleason grade groups 4 + 5, advanced tumor stage, lymph node metastasis, invasion, and high-risk D’Amico classification were significantly associated with biochemical recurrence in the patients (p < 0.001). MMP-11 rs131451 “TC + CC” polymorphic variants were associated with advanced clinical stage (T stage; p = 0.007) and high-risk D’Amico classification (p = 0.015) in patients with biochemical recurrence. These findings demonstrate that MMP-11 polymorphisms were not associated with prostate cancer susceptibility; however, the rs131451 polymorphic variant was associated with late-stage tumors and high-risk D’Amico classification in prostate cancer patients with biochemical recurrence. Thus, the MMP-11 SNP rs131451 may contribute to the tumor development in prostate cancer patients with biochemical recurrence.

Statin use and risk of prostate cancer biochemical recurrence after radical prostatectomy

BackgroundMultiple studies have investigated the role of statins in prostate cancer (CaP), the leading cause of cancer related death in men. Retrospective cohort studies investigating the correlation between statin use and biochemical recurrence free (BCRF) survival in men with CaP have been inconclusive. ObjectivesIn the largest reported surgical cohort to date, we investigated the effect of statin therapy on BCRF and overall survival in patients with CaP who have undergone radical prostatectomy (RP). Patients and methodsWe performed a retrospective analysis of men (n = 3,088) participating in the NCI funded Specialized Program of Research Excellence (SPORE) in CaP at Northwestern University (NM) in Chicago, Illinois. Patients were treated with RP between 2002 and 2015. Patients in the statin users group received treatment within 2 years prior to or subsequent to RP. Wilcoxon rank-sum and Fisher's exact tests were used to compare age, race, Gleason score, clinical staging, and pathological stage between statin users and nonstatin users. ResultsThe analysis identified 1,222 statin users and 1,865 nonusers (mean age 71 years, 92% Caucasian). After a median follow-up time of 49.0 months, the 5-year BCRF survival rate was 93.3% (95% confidence interval [CI]: 91.9–94.8%) among statin users and 88.6% (95% CI: 87.1%–90%) among nonusers (log-rank P< 0.001). After 10 years, the progression-free survival (PFS) was 91.7% (95% CI: 90.1%–93.3%) among statin users and 86.5% (95% CI: 84.4%–88.2%) among nonusers (log-rank P< 0.001). ConclusionsExtended follow-up data in this large surgical cohort show statin use improves BCRF but not overall survival in RP patients.

PUMA and NOXA Expression in Tumor-Associated Benign Prostatic Epithelial Cells Are Predictive of Prostate Cancer Biochemical Recurrence

Simple SummaryAfter receiving a diagnosis of prostate cancer, patients follow a routine treatment plan based on tumor grade, stage and prostate-specific antigen (PSA) level. However, studies in other cancers have shown the importance of using biomarkers to personalize treatments. With no approved biomarkers presently in use in prostate cancer, there is a clinical need to develop such stratification tools. Here our study shows that PUMA and NOXA are markers that have a high prognostic value when looking at their presence in both benign and tumor glands within the prostate. Hence, the presence of these markers may help to better predict outcomes at diagnosis. Incorporating these markers into clinical practice may eventually lead to selective treatment options in newly diagnosed patients. This in turn should lead to better cancer control, potentially lowering the morbidity and mortality due to prostate cancer.Background: Given that treatment decisions in prostate cancer (PC) are often based on risk, there remains a need to find clinically relevant prognostic biomarkers to stratify PC patients. We evaluated PUMA and NOXA expression in benign and tumor regions of the prostate using immunofluorescence techniques and determined their prognostic significance in PC. Methods: PUMA and NOXA expression levels were quantified on six tissue microarrays (TMAs) generated from radical prostatectomy samples (n = 285). TMAs were constructed using two cores of benign tissue and two cores of tumor tissue from each patient. Association between biomarker expression and biochemical recurrence (BCR) at 3 years was established using log-rank (LR) and multivariate Cox regression analyses. Results: Kaplan–Meier analysis showed a significant association between BCR and extreme levels (low or high) of PUMA expression in benign epithelial cells (LR = 8.831, p = 0.003). Further analysis revealed a significant association between high NOXA expression in benign epithelial cells and BCR (LR = 14.854, p < 0.001). The combination of extreme PUMA and high NOXA expression identified patients with the highest risk of BCR (LR = 16.778, p < 0.001) in Kaplan–Meier and in a multivariate Cox regression analyses (HR: 2.935 (1.645–5.236), p < 0.001). Conclusions: The combination of PUMA and NOXA protein expression in benign epithelial cells was predictive of recurrence following radical prostatectomy and was independent of PSA at diagnosis, Gleason score and pathologic stage.

Diagnostic Performance and Clinical Impact of Gallium-68 Prostate-Specific Membrane Antigen (PSMA) PET/CT Imaging in Early Relapsed Prostate Cancer after Radical Therapy: Phase 3, Prospective, Multicenter Study (IAEA-PSMA Study)

Introduction: Biochemical recurrence (BCR) is a major clinical challenge in patients with Prostate Cancer (PCa), as rising PSA occurs in about 20-30% of patients treated with radical prostatectomy and up to 60% in patients treated primarily with radiotherapy. Patients may have local recurrence in the pelvis or in distant sites. The location and burden of recurrent disease is mandatory in guiding subsequent therapies. Standard practice for BCR in PCa includes computed tomography and bone scintigraphy, both known for limited diagnostic performance. The use of positron emission tomography (PET) with prostate-specific membrane antigen (PSMA) was introduced in clinical practice in the past few years due to its better accuracy. The present phase 3, prospective, multicentric, international study was planned to evaluate the diagnostic performance and clinical impact of [68Ga]Ga-PSMA-11 PET/CT in evaluating patients with biochemical recurrent PCa; the study was promoted and supported by the IAEA. Methods: Patients with PCa who have undergone primary definitive treatment and presented with rising PSA levels were recruited to the study. Overall 17 centers from 15 countries (Azerbaijan, Brazil, Colombia, India, Israel, Italy, Jordan, Lebanon, Malaysia, Mexico, Pakistan, Poland, South Africa, Turkey, and Uruguay) were involved. Images and data were centrally reviewed; data were collected and assessed for site of findings ([68Ga]Ga-PSMA-11 pathologic uptake), positivity rate (percentage of patients with a positive [68Ga]Ga-PSMA-11 PET/CT) and impact on patient management. Regarding PET findings, a composite reference standard was used, including pathology, correlative imaging, PSA response; regarding management, the reference included changes in the treating physician’s documented clinical plans before and after PET; all patients have at least 6 months clinical follow-up. Results: 1198 patients were prospectively enrolled between November 2017 and December 2019; 1004 patients had complete data for final evaluation. [68Ga]Ga-PSMA-11 PET/CT was positive in 654/1004 patients (65.1%); lesions were identified as: prostate/prostatic bed only in 13.7% of the cases; pelvic lymph nodes only in 20.5%, and with any metastatic disease in 27.0%. There was a correlation between [68Ga]Ga-PSMA-11 PET/CT positivity and Gleason score (p<0.001): detection rate was 371/613 (60.5%) in patients with Gleason 7, 130/196 (66.3%) in Gleason 8, 140/180 (77.8%) in Gleason 9 and 13/15 (86.7%) in Gleason 10. There was also statistically significant correlation between lesions identified by [68Ga]Ga-PSMA-11 PET/CT and PSA values (p<0.001): detection rate was 21/41 (51.2%) for PSA <0.2, 84/188 (44.7%) for PSA between 0.2-0.5, 124/232 (53.4%) for PSA 0.5-1.0, 158/235 (67.2%) for PSA ≥1 and <2, 171/206 (83.0%) for PSA ≥2 and <4, and 96/102 (94,1%) in PSA 4 to 10. Finally, treatment was modified based on PET PSMA results in 56.8% of patients. The [68Ga]Ga-PSMA-11 PET/CT positivity rate was consistent and not statistically different among the different countries. Conclusion: This is the largest multicenter international prospective trial on [68Ga]Ga-PSMA-11 PET/CT, and it confirmed the capability of [68Ga]Ga-PSMA-11 PET /CT to detect local and metastatic recurrence in most men with BCR. Based on imaging results, most men had a change in treatment approach. This study demonstrates the reliability of [68Ga]Ga-PSMA-11 PET/CT in PCa BCR, and the worldwide feasibility of such imaging approach. Funding Statement: The study was promoted and supported by the IAEA. Declaration of Interests: The authors have no conflict of interest. Ethics Approval Statement: All centers obtained local ethical clearance for prospective recruitment of patients and data collection, according to national regulations.

Construction and Validation of a Robust Cancer Stem Cell-Associated Gene Set-Based Signature to Predict Early Biochemical Recurrence in Prostate Cancer.

Background Postoperative early biochemical recurrence (BCR) was an essential indicator for recurrence and distant metastasis of prostate cancer (PCa). The aim of this study was to construct a cancer stem cell- (CSC-) associated gene set-based signature to identify a subgroup of PCa patients who are at high risk of early BCR. Methods The PCa dataset from The Cancer Genome Atlas (TCGA) was randomly separated into discovery and validation set. Patients in discovery set were divided into early BCR group and long-term survival group. Propensity score matching analysis and differentially expressed gene selection were used to identify candidate CSC-associated genes. The LASSO Cox regression model was finally performed to filter the most useful prognostic CSC-associated genes for predicting early BCR. Results By applying the LASSO Cox regression model, we built a thirteen-CSC-associated gene-based early BCR-predicting signature. In the discovery set, patients in high-risk group showed significantly poorer BCR free survival than that patients in low-risk group (HR: 4.91, 95% CI: 2.75–8.76, P < 0.001). The results were further validated in the internal validation set (HR: 2.99, 95% CI: 1.34–6.70, P = 0.005). Time-dependent ROC at 1 year suggested that the CSC gene signature (AUC = 0.800) possessed better predictive value than any other clinicopathological features in the entire TCGA cohort. Additionally, survival decision curve analysis revealed a considerable clinical usefulness of the CSC gene signature. Conclusions We successfully developed a CSC-associated gene set-based signature that can accurately predict early BCR in PCa cancer.

Factors affecting biochemical recurrence of prostate cancer after radical prostatectomy in patients with positive and negative surgical margin.

PurposeTo investigate the clinical and pathological predictive factors affecting biochemical recurrence (BCR) after radical prostatectomy (RP) in patients with positive and negative surgical margin (SM).MethodsPatients who underwent RP were retrospectively reviewed for the study. Demographic, clinical, pathological and oncological data were evaluated. All data were compared between patients with positive SM and negative SM to detect factors associated with SM status. Later, patients were divided into two groups as BCR-negative and BCR-positive groups. Data were separately compared between BCR groups for all patients, SM-negative and SM-positive patients, respectively.ResultsA total of 254 patients with a mean age of 63.5 years and the mean prostate-specific antigen of 10.9 ng/ml were evaluated in the study. SM positivity was found to be an independent prognostic factor for BCR (p = 0.013, Odds Ratio (OR): 0.267, 95% Confidence Interval (CI): 0.094-0.755). In SM-positive patients, biopsy Gleason Score and International Society of Urological Pathology grade were found to be independent predictive factors for BCR (p < 0.05). However, only tumor to SM distance (TSMD) was found to be an independent risk factor for BCR (p = 0.024) in SM-negative patients. The predictive cutoff value of the TSMD was found to be 75 μm for BCR (100% sensitivity and 63.9% specificity) (AUC = 0.803, p = 0.024). Although all of 46 patients with >75 μm TSMD were recurrence free, 5 of 31 patients with <75 μm TSMD had BCR (p = 0.009; OR: 0.839 CI: 0.719–0.979).ConclusionHigh Gleason Score and International Society of Urological Pathology grade of biopsy were found to be associated with BCR in SM-positive patients. For SM-negative patients, only TSMD was found to be associated with BCR after RP.

Detection Rate of Prostate Specific Membrane Antigen Tracers for Positron Emission Tomography/Computerized Tomography in Prostate Cancer Biochemical Recurrence: A Systematic Review and Network Meta-Analysis.

Restaging of prostate cancer in patients with biochemical recurrence after radical treatment remains a challenging clinical scenario as current imaging modalities are suboptimal. To date, prostate specific membrane antigen positron emission tomography/computerized tomography seems to represent a very promising diagnostic tool in this setting. Therefore, we evaluated the detection rate of several positron emission tomography/computerized tomography prostate specific membrane antigen based tracers in the restaging of prostate cancer in patients with biochemical recurrence. According to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement, a systematic search was performed across MEDLINE®, Embase® and Web of Science™. PICOS (Patient, Intervention, Comparator, Outcome, Study Type), criteria consisted of P: patients with biochemical recurrence after radical prostatectomy and/or radiation therapy as primary treatment; I: studies using gallium-68-prostate specific membrane antigen-11, gallium-68-prostate specific membrane antigen inhibitor for imaging and therapy, gallium-68-trishydroxypyridinone-prostate specific membrane antigen, copper-64-prostate specific membrane antigen-617, fluorine-18-DCFPyL or fluorine-18-prostate specific membrane antigen-1007; C: no control group or positron emission tomography/computerized tomography comparative studies; O: patient specific overall detection rate; and S: retrospective/prospective studies. A meta-analysis of proportions and a network meta-analysis were performed. Heterogeneity was assessed using Cochran Q and I2 statistics. Quality was assessed by QUADAS-2 (University of Bristol, Bristol, United Kingdom). Funnel plots and Egger test were used for publication biases. A total of 43 studies including 5,832 patients were identified and included in the analysis. An overall detection rate of 74.1% (95% CI 69.2%-78.5%) was found, with no differences between tracers. The overall detection rates were 33.7%, 50.0%, 62.8%, 73.1% and 91.7% % in prostate specific antigen subgroups of less than 0.2 ng/ml, 0.2 to 0.49 ng/ml, 0.50 to 0.99 ng/ml, 1.0 to 1.99 ng/ml, and 2.0 ng/ml or greater, respectively. No difference between tracers was found according to prostate specific antigen doubling time or prostate specific antigen velocity. No tracer proved superior to the others through network meta-analysis. High heterogeneity and inconsistency were found across all analyses. Included studies showed a low risk of bias. Prostate specific membrane antigen positron emission tomography/computerized tomography for prostate cancer restaging in patients with biochemical recurrence achieves best detection rates (over 70%) if prostate specific antigen is below 1 ng/ml. At lower prostate specific antigen levels the detection rate of prostate specific membrane antigen positron emission tomography/computerized tomography is lower (33.7% for levels below 0.2 ng/ml and 50% for levels 0.2 to 0.49 ng/ml), despite being better than "older" tracers such as choline based positron emission tomography or computerized tomography/bone scintigraphy. Furthermore, no prostate specific membrane antigen tracer can be currently considered superior to others. Further studies are needed to better define the diagnostic performance and role of these imaging techniques.

Phase II trial of SM-88, a cancer metabolism based therapy, in non-metastatic biochemical recurrent prostate cancer

SummaryBackground Androgen deprivation therapy (ADT) is a standard treatment for high-risk biochemically-recurrent, non-metastatic prostate cancer (BRPC) but is not curative and associated with toxicity. Racemetyrosine (SM-88) is an amino-acid analogue used with methoxsalen, phenytoin, and sirolimus (MPS) to enhance SM-88 activity. Method A phase 1b/2, open-label trial in BRPC and rising PSA. Patients were given daily SM-88 (230 mg BID), methoxsalen (10 mg), phenytoin (50 mg), and sirolimus (0.5 mg)). Outcome measures included changes in PSA, circulating tumor cells (CTCs) and imaging. Results 34 subjects were screened, 23 treated and 21 remained on study for ≥12 weeks. The median PSA was 6.4 ng/ml (range 1.7–80.1); doubling-time 6.2 months (range 1.4–36.6) and baseline testosterone 319.1 ng/ml (range 2.5–913.7). Median duration of therapy was 6.5 months (2.6–14.0). CTCs (median 48.5 cells/4 ml (range 15–268) at baseline) decreased a median of 65.3% in 18 of 19 patients. For patients who achieved an absolute CTC nadir count of <10 cells/4 ml (n = 10), disease control was 100% i.e. no metastases or PSA progression, while on trial (p = 0.005). PSA fell by ≥50% in 4.3% (1 subject). No patients developed metastatic disease while on treatment (metastases free survival =100%). There were no treatment-related adverse events (AEs) and quality of life was unchanged from baseline on the EORTC QLQ-C30 and QLQ-PR25. Testosterone levels rose slightly on SM-88 and were unrelated to efficacy or toxicity. Conclusions Use of SM-88 was associated with disease control while maintaining QOL. SM-88 may delay the need for ADT and the associated hormonal side effects. Larger trials are planned.Trial registration number, date of registration - NCT02796898, June 13, 2016

11C-choline positron emission tomography/computed tomography for detection of disease relapse in patients with history of biochemically recurrent prostate cancer and prostate-specific antigen ≤0.1 ng/ml.

The objective was to evaluate the diagnostic performance of surveillance11 C-choline positron emission tomography/computed tomography (PET/CT) for the detection of disease relapse in patients with a history of biochemically recurrent (BCR) prostate cancer (PCa) and prostate-specific antigen (PSA) ≤0.1 ng/ml. We included patients who had been treated for BCR PCa and had a surveillance11 C-choline PET/CT at serum PSA ≤0.1 ng/ml. Positive surveillance PET/CT was defined as a study that identified a new tracer-avid lesion or new tracer uptake in a previously treated lesion or both. Findings were confirmed against a composite radiologic-pathologic gold standard. Time to recurrence association analyses were performed for disease relapse risk with the use of Cox proportional hazards regression. In total, 13 (12.1%) of the 107 patients had positive surveillance PET/CT scans, confirmed on pathologic assessment (n = 5) and subsequent imaging (n = 8). Among these 13 patients, ten had distant metastases, two had local recurrence, and one had both. Nine of the ten patients with metastases had oligometastatic disease defined as the presence of ≤3 metastases. Serum PSA became detectable again in only seven patients with positive surveillance PET/CT, after a mean interval from surveillance PET/CT of 292 days (range: 105-543 days). We identified an association of N stage with increased risk of recurrence (hazard ratio = 3.85; P = 0.036) although this was not significant after accounting for multiple testing. Surveillance11 C-choline PET/CT can detect early disease relapse at serum PSA ≤0.1 ng/ml in patients with a history of BCR PCa.

The effects of PSA kinetics on the outcome of hypofractionated salvage radiotherapy for biochemical recurrence of prostate cancer after prostatectomy.

The feasibility and efficacy of hypofractionated salvage radiotherapy (HS-RT) for prostate cancer (PC) with biochemical recurrence (BR) after prostatectomy, and the usefulness of prostate-specific antigen (PSA) kinetics as a predictor of BR, were evaluated in 38 patients who received HS-RT without androgen deprivation therapy between May 2009 and January 2017. Their median age, PSA level and PSA doubling time (PSA-DT) at the start of HS-RT were 68 (53–74) years, 0.28 (0.20–0.79) ng/ml and 7.7 (2.3–38.5) months, respectively. A total dose of 60 Gy in 20 fractions (three times a week) was three-dimensionally delivered to the prostate bed. After a median follow-up of 62 (30–100) months, 19 (50%) patients developed a second BR after HS-RT, but only 1 patient died before the last follow-up. The 5-year overall survival and BR-free survival rates were 97.1 and 47.4%, respectively. Late grade 2 gastrointestinal and genitourinary morbidities were observed in 0 and 5 (13%) patients, respectively. The PSA level as well as pathological T-stage and surgical margin status were regarded as significant predictive factors for a second BR by multivariate analysis. BR developed within 6 months after HS-RT in 11 (85%) of 13 patients with a PSA-DT < 10 months compared with 1 (17%) of 6 with a PSA-DT ≥ 10 months (median time to BR: 3 vs 14 months, P < 0.05). Despite the small number of patients, our HS-RT protocol seems feasible, and PSA kinetics may be useful for predicting the risk of BR and determining the appropriate follow-up schedule.

Predictive value of Prostate Specific Antigen variations in the last week of salvage radiotherapy for biochemical recurrence of prostate cancer after surgery: A practical approach.

BackgroundAbout a third of patients who underwent radical prostatectomy for prostate cancer (Pca) develop a biochemical failure (BF) within 10 years from surgery, and about a half of them receive salvage radiation therapy (SRT). Factors to predict risk to relapse after SRT are still lacking. Dynamic models, based on the assessment of changes in Prostate Specific Antigen (PSA) postsurgery seem to show good reliability.AimsThe goal of the study was to identify a simple analytical method for the postsalvage radiation therapy biochemical failure (post‐SRTBF) prediction before the end of the SRT, regardless of the PSA value at the beginning of the treatment (PSA start), measuring the PSA values at the start and 1 week before the end of SRT.MethodsIn a series of 83 patients treated with SRT for BF of Pca we measured PSA values at the first day and 1 week before the end of SRT. These values were used to define an analytical method for the post‐SRTBF prediction.ResultsPSA value in patients without post‐SRTBF show a significant difference in term of difference during the SRT with respect to patients with post‐SRTBF. Starting from this difference, we identified a simple and practical analytical method for the post‐SRTBF prediction before the end of the SRT. The data corresponds with the model and the analytical method is highly predictive (Sensitivity = 81%, Specificity = 85%, Accuracy = 83%).ConclusionThis study offers a new tool to early predict Pca relapse overtime and to select patients who can benefit from an early additional systemic treatment.