Browse Articles

Digital physiological monitoring for personalized prediction of physical function and fatigue in men with castration sensitive prostate cancer.

124 Background: Androgen deprivation therapy (ADT) associated fatigue and functional impairment presents challenges to patient quality of life (QOL) and treatment adherence. Clinical features and biomarkers predictive of ADT-associated side effects remain elusive. Objective measures of physical function may have the potential to prognosticate side effects for men with prostate cancer, in particular fatigue. Methods: Men with castration sensitive prostate cancer (CSPC), initiating ADT as monotherapy or in combination with an androgen receptor signaling inhibitor (ARSI), enrolled in this prospective observational study. Patients underwent continuous mobility monitoring for 12 months after ADT initiation. Step count, heart rate and sleep were measured via smartwatch. Fatigue severity and QOL were assessed monthly using the FACIT-Fatigue and FACT-P surveys, respectively. Descriptive statistics and linear mixed modeling were used for analysis. Results: 19 CSPC patients were analyzed: mean age 65.7 years (SD 7.7), 78.9% high risk localized/oligometastatic, 94.7% receiving ADT+radiation with or without an ARSI. Total weekly compliance was 91.6% (SD 5.5%). Average daily baseline step-count was 3,570 (SD 1,881) and declined by 23.9% at 12-months. A statistically weak inverse correlation between step count and fatigue severity was observed (R2=0.075). This prompted further exploratory analysis of individual step count as a predictive measure of physical function. To control for high inter-subject variability, a linear mixed model was used. Individual baseline steps were modeled as a random variable with a mean of 2,782 (SD 1,814; CI [1130.15, 4435.07]; p=0.001). Time on ADT, radiation status, HR and sleep duration were included in this model. Mean daily step count was predicted to decrease by 6.22 steps/week (CI [-10.75, -1.68]; p<.001). Weekly radiation was associated with an average decrease of 275.91 steps (CI [-498.18, -53.32]; p=0.015). Daily and nightly HR was associated with a mean linear increase of 110.98 steps/BPM (CI [88.12, 134.08]; p<0.001) and 100.20 steps/BPM (CI [-122.07, -78.47]; p<0.001), respectively. 1 hour of measured sleep was associated with a decrease of 183.69 steps (CI [-261.98, -104.34]; p<0.001). Overall correlation between actual and predicted step count was 0.88 (R2=0.78). Conclusions: Digital activity monitoring is feasible for men with CSPC on ADT. A weak negative correlation was found between FACIT fatigue severity and average daily step count, while our individualized model accurately predicted daily step count at any point during a 1 year ADT period. While further validation with larger sample sizes is needed, personalized activity predictions may have application in the identification of patients at risk for severe functional impairment, demonstrating value in routine clinical care and clinical trials. Clinical trial information: NCT05390827 .

Identifying engagement strategies for Hispanic youth with anxiety: A youth-centered, Design-Thinking approach

Anxiety is the most common and widespread mental health disorder impacting youth between the ages of 10–19. Youth of color including Hispanic youth are disproportionately impacted. Fewer than 20% of youth of color who need mental health services are receiving them. However, we know relatively little about how to best engage Hispanic youth to increase their use of mental health services. The aims of this study were to better understand the personal, environmental, and behavioral factors that impact Hispanic adolescents help-seeking behaviors and to identify the important criteria needed to develop an appealing intervention that would increase engagement with mental health services. This study used a Design Thinking process—a participatory research approach that included qualitative and engaged methods. In-depth interviews (n = 8) and a Design Thinking workshop (n = 11 participants) were conducted with Hispanic youth with anxiety residing in the San Francisco Bay Area. In-depth interviews were coded using Social Cognitive Theory to identify key themes that impact an adolescent’s decision to seek help. The 90-minute workshop included ideation and Design Thinking activities including personas, mind-mapping, and analytical problem-solving to identify the most important tools and strategies that could be used to manage anxiety. The study identified several themes that directly impact program design, including barriers to seeking help for anxiety, coping strategies, sources of support, and specific program ideas. The findings revealed that Hispanic youth want a culturally relevant technology-based program that provides easily accessible educational information and coping strategies delivered in an engaging format that also facilitates mental health support with a trusted adult. The results reinforce the need to develop culturally inclusive and innovative programs designed specifically for priority populations to increase youth engagement with mental health services.

Culture of cryopreserved first trimester placental tissues to study syncytial renewal

Phase 1 dose escalation (DEs) & expansion (DEx) study to evaluate the safety & efficacy of IDE397 plus sacituzumab-govitecan in patients with advanced urothelial carcinoma (UC) with MTAP deletion (MTAPdel).

Long follow-up quality of life outcomes from an investigator-initiated randomized trial of enzalutamide versus abiraterone plus prednisolone in docetaxel-untreated castration-resistant prostate cancer.

52 Background: Head-to-head comparison between enzalutamide (ENZ) and abiraterone plus prednisolone (ABI) demonstrated similar survival benefit for castration-resistant prostate cancer. We analyzed quality of life (QOL) reported over time in each treatment arm as sub-analysis study. Methods: ENABLE study for PCa, an investigator-initiated, multicenter, phase 3 randomized controlled trial, was conducted. FACT-G QOL questionnaires were reported by patients at timepoints. We analyzed questionnaires up to 48 months, including the detailed assessment of subscales which consist of physical, social, emotional, and functional well-being. Results: In total 92 patients in each arm included, 79 and 77 in the ENZ and ABI arm answered questionnaires up to 24 months. There were no significant differences in overall survival and time to PSA progression between arms (P=0.4365 and P=0.2458). Although ENZ did not change the total score of FACT-G during treatment (P=0.8552), ABI significantly deteriorated it gradually (P=0.0002). In ABI arm, the standard dose (1000 mg/day) significantly deteriorated the total score of FACT-G chronologically (n=57, P=0.0002), meanwhile the modified dose (750 mg/day or less) did not change it during treatment (n=15, P=0.1816). In the subscale analysis, ENZ did not deteriorate any subscales, whereas ABI deteriorated social and functional well-beings (P=0.0149 and P=0.0005, respectively). Further dissection of subscale analysis revealed that the modified dose of ABI did not deteriorate social and functional well-beings (P=0.277 and P=0.4026, respectively) but the standard dose of ABI significantly deteriorated them (P=0.0010 and P<0.0001, respectively). Conclusions: A head-to-head comparison of QOL between ENZ- and ABI-treated castration-resistant prostate cancer patients was performed for the first time. ABI deteriorated QOL chronologically and the standard dose of ABI was a main cause of the deterioration in QOL. The modified dose of ABI may be a better treatment option. Clinical trial information: UMIN000015529 .

Association of clinical characterization of renal cell carcinoma (RCC) with merlin protein deficiency and biallelic loss of <i>NF2</i> .

506 Background: Neurofibromin-2 (NF2) is a tumor suppressor gene that encodes the scaffolding protein merlin and is commonly mutated in rare RCC subtypes: unclassified (uRCC), papillary (pRCC), collecting duct carcinoma (CDCA), and the emerging entity, biphasic hyalinizing psammomatous (BHP-RCC). Merlin loss/deficiency by immunohistochemistry (IHC) was recently demonstrated as a reliable surrogate marker of NF2 genomic alterations (GAs). We report the first clinical outcomes of RCC patients (pts) with merlin-deficiency/biallelic loss of NF2, treated with immune checkpoint inhibitor (ICI) and vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKI) therapies. Methods: In our single institutional cohort, we identified 27 pts with high-grade morphology suggestive of BHP-RCC or unclear subtype. All pts had merlin deficiency (by IHC) and 12/16 pts with genomic data were found to have also had biallelic NF2 loss (by next-generation sequencing). Overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were evaluated. Survival curves were generated using the Kaplan-Meier method. Results: In the overall cohort (N=27), histologic subtypes included pts with BHP-RCC (N=19), uRCC (N=6), pRCC (N=1), and CDCA (N=1). The median age at diagnosis was 56 and 74.1% (N=20) had metastatic disease. Seventeen pts received systemic treatment and 76.5% (N=13) were treated with ICI-based regimens (Table). In metastatic cohort, median PFS and OS were 4.9 and 24.5 months, respectively. ORR was 28.6% in metastatic pts treated with systemic treatment, with the rate of 18.2% and 66.7% (p=0.18) in those treated with ICI and non-ICI, respectively. Pts treated with ICI and non-ICI had also similar OS (p=0.44), and PFS (p=0.14). In pts with “classic” BPH-RCC morphology who received systemic treatment (N=10), ORR was 25% and median PFS was 4.9 months, while OS did not reach median. In metastatic other merlin-deficient subtypes who received systemic treatment (N=7), ORR was 33.3%, and median PFS and OS were 6.6 and 24.5 months, respectively. No statistically significant differences in ORR (p=1.00), PFS (p=0.93) or OS (p=0.60) were observed between BHP-RCC and other merlin-deficient subtypes. Conclusions: Merlin protein loss by IHC has emerged as a surrogate for biallelic NF2 GAs, which are associated with rare and aggressive RCC subtypes including BHP-RCC. Despite exposure to standard ICI and VEGFR TKI therapies, few pts with merlin deficient RCC derived clinical benefit and prognosis remains poor. Systemic treatment for metastatic disease (n=17). ICINivolumab+IpilimumabNivolumab+Ipilimumab+CabozantinibNivolumab+CabozantinibPembrolizumab+AxitinibAtezolizumab+BevacizumabAtezolizumabNon-ICICabozantinibEverolimusChemotherapy 13 (76.5) 6 (35.2)3 (17.6)1 (5.8)1 (5.8)1 (5.8)1 (5.8) 4 (23.5) 2 (11.7)1 (5.8)1 (5.8)

The systematic techno-stylistic and chemical study of glass beads from post-15th century West African sites

The systematic chemical analysis of large collections of archaeological glass beads is essential to better understand trade patterns at different times around the world. Glass beads’ trade towards and within sub-Saharan West Africa grew exponentially over time to culminate with the establishment of the Atlantic Trade. Although these artefacts are very commonly found in archaeological contexts dating after the 15th century CE, the assemblages are generally poorly studied from a chemical point of view. We present here the study of 916 glass beads found in five archaeological sites in Ghana, Mali, and Senegal, in contexts dated between the 15th and the mid-20th century CE. Besides the techno-stylistic classification of the whole assemblage, the compositional study of a sub-group of 578 monochrome and polychrome glass beads was performed. The 798 glass samples composing the selected beads were therefore classified based on their main chemical composition. Moreover, major, minor, and trace elements analysis by Laser Ablation-Inductively Coupled Plasma-Mass Spectrometry (LA-ICP-MS) and the statistical analysis of the results by Principal Component Analysis (PCA) led to the identification of the probable origin of the glass. Different suppliers were distinguished for the Ghanaian earlier beads and the Senegalese and Malian later ones, in relation to the different European trade partners at different times.

Investigation on morphological and molecular fingerprints of penguin brain using label-free optical imaging and spectroscopic techniques

Abstract The morphology and molecular study of the penguin brain are crucial to define its survival in the extreme conditions of Antarctica. The present study focusses on extracting different optical parameters of the penguin brain using label-free optical imaging and spectroscopic techniques. In label-free optical imaging, we have used quantitative phase imaging, which provides morphological information about the neurons in brain tissue, giving the quantitative phase value of 5 to 20 radians corresponding to the 8 µm tissue section. In label-free spectroscopic techniques, we have used autofluorescence and Raman spectroscopy. Autofluorescence spectroscopy provides molecular information about nicotinamide dinucleotide, flavins, lipofuscins, and porphyrins in the brain’s spectral range of 420 nm to 700 nm. Raman spectroscopy provides multiple peaks associated with different molecules in the brain; among them, few signals are observed at approximately 1305 cm−1, 1448 cm−1, and 1661 cm−1, which correspond to vibrational modes indicative of vibrational features within lipids and protein structures, as well as the presence of amide groups within brain tissue constituents. All these techniques provide the microscopic and molecular fingerprint of the penguin brain, which can be useful for understanding penguin’s anatomical, physiological, and social behavior.

Decipher risk stratification of radiorecurrent prostate cancer: Correlative analysis of the F-SHARP trial of salvage reirradiation.

419 Background: A third of patients with biochemical recurrence after radiation (RT) have intraprostatic radiorecurrence (IPR) on PSMA PET/CT. Patients with IPR have worse metastasis-free survival - a surrogate for progression to lethal prostate cancer (PCa). We previously reported the results from our F-SHARP clinical trial that demonstrated salvage reirradiation using focal dose-escalated high dose rate (HDR) brachytherapy is safe and effective. Here, we examine the Decipher score to determine if it could be a tool to risk stratify patients with IPR. Methods: F-SHARP (NCT03312972) is a multi-institutional phase I/II trial of focal dose-escalated salvage HDR for IPR. Patients were recruited from 2017-2023 at 3 centers. Eligibility criteria included a history of localized PCa treated with any form of definitive RT and biopsy-proven IPR with no regional or distant metastasis. Of the 62 participants, 37 consented for the biomarker correlative study and 31 (50%) had sample data passing quality control for Decipher analysis (Veracyte, San Diego, CA). De-identified data from 146,940 patients tested (2016-2024) with the Decipher prostate genomic classifier were retrieved from the GRID registry (NCT02609269) and used to create a matched cohort based on NCCN risk at diagnosis. Univariable Cox proportional hazards models were used to compare oncologic, CTCAE v4.03 toxicity, and EPIC-26 hrQoL events by Decipher risk group. Results: The biomarker cohort had similar baseline characteristics to the overall trial cohort. 30% received ADT with initial RT (73% external beam, 27% LDR brachytherapy). At recurrence, 71% had high Decipher risk (median score 0.67) as compared to only 35% (median score 0.48) in the matched GRID cases (n=130,760). Median time from initial RT to enrollment in Decipher low (&lt;0.45) was 16.9 years, compared to 8.0 and 7.4 years in the intermediate (0.45-0.6) and high (&gt;0.6) score patients. Median follow up was 32.3 months. Decipher score was not associated with toxicity or quality of life post-HDR (all p&gt;0.05). As depicted in the table, higher Decipher score was associated with an increased risk of biochemical progression-free survival (bFS; p=0.03), local recurrence-free survival (LRFS; p=0.04), and radiographic progression-free survival (rPFS; p=0.01). At 3 years, bPFS was 43% vs. 75%, LRFS was 58% vs. 100%, and rPFS was 42% vs. 100% for Decipher high vs. lower risk (&lt;0.6). Conclusions: Salvage reirradiation is a growing indication for RT in PCa. This is the first use of genomic risk stratification in this setting. Nearly a third of patients with IPR have a lower Decipher risk score, and our data suggest especially favorable outcomes with salvage HDR. Future studies to determine how Decipher risk stratification can be used to tailor further treatment intensification with systemic therapy for those most at risk of reirradiation failure are warranted. Clinical trial information: NCT03312972 . Endpoint Hazard Ratio per 0.1 unit (95% CI) bPFS 1.70 (1.05-2.75) LRFS 2.30 (1.02-5.18) rPFS 2.47 (1.23-4.97)

Incidence of EMBARK and EAU high-risk biochemical recurrence and prostate cancer mortality: A real-life population-based study.

372 Background: The EMBARK trial proved the efficacy of enzalutamide plus leuprolide in patients with prostate cancer (PCa) who have had high-risk biochemical recurrence (BCR). Different criteria are currently used to define high-risk BCR. The aim of this study was to evaluate the incidence of several definitions of High-risk BCR after radical prostatectomy (RP) or radiotherapy (RT) and their association with PCa specific mortality (PCSM). Methods: Population-based study including 17,753 men undergoing RP (n=12,010) or RT (n=5743) with curative intent (cT1-3, cM0) and PSA follow-up in Stockholm between 2003 and 2021. Follow-up for all patients was until death, emigration, or end of the study period (December 31, 2021). Primary outcomes were the cumulative incidence of any BCR (RP: PSA≥ 0.2; RT: PSA≥ nadir+2) and high-risk BCR (according to EAU and Embark criteria) estimated using the Kaplan Mayer method and PCSM accounting for competing risk. Results: The 10-year cumulative incidences of any BCR, EAU, and Embark high-risk BCR were 25% (95% CI 24, 26), 10% (9, 11), 4% (3, 4) after RP and 20% (19, 22), 10% (9, 11) and 10% (9, 11) after RT. Median time from RP to high-risk BCR was 12.6 (5.8, 25.7) months for EAU criteria and 11.8 (5.1, 22.3) months for Embark criteria. Similarly median time from RT to high-risk BCR was 21.2 (11.3, 45.9) months for EAU criteria and 23.4 (14.3, 38.3) months for Embark criteria.After RP, the 10-year Cumulative incidences of PCSM were 11% (95% CI: 9, 13), 17% (14, 21) and 30% (24, 37) for any BCR, EAU and Embark high-risk BCR, respectively. After RT, the 10-year PCSM cumulative incidences were 39% (35, 44), 50% (45, 56) and 49% (42, 55), respectively. Conclusions: Incidence of High-Risk BCR vary according to the definition used and primary treatment. High risk BCR usually happen early after treatment and most patients with any PSA elevation will never experience High-risk BCR during the follow-up. Embark criteria currently represent the more stringent criteria with a very high risk of PCSM. Pattern of presentations of BCR, and high-risk BCR according to EAU and EMBARK criteria after radical prostatectomy or radiotherapy. Primary treatment Radical Prostatectomy Radiotherapy PSA&gt; 0.2 N=2501 EAU High Risk BCR N=1119 EMBARK High Risk BCR N=386 PSA&gt;Nadir + 2 N=836 EAU High Risk BCR N=427 EMBARK High Risk BCR N=456 Time frame, n (%) 0-1 year 660 (26.4%) 535 (47.8%) 199 (51.6%) 117 (14.0%) 117 (27.4%) 96 (21.1%) 1-3 years 757 (30.3%) 392 (35.0%) 139 (36.0%) 297 (35.5%) 171 (40.0%) 229 (50.2%) 3-5 years 463 (18.5%) 111 (9.9%) 29 (7.5%) 198 (23.7%) 79 (18.5%) 109 (23.9%) 5-7 years 286 (11.4%) 48 (4.3%) 10 (2.6%) 85 (10.2%) 23 (5.4%) 16 (3.5%) &gt;7 years 335 (13.4%) 33 (2.9%) 9 (2.3%) 139 (16.6%) 37 (8.7%) 6 (1.3%) Time to BCR, n (%) 29.7 (11.3, 59.6) 12.6 (5.8, 25.7) 11.8 (5.1, 22.3) 36.6 (18.6, 62.4) 21.2 (11.3, 45.9) 23.4 (14.3, 38.3)

Genome-wide burden survival tests for patients with metastatic prostate cancer on androgen receptor-targeted therapies in the Million Veterans Program dataset.

251 Background: Literature suggests various genes influence metabolism and treatment response in prostate cancer. While the androgen receptor gene is the primary target for hormonal treatment, studies increasingly highlight the roles of genes in lipid metabolism and pharmacogenetics, including APOE, BGN, AHSG, CYP2D6, SLC2A4 , and HSD3B1 . Genes allowing androgens to enter cells more efficiently may increase therapy resistance, worsening outcomes in recurrent or metastatic disease. An understanding of biomarkers and resistance mechanisms is essential to address this issue. We conducted a genome-wide search for genes that exhibit an effect on survival in patients on androgen receptor-targeted therapies. Methods: We developed two models: Model 1 identified 5,107 patients with metastatic prostate cancer receiving androgen deprivation therapy; model 2 focused on a subgroup 2,240 patients on abiraterone. We performed 18,544 distinct gene-level tests across the human genome using all coding variants within each gene, analyzing rare (minor allele frequency &lt;1%) loss-of-function variants, and rare loss-of-function and missense variants. All analyses used the Veterans Administration’s Million Veterans Program (MVP) whole genome Release2 genomic data (96K males). We conducted separate analyses for African and European ancestry subjects. Gene-level survival analysis was performed using the SeqMeta R package that performs burden, Skat, and Skat-O tests. A Bonferroni correction was applied for 82,567 tests, requiring p&lt;6.06E-7 to establish significance and p&lt;5.00E-6 for suggestive evidence. Individual survival analyses were conducted on all SNPs within each significant gene. Results: Gene-level tests identified OR1G1 (burden p=1.87E-7, OR=0.17), PCDHGB1 (burden p= 2.92E-07, OR=0.61) and CLPB (burden p=3.34E-07, OR=0.30) as significantly associated with prostate cancer survival, while SNX18 demonstrated a suggestive association (Skat-O p=3.40E-6) among European ancestry subjects in model 1. Among African ancestry subjects, the best performing gene was UBD (burden p= 2.61E-06, OR=0.76). Analyses of rare loss-of-function and loss-of-function or missense variants failed to achieve significant or suggestive evidence. Model 2 did not reveal any significant findings. Additional variant level survival analyses revealed 4 significant SNPs from UBD including chr6.29555893.C.A, chr6.29556082.G.C, chr6.29556095.A.G_A, chr6.29556226.A.G_A (1 copy HR 3.1, 2 copies HR 3.7, p &lt;.05) and SNP chr5.54519665.A.C_A from gene SNX18 (1 copy HR 1.5 p &lt;.05). Conclusions: Our results indicate variants within several genes may influence prostate cancer survival by causing resistance to androgen-receptor targeted therapies and warrant follow-up in external datasets for validation.

Effects of whole-body vibration training as an adjunct to conventional rehabilitation exercise on pain, physical function and disability in knee osteoarthritis: A systematic review and meta-analysis

Background Knee osteoarthritis (KOA) is a prevalent degenerative joint condition that impairs mobility and quality of life. While whole-body vibration training (WBVT) shows promise as an adjunct to conventional KOA rehabilitation, its efficacy remains unclear due to inconsistent clinical evidence. Objective To elucidate the combined effects of WBVT and rehabilitation exercise on pain, physical function, and disability in KOA management through a systematic review and meta-analysis. Methods A comprehensive search was conducted across eight electronic databases (PubMed, Web of Science, Embase, PEDro, SPORTDiscus, Scopus, ScienceDirect, and China National Knowledge Infrastructure) up to February 2024. Inclusion criteria were (i) randomized controlled trials comparing combined WBVT and rehabilitation exercise versus rehabilitation alone in KOA (ii) reported clinical outcomes (iii) human studies, and (iv) publications in English or Chinese. Trial quality was assessed using the PEDro scale and Cochrane risk-of-bias tool. The meta-analysis employed random-effects models in Review Manager 5.3 to account for heterogeneity, supported by sensitivity analyses for robustness and subgroup analyses on WBVT frequency effects. Results Sixteen RCTs comprising 589 participants were included. The systematic review found that WBVT combined with conventional rehabilitation significantly reduced pain and improved physical function in KOA patients. The meta-analysis quantified these effects, showing that WBVT significantly (i) reduced knee pain (MD = −0.43, 95% CI [−0.70, −0.16], p = 0.002), with greater reductions observed from high-frequency WBVT, and (ii) increased isokinetic knee peak torque compared to rehabilitation exercise alone. No significant differences were found in balance, functional mobility, and disability outcomes. Sensitivity analysis of high-quality trials supported these results. However, the heterogeneity among studies and variations in control group interventions warrant cautious interpretation. Conclusion WBVT seems to be effective in reducing pain and enhancing muscle strength in KOA patients when used in conjunction with conventional rehabilitation. Future high-quality RCTs must standardize WBVT protocols, emphasize long-term follow-up, and refine dosage for clinically meaningful outcomes. Systematic review registration: International prospective register of systematic reviews (PROSPERO CRD42024508386)

Factors associated with false-positive screening mammography in São Paulo, Brazil

Mevrometostat (PF-06821497) in combination with enzalutamide for androgen receptor pathway inhibitor (ARPI)-naïve patients with metastatic castration-resistant prostate cancer (mCRPC): The phase 3, randomized MEVPRO-2 trial.

TPS287 Background: Mevrometostat (PF-06821497) is a potent, selective inhibitor of the histone methyltransferase enhancer of zeste 2 (EZH2), which is canonically involved in epigenetic repression of target genes. In prostate cancer, EZH2 overexpression is associated with poor prognosis, contributing to disease progression through transcriptional repression of tumor suppressor genes and androgen receptor (AR) activation, co-regulation of AR-mediated transcriptional programs, and cell cycle deregulation through methylation of non-histone targets. Given the associations between EZH2 and the AR, the addition of an EZH2 inhibitor to ARPI is hypothesized to extend the duration of clinical response and delay antiandrogen resistance compared with ARPI alone. In a nonrandomized, phase 1 dose-escalation study, objective responses to mevrometostat with enzalutamide were observed in patients with CRPC and prior abiraterone or enzalutamide treatment (NCT03460977; Schweizer MT, et al. J Clin Oncol . 2024;42(16_suppl):5061). Despite guideline recommendations of treatment intensification with ARPIs or chemotherapy for metastatic castration-sensitive prostate cancer (mCSPC), many patients do not receive ARPIs at the mCSPC stage. MEVPRO-2 (NCT06629779) will evaluate mevrometostat plus enzalutamide compared with enzalutamide alone in ARPI-naïve patients with mCRPC. Methods: MEVPRO-2 is a global, double-blind, randomized, phase 3 trial. Key inclusion criteria are males, ≥18 years, with progressive mCRPC, castrate testosterone of ≤50 ng/dL, Eastern Cooperative Oncology Group performance status of 0 or 1, and life expectancy of ≥12 months. Patients with systemic treatments for mCRPC (except androgen deprivation therapy and first-generation antiandrogens) are excluded. Approximately 900 patients will be randomized 1:1 to receive mevrometostat (875 mg, twice daily) with enzalutamide (160 mg, once daily) or placebo with enzalutamide. The primary endpoint is blinded independent central review-assessed radiographic progression-free survival per Response Evaluation Criteria in Solid Tumours 1.1 (soft tissue) or Prostate Cancer Working Group 3 (bone). Key secondary endpoints are overall survival and time to pain progression (Brief Pain Inventory – Short Form question 3 or opioid use). Hazard ratios and 95% confidence intervals will be estimated using a Cox proportional hazard model, stratified by prior docetaxel and presence of hepatic metastases. P-values will be provided using a stratified log-rank test. Safety and tolerability will also be assessed. Clinical trial information: NCT06629779 .

Outcomes of different therapeutic modalities for patients with metachronous oligometastatic renal-cell carcinoma (RCC): Analyses of a single-institution database.

553 Background: There is limited data in the literature concerning the management of patients (pts) with metachronous oligometastatic RCC. This study aimed to compare survival outcomes with various therapeutic modalities from a referral center cohort database. Methods: Pts with recurrent RCC from previous radical surgery for localized tumor, presenting with ≤5 metastatic lesions, were retrospectively analyzed. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS) and PFS from subsequent therapy (PFS2). Descriptive statistics and Cox-proportional hazard-regression models for PFS and OS were used. Survival rates were estimated with Kaplan-Meier method. P-values &lt;0.05 were considered statistically significant. Results: In total, 142 pts were identified, treated from 02/2006 to 08/2023. 30 pts received active surveillance (AS), 48 metastasectomy (M), 30 stereotactic body radiotherapy (SBRT) and 34 first-line systemic therapy (1L). Median follow-up was 61.4 months (mo). There were no significant differences between groups according to age (p=0.29), ECOG performance status (p=0.99), Charlson Comorbidity Index (CCI) (p=0.81), International Metastatic RCC Database Consortium (IMDC) score (p=0.06) and time to metastatic relapse (p=0.27). The number of organs involved (NO) and the number of lesions (NL) were significantly different between groups with lower lesion counts for RT in both cases (p=0.02 and p&lt;0.001, respectively), while sites of metastases (SM) did not differ (p=0.09). Subsequent therapies consisted of AS (2%), M (10.2%), SBRT (10%) and systemic therapy (77.5%). Median PFS was 14 mo for AS (95% CI: 9-26), 15 mo for M (95% CI: 10-49), 21 mo for RT (95% CI: 12-48), and 12 mo for 1L (95% CI: 10-16), with significant differences observed across treatment arms (p=0.026). No significant differences were found in OS (p=0.05) or in PFS2 (p=0.57). ECOG performance status was associated with OS (HR: 2.13, 95% CI: 1.34-3.11, p=0.002) but not with PFS (HR: 1.02, 95% CI: 0.75-1.40, p=0.85). No significant associations were found between CCI and either PFS or OS (HR: 0.94, p=0.16 and HR:1.12, p=0.19 respectively). Additionally, no associations were found between time of recurrence and neither PFS (HR: 0.99, 95% CI:0.99-1.00, p=0.07) nor OS (HR:0.99, 95% CI: 0.98-1.00, p=0.08). NO, SM and NL were not associated with either PFS or OS. Conclusions: The study highlights the importance of multidisciplinary discussions in pts with metachronous oligometastatic RCC, as there are potentially significant differences in PFS across treatment strategies. Limitations include retrospective nature, potential selection and confounding biases.

Use of urinary cell-free DNA methylation assay to identify tumor fraction for early detection and recurrence monitoring in urothelial carcinoma.

844 Background: Urothelial carcinoma (UC) remains one of the most common urologic cancers, presenting challenges in both initial diagnosis and follow-up due to the invasive nature of traditional diagnostic procedures. Urinary cell-free DNA (ucfDNA) analysis offers a non-invasive alternative, with DNA methylation patterns providing a promising avenue for identifying tumor-derived cfDNA. This study explores the utility of ucfDNA methylation-based tumor fraction (mTF) for early detection and monitoring recurrence in UC patients. Methods: A case-control study was conducted with 121 participants, analyzing ucfDNA from patients with pathologically confirmed malignant tumors and benign lesions. A panel of UC-specific methylation markers was developed to quantify tumor-derived ucfDNA in a tissue-agnostic manner. The methylation-based tumor fraction (mTF) was then correlated with reference circulating tumor DNA (ctDNA) levels and clinical urine cytology indicators. Results: Our analysis revealed a significantly higher mTF in UC patients compared to controls (Wilcoxon test, p-value = 3.3 x 10 -9 ). Utilizing mTF as an independent biomarker for distinguishing malignant from benign cases achieved a positive predictive value (PPV) of 92% and a negative predictive value (NPV) of 90%. Moreover, relapse signals (mTF &gt; 0.005) were detected in follow-up urine samples from all patients (7/7) who had undergone transurethral resection of bladder tumor (TURBT). Conclusions: The urinary cfDNA methylation-based tumor fraction presents a promising non-invasive biomarker for both early detection and recurrence monitoring of urothelial carcinoma. This approach could significantly improve patient management by providing a valuable tool for diagnosis and ongoing surveillance, underscoring the need for innovative diagnostic strategies in UC.

Saikosaponin A alleviates depressive-like behavior induced by reserpine in mice by regulating gut microflora and inflammatory responses

Saikosaponin A (SSA), a key ingredient of Chaihu-Shugan-San, has been shown to possess anti-inflammatory, antioxidant and antidepressant properties. Therefore, the present study aimed to investigate the potential mechanism of action and the effect of SSA on reserpine-induced depressive-like symptoms in mice. Establishing mouse model of depression using intraperitoneal injection of reserpine (RSP). Forced swimming test, tail suspension test and sucrose preference test were used to assess depression-like behavior in mice. The results showed that mice exposed to RSP not only showed weight loss and depressive behavior, but also elevated levels of IL-1β and TNF-α, as well as upregulated levels of reactive oxygen species (ROS) and lipid peroxides in the hippocampus. Detection of changes in the intestinal flora of mice using 16S rRNA, it was observed that the intestinal flora changed following SSA treatment. Not only was there an increase in the overall abundance of the intestinal microbiota, but there was also a significant down-regulation of the Firmicutes and an up-regulation of the Verrucomicrobia at the phylum level. Furthermore, SSA treatment markedly improved depressive-like behavior induced by RSP, alleviated damage to the hippocampus, elevated levels of monoamine neurotransmitters, suppressed inflammatory factors in the hippocampus, reduced hippocampal oxidative stress, and restored gut microbiota disruption in RSP-induced mice. The findings propose that SSA has the potential to alleviate depressive symptoms in mice by enhancing monoamine neurotransmitter levels, suppressing hippocampal inflammation, and modifying gut microbial composition.

The role of gut microbiota at different developmental stages in the adaptation of the Etiella zinckenella to a plant host

Concomitant G-CSF use in maintaining an efficacious dose and safe delivery of docetaxel in combination with darolutamide in patients with metastatic hormone sensitive prostate cancer (mHSPC): ARASENS, a phase 3 study.

152 Background: In ARASENS, darolutamide (DARO) + androgen deprivation therapy (ADT) + docetaxel (DOC) significantly reduced risk of death by 32.5% vs placebo (PBO) + ADT + DOC in patients (pts) with mHSPC, with a similar incidence of treatment-emergent adverse events (TEAEs) between DARO and PBO treatment arms. DOC is associated with the risk of febrile neutropenia, which can be managed by DOC dose reduction and/or use of granulocyte colony stimulating factor (G-CSF). We report the impact of DOC dose intensity on the safety and efficacy of the ARASENS triplet regimen and evaluate the benefits of G-CSF use in maintaining effective dose and safe delivery of DOC. Methods: Pts were randomized to receive DARO 600 mg orally twice daily or PBO, with ADT + DOC. Baseline characteristics, G-CSF use, safety, overall survival (OS), and time to prostate-specific antigen (PSA) progression were analyzed according to DOC relative dose intensity (RDI; ≤85% vs &gt;85%), defined as the ratio of DOC dose received vs protocol-defined full planned dose (75 mg/m 2 × 6 cycles). Results: Of the 1305 pts (DARO n=651; PBO n=654), 32 (2%) never received DOC or had no RDI data; 800 (60%) had DOC dose modifications. Of 1273 pts with DOC RDI data (DARO n=637; PBO n=636), &gt;97% received an efficacious dose (RDI &gt;80%), and use of DARO did not impact DOC RDI. Concomitant G-CSF was used in 48% (DARO) and 46% (PBO) of pts with DOC dose modifications vs 42% (DARO) and 45% (PBO) in the overall population, and was mainly used for secondary prophylaxis after first DOC dose in both the DOC dose modification population (DARO 184/186 [99%]; PBO 188/190 [99%]) and the overall population (DARO 269/272 [99%]; PBO 282/284 [99%]). G-CSF use was higher in pts with DOC RDI ≤85% (DARO 70%; PBO 74%) vs RDI &gt;85% (DARO 39%; PBO 41%). Pt demographics and baseline disease characteristics were broadly similar between RDI ≤85% and &gt;85% subgroups; &gt;60% of pts with RDI ≤85% were from Asia Pacific. Incidences of grade ≥3 TEAEs/grade ≥3 neutropenia/grade ≥3 febrile neutropenia were higher with DOC RDI ≤85%, but DOC discontinuation rates were similar between RDI subgroups (≤85%: DARO 7%, PBO 11%; &gt;85%: DARO 8%, PBO 11%). TEAEs leading to DOC dose modification were higher with DOC RDI ≤85% (DARO 93%; PBO 97%) vs RDI &gt;85% (DARO 26%; PBO 25%). OS and time to PSA progression were similar between the RDI ≤85% and &gt;85% subgroups within each treatment group. Conclusions: Appropriate DOC dose modification and G-CSF use allowed almost all pts (97%) to receive an efficacious dose of DOC, with no difference in OS and time to PSA progression for RDI ≤85% vs &gt;85%. Addition of DARO to ADT + DOC did not increase DOC dose modification rates or G-CSF use. Clinical trial information: NCT02799602 .

A non-coding RNA based classifier for favorable outcomes in clinically organ confined bladder cancer.

831 Background: Long non-coding RNA (lncRNA)-based genomic profiling has suggested utility to identify a distinct tumor subgroup corresponding to a favorable prognosis in patients with bladder cancer. Here, we further evaluate a genomic classifier in a cohort of patients undergoing radical cystectomy (RC). Methods: Transcriptome-wide expression profiling using Decipher Bladder was performed on TURBT samples from a cohort of patients with high grade, clinically organ confined (cTa-T2N0M0) UC who subsequently underwent RC without any neoadjuvant therapy (n=226). LncRNA-based luminal favorable status was determined using a previously developed genomic classifier. The primary endpoint was overall survival (OS) following surgery. Secondary endpoints included cancer-specific mortality and upstaging at RC. Results: In the study, 134 patients were clinical NMIBC (cTa/Tis/T1) and 92 patients were cT2. We identified 60 patients with luminal favorable subtype, all of which showed robust gene expression patterns associated with less aggressive bladder cancer biology. On MVA, patients with the luminal favorable subtype (vs. without) were significantly associated with lower odds of upstaging to pT3+ disease (OR [95% CI] 0.32 [0.12-0.82], p = 0.02), any upstaging (OR [95% CI] 0.41 [0.20-0.83], p = 0.01), and any upstaging and/or pN+ (OR [95% CI] 0.50 [0.25-1.00], p = 0.05). Luminal favorable bladder cancer was significantly associated with better OS (HR 0.33 [95% CI 0.15-0.74], p=0.007). Conclusions: This study validates the performance of the genomic classifier for identifying urothelial carcinomas with a luminal favorable subtype, harboring less aggressive tumor biology.