Early-stage Prostate Cancer Patients Research Articles

Drastic Synergy of Lovastatin and Antrodia camphorata Extract Combination against PC3 Androgen-Refractory Prostate Cancer Cells, Accompanied by AXL and Stemness Molecules Inhibition.

Prostate cancer (PC) is the second most frequently diagnosed cancer and the fifth leading cause of cancer-related death in males worldwide. Early-stage PC patients can benefit from surgical, radiation, and hormonal therapies; however, once the tumor transitions to an androgen-refractory state, the efficacy of treatments diminishes considerably. Recently, the exploration of natural products, particularly dietary phytochemicals, has intensified in response to addressing this prevailing medical challenge. In this study, we uncovered a synergistic effect from combinatorial treatment with lovastatin (an active component in red yeast rice) and Antrodia camphorata (AC, a folk mushroom) extract against PC3 human androgen-refractory PC cells. This combinatorial modality resulted in cell cycle arrest at the G0/G1 phase and induced apoptosis, accompanied by a marked reduction in molecules responsible for cellular proliferation (p-Rb/Rb, Cyclin A, Cyclin D1, and CDK1), aggressiveness (AXL, p-AKT, and survivin), and stemness (SIRT1, Notch1, and c-Myc). In contrast, treatment with either AC or lovastatin alone only exerted limited impacts on the cell cycle, apoptosis, and the aforementioned signaling molecules. Notably, significant reductions in canonical PC stemness markers (CD44 and CD133) were observed in lovastatin/AC-treated PC3 cells. Furthermore, lovastatin and AC have been individually examined for their anti-PC properties. Our findings elucidate a pioneering discovery in the synergistic combinatorial efficacy of AC and clinically viable concentrations of lovastatin on PC3 PC cells, offering novel insights into improving the therapeutic effects of dietary natural products for future strategic design of therapeutics against androgen-refractory prostate cancer.

Spatial whole transcriptome profiling of primary tumor from patients with metastatic prostate cancer.

Prostate cancer (PCa) is a highly heterogeneous disease in terms of its molecular makeup and clinical prognosis. The prostate tumor microenvironment (TME) is hypothesized to play an important role in driving disease aggressiveness, but precise mechanisms remain elusive. In our study, we used spatial transcriptomics to explore for the first time the spatial gene expression heterogeneity within primary prostate tumors from patients with metastatic disease. In total, we analyzed 5459 tissue spots from three PCa patients comprising castration-resistant (CRPC) and neuroendocrine (NEPC) disease stages. Within CRPC, we identified a T cell cluster whose activity might be impaired by nearby regulatory T cells, potentially mediating the aggressive disease phenotype. Moreover, we identified Hallmark signatures of epithelial-mesenchymal transition in a cancer-associated fibroblast (CAF) cluster, indicating the aggressive characteristic of the primary TME leading to metastatic dissemination. Within NEPC, we identified active immune-stroma cross-talk exemplified by significant ligand-receptor interactions between CAFs and M2 macrophages. Further, we identified a malignant cell population that was associated with the down-regulation of an immune-related gene signature. Lower expression of this signature was associated with higher levels of genomic instability in advanced PCa patients (SU2C cohort, n = 99) and poor recurrence free survival in early-stage PCa patients (TCGA cohort, n = 395), suggesting prognostic biomarker potential. Taken together, our study reveals the importance of whole transcriptome profiling at spatial resolution for biomarker discovery and for advancing our understanding of tumor biology.

CRISPR-Cas12a powered multifunctional DNA nanodumbbell lock biosensor for multiple molecular detection

Detection of multiple biomarkers for accurate diagnosis of disease is highly desirable but remains challenging. Here, we developed a versatile diagnostic biosensor (SMARTLOCK) through the unique combination of DNA tetrahedron, nonlinear HCR and CRISPR-Cas12a system for simultaneous detection of multiple nucleic acids, small molecules, proteins and different types of combinations. Two DNA tetrahedrons are assembled into a functional dumbbell lock, which was unlocked by the target molecules, thereby triggering a two-stage signal amplification of nonlinear HCR and CRISPR-Cas12a to generate powerful fluorescence signals. The capability of multi-target simultaneous detection of SMARTLOCK is demonstrated in the detection of miR-141, miR-375, miR-21, ATP, cortisol, insulin and their combinations. SMARTLOCK could selectively (specificity = 93.3%) and sensitively (sensitivity = 90%) distinguish early-stage prostate cancer (PCa) patients (n = 10) from healthy donors (n = 30). Measurement of two PCa-related RNAs (miR-141 and miR-375) shows the potential of SMARTLOCK to be a highly accurate and low-cost tool for the screening, diagnosis and prognosis of various diseases.

Predictor of adverse pathology in patients who underwent deferred radical prostatectomy following active surveillance: Results from multi-institutional prospective observational cohort in the PRIAS-JAPAN.

350 Background: Intraductal carcinoma of the prostate (IDC-P) and invasive cribriform are key prognostic pathologies among early stage prostate cancer patients; however, predictors of adverse pathology, including these types, remain unknown. In men who opted for active surveillance (AS), we aimed to examine the association between adverse pathology and patient characteristics, utilizing radical prostatectomy (RP) specimens. Methods: We re-reviewed available RP specimens from 1035 men prospectively enrolled in the PRIAS-JAPAN cohort between January 2010 and September 2020. We defined adverse pathology on RP specimen as Gleason grade group of ≥3, pT-stage≥T3, pN positivity, or the presence of IDC-P or invasive cribriform. And, we examined the predictive factors associated with adverse pathology, using factors at AS enrollment and before RP. Results: Out of 162 men underwent RP, available 137 RP specimens were analyzed. The percentage of adverse pathology was 48.9% (67 patients), including 8.8% in IDC-P and 29.9 % in invasive cribriform. Men with adverse pathology had lower prostate specific antigen recurrence-free survival than those without them (log rank P = 0.0189). On multivariate logistic regression analyses, increasing age at AS enrollment and before RP were the predictive factors for adverse pathology (Odds ratio [OR], 1.1; 95% confidence interval [CI]: 1.02-1.19, P = 0.0178, OR, 1.12; 95% CI: 1.02-1.22, P=0.0126), not magnetic resonance imaging findings. Conclusions: Aging is significantly associated with adverse pathology including IDC-P or cribriform. The results suggest that relaxing scheduled examinations during AS depending on age is not practical. Clinical trial information: UMIN000048095 .

Poorly Controlled Diabetes Mellitus Increases the Risk of Deaths and Castration-Resistance in Locally Advanced Prostate Cancer Patients

The association between DM and prostate cancer progression remains controversial. Previous studies mainly focused on early stage prostate cancer patients. We aimed to study the association between DM and prostate cancer progression in locally advanced prostate cancer patients. 598 locally advanced prostate cancer patients in a top tertiary hospital in China between 2012 and 2021 were divided into three groups based on the postoperative average HbA1c level. The follow-up time is 46.96 ± 27.07 months. Three hundred and forty-eight (58.2%) were normal glucose, 175 (29.3%) were moderate glucose, and 75 (12.5%) were high glucose. Higher postoperative-average HbA1c was associated with poorer OS, PCSM, and PSA-RFS. We concluded that poorly controlled DM was correlated with poorer OS, PCSM, and PSA-RFS in locally advanced prostate cancer patients.

PSMA-RLT in Patients with Metastatic Hormone-Sensitive Prostate Cancer: A Retrospective Study

Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) is a novel treatment for patients with castration-resistant prostate cancer (CRPC). Given the mode of action, patients in an earlier disease stage, such as hormone-sensitive prostate cancer (HSPC), are also likely to benefit from [177Lu]Lu-PSMA- (177Lu-PSMA) or [225Ac]Ac-PSMA-radioligand treatment (225Ac-PSMA). In this retrospective study, we analyzed the safety and efficacy of PSMA-RLT in early-stage and hormone-sensitive metastatic prostate cancer patients. A retrospective study was performed in patients who received 177Lu-PSMA and/or 225Ac-PSMA with early-stage metastatic prostate cancer. The primary outcome parameter evaluated in this study was the progression-free survival (PFS) after PSMA-RLT and toxicity according to the Common Terminology Criteria for Adverse Events. Secondary outcome parameters were prostate-specific antigen (PSA) response and the date of onset of CRPC state. In total, 20 patients were included of which 18 patients received 177Lu-PSMA radioligand and two patients received tandem treatment with both 177Lu-PSMA and 225Ac-PSMA radioligands. Patients received a median of 2 treatment cycles (range 1-6) and a median activity of 6.2 GBq 177Lu-PSMA per cycle (interquartile range (IQR) 5.2-7.4 GBq). PSMA-RLT was overall well-tolerated. The most common grade 1-2 side effects were xerostomia (n = 6) and fatigue (n = 8), which were only temporarily reported. One patient that received 225Ac-PSMA developed grade 3-4 bone marrow toxicity. The median PFS was 12 months (95% confidence interval (CI), 4.09-19.9 months). Seventeen (85%) patients had a ≥50% PSA response following PSMA-RLT. One patient developed CRPC 9 months following PSMA-RLT. In this small cohort study, PSMA-RLT appeared safe and showed encouraging efficacy for (metastasized) early-stage and hormone-sensitive prostate cancer patients. Prospective studies are awaited and should include long-term follow-up.

Clinical outcomes of intraductal carcinoma or cribriform in radical prostatectomy specimens of men opting for active surveillance: data from the PRIAS-JAPAN study.

Among early stage prostate cancer patients, intraductal carcinoma of the prostate (IDC-P) and invasive cribriform are key prognostic factors; however, their presence and clinical significance following active surveillance (AS) are unknown. In men who opted for AS, we aimed to examine the presence and impact of IDC-P or cribriform, utilizing radical prostatectomy (RP) specimens. We re-reviewed 137 RP specimens available in the PRIAS-JAPAN prospective cohort between January 2010 and September 2020. We assessed the presence of IDC-P or cribriform, and compared the patients' characteristics and prostate-specific antigen (PSA) recurrence-free survival after RP between groups with and without IDC-P or cribriform. In addition, we examined the predictive factors associated with IDC-P or cribriform. The percentage of patients with IDC-P or cribriform presence was 34.3% (47 patients). IDC-P or cribriform pattern was more abundant in the higher Gleason grade group in RP specimens (P < 0.001). The rates of PSA recurrence-free survival were significantly lower in the IDC-P or cribriform groups than in those without them (log rank P = 0.0211). There was no association between IDC-P or cribriform on RP with the Prostate Imaging-Reporting and Data System (PI-RADS) 4,5 score on magnetic resonance imaging (MRI) before RP even with adjustments for other covariates (OR, 1.43; 95% confidence interval [CI] 0.511-3.980, P = 0.497). IDC-P or cribriform comprised approximately one-third of all RP specimens in men who underwent RP following AS, confirming their prognostic significance.

Abstract 3220: Patient communication efficacy, information seeking, and treatment regret among early-stage prostate cancer survivors

Abstract Background: Most men with prostate cancer lack sufficient knowledge of their illness at the time they are diagnosed to make informed decisions about treatment. The ways patients interact with physicians can influence the quality of treatment-related information that is received and impact emotional well-being. Regret is a common negative affect that patients, providers, and care givers seek to avoid. This study investigated the relationship between patient communication efficacy, treatment information seeking behaviors, and decision regret within a sample of early-stage prostate cancer survivors. Methods: Sixty-three men diagnosed with early-stage prostate cancer (Stage T1 or T2) completed self-administered questionnaires. Men who were actively monitoring or undergoing definitive treatment were eligible for inclusion. The 67-item data collection tool captured patient demographics, cancer treatment information seeking behaviors, and psychosocial characteristics. Communication efficacy was measured using the validated Perceived Efficacy Patient Physicians Interaction (PEPPI-10, α=.94) scale. Decision regret was assessed using a validated 5-item measure (Brehaut et al., 2003). Descriptive and comparative analyses were conducted using SPSS Version 25. Results: A majority of participants were White (58.7%), married/partnered (79.4%), privately insured (54.2%) and graduated college (75.0%). More than two-thirds (77.8%) wanted to assume an active role during treatment decision-making. Most respondents (58.1%) fell within the high efficacy communication group (+/- 1/2 s.d. of the mean). A majority of men did not regret their initial treatment choice (82.5%). Men who regretted their initial treatment choice reported significantly more unmet treatment information needs (Mean= 5.63) than those who did not regret (Mean= 2.78) their treatment decision [t(60) = 2.084, p = .041]. Independent samples t-test results showed a statistically significant relationship between regret and communication efficacy [t(60) = -2.38, p =.021]. The two situations where men who regretted their decisions reported lower levels of communication efficacy were getting doctors to pay attention to what they have to say [t(60) = -3.39, p = .001] and making the most of their visit with the doctor [t(60) = -2.22, p = .030]. Perceived communication efficacy marginally differentiated men who regretted and did not regret their treatment decisions in two more clinical situations [t(60) = -1.92, p = .060; t(60) = -1.97, p = .054]. Conclusion: Communication efficacy appears to impact patient treatment information seeking behaviors and decision regret. Communication interventions need to be developed to increase early stage prostate cancer patients’ level of confidence when seeking treatment information to enhance their emotional well-being and quality of life. Citation Format: Levi Ross, Jordan S. Young, Jala Lockhart, Torhonda Lee, Ashley Bowers, Guleer Shabab, Michael A. Preston. Patient communication efficacy, information seeking, and treatment regret among early-stage prostate cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3220.

The Prognostic Value of PI-RADS Score in CyberKnife Ultra-Hypofractionated Radiotherapy for Localized Prostate Cancer.

Simple SummaryMagnetic resonance imaging is commonly used in pre-treatment prostate cancer diagnostics. The assessment includes a five-stage scale classification called Prostate Imaging-Reporting and Data System (PI-RADS), routinely used to describe the probability of finding a clinically significant cancer. Less is known about the association of PI-RADS score with patients’ prognosis. Our retrospective study aimed to assess the association between pre-treatment PI-RADS score and risk of developing metastases, based on a cohort of 152 patients treated with ultra-hypofractionated CyberKnife radiotherapy for low or intermediate-risk group prostate cancer. PI-RADS score and the size of the target lesion proved to be significantly associated with the risk of developing metastases, suggesting that the introduction of PI-RADS score to initial risk assessment could improve the patient-tailored management of prostate cancer.Prostate Imaging-Reporting and Data System (PI-RADS) has been widely implemented as a diagnostic tool for significant prostate cancer (PCa); less is known about its prognostic value, especially in the setting of primary radiotherapy. We aimed to analyze the association between PI-RADS v. 2.1 classification and risk of metastases, based on a group of 152 patients treated with ultra-hypofractionated stereotactic CyberKnife radiotherapy for localized low or intermediate risk-group prostate cancer. We found that all distant failures (n = 5) occurred in patients diagnosed with a PI-RADS score of 5, and axial measurements of the target lesion were associated with the risk of developing metastases (p < 0.001). The best risk stratification model (based on a combination of greatest dimension, the product of multiplication of PI-RADS target lesion axial measurements, and age) achieved a c-index of 0.903 (bootstrap-validated bias-corrected 95% CI: 0.848–0.901). This creates a hypothesis that PI-RADS 5 and the size of the target lesion are important prognostic factors in early-stage PCa patients and should be considered as an adverse prognostic measure for patients undergoing early treatment such as radiation or focal therapy.

Dosimetric Predictors of Toxicity in Patients With Early-Stage Prostate Cancer Treated With Moderately Hypofractionated IMRT or PBT: A Multi-Institutional Analysis

<h3>Purpose/Objective(s)</h3> Limited published data address modifiable risk factors for significant toxicity complicating moderately hypofractionated schedules of intensity-modulated radiation therapy (IMRT) and proton-beam therapy (PBT) in patients with early-stage prostate cancer (PC). This study explored dosimetric predictors of Grade 3+ gastrointestinal (GI) and genitourinary (GU) toxicity following IMRT or PBT in this patient population. <h3>Materials/Methods</h3> The study population included patients from five tertiary referral centers treated from 2002-2018 for low- or intermediate-risk biopsy-proven prostate adenocarcinoma. All patients were treated with moderately hypofractionated radiation defined as 250–300 cGY per daily fraction given over 4-6 weeks. Primary outcomes were late GI and GU toxicity as defined by CTCAE v4.0. Dosimetric variables included PTV max dose, PTV volume, bladder V31 Gy, bladder V50 Gy, bladder V70 Gy, bladder max dose, rectum V31 Gy, rectum V50 Gy, rectum V70 Gy, rectum max dose, penile bulb V10 Gy, penile bulb V15 Gy, and the left and right femoral head V40 Gy. The association of dosimetric variables with treatment toxicity was assessed with the Wilcoxon signed-rank test. <h3>Results</h3> Dosimetric data were obtained for 1139 patients, including 667 treated with IMRT and 472 treated with PBT. Median follow-up for the two groups was 46.0 and 48.5 months, respectively. Late toxicity rates for the total population were 4.7% for Grade 3+ GU toxicity and 1.5% for Grade 3+ GI toxicity. Grade 3+ GU toxicity was associated with prostate volume, bladder V31 Gy and bladder V50 Gy (<i>P</i> = 0.016, <i>P</i> = 0.018, <i>P</i> = 0.028), but not with bladder V70 Gy or maximum dose to the bladder. Grade 3+ GI toxicity was not associated with any of the dosimetric variables. When analyzed by treatment group, Grade 3+ GU toxicity was observed in 3% of the IMRT cohort and 1.7% of the PBT cohort. Grade 3+ GI toxicity was seen only in PBT and was observed in 1.5% of patients. Proton plans were associated with less radiation exposure of rectum and bladder at lower doses (rectum V31 Gy: 13% vs 16%, <i>P</i> < 0.001; bladder V31 Gy: 18% vs 26%, <i>P</i> < 0.001), while IMRT was associated with less radiation exposure of rectum and bladder at higher doses (rectum V70 Gy: 0.4% vs 2%, <i>P</i> < 0.001; bladder V70 Gy: 1% vs 3%, <i>P</i> < 0.001). Photon plans yielded superior V40 Gy to the femoral heads, and superior V10 Gy and V15 Gy to the penile bulb (<i>P</i> < 0.001, <i>P</i> < 0.003, <i>P</i> < 0.002). <h3>Conclusion</h3> In this multi-institutional analysis of 1139 early-stage PC patients treated with moderately hypofractionated IMRT or PBT, risk of serious late GU and GI complications was low for both treatment groups. Analysis of the dosimetric variables identified an association of Grade 3+ GU toxicity with low-dose radiation exposure of the bladder. Grade 3+ GI toxicity was unrelated to dosimetric variables. PBT plans yielded less exposure of non-target organs to lower-dose radiation while IMRT plans yielded less exposure of non-target organs to higher-dose radiation.

China county-based prostate specific antigen screening for prostate cancer and a cost-effective analysis.

BackgroundProstate cancer is one of the most common malignant tumors worldwide, and is the third-leading cause of cancer death in men. Nearly 70% of new prostate cancer patients in China are locally advanced or widely metastatic with poor prognosis. Providing active treatment to early stage prostate cancer patients can improve the prognosis of prostate cancer patients. Thus, this study sought to evaluate the economy of early prostate specific antigen (PSA) screening for high-risk prostate cancer.MethodsBased on the data collected from the PSA screening activities of 11 county hospitals from October 2019 to April 2021, this study evaluated a high-risk prostate cancer population who received PSA screening and their quality of life and economy. The screening population comprised males aged over 50 years. All screening patients were tested for PSA. If the PSA value is unnormal, a further diagnosis based on magnetic resonance imagining (MRI) or a transrectal ultrasound-guided prostate biopsy were performed. The decision-tree and Markov model was used to simulate the process of disease development of high-risk prostate cancer patients who underwent screenings and those who did not, and the incremental cost-effectiveness ratio was also evaluated.ResultsA total of 13,726 men received a PSA screening. Of these, 1,062 men had abnormal PSA values, and 73 of these were diagnosed with prostate cancer. Of these 73 patients, 40, 21, and 12 had early stage, mid-stage, and late-stage prostate cancer, respectively. Compared to the patients unscreened, the 1,000 patients who received an early PSA screening increased their quality-adjusted life year (QALY) by 15.69 years; however, each QALY had an additional cost of 38,550 yuan, which was lower than the willingness to pay threshold of 72,447 yuan (per capita gross domestic product in 2020).ConclusionsFor high-risk prostate cancer patients, early screenings have a cost-effective advantage over no screenings. Thus, early screening should be vigorously promoted for high-risk prostate cancer patients.

Effect of Dickkopf-1 (Dkk-1) and SP600125, a JNK Inhibitor, on Wnt Signaling in Canine Prostate Cancer Growth and Bone Metastases.

Human Dickkopf-1 (Dkk-1) upregulates a noncanonical Wnt/JNK pathway, resulting in osteoclast stimulation, cell proliferation, and epithelial-to-mesenchymal transition (EMT) of cancer cells. Ace-1-Dkk-1, a canine prostate cancer (PCa) cell line overexpressing Dkk-1, was used to investigate Wnt signaling pathways in PCa tumor growth. SP600125, a JNK inhibitor, was used to examine whether it would decrease tumor growth and bone tumor phenotype in canine PCa cells in vitro and in vivo. Ace-1-VectorYFP-Luc and Ace-1-Dkk-1YFP-Luc cells were transplanted subcutaneously, while Ace-1-Dkk-1YFP-Luc was transplanted intratibially into nude mice. The effects of Dkk-1 and SP600125 on cell proliferation, in vivo tumor growth, and bone tumor phenotype were investigated. The mRNA expression levels of Wnt/JNK-related genes were measured using RT-qPCR. Dkk-1 significantly increased the mRNA expression of Wnt/JNK-signaling-related genes. SP600125 significantly upregulated the mRNA expression of osteoblast differentiation genes and downregulated osteoclastic-bone-lysis-related genes in vitro. SP600125 significantly decreased tumor volume and induced spindle-shaped tumor cells in vivo. Mice bearing intratibial tumors had increased radiographic density of the intramedullary new bone, large foci of osteolysis, and increased cortical lysis with abundant periosteal new bone formation. Finally, SP600125 has the potential to serve as an alternative adjuvant therapy in some early-stage PCa patients, especially those with high Dkk-1 expression.

Cancer in the Shadow of COVID: Early-Stage Breast and Prostate Cancer Patient Perspectives on Surgical Delays Due to COVID-19.

BackgroundDuring the height of the coronavirus disease 2019 (COVID-19) pandemic, elective surgeries, including oncologic surgeries, were delayed. Little prospective data existed to guide practice, and professional surgical societies issued recommendations grounded mainly in common sense and expert consensus, such as medical therapy for early-stage breast and prostate cancer patients. To understand the patient experience of delay in cancer surgery during the pandemic, we interviewed breast and prostate cancer patients whose surgeries were delayed due to the pandemic.Patients and MethodsPatients with early-stage breast or prostate cancer who suffered surgical postponement at Brigham and Women’s Hospital (BWH) were invited to participate. Semi-structured telephone interviews were conducted with 21 breast and prostate cancer patients. Interviews were transcribed, and qualitative analysis using ground-theory approach was performed.ResultsMost patients reported significant distress due to cancer and COVID. Key themes that emerged included the lack of surprise and acceptance of the surgical delays but endorsed persistent cancer- and delay-related worries. Satisfaction with patient–physician communication and the availability of a delay strategy were key factors in patients’ acceptance of the situation; perceived lack of communication prompted a few patients to seek care elsewhere.DiscussionThe clinical effect of delay in cancer surgery will take years to fully understand, but there are immediate steps that can be taken to improve the patient experience of delays in care, including elicitation of individual patient perspectives and ongoing communication. More work is needed to understand the wider experiences of patients, especially minority, socioeconomically disadvantaged, and uninsured patients, who encounter delays in oncologic care.Graphical Supplementary InformationThe online version contains supplementary material available at 10.1245/s10434-021-10319-0.

P2PSA-associated parameters are significant predictors of reclassification of first-year protocol biopsy on active surveillance for early-stage prostate cancer patients: From the PRIAS-JAPAN study.

153 Background: 44 Japanese institutions have joined the Prostate Cancer Research International: Active Surveillance (PRIAS) study as PRIAS-JAPAN. As an side study, PRIAS-JAPAN investigates the usefulness of [-2] proPSA (p2PSA), a precursor of PSA, as a predictive marker for the reclassification during active surveillance patients. In this study, we aimed to evaluate the usefulness of p2PSA related parameters to predict the reclassification of first year protocol biopsy (1yr PBx). Methods: 19 institutions participated in this side study which started in January 2013. All participants were eligible for PRAIS inclusion criteria. These patients were required to receive blood sampling on every visit and protocol biopsy after inclusion. PSA and PSA isoforms (free-PSA, p2PSA) were measured in serum samples and parameters (%free-PSA, %p2PSA, phi) were also calculated. Mann-Whitney U test was used to compare continuous variables between reclassification and non-reclassification groups. Fisher's exact test and Chi-squared test with yates' continuity correction were used for categorical variables. Multivariable logistic regression models were used to predict the risk of reclassification. To assess the predictive power for reclassification, we plotted ROC curves and calculated the AUC. Decision curve analysis (DCA) was used to evaluate whether adding variables to the baseline (age, PSA, prostate volume) model would yield net clinical benefit. Results: From January 2013 to July 2017, this study enrolled 237patients. 99 patients were excluded for the reason of discontinuation of AS, non-adherence of protocol blood sampling and rejection of biopsy. 138patients were able to analyzed PSA, PSA isoforms and its parameters at the time of inclusion and 1yr PBx. Patients who showed reclassification were significantly higher level of %p2PSA at inclusion and %p2PSA and phi just before 1yr PBx. Multivariate analyses showed %p2PSA at inclusion (p= 0.04), %p2PSA (p= 0.01) and Phi (p= 0.008) before 1yr PBx were statistically significant predictors of reclassification at 1yr PBx. ROC analysis revealed that %p2PSA before 1yr PBx (AUC 0.674) and phi before 1yr PBx (AUC 0.669) were a significant discriminant factor in predicting reclassification. DCA analysis showed that phi before 1yr PBx had a highest net benefit in the range of clinically plausible risk threshold (10–40%). Conclusions: %p2PSA and Phi before 1yr PBx have good prediction power and phi is a most useful indicator of clinical decision making about active surveillance. Clinical trial information: UMIN 000009876.

Characterization of the perioperative changes of exosomal immune-related cytokines induced by prostatectomy in early-stage prostate cancer patients

BackgroundMyeloid-derived suppressor cells (MDSCs) are relevant in prostate cancer microenvironment collaborating in tumor development. The main tumor marker used in this disease, prostate-specific antigen (PSA), does not provide information related to this tumor microenvironment. Cancer cells secrete exosomes carrying bioactive molecules contributing to MDSCs recruitment and induction. The aim of this study was to characterize the perioperative changes of exosomal cytokines relevant in MDSCs recruitment induced by prostatectomy in prostate cancer patients. MethodsBlood was drawn from 26 early-stage prostate cancer patients before and after radical prostatectomy and from 16 healthy volunteers. Serum exosomes were separated by precipitation. Cytokines related with MDSC cell recruitment and activation CCL2, CXCL2, CXCL5, CXCL8, CXCL12, MIF, S100A9 and TGF-ß were measured in serum and serum-derived exosomes using immunometric assays. ResultsAll cytokines were detected both in serum and exosomes, except for CXCL12, which was detected only in serum. Exosomes were enriched specially in MIF, TGF-ß and CXCL2. Presurgical MIF levels in exosomes correlated negatively with serum PSA. Also, presurgical TGF-ß decreased both in serum and exosomes as Gleason score rises. Patientś presurgical exosomes had increased CCL2, CXCL5 and TGF-ß levels than exosomes from healthy controls. These differences were not observed when cytokines were analyzed in serum, except for TGF-ß. Cytokine levels of CCL2, CXCL5 decreased in patients’ postsurgical exosomes, while TGF-ß further increased. On the contrary, S100A9 levels were lower in patientś presurgical exosomes but increased after radical prostatectomy. ConclusionsBlood exosomal content in cytokines constitute an attractive source to evaluate MDSCs immunomodulators providing additional information related to tumor microenvironment in prostate cancer.

A Pooled Toxicity Analysis of Moderately Hypofractionated Proton Beam Therapy and Intensity Modulated Radiation Therapy in Early-Stage Prostate Cancer Patients.

Data comparing moderately hypofractionated intensity modulated radiation therapy (IMRT) and proton beam therapy (PBT) are lacking. We aim to compare late toxicity profiles of patients with early-stage prostate cancer treated with moderately hypofractionated PBT and IMRT. This multi-institutional analysis included patients with low- or intermediate-risk biopsy-proven prostate adenocarcinoma from 7 tertiary referral centers treated from 1998 to 2018. All patients were treated with moderately hypofractionated radiation, defined as 250 to 300 cGy per daily fraction given for 4 to 6 weeks, and stratified by use of IMRT or PBT. Primary outcomes were late genitourinary (GU) and gastrointestinal (GI) toxicity. Adjusted toxicity rates were calculated using inverse probability of treatment weighting, accounting for race, National Comprehensive Cancer Network risk group, age, pretreatment International Prostate Symptom Score (GU only), and anticoagulant use (GI only). A total of 1850 patients were included: 1282 IMRT (median follow-up 80.0 months) and 568 PBT (median follow-up 43.9 months). Overall toxicity rates were low, with the majority of patients experiencing no late GU (56.6%, n = 1048) or late GI (74.4%, n = 1377) toxicity. No difference was seen in the rates of late toxicity between the groups, with late grade 3+ GU toxicity of 2.0% versus 3.9% (odds ratio [OR] 0.47; 95% confidence interval 0.17-1.28) and late grade 2+ GI toxicity of 14.6% versus 4.7% (OR 2.69; confidence interval 0.80-9.05) for the PBT and IMRT cohorts, respectively. On multivariable analysis, no factors were significantly predictive of GU toxicity, and only anticoagulant use was significantly predictive of GI toxicity (OR 1.90; P = .008). In this large, multi-institutional analysis of 1850 patients with early-stage prostate cancer, treatment with moderately hypofractionated IMRT and PBT resulted in low rates of toxicity. No difference was seen in late GI and GU toxicity between the modalities during long-term follow-up. Both treatments are safe and well tolerated.

The Predictive Role of Prostate-Specific Antigen Changes Following Transurethral Resection of the Prostate for Patients with Localized Prostate Cancer.

Simple SummaryA part of localized prostate cancer (PC) was an incidental finding in patients who received transurethral resection of the prostate (TURP) for urinary symptoms. The present study examined whether changes in prostate-specific antigen (PSA) levels after TURP possess a predictive value for localized PC. Our data revealed that patients at intermediate risk who are associated with tumor involvement ≤5% in TURP specimens, PSA_TURP ≤ 4 ng/mL, and ≥68% PSA reduction following TURP might be suitable for conservation management instead of immediate local therapy. Moreover, for patients with no pre-TURP PSA, Gleason score (GS) < 7, and low PSA_TURP could potentially be utilized to select which patients could be considered for conservative management after TURP. The findings suggest the pathologic finding of TURP and changes in PSA could be used as adjuvant markers to guide a risk-adaptive strategy for patients with localized PC.Regarding localized prostate cancer (PC), questions remain regarding which patients are appropriate candidates for conservative management. Some localized PC was an incidental finding in patients who received transurethral resection of the prostate (TURP) for urinary symptoms. It is known that TURP usually affects the level of prostate-specific antigen (PSA). In the present study, we examined whether changes in PSA levels after TURP possess a predictive value for localized PC. We retrospectively reviewed the clinical data of 846 early-stage PC patients who underwent TURP for urinary symptoms upon diagnosis at our hospital. Of 846 patients, 687 had tumor involvement in TURP specimens, and 362 had post-TURP PSA assessment. Our data revealed that, in addition to low GS and PSA levels at diagnosis, ≤5% tumor involvement in TURP specimens, greater PSA reduction (≥68%) following TURP, and post-TURP PSA ≤ 4 were significantly associated with better progression-free survival (PFS). Survival analysis revealed that the addition of prostate-directed local therapy significantly improved PFS in intermediate- and high-risk groups, but not in the low-risk group. Moreover, in the intermediate-risk group, local therapy improved PFS only for patients who were associated with post-TURP PSA > 4 ng/mL or <68% PSA reduction following TURP. We also found that local therapy had no obvious improvement in PFS for those with post-TURP ≤ 4 ng/mL regardless of pre-TURP PSA. In conclusion, conservative management is considered for patients at low or intermediate risk who have greater PSA reduction following TURP and low post-TURP PSA. Therefore, the levels of PSA following TURP might be helpful for risk stratification and the selection of patients for conservative management.

Hypofractionated Short Course Radiation Treatment Results in Systemic Immune Activation and Upregulation of the PD-1/PD-L1 Exhaustion Axis: A Prospective Pilot Study in Early Stage Prostate Cancer Patients

Hypofractionated Short Course Radiation Treatment Results in Systemic Immune Activation and Upregulation of the PD-1/PD-L1 Exhaustion Axis: A Prospective Pilot Study in Early Stage Prostate Cancer Patients

Explained variation under the additive hazards model.

We study explained variation under the additive hazards regression model for right-censored data. We consider different approaches for developing such a measure, and focus on one that estimates the proportion of variation in the failure time explained by the covariates. We study the properties of the measure both analytically, and through extensive simulations. We apply the measure to a well-known survival dataset as well as the linked surveillance, epidemiology, and end results-Medicare database for prediction of mortality in early stage prostate cancer patients using high-dimensional claims codes.

First-in-human study of anticancer immunotherapy drug candidate mobilan: safety, pharmacokinetics and pharmacodynamics in prostate cancer patients.

Toll-like receptor 5 (TLR5) controls endogenous immune responses to pathogens and is a promising target for pharmacological stimulation of anti-tumor immunity. Mobilan is an innovative gene therapy agent consisting of a non-replicating bicistronic adenovirus directing constitutive expression of human Toll-like receptor 5 (TLR5) and the secreted flagellin-based TLR5 agonist, 502s. In mice, Mobilan injection into prostate tumors resulted in autocrine TLR5 signaling, immune system activation, and suppression of tumor growth and metastasis. Here we report a first-in-human placebo-controlled clinical study of Mobilan aimed at evaluating safety, tolerability, pharmacokinetics and pharmacodynamics of a single intra-prostate injection of Mobilan in early stage prostate cancer patients. Mobilan was safe and well-tolerated at all tested doses; thus, the maximum tolerated dose was not identified. Injection of Mobilan induced signs of self-resolving inflammation not present in placebo-injected patients, including transient elevation of PSA and cytokine (G-CSF, IL-6) levels, and increased lymphoid infiltration in prostate tissue. The highest dose of Mobilan (1011 viral particles) produced the best combination of safety and pharmacodynamic effects. Therefore, Mobilan is well-tolerated and induces the expected pharmacodynamic response in humans. These results support further clinical development of Mobilan as a novel immunotherapy for prostate cancer.