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Prostate-specific antigen (PSA) response in Black patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with apalutamide (APA) versus abiraterone acetate (ABI): A real-world comparison.

50 Background: Treatment for patients with mCSPC include androgen deprivation therapy (ADT) with the addition of androgen receptor pathway inhibitors (ARPIs). APA and ABI are two ARPIs approved for use with ADT in patients with mCSPC. However, there is limited information on the comparative effectiveness of ARPIs among Black patients. Deep PSA decline ≥90% (PSA90) following initiation of an ARPI is associated with delayed disease progression and improved survival outcomes. This study aimed to compare the proportion of Black patients with mCSPC with PSA90 response by 6 months after APA or ABI initiation. Methods: A retrospective analysis was conducted where Black patients were assigned to exclusive cohorts based on the first APA or ABI dispensation or pharmacy claim on or after 9/17/2019 (index date). Clinical data from US community urology practices (PPS Analytics) were linked with insurance claims data (Komodo; 1/1/2016-12/31/2023). Black patients with ≥12 months of pre-index clinical activity were required to have a diagnosis for metastasis in the absence of castration resistance. Patients were followed from the index date until the earliest of index ARPI discontinuation or switch, radiopharmaceutical initiation, or end of clinical activity/data availability. Pre-index characteristics were balanced between cohorts using inverse-probability of treatment weighting. PSA90 was defined as the earliest ≥90% decline in PSA relative to pre-index PSA. Weighted Kaplan-Meier analysis and a Cox proportional hazards model were used to compare the proportion of patients achieving PSA90 and time-to-PSA90 response. Results: A total of 363 Black patients were identified. The 236 APA and 127 ABI patients’ pre-index characteristics were balanced after weighting (Table). Mean on-treatment follow-up was 11.1 months (APA) and 9.4 months (ABI). The mean number of PSA tests were 4.0 (APA) and 5.3 (ABI). By 6 months post-index, PSA90 response was achieved by a significantly greater proportion of APA patients, as compared to ABI patients (65.4% vs 49.0%; hazard ratio: 1.66 [95% confidence interval: 1.18, 2.35], p=0.004). Median time-to-PSA90 response was 3.3 months for APA and 9.1 months for ABI. Conclusions: This real-world study of patients with mCSPC showed that a higher proportion of Black patients initiating APA, as compared to ABI, attained a PSA90 response within 6 months of treatment initiation, consistent with findings in the overall population. Selection of appropriate ARPIs may reduce health disparities among Black patients with mCSPC. Weighted pre-index characteristics. APA N=236 ABI N=127 Standardized difference (%) Mean age, years 70.1 69.2 9.5 Metastasis type (%) Nodal 59.5 62.6 6.3 Bone 59.2 54.7 9.1 Visceral 14.4 11.6 8.4 Prior use of ADT (%) 88.7 86.6 6.6 Mean PSA level, ng/mL 23.8 24.1 0.6

Removal of sulfate pollutant from different samples of a river water using nanozeolite technology, case study: Gamasiab River, Iran

Human activities significantly impact on river water quality as a crucial water source. A study in the Gamasiab River analyzed samples from 16 points at three time periods, assessing element concentrations. The most polluted station was identified using spectrophotometric testing and treated with natural and modified zeolite nanoparticles for purification. Various acid and base combinations modified the nanoparticles, optimizing their effectiveness as adsorbents through tests under different conditions. Utilizing the Design Expert model, theoretical adsorption values were determined based on pH and adsorbent-pollutant ratio. The modified samples demonstrated 77% efficiency with 0.2 molar nitric and sulfuric acid. Interaction studies showed how phosphate and nitrate ions affected sulfate adsorption. Optimal adsorption conditions were defined at pH = 9.6 and D/C = 17.01, achieving 86.5% pollutant adsorption. The Freundlich isotherm, with a coefficient of determination of 0.92, was chosen over the Langmuir isotherm (0.79) for its superior performance. Therefore, applying zeolite nanoparticles efficiently eliminated sulfate pollutants from surface water resources at the laboratory.

Berberine attenuates obesity-induced skeletal muscle atrophy via regulation of FUNDC1 in skeletal muscle of mice

Phenotypic and genetically predicted leukocyte telomere length and prostate cancer risk: Results from a large-scale longitudinal cohort study.

404 Background: Previous studies on the correlation between leukocyte telomere length (LTL) and prostate cancer (PCa) have shown contradictory results. Our study aims to further explore the potential relationship between LTL and PCa. Methods: In this study, a total of 229,022 male individuals were enrolled from the UK Biobank to investigate this association . Both unadjusted and covariates-adjusted Cox proportional hazards regression models were employed. The primary outcome was defined as the diagnosis of incident prostate cancer using in-patient data and the death registry of the UKB cohort. To validate the reliability of the primary findings, secondary analyses, including Mendelian randomization (MR) were conducted. Results: The primary analysis demonstrated that longer LTL was substantially associated with higher risk of prostate cancer, with associations remaining robust after adjusting for potential covariates (HR: 1.444, 95% CI: 1.247-1.673, P < 0.001). Similar results were observed when LTL was analyzed as both a continuous and categorical variable, and the association were shown to be inversely U-shaped. At the genetic level, the association was further validated using MR across different prostate cancer databases, with results consistent with our primary analysis. Conclusions: Our findings offer compelling evidence that leukocyte telomere length is an important risk factor for prostate cancer. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between leukocyte telomere length (analyzed both as a continuous variable and by quartile categories) and prostate cancer risk in the UK Biobank study. 　 Model I Model II Model III Cases N Median HR 95%CI HR 95%CI HR 95%CI 10693 198830 0.810 1.505 1.301-1.741 1.454 1.256-1.683 1.444 1.247- 1.673 　 　 　 <0.001 　 <0.001 　 <0.001 　 2761 49708 0.683 ref ref ref 2782 49707 0.773 1.088 1.032 -1.147 1.087 1.031 - 1.145 1.084 1.029-1.143 2607 49707 0.849 1.090 1.033-1.151 1.086 1.029-1.146 1.084 1.028-1.144 2543 49708 0.960 1.187 1.124-1.253 1.174 1.112- 1.240 1.170 1.108-1.236 　 　 　 <0.001 　 <0.001 　 <0.001 　 Model I adjust for age; Model II adjust for demographic variables (age; ethnic background) and socioeconomic variables (socioeconomic status; education); Model III adjust for demographic variables (age class; ethnic background) socioeconomic variables (socioeconomic status; education) and lifestyle variables (alcohol intake frequency; smoking history; body mass index; duration of walks; sleep duration; blood pressure).

Genomic alterations in intraductal prostate cancer: Insights from the Genomic Umbrella Neoadjuvant study (GUNS) in high-risk localized disease.

417 Background: Intraductal carcinoma of the prostate (IDC) is an aggressive histological variant of prostate cancer, characterized by the presence of malignant cells within the prostatic ducts. Retrospective studies have shown IDC linked to higher tumor grades and odds of lymphatic metastasis and worse oncological outcomes. In patient derived xerograph models, IDC can persist after castration, with a subpopulation of castrate tolerant cells able to regenerate upon testosterone restoration. This suggests that IDC contributes to therapy resistance and highlights the need to understand molecular alterations of IDC. This study aims to evaluate genomic profiles of these tumors in the GUNS trial. Methods: From 9/2021 to 8/2024, GUNS enrolled 95 patients in Canada. Diagnostic biopsies underwent Tempus’ CLIA-certified 648-gene panel DNA sequencing. A total of 93 patients were evaluable for genomic alterations. Of those, 81 additionally had immunohistochemistry (IHC) staining for PTEN. All biopsy specimens were centrally reviewed by TvK. Associations between IDC and genomic alterations or PTEN IHC staining (positive vs. negative/heterogeneous) were assessed by Fisher’s exact test, and the false discovery rate (FDR) was controlled using the Benjamini-Hochberg method. Only genomic alterations annotated as biologically significant by Tempus were considered for analysis. Results: Of the 93 evaluable patients, 36 (39%) had IDC on biopsy. PTEN IHC status showed a significant association with IDC status, with negative or heterogeneous PTEN IHC staining being more prevalent among IDC-positive cases (p = 0.002; FDR q = 0.05). Specifically, PTEN IHC staining was negative/heterogeneous in 15/32 (47%) IDC-positive cases but only 7/49 (14%) IDC-negative cases. Genomic PTEN (22% vs. 7%) and TP53 (19% vs. 9%) alterations were also more common in IDC-positive cases than IDC-negative cases, although these trends were not statistically significant. Conversely, CDKN1B was exclusively altered in IDC-negative cases (0% vs. 9%), and BRCA2 alterations (germline or somatic) were also more frequent in IDC-negative cases (3% vs 11%), but these observations were also not statistically significant. Relatively low frequencies of genomic alterations were likely impediments to statistical significance, warranting larger sample sizes to assess these trends. Conclusions: Negative or heterogeneous PTEN IHC staining was more common in IDC-positive cases, consistent with the known association between PTEN loss and aggressive disease. PTEN IHC status, along with other genetic markers, may help to define subgroups within prostate cancer that differ in their underlying biology and response to neoadjuvant treatment. This highlights the importance of integrating molecular and histological data to better understand prostate cancer progression and to tailor therapeutic approaches.

Access to immune checkpoint inhibitors (ICI) in patients randomized to the control arm of ICI phase 3 trials in urothelial and renal cell cancers.

448 Background: We investigated access to ICIs in patients (pts) randomized to the control arm across positive phase 3 trials for renal cell carcinoma (RCC) and urothelial carcinoma (UC) with an ICI-based regimen. Methods: A search of clinicaltrials.gov was performed in October 2024 including, “renal cell carcinoma” OR “urothelial cancer”, “immune”, and “phase 3”, producing 64 results. These were limited to trials with an investigational arm containing ICI therapy and without an ICI in the control arm, no cross over in initial trial design, and demonstrated overall survival benefit in the adjuvant or metastatic setting (any line). Analysis included completed studies with minimum median follow-up of 12 months and the most recent published subsequent therapy data. Results: Final analysis included 8 international trials (n=6 RCC; n=4 UC, table). Two trials (CheckMate 025, KEYNOTE-045) were conducted before ICI were approved for advanced UC and RCC. For RCC (n=5,138 pts enrolled from 2014-2019) each trial tested a PD-1 inhibitor (pembrolizumab n=3; nivolumab n=3) alone or in conjunction with a tyrosine kinase inhibitor (axitinib n=1; cabozantinib n=1; lenvatinib n=1) or a CTLA-4 inhibitor (ipilimumab n=1). Control arm consisted of a non-ICI regimen (sunitinib n=4; everolimus n=1; placebo n=1). Approximately 57% of pts randomized to the control arm received subsequent therapy, 67% of which was an ICI. For UC (n=2,736 pts enrolled from 2015-2022) each trial tested a PD-(L)1 inhibitor (avelumab n=1; pembrolizumab n=2; nivolumab n=1) alone or in combination with enfortumab vedotin (n=1) or gemcitabine-cisplatin (n=1). Control arm consisted of chemotherapy (n=3) or best supportive care (n=1). Approximately 59% of pts randomized to the control arm received subsequent therapy, 75% of which was an ICI. Conclusions: Pts randomized to the control arm of phase 3 ICI trials in UC and RCC did not consistently receive ICIs upon progression. Understanding how access to subsequent therapies impacts overall survival, further research is warranted to identify possible causes, including availability of ICIs in different geographical regions, loss to follow-up, or clinical deterioration of pts. Cancer Renal Cell Carcinoma Urothelial Carcinoma Trial CheckMate 025 CheckMate 214 KEYNOTE-426 CheckMate 9ER CLEAR KEYNOTE-564 KEYNOTE-045 JAVELIN Bladder 100 EV-302 CheckMate 901 Median Follow-Up (months) 72.0 67.7 39.9 44.0 33.0 57.2 14.1 39.6 17.2 33.6 Pts on Control Arm (number) 411 546 429 328 357 498 272 350 444 304 Any Subsequent Systemic Therapy (number, %) 296, 72.0% 372, 67.6% 300, 69.9% 133, 40.5% 221, 61.9% 145, 29.1% 91, 33.5% 252, 72.0% 313, 70.5% 156, 51.3% Pts on Control Arm that Received ICIs as Subsequent Systemic Therapy (number, %) 107/296, 36.1% 227/372, 61.0% 240/300, 80.0% 121/133, 90.1% 188/221, 85.1% 101/148, 68.2% 35/91, 38.5% 186/252, 73.8% 260/313, 83.1% 126/156, 80.8%

Impact of parental education on number of under five children death per mother in Bangladesh

One of the leading challenges of social development is the reduction of children’s deaths under the age of five. The primary focus of this research is to study the potential impact of parental education on under five children death in Bangladesh utilizing a secondary dataset extracted from the Bangladesh Demographic and Health Survey (BDHS), 2017–18. The total count of deceased children within a family is a non-negative numerical variable. The mean number of under five children death per 100 mothers is found to be 20 with variance of around 27, which indicates the presence of overdispersion. As the response variable exhibits 84.2% zero counts, we have considered three regression models in this research; Poisson model, zero-inflated Poisson model, and zero-inflated negative binomial model. Finally, zero-inflated negative binomial model, exhibiting the lowest AIC value, indicates that both maternal and paternal education have significant protective impact on under five children death. Specifically, greater levels of formal education achieved by the parents are associated with a decreased rate of children death.

A Compact 2-D photonic crystal biomedical sensor for enhanced glucose concentration detection in urine

Abstract This study introduces a 2-D Photonic Crystal (PhC) biosensor designed, simulated, and evaluated for detecting glucose concentrations in urine by utilizing refractive index variations. The sensor demonstrates exceptional performance, achieving a sensitivity of 20,040.30 nm/RIU for glucose levels ranging from 0–15 mg/dl, a quality factor of 10,424.55, and a detection limit as low as 8 × 10−10, surpassing benchmarks reported in the literature. With compact dimensions of 16.8 × 17.6 µm2 and compatibility with modern fabrication techniques, the proposed design is well suited for integration into portable diagnostic devices. A comprehensive comparative analysis underscores its superior sensitivity, ultra-high quality factor, and compact design, establishing it as a major advancement in glucose detection technology.

HIF2α gene expression and clinical outcomes in patients with clear cell renal cell carcinoma with and without sarcomatoid differentiation.

539 Background: Clear cell renal cell carcinoma (ccRCC) with sarcomatoid differentiation (sRCC) is associated with poor survival. Recent studies have shown downregulation of hypoxia-related pathways in sRCC (Motzer et al., Cancer Cell, 2020; El Zarif, Semaan et al., Cell Reports, 2024). In this study, we sought to compare HIF2α expression levels in ccRCC, with and without sarcomatoid differentiation and investigate clinical outcomes of patients (pts) with sRCC treated with HIF2α inhibitors (HIF2αi). Methods: To assess HIF2α gene expression in sRCC, RNA-seq data was collected from 2 clinical trials: JAVELIN Renal 101 (JR101), and IMmotion151 (IM151), as well as publicly available data from The Cancer Genome Atlas (TCGA). Mean HIF2α expression levels were compared between ccRCC with and without sRCC using Wilcoxon Rank-Sum test. To evaluate the clinical outcomes of pts with sRCC treated with HIF2αi, we also collected clinical data from pts with ccRCC who were treated with HIF2αi-based therapies (Belzutifan or AB521). Progression-free survival (PFS) and overall survival (OS) were analyzed using log-rank test and multivariable Cox regression model accounting for IMDC risk group, line of therapy, and type of regimen (HIF2αi; HIF2αi + Vascular endothelial growth factor-targeted therapy (VEGF-TT); HIF2αi + Immunotherapy (IO) + VEGF-TT). Results: RNA-seq data from 2,075 pts with renal cell carcinoma with a clear cell component from TCGA (48 sRCC; 493 ccRCC), JR101 (97 sRCC; 639 ccRCC) and IM151 (110 sRCC; 688 ccRCC) were included. Expression of EPAS1 , which encodes for HIF2α, was significantly downregulated in pts with sRCC in TCGA (log(TPM) mean: 6.63 vs 9.95 in ccRCC ; p < 0.001), JR101 (8.71 vs 8.93 in ccRCC ; p = 0.04) and IM151 (8.05 vs 8.69 in ccRCC ; p < 0.0001). For the clinical cohort, 104 pts treated with HIF2αi were included; 13.5% (14/104) had sRCC. In univariate analysis, sRCC was significantly associated with worse PFS (median PFS = 4.8 months (mo) vs 11.3 mo in ccRCC; p = 0.021) and numerically worse OS (20 mo vs 41.1 mo in ccRCC; p = 0.21). In multivariable analysis, sRCC was associated with worse PFS (HR adjusted : 2.55; 95% CI: 1.32–4.90; p=0.005) (Table) and numerically worse OS (HR adjusted : 2.14; 95% CI: 0.9–5.1; p=0.08). Conclusions: This study suggests that the efficacy of HIF2αi may be limited in sRCC, possibly due to decreased dependency on HIF2α signaling. Our findings highlight the need for novel therapeutic strategies in sRCC. Multivariable analysis for PFS. Variable HR adjusted 95%CI p-value sRCC (yes vs no) 2.55 1.32 – 4.91 0.005 HIF2αi line of therapy 1.32 1.04 – 1.65 0.018 IMDC group (favorable vs intermediate) 0.95 0.54 – 1.67 0.853 IMDC group (poor vs intermediate) 1.69 0.79 – 3.62 0.176 IMDC group (missing vs intermediate) 1.39 0.54 – 3.57 0.488 Regimen (VEGF-TT + HIF2αi vs HIF2αi) 0.64 0.30 – 1.37 0.251 Regimen (IO + VEGF-TT + HIF2αi vs HIF2αi) 0.23 0.03 – 1.95 0.179

Mevrometostat (PF-06821497), an enhancer of zeste homolog 2 (EZH2) inhibitor, in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC): A randomized dose-expansion study.

LBA138 Background: Mevrometostat (M) is a potent and selective inhibitor of EZH2. Dose exploration of M + enzalutamide (E) + androgen deprivation therapy (ADT) showed a manageable safety profile with evidence of EZH2 pharmacodynamic inhibition, objective response (OR), and decline in prostate-specific antigen of ≥50% from baseline (PSA 50 ) in patients (pts) with mCRPC (NCT03460977). We report outcomes from the open-label, randomized, dose expansion part of this study. Methods: Pts with mCRPC who received prior abiraterone, ≤1 prior chemotherapy in any setting, with evidence of progression per modified Prostate Cancer Working Group 3 criteria were included. Pts receiving ADT were randomized 1:1 to M (orally, 1250 mg BID on empty stomach) + E (160 mg QD) or E, stratified by prior chemotherapy. Primary endpoints were radiographic progression-free survival (rPFS) per investigator assessment and safety. Secondary endpoints included OR by RECIST 1.1 (for pts with measurable disease at baseline), PSA 50 , and pharmacokinetics. Results: As of Sept 2, 2024,81 pts were included (M+E, n=41; E, n=40). Median (IQR) follow-up was 9.6 (3.1-14.5) mo. Median (range) age (yrs) was 70 (48-86) for M+E and 71.5 (50-86) for E. Overall, 43.9% of pts in the M+E group and 45.0% in the E group received prior taxane therapy. Median (95% CI) rPFS was 14.3 (7.5, not estimable) mo for M+E and 6.2 (4.1, 13.9) mo for E (hazard ratio 0.51; 90% CI 0.28, 0.95). In pts with measurable disease at baseline (M+E, n=15; E, n=14), OR rate (95% CI) was 26.7% (7.8, 55.1) for M+E (4 partial responses [PRs]) and 14.3% (1.8, 42.8) for E (2 PRs). Confirmed PSA 50 (95% CI) was observed in 34.1% (20.1, 50.6) of pts for M+E and 15.4% (6.0, 31.3) for E. Most common treatment-emergent adverse events (TEAEs) were diarrhea (78.0%), decreased appetite (58.5%), and dysgeusia (58.5%) for M+E, and asthenic conditions (42.5%), nausea (25.0%), and anemia (22.5%) for E. Grade ≥3 TEAEs were observed in 53.7% of pts in M+E (most common diarrhea, neutropenia and sepsis) and 42.5% in E. There were no treatment-related deaths. Geometric mean plasma exposures of M after multiple doses in combination with E were comparable for M 1250 mg on empty stomach and M 875 mg with food (AUC tau [h*ng/mL]: 1250 mg, 8733; 875 mg, 9631; C max [ng/mL]: 1250 mg, 2371; 875 mg, 1868). In M+E combination, M 875 mg with food had an improved safety profile compared with M 1250 mg on empty stomach. Conclusions: M+E shows improved outcomes vs E in pts with mCRPC, with a manageable AE profile. In M+E combination, M 875 mg with food has similar plasma exposure as M 1250 mg on empty stomach. Further investigation of M+E in pts with mCRPC is warranted. Disclosure: Pfizer's generative AI tool, MAIA, was used to draft this abstract (accessed: 2024-10-24); authors reviewed, edited, and take full responsibility for the content. Clinical trial information: NCT03460977 .

Radical cystectomy in female patients: Does the urinary diversion type affect postoperative complications?

752 Background: Data is limited on the possible impact of urinary diversion (UD) type on post cystectomy complications, particularly in women. This study aims to investigate this issue and identify predictors of post-cystectomy complications in female population. Methods: We utilized our prospectively maintained IRB-approved radical cystectomy (RC) database (#HS-01B014) to identify all female patients who underwent RC between 2003 and 2021. Patients were categorized into three groups based on their UD type: ileal conduit (IC), neobladder (NB) and continence cutaneous diversion (CCD). Demographics, baseline characteristics and postoperative complications were compared across the three groups. A multivariate logistic regression analysis was used to assess the predictors of complications at 90 days postoperatively. Results: A total of 531 female patients were included: 263 (49.5%) with IC, 206 (38.8%) with NB, and 62 (11.7%) with CCD. The table outlines the patients' demographics and perioperative characteristics. The overall 30-day complication rates were comparable across groups: 54.9% for NB, 51.6% for CCD, and 61.6% for IC (p = .195). Similarly, 90-day complication rates were also comparable (NB = 65.5%, CCD = 64.5%, IC = 70.3%; p = .456). 90-day complication subgroups including cardiac, pulmonary, gastrointestinal, hematologic, infectious, and neurologic were comparable between different UDs. However, genitourinary complications were significantly higher in CCD (32.3%) compared to IC (13.3%) and NB (14.6%) (p < .001). Multivariate analysis showed that patients with CCD had increased odds of 90-day genitourinary complications compared to NB (OR = 2.83 [95%CI: 1.38, 5.72], p= .001), while preoperative eGFR was protective (OR = 0.987 [95%CI; 0.977, 0.997], p = .010). Conclusions: Our results suggested that UD type has minimal influence on cumulative 30- and 90- day post-cystectomy complications. However, CCD was associated with an increased odds of 90-day genitourinary complications. Demographics and perioperative characteristics of patients stratified by urinary diversion type. Patient characteristics Neobladder(N = 206) Continent Cutaneous Diversion (N =62) Ileal conduit(N = 263) p Age (yrs.) 64.4 ± 9.8 64.2 ± 10.5 73.5 ± 10.4 <.001 Charleson Comorbidity Index 0 80 (38.8%) 25 (40.3%) 41 (15.6%) <.001 1 63 (30.6%) 11 (17.8%) 60 (22.8%) >=2 63 (30.6%) 26 (41.9%) 162 (61.6%) Preoperative eGFR (mL/min) 73.2 ± 24.7 72.3 ± 32.0 63.8 ± 29.0 <.001 Surgical Approach Open 196 (95.1%) 60 (96.8%) 177 (67.3%) <.001 Robotic assisted 10 (4.9%) 2 (3.2%) 86 (32.7%) Pathological Staging OC (< (y)pT2; pN0) 166 (80.6%) 44 (71.0%) 168 (63.9%) .002 EV (> (y)pT2; pN0) 26 (12.6%) 9 (14.5%) 62 (23.6%) LN+ (pN+) 14 (6.8%) 9 (14.5%) 33 (12.5%)

Climate change effects on ecosystem services: Disentangling drivers of mixed responses

Climate change is a pervasive hazard that impacts the supply and demand of ecosystem goods and services (EGS) that maintain human well-being. A recent review found that the impacts of climate change on EGS are sometimes mixed, posing challenges for managers who need to adapt to these changes. We expand on earlier work by exploring drivers of varying responses of EGS to climate within studies. We conducted a systematic review of English-language papers directly assessing climate change impacts on the supply, demand, or monetary value of ‘provisioning EGS’, ‘regulating EGS’, or ‘cultural EGS’. Ultimately, 44 papers published from December 2014 to March 2018 were analyzed. Nearly 66% of EGS were assessed for higher-income countries despite how lower-income countries disproportionately face negative climate impacts. Around 59% of observations or projections were mixed responses of EGS to climate change. Differences in climate impacts to EGS across space or climate scenarios were the most common causes of mixed responses, followed by mixed responses across time periods assessed. Disaggregating findings by drivers is valuable because mixed responses were often due to multiple drivers of variation. Carefully considering the decision context and desired outcome of a study will help select appropriate methodology to detect EGS variation. Although studies have often assessed relevant drivers of variation, assessing interactions of other sources of uncertainty and both climate and non-climate drivers may support more effective management decisions that holistically account for different values in the face of uncertainty.

IVC treatment between primary and second TURBT may improve the prognosis of high-risk NMIBC patients receiving BCG treatment

Mental health monitoring in clinical trials for FDA-approved genitourinary cancer treatments: A decade review.

696 Background: The treatment landscape for genitourinary (GU) malignancies, including bladder, kidney, and prostate cancers, has evolved with several novel therapies approved in the past decade. The importance of mental health in patients with cancer is being more and more recognized in the past years. This study evaluates the monitoring of mental health and psychiatric symptoms in trials leading to FDA approvals for GU cancers. Methods: We comprehensively reviewed trial protocols and publications for FDA-approved GU cancer therapies from 2015-2024. For each approved therapy, we examined whether psychiatric side effects were monitored, the tools used, and the timing of assessments. Results: Of 42 trials for 31 approved treatments, 85% (36/42) monitored some psychiatric monitored psychiatric or mental health-related outcomes. EORTC QLQ-C30, EQ-5D-5L, and BPI-SF were the most common tools used for monitoring. However, 15% of trials did not assess mental health, and long-term follow-ups were inconsistent as described in the table. Depression and anxiety were the most evaluated symptoms. Nonetheless, the majority of the other psychiatric manifestations were not consistently assessed throughout trials. Conclusions: Psychiatric monitoring is present in many GU trials but remains inconsistent. Mental health assessments are typically part of broader quality-of-life evaluations rather than focused psychiatric tools. Future trials should adopt standardized psychiatric assessments to better manage patient well-being during treatment. Psychiatric symptoms monitoring in FDA-approved GU cancer trials - 2015 to 2024. Symptom Assessed (%) Baseline Long-Term Publications Prostate Kidney Bladder Depression 80% Yes Yes No Yes Yes Yes Anxiety 80% Yes Yes No Yes Yes Yes Insomnia 61% Yes Yes Yes Yes Yes Yes Cognitive Impairment 38% Yes Yes No Yes Yes Yes Irritability 38% Yes Yes No Yes Yes Yes Emotional Lability 9% Yes Yes No Yes No Yes Delirium 2% No No No No Yes No Psychosis 2% No No No No Yes No

Efficacy of olaparib (ola) plus abiraterone (abi) versus placebo (pbo) plus abi in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with a germline or somatic BRCA mutation in the PROpel trial.

219 Background: PROpel (NCT03732820) met its primary endpoint showing statistically significant investigator-assessed (INV) radiographic progression-free survival (rPFS) benefit with ola + abi vs pbo + abi in first-line mCRPC in pts enrolled irrespective of homologous recombination repair gene mutation (HRRm) status (intention-to-treat [ITT] hazard ratio [HR] 0.66, 95% CI 0.54–0.81; P <0.001). At final prespecified analysis (ITT), median overall survival (OS) with ola + abi vs pbo + abi was 42.1 vs 34.7 months (HR 0.81, 0.67–1.00; P =0.054). In pts assigned to HRRm subgroups using aggregated tumor tissue and circulating tumor DNA (ctDNA) test results ( post hoc analyses), the greatest benefit for ola + abi vs pbo + abi was in pts with BRCAm (rPFS HR 0.23, 0.12–0.43; OS HR 0.29, 0.14–0.56). Concordance based on HRRm status between tumor tissue and ctDNA testing was also high (80% +ve, 87% -ve predictive agreement). We report post hoc efficacy analyses in pts with BRCAm of germline (g) or somatic (s) origin. Methods: PROpel was a double-blind Phase III trial. Pts were randomized 1:1 to ola (300 mg twice daily [bid]) or pbo, and abi (1000 mg once daily) + prednisone/prednisolone (5 mg bid) until disease progression, unacceptable toxicity, or withdrawal of consent. Tumor BRCAm status was determined using aggregated results from tumor tissue (FoundationOne CDx) and ctDNA (FoundationOne Liquid CDx) tests, and g/s status by blood test (Myriad MyRisk). Results: Of the 85 BRCAm pts, 77 were evaluable for g/s status by blood test. Of these, 32% (n=25) had a BRCAm of g origin and 68% (n=52) of s origin. HRs for pts with g and s BRCAm for rPFS (INV 0.13 and 0.19, BICR 0.15 and 0.17) and OS (0.23 and 0.26) all favored ola + abi vs pbo + abi (Table). Conclusions: Ola + abi showed clinical benefit vs pbo + abi for rPFS and OS in pts with g or s BRCAm, supporting earlier findings in the overall BRCAm population of PROpel. Also, as g testing alone does not detect s mutations, these results highlight the importance of robust biomarker testing (which is currently underutilized in real-world practice), including tumor tissue or ctDNA testing, to inform treatment options. Clinical trial information: NCT03732820 . Germline BRCAm, (n=25) Somatic BRCAm, (n=52) Ola + Abi(n=15) Pbo + Abi (n=10) Ola + Abi (n=27) Pbo + Abi (n=25) rPFS* (INV, primary endpoint) Events, n (%) 5 (33.3) 10 (100) 7 (25.9) 17 (68.0) Median rPFS NR 6.9 NR 11.1 HR 0.13 (0.04–0.38) 0.19 (0.07–0.45) rPFS*(BICR, sensitivity analysis) Events 5 (33.3) 10 (100) 6 (22.2) 18 (72.0) Median rPFS NR 5.9 NR 9.1 HR 0.15 (0.05–0.45) 0.17 (0.06–0.41) OS † (key secondary endpoint) Events, n (%) 5 (33.3) 9 (90.0) 6 (22.2) 15 (60.0) Median OS NR 18.4 NR 27.5 HR 0.23 (0.07–0.67) 0.26 (0.09–0.65) *Primary analysis, DCO 30 July 2021; † Final prespecified analysis, DCO 12 Oct 2022. BICR, blinded independent central review; DCO, data cutoff; NR, not reached.

Inclusion of patients with reduced performance status (ECOG 2 or higher) in FDA registrational trials for urothelial cancer.

680 Background: The Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) is a tool used to describe a cancer patient’s functional status and recruit participants into clinical trials. Clinical trials recruit patients with a good performance status (ECOG 0 or 1) which is not concordant with the real-world population. ASCO-Friends of Cancer Research in a joint statement has recommended the inclusion of patients with reduced PS in clinical trials. We evaluated the inclusion of patients with ECOG 2 or greater in urothelial cancer clinical trials leading to FDA approvals between 2014 and 2024. Methods: The US Food and Drug Administration (FDA) website was searched for all the drugs or drug combinations approved for the treatment of urothelial cancer in the last 10 years. We used identifiers like the drug name, trial name, and registration number to retrieve data on participant ECOG scores from public databases. The data was then tabulated and trends were analyzed. Results: The US FDA approved 16 drugs and combinations for the treatment of urothelial cancer from 2014-2024. The trials for these drugs enrolled a total of 5621 participants, of which only 107 (1.9%) belonged to ECOG PS 2 or more. ECOG data was not available for OLYMPUS trial. Only one of the trials included 3 participants with ECOG 3. Five trials did not have any participants belonging to ECOG 2 or higher. Most of the trials had percentage enrollment of ECOG 2 <10% except EV-201. Conclusions: Participants with ECOG 2 and greater have minimal enrolment in registrational clinical trials of urothelial cancer. This limits the options available for treatment of urothelial cancer in patients with reduced PS. Greater inclusion of poor PS patients is needed in future trials for greater health equity. Clinical trial Year Reduced PS% (ECOG 2 or higher) QUILT-3.0320 2024 3.5% BLC3001 2024 9.4% EV-302/KN-A39 2023 2.9% nadofaragene firadenovec-vncg 2022 2.5% CHECKMATE-274 2021 2.3% EV-201 2019 12.4% JNJ-42756493 2019 7.1% KEYNOTE-045 2017 1.1% CHECKMATE-901, EV-301, TROPHY, JAVELIN Bladder 100, KEYNOTE-057, durvalumab, atezolizumab 2016-2024 <1%

Automated gait event detection for exoskeleton-assisted walking using a long short-term memory model with ground reaction force and heel marker data

Traditional gait event detection methods for heel strike and toe-off utilize thresholding with ground reaction force (GRF) or kinematic data, while recent methods tend to use neural networks. However, when subjects’ walking behaviors are significantly altered by an assistive walking device, these detection methods tend to fail. Therefore, this paper introduces a new long short-term memory (LSTM)-based model for detecting gait events in subjects walking with a pair of custom ankle exoskeletons. This new model was developed by multiplying the weighted output of two LSTM models, one with GRF data as the input and one with heel marker height as input. The gait events were found using peak detection on the final model output. Compared to other machine learning algorithms, which use roughly 8:1 training-to-testing data ratio, this new model required only a 1:79 training-to-testing data ratio. The algorithm successfully detected over 98% of events within 16ms of manually identified events, which is greater than the 65% to 98% detection rate of previous LSTM algorithms. The high robustness and low training requirements of the model makes it an excellent tool for automated gait event detection for both exoskeleton-assisted and unassisted walking of healthy human subjects.

Contrast-enhanced magnetic resonance imaging based calf muscle perfusion and machine learning in peripheral artery disease

Real-world effectiveness and safety of avelumab first-line maintenance (1LM) treatment in patients with locally advanced or metastatic urothelial carcinoma (la/mUC): Second interim analysis of the AVENUE study.

706 Background: Avelumab 1LM is standard of care for patients with la/mUC without disease progression after 1L platinum-based chemotherapy (PBC) based on results from the JAVELIN Bladder 100 phase 3 trial. The AVENUE study is evaluating the effectiveness and safety of avelumab 1LM treatment in routine clinical practice in Germany, Spain, Switzerland, and Russia. Previous results showed the acceptable safety profile of avelumab 1LM in a heterogeneous real-world population. Here, we report initial effectiveness data and updated baseline and safety data from the second interim analysis. Methods: AVENUE is a prospective, noninterventional study in patients with la/mUC without disease progression after 1L PBC. Initiation of avelumab 1LM is decided by the treating physician prior to enrollment per local approval. Patients are followed for 36 mo. The primary objective is to evaluate the overall survival (OS) rate at 12, 24, and 36 mo. Secondary objectives include assessment of median OS, progression-free survival (PFS), tumor response, and safety. Results: By data cutoff (May 9, 2024), 177 patients had received avelumab 1LM (median follow-up, 10.0 mo). Median age was 70 years (range, 43-89) and 78% were male. ECOG PS was 0-1 in 89.3%, ≥2 in 5.1%, and not reported (NR) in 5.6%. Primary tumor site was upper or lower tract in 28.2% and 71.8%, respectively. 1L PBC regimen was gemcitabine + cisplatin in 61.0% (split dose in 8.5%), gemcitabine + carboplatin in 36.2%, and other/switch in 3.4%. Number of prior PBC cycles was <4, 4-6, >6, and NR in 12.4%, 84.2%, 2.8%, and 0.6%, respectively. Median time to avelumab 1LM initiation was 6.1 weeks (range, 0.3-80.4) and median treatment duration was 6.0 mo (range, 0.5-30.8). Median OS was not reached (95% CI, 17.0-not estimable) and 6- and 12-mo OS rates (95% CI) were 80.6% (73.9-85.7) and 69.1% (61.1-75.7), respectively. Median PFS was 5.8 mo (95% CI, 4.6-9.1) and 6- and 12-mo PFS rates (95% CI) were 50.0% (42.1-57.3) and 33.1% (25.2-41.2). Disease control rate (assessed up to 6 mo) was 66.9% (95% CI, 58.8-74.3). Treatment-related adverse events (TRAEs) occurred in 57.6%, were grade ≥3 in 15.8%, serious in 15.3%, and led to permanent discontinuation in 10.7%. The most common TRAEs of any grade (≥4.0%) were fatigue (9.6%), hyperthyroidism (5.1%), pruritus (4.5%), and diarrhea (4.0%). Grade ≥3 immune-related AEs and infusion-related reactions occurred in 6.2% and 3.4%, respectively. At last follow-up, 28.8% of patients remained on avelumab, and 34.5% and 8.5% had received second- or third-line treatment (enfortumab vedotin in 21.5% and 2.3%), respectively. Conclusions: Data from the second interim analysis of AVENUE confirm the effectiveness and acceptable safety profile of avelumab 1LM in patients with la/mUC treated in routine clinical practice, consistent with previous studies.

A phase 1/2 trial of durvalumab plus intravesical gemcitabine and docetaxel in BCG-unresponsive non-muscle invasive bladder cancer patients (HCRN GU16-243: ADAPT-BLADDER Cohort 4).

667 Background: A critical need persists to develop treatments for BCG-unresponsive (BCG-U) non-muscle invasive bladder cancer (NMIBC) patients (pts). The intravesical gemcitabine plus docetaxel (Gem/Doc) doublet and intravenous agents targeting the PD-(L)1 immune checkpoint have both demonstrated complete responses (CRs) in BCG-U NMIBC investigations. With this knowledge, we aimed to assess the clinical efficacy and safety of durvalumab (D) in combination with intravesical Gem/Doc. Methods: The multi-arm, multi-stage ADAPT-BLADDER trial design has been previously described (Hahn NM et al, Eur Urol 2023). Here, we report outcomes from the D + Gem/Doc (cohort 4) phase 1 and phase 2 expansion arms. In phase 1, BCG-U NMIBC patients were enrolled in a 6 + 3 + 3 fashion to establish safety. In phase 2, additional patients were enrolled to evaluate the primary endpoint of CR rate in the total study population and to provide a CR rate estimate within the subset of patients with CIS. Per protocol, phase 1 and 2 efficacy analyses were combined. Enrollment of pure papillary patients was capped to ensure at least 20 patients with CIS. Patients received D 1500 mg iv on day 1 of each 4-week cycle for up to 6 cycles. In addition, they received intravesical Gem 1000 mg + Doc 37.5 mg weekly for the first 6 weeks. Patients achieving a CR were encouraged, but not required, to receive Gem/Doc monthly maintenance therapy. Cystoscopic and urine cytology assessments were performed every three months in year one with a mandatory biopsy at 12-months in responding patients. Toxicity rates were reported per CTCAE v5.0. Results: Between 1/2022-10/2024, 40 pts enrolled (12 phase 1, 28 phase 2) from 6 sites. The study completed its full planned accrual. Demographics included: median age 69 years; 83% male; CIS (8 pts), high-grade (HG) T1 + CIS (7 pts), HG Ta + CIS (6 pts), HG Ta (13 pts) and HG T1 (6 pts). No dose limiting toxicities were observed in the phase 1 portion. Among 27 patients (15 CIS, 12 papillary) evaluable for response at the August 2024 data lock, a CR was observed in 24 patients (89%) (CIS – 13/15 (87%); Papillary – 11/12 (92%)). Evaluation of pts still receiving study treatment for CR and durability of response is ongoing. One pt (4%) progressed to muscle invasion on study treatment. Highest grade treatment-related adverse events observed were grade 1 – 12 (36%) pts, grade 2 – 11 (33%) pts, grade 3 – 2 (6%) pts (sepsis n=1, pneumonitis n=1), and grade 4 – 1 (3%) pt (cough n=1) respectively. One on-study death due to retroperitoneal bleed unrelated to study therapy was observed. Conclusions: Combination treatment with durvalumab plus intravesical gemcitabine and docetaxel demonstrates promising clinical efficacy with a high complete response rate. Observed adverse event type, frequency, and severity were consistent with prior durvalumab trial experiences. Clinical trial information: NCT03317158 .