Analysis of the immune-inflammatory indices for patients with metastatic hormone-sensitive and castration-resistant prostate cancer.

BACKGROUND: Inflammation plays a pivotal role in the progression of prostate cancer (PCa). Several immune-inflammatory indices, including neutrophil to lymphocyte ratio (NLR), derived neutrophil to lymphocyte ratio (dNLR), lymphocyte to monocyte ratio (LMR) and platelet to lymphocyte ratio (PLR), lung immune prognostic index (LIPI), systemic inflammation response index (SIRI) and systemic immune inflammation index (SII), have demonstrated their prognostic values in several solid malignancies. However, Comparisons of superiority with these seven indices' predictive efficacy within metastatic hormone-sensitive PCa (mHSPC) and metastatic castration-resistant PCa (mCRPC) remain uncertain. METHODS: We retrospectively included 407 patients diagnosed with mHSPC and 158 patients with mCRPC at West China Hospital from 2005 to 2022. The seven immune-inflammatory indices were computed based on hematological data of mHSPC at initial diagnosis and mCRPC at progression to CRPC. Prognostic value for castration-resistant prostate cancer-free survival (CFS), overall survival (OS), prostate-specific antigen progression-free survival (PSA-PFS) and prostate-specific antigen (PSA) response was assessed using Kaplan-Meier curves, Cox regression models, and chi-square tests. The predictive performance of each immune-inflammatory index was assessed using the area under the curve (AUC) in time-dependent receiver operating characteristic curve (ROC) analysis and C-index calculation. RESULTS: All seven immune-inflammatory indices were significantly associated with CFS and OS in the mHSPC cohort, as well as with PSA response, PSA-PFS, and OS in the mCRPC cohort. In the mHSPC cohort, LIPI consistently exhibited higher AUC values compared to NLR, dNLR, LMR, PLR, SII, and SIRI for predicting CFS and OS. This indicates that LIPI had a superior discriminative ability compared to the other indices (C-index of LIPI: 0.643 and 0.686 for CFS and OS, respectively). Notably, the predictive advantage of LIPI over other indices in the mHSPC stage diminished in the mCRPC stage. CONCLUSIONS: This study firstly confirmed the prognostic value of SII, SIRI and LIPI in mHSPC and mCRPC, and revealed that LIPI had a higher predictive power than NLR, dNLR, LMR, PLR, SII and SIRI in mHSPC. These non-invasive indices can enable clinicians to quickly assess the prognosis of patients.

Impact of proton pump inhibitors on the efficacy of androgen receptor signaling inhibitors in metastatic castration-resistant prostate cancer patients.

BACKGROUND: Proton pump inhibitors (PPIs) are widely used due to their affordability and minimal severe side effects. However, their influence on the efficacy of cancer treatments, particularly androgen receptor signaling inhibitors (ARSIs), remains unclear. This study investigates the impact of PPI usage on the treatment outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: A total of 117 mCRPC patients were retrospectively analyzed and divided into two groups based on the concomitant use of PPI at the initiation of ARSI treatment: PPI+ (n = 38) and PPI- (n = 79). Patient characteristics, including age at ARSI treatment administered, prostate-specific antigen (PSA) value at ARSI treatment administered, International Society of Urological Pathology grade group at prostate biopsy, metastatic site at ARSI treatment administered, prior docetaxel (DTX) treatment, and type of ARSI (abiraterone acetate or enzalutamide) were recorded. Progression-free survival (PFS), overall survival (OS), and PSA response rates were compared between the two groups. Patients were further stratified by clinical background to compare PFS and OS between the two groups. RESULTS: The PPI- group exhibited significantly extended PFS and a trend toward improved OS. For PSA response (reduction of 50% or more from baseline), the rates were 62.3% and 45.9% in the PPI- group and the PPI+ group, respectively. For deep PSA response (reductions of 90% or more from baseline), the rates were 36.4% and 24.3% in the PPI- group and the PPI+ group, respectively. The effects were consistent across subgroups divided by prior DTX treatment and type of ARSI administered. CONCLUSIONS: The administration of PPIs appears to diminish the therapeutic efficacy of ARSIs in mCRPC patients. Further prospective studies are needed to confirm these findings and explore the biological mechanisms involved.

A scoping review on intraoperative and postoperative surgical castration complications in domesticated equids.

BACKGROUND: Castration is the most common surgical procedure in domesticated equids; surgical techniques used and perioperative management vary considerably. OBJECTIVES: To identify and chart the current evidence on perioperative complications associated with different methods of surgical castration in domesticated equids. STUDY DESIGN: Joanna Briggs Institute systematic scoping review. METHOD: CAB Abstracts, Medline and Embase databases were searched using terms related to equine castration complications. Two authors independently and blindly screened publications against eligibility criteria. Data on study methods, perioperative management, surgical techniques, and perioperative complications were extracted. Surgical techniques were grouped into categories depending on technique; open, closed or half-closed, and whether the parietal tunic was open or closed at the end of surgery. RESULTS: The search identified 1871 publications; 71 studies met the final inclusion criteria. The data reported 76 734 castrations, most of which were open or closed, with the vaginal tunic remaining open at the end of surgery. Twenty-five studies reported information regarding surgical techniques and perioperative management, allowing detailed charting and comparisons, of which analgesia and antimicrobial usage varied notably. Eighteen different complications were reported, with swelling or oedema being the most common. Evisceration was most commonly reported in draught breeds and Standardbreds, and the risk appeared low if the parietal tunic was closed at the end of surgery. MAIN LIMITATIONS: Grey literature and studies not available in English were not included. Existing studies varied greatly in perioperative management, surgical techniques and reporting of outcomes, making evidence consolidation problematic. CONCLUSION: A lack of consensus regarding complication definitions creates uncertainty and discrepancies between complication rates associated with different surgical techniques and perioperative management. The implementation of standardised systems for describing surgical techniques and complications is recommended for future studies. A number of studies did not follow current recommendations for perioperative analgesia and use of antimicrobials.

A vitamin D-based strategy overcomes chemoresistance in prostate cancer.

BACKGROUND AND PURPOSE: Castration-resistant prostate cancer (CRPC) is a common male malignancy that requires new therapeutic strategies due to acquired resistance to its first-line treatment, docetaxel. The benefits of vitamin D on prostate cancer (PCa) progression have been previously reported. This study aimed to investigate the effects of vitamin D on chemoresistance in CRPC. EXPERIMENTAL APPROACH: Structure function relationships of potent vitamin D analogues were determined. The combination of the most potent analogue and docetaxel was explored in chemoresistant primary PCa spheroids and in a xenograft mouse model derived from a patient with a chemoresistant CRPC. KEY RESULTS: Here, we show that Xe4MeCF3 is more potent than the natural ligand to induce vitamin D receptor (VDR) transcriptional activities and that it has a larger therapeutic window. Moreover, we demonstrate that VDR agonists restore docetaxel sensitivity in PCa spheroids. Importantly, Xe4MeCF3 reduces tumour growth in a chemoresistant CRPC patient-derived xenograft. In addition, this treatment targets signalling pathways associated with cancer progression in the remaining cells. CONCLUSION AND IMPLICATIONS: Taken together, these results unravel the potency of VDR agonists to overcome chemoresistance in CRPC and open new avenues for the clinical management of PCa.

Gleason Pattern 5 May Be a Prognostic Factor in Radium-223 Treatment.

Background/Aim: Radium-223 treatment reduces the risk of death in patients with metastatic castration-resistant prostate cancer (CRPC). This study analyzed the prognostic factors in patients treated with radium-223 dichloride. Patients and Methods: Patients who received radium-223 dichloride were retrospectively analyzed. Prostate-specific antigen (PSA) response and alkaline phosphatase (ALP) decline rates were analyzed. Overall survival (OS) was evaluated using Kaplan-Meier curves, and prognostic factors for OS were assessed using Cox proportional hazards analysis. Results: Fifty-six patients were included in the study. The five-year OS rate in patients after diagnosis of CRPC was 62.2% [95% confidence interval (CI)=27.55-112.45], while the five-year OS rate in patients at the initiation of radium-223 treatment was 21.3% (95%CI=17.20-36.79). Six patients (11.1%) had a >50% PSA decline rate, and 10 (17.9%) had a >50% ALP decline rate. Cox proportional hazards analysis showed that PSA levels at the initiation of radium-223 treatment [hazard ratio (HR)=1.00; 95%CI=1.00-1.00; p=0.0054] and Gleason Pattern (GP) 5 (HR=5.42; 95%CI=1.08-27.27; p=0.0400) were associated with OS. Patients with GP 5 had a significantly poorer prognosis compared with patients with a GP ≤4. Early administration of radium-223 as a first- or second-line treatment was not associated with OS compared with late administration of radium-223 as a third-line or later treatment. Conclusion: GP 5 and high PSA levels at radium-223 initiation were associated with worse OS. Radium-223 as first- or second-line treatment was not associated with OS. Therefore, a treatment strategy for CRPC based on GP 5 is needed.

Genetically Engineered Membrane-Coated Nanoparticles for Enhanced Prostate-Specific Membrane Antigen Targeting and Ferroptosis Treatment of Castration-Resistant Prostate Cancer.

Conventional androgen deprivation therapy (ADT) targets the androgen receptor (AR) inhibiting prostate cancer (PCa) progression; however, it can eventually lead to recurrence as castration-resistant PCa (CRPC), which has high mortality rates and lacks effective treatment modalities. The study confirms the presence of high glutathione peroxidase 4 (GPX4) expression, a key regulator of ferroptosis (i.e., iron-dependent program cell death) in CRPC cells. Therefore, inducing ferroptosis in CRPC cells might be an effective therapeutic modality for CRPC. However, nonspecific uptake of ferroptosis inducers can result in undesirable cytotoxicity in major organs. Thus, to precisely induce ferroptosis in CRPC cells, a genetic engineering strategy is proposed to embed a prostate-specific membrane antigen (PSMA)-targeting antibody fragment (gy1) in the macrophage membrane, which is then coated onto mesoporous polydopamine (MPDA) nanoparticles to produce a biomimetic nanoplatform. The results indicate that the membrane-coated nanoparticles (MNPs) exhibit high specificity and affinity toward CRPC cells. On further encapsulation with the ferroptosis inducers RSL3 and iron ions, MPDA/Fe/RSL3@M-gy1 demonstrates superior synergistic effects in highly targeted ferroptosis therapy eliciting significant therapeutic efficacy against CRPC tumor growth and bone metastasis without increased cytotoxicity. In conclusion, a new therapeutic strategy is reported for the PSMA-specific, CRPC-targeting platform for ferroptosis induction with increased efficacy and safety.

PiRNA-4447944 promotes castration-resistant growth and metastasis of prostate cancer by inhibiting NEFH expression through forming the piRNA-4447944-PIWIL2-NEFH complex.

Castration-resistant prostate cancer (CRPC) is the leading cause of prostate cancer (PCa)-related death in males, which occurs after the failure of androgen deprivation therapy (ADT). PIWI-interacting RNAs (piRNAs) are crucial regulators in many human cancers, but their expression patterns and roles in CRPC remain unknown. In this study, we performed small RNA sequencing to explore CRPC-associated piRNAs using 10 benign prostate tissues, and 9 paired hormone-sensitive PCa (HSPCa) and CRPC tissues from the same patients. PiRNA-4447944 (piR-4447944) was discovered to be highly expressed in CRPC group compared with HSPCa and benign groups. Functional analyses revealed that piR-4447944 overexpression endowed PCa cells with castration resistance ability in vitro and in vivo, whereas knockdown of piR-4447944 using anti-sense RNA suppressed the proliferation, migration and invasion of CRPC cells. Additionally, enforced piR-4447944 expression promoted in vitro migration and invasion of PCa cells, and reduced cell apoptosis. Mechanistically, piR-4447944 bound to PIWIL2 to form a piR-4447944/PIWIL2 complex and inhibited tumor suppressor NEFH through direct interaction at the post-transcriptional level. Collectively, our study indicates that piR-4447944 is essential for prostate tumor-propagating cells and mediates androgen-independent growth of PCa, which extends current understanding of piRNAs in cancer biology and provides a potential approach for CRPC treatment.

Mechanism of baicalein in treatment of castration-resistant prostate cancer based on network pharmacology and cell experiments.

Objective: Baicalein, one of the most abundant flavonoids found in Chinese herb Scutellaria baicalensis Georgi, exhibits pharmacological activities against various cancers. However, the precise pharmacological mechanism of baicalein in treating castration-resistant prostate cancer (CRPC) remains elusive. This study aimed to elucidate the potential mechanism of baicalein against CRPC through a combination of network pharmacology and experimental approaches, thereby providing new avenues for research in CRPC treatment. Methods: The pharmacological and molecular properties of baicalein were obtained using the TCMSP database. Baicalein-related targets were collected from multiple sources including SwissTargetPrediction, PharmMapper and CTD. Targets related to CRPC were acquired from DisGeNET, GeneCards, and CTD. The protein-protein interaction (PPI) was analyzed using STRING 11.5, and Cytoscape 3.7.2 software was utilized to explore the core targets of baicalein on CRPC. GO and KEGG pathway enrichment analysis were performed using DAVID database. Cell experiments were carried out to confirm the validity of the targets. Results: A total of 131 potential targets of baicalein for the treatment of CRPC were obtained. Among them, TP53, AKT1, ALB, CASP3, and HSP90AA1, etc., were recognized as core targets by Cytoscape 3.7.2. GO function enrichment analysis yielded 926 entries, including 703 biological process (BP) terms, 84 cellular component (CC) terms and 139 molecular function (MF) terms. The KEGG pathway enrichment analysis unveiled 159 signaling pathways, mainly involved in Pathways in cancer, prostate cancer, AGE-RAGE signaling pathway in diabetic complications, TP53 signaling pathway, and PI3K-Akt signaling pathway, etc. Cell experiments confirmed that baicalein may inhibit the proliferation of CRPC cells and induce cell cycle arrest in the G1 phase. This effect could be associated with the TP53/CDK2/cyclin E1 pathway. In addition, the results of CETSA suggest that baicalein may directly bind to TP53. Conclusion: Based on network pharmacology analysis and cell experiments, we have predicted and validated the potential targets and related pathways of baicalein for CRPC treatment. This comprehensive approach provides a scientific basis for elucidating the molecular mechanism underlying the action of baicalein in CRPC treatment. Furthermore, these findings offer valuable insights and serve as a reference for the research and development of novel anti-CRPC drugs.

Synthesis of curcumin derivatives targeting androgen receptor for castration-resistant prostate cancer therapy.

In this work, a series of curcumin derivatives (1a-1h, 2a-2g, and 3a-3c) were synthesized for the suppression of castration-resistant prostate cancer cells. All synthesized compounds were characterized by 1H NMR, 13C NMR, HRMS, and melting point. The in vitro cytotoxicity study shows that compounds 1a, 1e, 1f, 1h, 2g, 3a, and 3c display similar or enhanced cytotoxicity against 22Rv1 and C4-2 cells as compared to ASC-J9, other synthesized compounds display reduced cytotoxicity against 22Rv1 and C4-2 cells as compared to ASC-J9. Molecular docking simulation was performed to study the binding affinity and probable binding modes of the synthesized compounds with androgen receptor. The results show that all synthesized compounds exhibit higher cdocker interaction energies as compared to ASC-J9. Compounds 1h, 2g, and 3c not only show strong cytotoxicity against 22Rv1 and C4-2 cells but also exhibit high binding affinity with androgen receptor. In androgen receptor suppression study, compounds 1f and 2g show similar androgen receptor suppression effect as compared to ASC-J9 on C4-2 cells, compound 3c displays significantly enhanced AR suppression effect as compared to ASC-J9, 1f and 2g. Compounds 1a, 1e, 1f, 1h, 2g, 3a and 3c prepared in this work have significant potential for castration-resistant prostate cancer therapy.

Feasibility of Indirect Treatment Comparisons Between Niraparib Plus Abiraterone Acetate and Other First-Line Poly ADP-Ribose Polymerase Inhibitor Treatment Regimens for Patients with BRCA1/2 Mutation-Positive Metastatic Castration-Resistant Prostate Cancer.

INTRODUCTION: Poly(ADP-ribose) polymerase inhibitors (PARPi) are a novel option to treat patients with metastatic castration-resistant prostate cancer (mCRPC). Niraparib plus abiraterone acetate and prednisone (AAP) is indicated for BRCA1/2 mutation-positive mCRPC. Niraparib plus AAP demonstrated safety and efficacy in the phase 3 MAGNITUDE trial (NCT03748641). In the absence of head-to-head studies comparing PARPi regimens, the feasibility of conducting indirect treatment comparisons (ITC) to inform decisions for patients with first-line BRCA1/2 mutation-positive mCRPC has been explored. METHODS: A systematic literature review was conducted to identify evidence from randomized controlled trials on relevant comparators to inform the feasibility of conducting ITCs via network meta-analysis (NMA) or population-adjusted indirect comparisons (PAIC). Feasibility was assessed based on network connectivity, data availability in the BRCA1/2 mutation-positive population, and degree of within- and between-study heterogeneity or bias. RESULTS: NMAs between niraparib plus AAP and other PARPi regimens (olaparib monotherapy, olaparib plus AAP, and talazoparib plus enzalutamide) were inappropriate due to the disconnected network, differences in trial populations related to effect modifiers, or imbalances within BRCA1/2 mutation-positive subgroups. The latter issue, coupled with the lack of a common comparator (except for olaparib plus AAP), also rendered anchored PAICs infeasible. Unanchored PAICs were either inappropriate due to lack of population overlap (vs. olaparib monotherapy) or were restricted by unmeasured confounders and small sample size (vs. olaparib plus AAP). PAIC versus talazoparib plus enzalutamide was not possible due to lack of published arm-level baseline characteristics and sufficient efficacy outcome data in the relevant population. CONCLUSION: The current randomized controlled trial evidence network does not permit robust comparisons between niraparib plus AAP and other PARPi regimens for patients with 1L BRCA-positive mCRPC. Decision-makers should scrutinize any ITC results in light of their limitations. Real-world evidence combined with clinical experience should inform treatment recommendations in this indication.

The correlation between TRIM28 expression and immune checkpoints in CRPC.

This study delves into the unexplored realm of castration-resistant prostate cancer (CRPC) by investigating the role of TRIM28 and its intricate molecular mechanisms using high-throughput single-cell transcriptome sequencing and advanced bioinformatics analysis. Our comprehensive examination unveiled dynamic TRIM28 expression changes, particularly in immune cells such as macrophages and CD8+ T cells within CRPC. Correlation analyses with TCGA data highlighted the connection between TRIM28 and immune checkpoint expression and emphasized its pivotal influence on the quantity and functionality of immune cells. Using TRIM28 knockout mouse models, we identified differentially expressed genes and enriched pathways, unraveling the potential regulatory involvement of TRIM28 in the cGAS-STING pathway. In vitro, experiments further illuminated that TRIM28 knockout in prostate cancer cells induced a notable anti-tumor immune effect by inhibiting M2 macrophage polarization and enhancing CD8+ T cell activity. This impactful discovery was validated in an in situ transplant tumor model, where TRIM28 knockout exhibited a deceleration in tumor growth, reduced proportions of M2 macrophages, and enhanced infiltration of CD8+ T cells. In summary, this study elucidates the hitherto unknown anti-tumor immune role of TRIM28 in CRPC and unravels its potential regulatory mechanism via the cGAS-STING signaling pathway. These findings provide novel insights into the immune landscape of CRPC, offering promising directions for developing innovative therapeutic strategies.

Comparison of oncological outcomes of upfront androgen receptor signaling inhibitors and combined androgen blockade in Japanese patients with metastatic castration-sensitive prostate cancer.

In recent years, randomized controlled trials have demonstrated that upfront androgen receptor signaling inhibitors (ARSIs) prolong overall survival (OS) compared with androgen deprivation therapy (ADT) alone or combined androgen blockade (CAB) in patients with metastatic castration-sensitive prostate cancer (mCSPC). However, it remains unclear whether upfront ARSI is superior to CAB in Asian populations, among which the efficacy of ADT/CAB is considered relatively high. In this study, we compared the oncological outcomes of upfront ARSI and CAB in Japanese patients with mCSPC. Patients with mCSPC who underwent systemic therapy between May 2009 and October 2023 were enrolled retrospectively. Propensity score matching (PSM) was performed to compare the castration-resistant prostate cancer-free survival (CRPC-FS), cancer-specific survival (CSS), and OS between patients treated with upfront ARSI (ARSI group) and those treated with CAB (CAB group). In total, 30 and 142 patients were enrolled in the ARSI and CAB groups, respectively. After PSM (25 patients in each group), CRPC-FS was significantly longer in the ARSI group than in the CAB group (median: 36.7 vs. 12.3 months, hazard ratio: 0.44, 95% confidence interval: 0.20-0.97, p = 0.035). No significant differences were observed in CSS or OS between the two groups. In conclusion, when compared to CAB, upfront ARSI might have the potential to extend CRPC-FS among individuals in the Japanese population.

Perineural Invasion as a Risk Factor For Soft Tissue Progression in Patients With Metastatic Castration-Resistant Prostate Cancer After Abiraterone Resistance.

BACKGROUND: Prostate cancer presents with soft tissue progression (STP) is highly aggressive. We analyzed the risk factor for STP in patients with metastatic castration-resistant prostate cancer (mCRPC) who developed abiraterone acetate (AA) resistance. METHODS: This retrospective study included patients with mCRPC who received AA between February 2018 and July 2022. STP was defined as recurrent lesions in situ, multiple regional lymph node metastases (mLNM), or visceral metastases. Clinical features of patients with STP were analyzed, and risk factors for STP were further investigated. RESULTS: Sixty-three patients (mean age, 75.0 years; median follow-up time, 22.3 months) were included in this study. Twenty-three patients (36.5%) presented STP during follow up, the overall survival (OS) after STP was 4.6 months. The serum neuron-specific enolase (NSE) were significantly elevated in patients with STP. Biopsies for 8 patients with STP showed neuroendocrine prostate cancer (NEPC, n = 5) was the major pathological types. Further analysis showed that perineural invasion (PNI) in primary tumor were the independent risk factors (HR = 3.145, P = 0.020) for STP, and PNI was related to the aggressiveness of tumor. Patients with PNI showed shorter castration-resistant progression free survival (median, 23.73 months vs. 25.59 months) and STP progression free survival (median, 19.7 months vs. not reached) compared with patients without PNI. CONCLUSIONS: STP showed extremely poor prognoses in patients with mCRPC after AA resistance, NEPC is the main pathological type of STP, and PNI in primary tumor was an independent risk factor for STP and indicated poor prognosis of prostate cancer.

A Real World Observational Study Characterizing Patients With Advanced Prostate Cancer Treated With or Without Androgen Receptor-Pathway-Inhibitor Therapies in Alberta, Canada.

BACKGROUND: Data are needed to improve the current understanding of clinical management and characteristics of patients with advanced prostate cancer (PC) treated with androgen receptor pathway inhibition (ARPI) therapy. METHODS: This retrospective cohort study using real-world, population-level data from Alberta, Canada included all individuals diagnosed in 2017-2020 with de novo metastatic castration-sensitive PC (mCSPC) or nonmetastatic castration-resistant PC (nmCRPC) who initiated androgen deprivation therapy (ADT). For mCSPC, patients were classified as ARPI-exposed if they received an ARPI within 180 days of initiating ADT, while patients with nmCRPC were classified as ARPI-exposed if they received an ARPI within 2 years of diagnosis. RESULTS: This study included 976 patients with mCSPC and 233 with nmCRPC of which 33.5% and 25.3% received an ARPI, respectively. The proportion of patients with mCSPC treated with an ARPI increased considerably for patients diagnosed in 2020 compared to 2017 (56.2% vs. 6.0%). In contrast, the use of ARPI to treat nmCRPC only increased marginally from 2017 to 2019/2020 (19.7% vs. 28.9%). Patients with mHSPC who were ARPI-exposed had longer median survival than patients who were ARPI-naive (38.47 (95% CI = 32.84-NA) vs. 34.19 (95% CI = 33.33-38.83; P = .03)), with a higher proportion of patients surviving to 2-years. For nmCRPC, survival was similar between ARPI-exposed and ARPI-naive. In multivariable analyses, receiving ARPI for mCSPC was associated with younger patient age, more recent diagnoses, fewer comorbidities, a higher number of metastatic sites, referral to a medical oncologist as well as receiving surgery and radiation before ADT. Receiving ARPI for nmCRPC was associated with referral to a medical oncologist, younger age, and more recent diagnoses. CONCLUSIONS: Outcome analyses in this population suggest a continued unmet clinical need and complex clinical management pathways. Given that treatment pathways have evolved considerably, continued follow-up to understand the impact of these advancements on patient outcomes are warranted.

Increased circulating polymorphonuclear myeloid-derived suppressor cells are associated with prognosis of metastatic castration-resistant prostate cancer.

Introduction: Myeloid-derived suppressor cell (MDSC) exhibits immunosuppressive functions and affects cancer progression, but its relationship with prostate cancer remains unclear. We elucidated the association of polymorphonuclear MDSC (PMN-MDSC) and monocytic MDSC (M-MDSC) levels of the total peripheral blood mononuclear cells (PBMCs) with prostate cancer progression and evaluated their roles as prognostic indicators. Methods: We enrolled 115 patients with non-metastatic hormone-sensitive prostate cancer (nmHSPC, n = 62), metastatic hormone-sensitive prostate cancer (mHSPC, n = 23), and metastatic castration-resistant prostate cancer (mCRPC, n = 30). Subsequently, the proportions of MDSCs in each disease progression were compared. Log-rank tests and multivariate Cox regression analyses were performed to ascertain the associations of overall survival. Results: The patients with mCRPC had significantly higher PMN-MDSC percentage than those with nmHSPC and mHSPC (P = 7.73 × 10-5 and 0.0014). Significantly elevated M-MDSC levels were observed in mCRPC patients aged <70 years (P = 0.016) and with a body mass index (BMI) <25 kg/m2 (P = 0.043). The high PMN-MDSC group had notably shorter median survival duration (159 days) than the low PMN-MDSC group (768 days, log-rank P = 0.018). In the multivariate analysis including age, BMI, and MDSC subset, PMN-MDSC was significantly associated with prognosis (hazard ratios, 3.48; 95% confidence interval: 1.05-11.56, P = 0.042). Discussion: PMN-MDSC levels are significantly associated with mCRPC prognosis. Additionally, we highlight the remarkable associations of age and BMI with M-MDSC levels in mCRPC, offering novel insights into MDSC dynamics in prostate cancer progression.

Physician preferences for nonmetastatic castration-resistant prostate cancer treatment in China.

Introduction: The treatment preferences of Chinese physicians who treat nonmetastatic castration-resistant prostate cancer (nmCRPC) and how they weigh the benefits and risks of nmCRPC treatment are still unknown. This study aimed to evaluate Chinese physicians' benefit-risk treatment preferences for nmCRPC and assist in setting nmCRPC treatment goals. Methods: A paper-based discrete choice experiment (DCE) survey was administered to 80 nmCRPC-treating physicians. DCE responses were analyzed to produce the preference weight and the relative importance score for each attribute level. The marginal rate of substitution (MRS) was used to quantify the amount of overall survival (OS) physicians were willing to trade for a reduction in treatment-related adverse events (AEs). We further conducted the exploratory analysis, stratifying physicians from 5 perspectives into different subgroups and examining the treatment preferences and OS trade-off in each subgroup. Results: In terms of efficacy attributes, physicians placed greater emphasis on OS than time to pain progression. With regard to safety attributes, serious fracture was perceived as the most important AE by physicians, followed by serious fall, cognitive problems, skin rash, and fatigue. In the exploratory analysis, we found generally that physicians with less clinical practice experience and those from more economically developed regions placed more emphasis on AEs and were willing to give up more of their patients' OS to reduce the risk of AEs. Conclusion: Physicians from mainland China value the importance of minimizing treatment-related AEs when considering different treatment options for patients with nmCRPC, and they are willing to trade a substantial amount of OS to avoid AEs.

Development and Validation of a Clinic Machine Learning Classifier for the Prediction of Risk Stratifications of Prostate Cancer Bone Metastasis Progression to Castration Resistance.

Objective: To explore the predictive factors and predictive model construction for the progression of prostate cancer bone metastasis to castration resistance. Methods: Clinical data of 286 patients diagnosed with prostate cancer with bone metastasis, initially treated with endocrine therapy, and progressing to metastatic castration resistant prostate cancer (mCRPC) were collected. By comparing the differences in various factors between different groups with fast and slow occurrence of castration-resistant prostate cancer (CRPC). Kaplan-Meier survival analysis and COX multivariate risk proportional regression model were used to compare the differences in the time to progression to CRPC in different groups. The COX multivariate risk proportional regression model was used to evaluate the impact of candidate factors on the time to progression to CRPC and establish a predictive model. The accuracy of the model was then tested using receiver operating characteristic (ROC) curves and decision curve analysis (DCA). Results: The median time for 286 mCRPC patients to progress to CRPC was 17 (9.5-28.0) months. Multivariate analysis showed that the lowest value of PSA (PSA nadir), the time when PSA dropped to its lowest value (timePSA), and the number of BM, and LDH were independent risk factors for rapid progression to CRPC. Based on the four independent risk factors mentioned above, a prediction model was established, with the optimal prediction model being a random forest with area under curve (AUC) of 0.946[95% CI: 0.901-0.991] and 0.927[95% CI: 0.864-0.990] in the training and validation cohort, respectively. Conclusion: After endocrine therapy, the PSA nadir, timePSA, the number of BM, and LDH are the main risk factors for rapid progression to mCRPC in patients with prostate cancer bone metastases. Establishing a CRPC prediction model is helpful for early clinical intervention decision-making.

Androgen deprivation-induced senescence confers sensitivity to a senolytic strategy in prostate cancer.

We have previously demonstrated that androgen-dependent prostate cancer (PCa) cell lines enter a state of senescence following exposure to androgen deprivation therapies (ADT). ADT-induced senescence was found to be transient, as senescent cells develop castration resistance and re-emerge into a proliferative state even under continuous androgen deprivation in vitro. Moreover, the BCL-XL/BCL-2 inhibitor, ABT-263 (navitoclax), an established senolytic agent, promoted apoptosis of senescent PCa cells, suppressing proliferative recovery and subsequent tumor cell outgrowth. As this strategy has not previously been validated in vivo, we used a clinically relevant, syngeneic murine model of PCa, where mice were either castrated or castrated followed by the administration of ABT-263. Our results largely confirm the outcomes previously reported in vitro; specifically, castration alone results in a transient tumor growth suppression with characteristics of senescence, which is prolonged by exposure to ABT-263. Most critically, mice that underwent castration followed by ABT-263 experienced a statistically significant prolongation in survival, with an increase of 14.5 days in median survival time (56 days castration alone vs. 70.5 days castration + ABT-263). However, as is often the case in studies combining the promotion of senescence with a senolytic (the "one-two" punch approach), the suppression of tumor growth by the inclusion of the senolytic agent was transient, allowing for tumor regrowth once the drug treatment was terminated. Nevertheless, the results of this work suggest that the "one-two" punch senolytic strategy in PCa may effectively interfere with, diminish, or delay the development of the lethal castration-resistant phenotype.

Genomic Determinants Associated with Modes of Progression and Patterns of Failure in Metachronous Oligometastatic Castration-sensitive Prostate Cancer.

BACKGROUND AND OBJECTIVE: Oligometastatic castration-sensitive prostate cancer (omCSPC) represents an early state in the progression of metastatic disease for which patients experience better outcomes in comparison to those with higher disease burden. Despite the generally more indolent nature, there is still much heterogeneity, with some patients experiencing a more aggressive clinical course unexplained by clinical features alone. Our aim was to investigate correlation of tumor genomics with the mode of progression (MOP) and pattern of failure (POF) following first treatment (metastasis-directed and/or systemic therapy) for omCSPC. METHODS: We performed an international multi-institutional retrospective study of men treated for metachronous omCSPC who underwent tumor next-generation sequencing with at least 1 yr of follow-up after their first treatment. Descriptive MOP and POF results are reported with respect to the presence of genomic alterations in pathways of interest. MOP was defined as class I, long-term control (LTC; no radiographic progression at last follow-up), class II, oligoprogression (1-3 lesions), or class III, polyprogression (≥4 lesions). POF included the location of lesions at first failure. Genomic pathways of interest included TP53, ATM, RB1, BRCA1/2, SPOP, and WNT (APC, CTNNB1, RNF43). Genomic associations with MOP/POF were compared using χ2 tests. Exploratory analyses revealed that the COSMIC mutational signature and differential gene expression were also correlated with MOP/POF. Overall survival (OS) was calculated via the Kaplan-Meier method from the time of first failure. KEY FINDINGS AND CLINICAL IMPLICATIONS: We included 267 patients in our analysis; the majority had either one (47%) or two (30%) metastatic lesions at oligometastasis. The 3-yr OS rate was significantly associated with MOP (71% for polyprogression vs 91% for oligoprogression; p = 0.005). TP53 mutation was associated with a significantly lower LTC rate (27.6% vs 42.3%; p = 0.04) and RB1 mutation was associated with a high rate of polyprogression (50% vs 19.9%; p = 0.022). Regarding POF, bone failure was significantly more common with tumors harboring TP53 mutations (44.8% vs25.9%; p = 0.005) and less common with SPOP mutations (7.1% vs 31.4%; p = 0.007). Visceral failure was more common with tumors harboring either WNT pathway mutations (17.2% vs 6.8%, p = 0.05) or SPOP mutations (17.9% vs 6.3%; p = 0.04). Finally, visceral and bone failures were associated with distinct gene-expression profiles. CONCLUSIONS AND CLINICAL IMPLICATIONS: Tumor genomics provides novel insight into MOP and POF following treatment for metachronous omCSPC. Patients with TP53 and RB1 mutations have a higher likelihood of progression, and TP53, SPOP, and WNT pathway mutations may have a role in metastatic organotropism. PATIENT SUMMARY: We evaluated cancer progression after a first treatment for metastatic prostate cancer with up to five metastases. We found that mutations in certain genes were associated with the location and extent of further metastasis in these patients.