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Smooth muscle contractility of laser-enucleated prostate tissues and impacts of preoperative α1-blocker treatment in patients with and without catheterization

Abstract Prostate smooth muscle contraction is central in treatment of voiding symptoms in benign prostatic hyperplasia (BPH). Tissues from transurethral resection of the prostate (TURP) and radical prostatectomy (RP) for prostate cancer are widely used to study contractions. However, findings are limited by traumatization in TURP, and uncertain relationship to BPH in RP tissues. This study aims to examine contractions of laser-enucleated tissues. Tissues from holmium/thulium laser enucleation (HoLEP/ThuLEP) and TURP were contracted by KCl, noradrenaline and electric field stimulation (EFS) in an organ bath. Contractions were compared to RP tissues in previous studies. KCl-induced contractions averaged 2.5 mN, 0.7 mN and 3.3 mN in tissues from HoLEP/ThuLEP, TURP and RP, with non-responsive tissues included (2.4% HoLEP/ThuLEP, 37% TURP). Maximum EFS-induced contractions (Emax) averaged 47% of KCl in HoLEP/ThuLEP tissues, 27% in TURP tissues, and 68–235% in 21 previous studies with RP tissues. Emax values for noradrenaline averaged 99.7% in HoLEP/ThuLEP tissues, 56% in TURP tissues, and ranged from 92 to 260% in RP tissues. Preoperative α1-blocker treatment reduced EFS- and noradrenaline-induced contractions, and increased EC50 values for noradrenaline in laser-enucleated, catheterized patients, but not in patients without catheterization. Also, the ex vivo application of α1-blockers increased the EC50 values for noradrenaline and reduced Emax for EFS. Laser-enucleated tissues allow investigation of prostate smooth muscle contraction in medication-refractory voiding symptoms. Different impacts of preoperative α1-blocker treatment on ex vivo contractility in tissues from patients with and without catheterization point to clinically relevant heterogeneity of patients undergoing surgery for BPH.

The impact of social vulnerability on perceived health in individuals with bladder cancer.

678 Background: Bladder cancer is the sixth most common malignancy in the United States. Social determinants of health (SDOH) have been increasingly recognized as drivers of disparities in cancer care. Improved understanding of the role of social vulnerabilities could better inform the cancer care delivery interventions towards equitable cancer care for bladder cancer patients. We aimed to study the impact of key SDOH measures (everyday discrimination, supportive relationships, neighborhood characteristics, and food and housing security) on the perception of overall health in bladder cancer patients using a publicly available database. Methods: A cross-sectional study was conducted using overall health and SDOH survey data collected by the National Institutes of Health All of Us Research Program from June 2017 to June 2022. Ordinal logistic regression was utilized to assess associations between overall perception of health and each specific SDOH survey domain. All statistical tests were two-sided, and a p-value less than 0.05 was statistically significant; multiplicity adjustments were not made. The Statistical package (0.13.5) of Python (Version 3.1) was used for all statistical analyses. Results: 1,796 participants with bladder cancer met the inclusion criteria. 640 (38.58%) had completed the SDOH surveys and were considered for analysis. Of the total population, there was a significant male preponderance (66.1% vs 31%). 559 (87.3%) were White, 3.4% Black or African American, and 3.6% with Hispanic ethnicity. In the ordinal logistic regression models. for every unit increase in the score of the supportive relationships SDOH domain (more supportive relationships), participants were 4% (OR = 1.04, 95% CI = [1.018, 1.053], p<0.0001) more likely to have a higher perception of general health. Similarly for every unit increase in the food and housing security domain (more secure food and housing status), participants are 19% ((OR =1.19, 95%CI= [1.06,1.34], p 0.004) more likely to have a higher perception of general well-being. Controlling for all other variables, Black race, Hispanic ethnicity, smokers, and age less than 65 years were independently significant for poor perception of overall health (p < 0.05). Conclusions: This is one of the first studies evaluating the role of each component of SDOH on the perception of overall health in bladder cancer patients. Our study demonstrates a clear predictive link between social determinants of health and the perceived overall health of bladder cancer patients. Specifically, stronger social support networks and secure access to food and housing were significantly associated with a more positive perception of health. These findings suggest that future directions in bladder cancer care should prioritize the development and implementation of comprehensive care models that address these social needs.

CHAPTER-Platform-201: Phase 2 trial of pimitespib plus enzalutamide for patients with metastatic castration-resistant prostate cancer.

TPS296 Background: Metastatic castration-resistant prostate cancer (mCRPC) patients (pts), especially those who experience disease progression while on androgen receptor signaling inhibitor (ARSI) therapy, have a poor prognosis and limited treatment options. Although taxanes are an available options, a second ARSI is more frequently used in this setting because of the toxicity of taxanes, pts’ preference, and comorbidities. However, the efficacy of a second ARSI is limited because of cross-resistance. The main mechanisms of cross-resistance are androgen receptor (AR) genomic alterations (AR amplification and mutation), AR splice variants, and upregulation of the glucocorticoid receptor (GR) and components of the PI3K/AKT pathway. Therefore, new treatment options for mCRPC after ARSI therapy are urgently needed. Pimitespib (PIMI) is a novel heat shock protein 90 (HSP90) inhibitor approved for treating Gastrointestinal Stromal Tumor. HSP90 is a molecular chaperone and forms the structure of client proteins. Many of HSP90's client proteins, such as AR and GR, which represent components of the PI3K/AKT pathway, have been identified as prostate cancer-related proteins required for tumor development; their activation depends on HSP90. PIMI suppresses the expression of AR and GR, which are client proteins related to bypass pathways, such as the PI3K/AKT pathway, by inhibiting HSP90 expression; this may help overcome acquired resistance to ARSI. This phase 2 study investigated the efficacy of PIMI in combination with enzalutamide (ENZ) in pts with mCRPC refractory to ARSI. Methods: This phase 2 study was conducted in pts with mCRPC who showed disease progression on one ARSI. The study includes two parts: feasibility part (FP) and expansion part (ExP). The FP is evaluated with six pts to determine the maximum tolerated dose of PIMI (160 mg/day or 120 mg/day, orally; 5 days on/2 days off) in combination with a standard dose of ENZ (160 mg/day, orally; once daily). The ExP is an open-label, randomized trial evaluating the efficacy and safety of a determined dose of PIMI in combination with ENZ versus ENZ monotherapy. Forty pts are randomized 1:1 to each arm. The primary endpoint of FP is dose-limiting toxicity, and ExP is blinded independent central review of radiographic progression-free survival (rPFS). The secondary endpoints include investigator-assessed rPFS, overall survival, objective response rate, pharmacokinetics, and safety. Among pts for whom mCRPC was diagnosed, those with histologically or cytologically confirmed prostate adenocarcinoma and prior refractory status to one ARSI are eligible for enrollment. Pts who had received taxanes for mCRPC are excluded. Enrollment began in July 2023 and is currently ongoing. Clinical trial information: 2031230263 .

Beyond survival: Understanding the social dimensions of prostate cancer.

28 Background: Prostate cancer carries one of the highest burdens of racial disparities in outcomes in oncology. Understanding social determinants of health (SDOH), which measure inequities in healthcare, could give us insight into quality improvement strategies. We aimed to study the impact of key SDOH measures (everyday discrimination, supportive relationships, neighborhood characteristics, and food and housing security) on the perception of overall health in prostate cancer survivors using a publicly available database. Methods: A cross-sectional study was conducted using overall health and SDOH survey data collected by the National Institutes of Health All of Us Research Program from June 2017 to June 2022. Ordinal logistic regression was utilized to assess associations between overall perception of health and each specific SDOH survey domain. All statistical tests were two-sided, and a p-value less than 0.05 was statistically significant; multiplicity adjustments were not made. The Statistical package (0.13.5) of Python (Version 3.1) was used for all statistical analyses. Results: 5,909 male participants with prostate cancer met the inclusion criteria. 2,280 (38.58%) had completed the SDOH surveys and were considered for analysis. Of those, 1,966 (86%) were White, 5.88% Black or African American, and 3.55% Hispanic in ethnicity. In the ordinal logistic regression models, for every unit increase in the SDOH neighborhood characteristics score, the odds of having a higher perception of general health increased by 3% (OR 1.03, 95% CI = [1.02, 1.04], p < 0.0001). For every unit increase in the SDOH day-to-day discrimination score, the odds of having a higher perception of general health increased by 3% (OR 1.03, 95% CI = [1.02, 1.04], p < 0.0001). For every unit increase in the score of the supportive relationships SDOH domain, participants were 4% (OR = 1.04, 95% CI = [1.035, 1.053]) more likely to have a higher perception of general health. Controlling for all other variables, Black race, Hispanic ethnicity, a history of mental health disorders, smokers, and age less than 65 years were independently significant for poor perception of overall health (p < 0.05). Conclusions: While SDOH have been linked with prostate cancer-specific mortality, this is one of the first studies evaluating the role of each component of SDOH on the perception of overall health. We highlighted that factors including neighborhood, discrimination, and supportive relationships have a quantifiable impact on health. Our study provides objective predictive changes in the overall perception of health. Using our variables as a model to predict the effect of changes in these determinants and tailor support to individual needs could ultimately improve quality of life.

Population attributable fraction of dietary risk factors for cancer mortality with a focus on gastrointestinal cancers in a population based cohort study

Abstract Diet and nutrition are critical factors influencing cancer, the second leading cause of death worldwide. This study evaluated dietary risk factors and cancer mortality. 49,773 participants aged 40–75 years from the Golestan Cohort Study (GCS) were followed for a median of 15 years. Dietary intake was assessed using a validated food frequency questionnaire. Cox proportional hazard models estimated hazard ratios (HRs) and 95% confidence intervals (CIs), while population attributable fractions (PAFs) quantified the impact of reducing dietary risk factors. Low fruit intake accounted for 4.7% (95% CI: 0.5-8.7%) of all cancer deaths and 4.91% (95% CI: 0-9.85%) of male cancer deaths. It contributed to 23.5% (95% CI: 4.7-38.59%) of pancreatic cancer mortality in both sexes and 29.36% (95% CI: 5.15-47.38%) of male pancreatic cancer deaths. Low omega-3 intake increased esophageal and gastric cancer mortality risks, with PAFs of 21.65% (95% CI: 1.14-37.9%) and 21.46% (95% CI: 2.81-36.53%), respectively. In females, low omega-3 intake accounted for 38.68% (95% CI: 4.05-60.81%) of gastric cancer deaths. Low fruit and omega-3 consumption elevated cancer mortality risk. Community- and individual-level interventions are essential to enhance nutrient intake and reduce cancer mortality.

Multicenter analysis of high-dose chemotherapy (HDCT) regimens for recurrent germ cell tumors (GCTs).

631 Background: HDCT is an established salvage treatment for patients (pts) with recurrent germ cell tumors (GCTs). However, comparative analyses between contemporary HDCT approaches are lacking. This study presents an updated, multi-center analysis of the two most commonly used HDCT regimens: 1) Carboplatin 700 mg/m² and etoposide 750 mg/m² (CE) for two cycles, and 2) Carboplatin AUC 7-8 and etoposide 400 mg/m² for three cycles following two cycles of paclitaxel 200 mg/m² and ifosfamide 2000 mg/m² (TICE). We also included less common high-dose carboplatin-based regimens. Methods: Data from four high-volume referral centers were pooled and included pts treated with HDCT for recurrent GCTs between 1/1/2010 and 1/1/2024. Pts received either CE, TICE, or other regimens, though formal comparisons focused on the CE and TICE cohorts. Statistical tests used included Fisher’s exact test and Wilcoxon rank-sum test for qualitative and quantitative variables, respectively. Kaplan-Meier and log-rank tests were used to estimate and compare relapse-free survival (RFS) and overall survival (OS). Analyses were conducted using R Statistical Software, version 4.3.1. Results: A total of 111 pts were included: 50 received CE (45%), 32 received TICE (29%), and 29 received other high-dose carboplatin-based regimens (26%). Median age at diagnosis was 28.5 years (range 14-58), with the majority being Hispanic (56.8%) and having non-seminomatous GCT (76.6%). Six (12%) and four (12.5%) pts in the CE and TICE cohorts, respectively, had primary mediastinal disease. Late relapses, defined as disease recurrence occurring more than 2 years after first-line treatment, were rare, affecting 1 pt (3%) from the CE cohort and 3 pts (6%) in the TICE cohort. Most pts (43.2%) had International Germ Cell Cancer Collaborative Group poor risk disease at diagnosis. HDCT was administered as second-line therapy in 47.7% of patients and as third-line or beyond in 51.4%, with comparable distribution between TICE (53.1%) and CE (46%). patients receiving transplant as third-line (p=0.459). After a median follow-up of 55.5 months post-transplant, no significant difference in median RFS was observed between TICE and CE (10.2 vs 5.9 months; HR 0.91, 95% CI [0.54, 1.51], p = 0.706). There was a trend toward improved median OS for TICE compared to CE (57.2 vs 19.8 months; HR 0.67, 95% CI [0.37, 1.2], p = 0.18). Previously published prognostic scores using the Beyer, Einhorn, and International Prognostic Factor Study Group models accurately stratified pts by RFS and OS. Subgroup analysis suggested a possible benefit of TICE over CE in higher-risk patients. Conclusions: This multicenter analysis found no significant difference in RFS between the CE and TICE regimens though a trend toward improved OS with TICE was observed, particularly in pts with higher-risk disease.

Prospective observational study in Japanese patients with metastatic castration-sensitive prostate cancer (mCSPC) with or without intraductal carcinoma of the prostate (IDC-P).

87 Background: Intraductal carcinoma of the prostate (IDC-P) is a high-grade, high-volume, invasive form of prostate cancer (PCa) associated with poor clinical outcomes. The International Society of Urological Pathologists (ISUP) recommends incorporating IDC-P into the Gleason scoring system. However, existing data on survival outcomes for prostate cancer patients with IDC-P are primarily based on retrospective analyses. This study aims to prospectively evaluate the survival outcomes of Japanese patients with metastatic castration-sensitive prostate cancer (mCSPC), with and without IDC-P, using real-world data from a multi-institutional observational study. Methods: Between 2018 and 2021, we prospectively enrolled 102 de novo mCSPC patients from affiliated healthcare institutions. Eligible patients were those diagnosed with mCSPC via prostate needle biopsy and classified as high-risk according to the LATITUDE criteria. All participants underwent a standard extended biopsy (≥10 cores) to diagnose IDC-P, ensuring minimal sampling error. A single genitourinary pathologist reviewed all biopsy slides based on the 2019 ISUP grading system. Patients received treatment with androgen receptor signaling inhibitors (ARSI) with or without docetaxel. Results: The median age of the patients was 72 years (range 57–92), and the median serum PSA level was 441 ng/mL (range 3.9–9807 ng/mL). The median follow-up period was 38.3 months (range 8.2–67.4 months). All patients had a Gleason grade ≥ 3, with 66 (64.7%) exhibiting a Gleason pattern 5. Lymph node metastasis was present in 67 patients (65.7%), visceral metastasis in 23, and bone metastasis in all patients. IDC-P was identified in 86 patients (84%). Multivariate analysis revealed that elevated lactate dehydrogenase (LDH) levels and the presence of IDC-P were independent predictors of poor castration-resistant prostate cancer (CRPC)-free survival (HR 4.387, p<0.001; HR 2.009, p=0.01) and progression-free survival (PFS2) (HR 6.801, p<0.001; HR 1.796, p=0.016). Conclusions: This prospective observational study demonstrated that higher LDH levels and the presence of IDC-P in biopsy samples were significantly associated with poorer survival outcomes in Japanese patients with mCSPC. These findings underscore the prognostic importance of IDC-P in mCSPC management.

Evaluating cost-effectiveness in the evolving treatment landscape for metastatic urothelial carcinoma.

695 Background: Metastatic urothelial carcinoma (mUCa) is the most expensive cancer to treat on a per-patient basis, largely due to the need for frequent interventions and costly follow-up care. In examining first-line therapies, combinations such as enfortumab-vedotin plus pembrolizumab (EV + P) and gemcitabine/cisplatin plus nivolumab show substantial overall survival advantages over the standard treatment (SoC) of gemcitabine/cisplatin. This study presents a cost-effectiveness analysis for mUCa. Methods: We developed a Markov model from a payer's perspective, utilizing clinical data derived from the Phase III Checkmate-901 and EV302/Keynote-A39 trials. To identify the optimal treatment from a socioeconomic standpoint, we employed Monte Carlo simulation, focusing on Germany and the United States (US). Subsequently, we compared the incremental cost-effectiveness ratio (ICER) for each treatment modality across various willingness-to-pay (WTP) thresholds. Results: At a lifetime horizon, SoC, gemcitabine/cisplatin plus nivolumab and EV + P were associated with average costs of €163,424 (US: $458,006), €206,853 (US: $597,802), and €401,170 (US: $1,228,455), respectively, while achieving QALYs of 1.21, 1.71, and 2.31, respectively. The ICERs for the newer treatment strategies were €87,340 (US: $281,142) for gemcitabine/cisplatin plus nivolumab and €216,140 (US: $700,448) for EV + P. At a commonly accepted WTP threshold of €/$100,000, gemcitabine/cisplatin plus nivolumab emerged as the optimal strategy in Germany, while EV + P would necessitate a price reduction of 46% (US: 82%) to achieve cost-effectiveness. Conclusions: QALYs nearly double with the combination of EV + P compared to the current SoC; however, the associated costs may not be justifiable from a strict socioeconomic perspective. Despite offering lower oncological benefits, gemcitabine/cisplatin plus nivolumab should be considered for first-line therapy due to its favorable cost-effectiveness, particularly in Europe. Furthermore, identifying individual risk factors is crucial for optimizing therapeutic responses and managing treatment costs in the future.

The prevalence and associated risk factors of primary dysmenorrhea among women in Beijing: a cross-sectional study

AI-driven prediction of prostate cancer risk: A comparative analysis with C the Signs in the Mayo Clinic data platform.

371 Background: Prostate cancer is the most common malignancy in men globally and remains among the top five leading causes of cancer-related deaths. Emerging evidence suggests that early identification of symptoms can detect localized disease thus enabling opportunities for curative intent treatments. This study evaluates the use of the AI-powered prediction model, C the Signs, to passively screen for prostate cancer by leveraging data from electronic medical records (EMRs), offering a novel pathway for identifying high-risk individuals. Methods: A retrospective analysis was conducted using the Mayo Data Platform, encompassing 418,477 male patient records, of which 16,835 were diagnosed with prostate cancer. C the Signs identified patients at risk based solely on their EMR data, utilizing AI-driven pattern recognition. Sensitivity and specificity analyses were performed to assess the prediction model’s accuracy. Additionally, we examined the time-to-diagnosis advantage for patients flagged by the model compared to traditional physician clinical diagnoses. Results: C the Signs demonstrated a sensitivity of 83.3% and a specificity of 52.5% for identifying patients at risk of prostate cancer. Notably, 31.8% of prostate cancer cases were identified at risk up to five years earlier by the model compared to traditional physician clinical diagnosis. Conclusions: The integration of AI-driven prediction models like C the Signs into prostate cancer screening pathways provides an opportunity to enhance early detection, particularly in symptomatic individuals. Compared to prostate-specific antigen (PSA) testing, the model achieved equivalent sensitivity and 38% higher specificity, positioning it as a valuable companion tool for improving patient outcomes.

Addition of darolutamide to first line treatment of metastatic castration-resistant prostate cancer (mCRPC): A randomized open label phase II trial (SAKK 08/23).

TPS280 Background: The implementation of androgen-receptor pathway inhibitors (ARPI) +/- docetaxel (doce) in addition to androgen deprivation therapy (ADT)in metastatic hormone sensitive prostate cancer (mHSPC) has limited the therapeutic options in the mCRPC setting. In the SAKK 08/16 trial, darolutamide (daro) maintenance demonstrated prolonged radiographic progression-free survival (rPFS) compared to placebo in patients (pts) with mCRPC who had received prior ARPI, and did not progress during taxane therapy. This benefit was more pronounced in pts with a response to the prior ARPI. Continuing enzalutamide in addition to doce versus a switch to doce alone after progression on enzalutamide in later line mCRPC has been demonstrated to prolong PFS in a phase 3 trial. The continued maximal androgen-receptor (AR) blockage in the mCRPC first-line setting in addition to a standard of care could potentially control persistent AR-pathway sensitive clones. Daro is an optimal drug for the use as ARPI maintenance because of its favourable safety profile and a low potential for drug-drug interactions.We hypothesize that the addition of daro to a first-line SOC in mCRPC in pts with a prior long response to ADT and ARPI in mHSPC improves rPFS. Methods: SAKK 08/23 is an international open-label randomized phase 2 trial enrolling pts with ECOG 0-2 having progressed to mCRPC with a response to prior ADT-ARPI combination for at least 18 months showing at least a 50% PSA response or partial remission according to RECIST. Pts must not have received treatment for mCRPC. Pretreatment with doce in mHSPC is allowed. Patients will be randomized 1:1 to receive physician’s choice standard of care (SOC: doce, cabazitaxel, 177 lutetium-PSMA, radium-223 or olaparib) or SOC with daro. Treatment with daro will be continued until progression according to PCWG3. Stratification factors include country and treatment with taxanes versus radium-223 versus 177 lutetium-PSMA vs olaparib. The primary endpoint is rPFS. Secondary endpoints include overall survival, time to symptomatic/clinical progression, event-free survival, time to PSA progression by PCWG3, objective response rate according to RECIST, PSA response and PSA response duration. Without daro we expect a median rPFS of 6 months for taxanes, radium-223 and Olaparib and 8 months for 177 lutetium-PSMA. Assuming a three months increase in median rPFS with the addition of daro 121 events are needed (one-sided type I error of 10%, power of 80%) which leads to a sample size of 162 patients (including 10% dropout after one year). The trial will enroll pts in Switzerland and Spain. Accrual to the study is currently ongoing. Clinical trial information: NCT06401980 .

The prognostic significance of prostate-specific antigen dynamics during abiraterone therapy in patients with high-risk metastatic hormone-sensitive prostate cancer.

78 Background: The depth reduction in prostate-specific antigen (PSA) levels serves as a prognostic indicator for patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC) undergoing treatment with abiraterone. However, the potential impact of the duration of PSA level depth reduction on prognosis remains uncertain. Methods: We conducted a comprehensive review of data from 153 high-risk mHSPC patients undergoing first-line abiraterone therapy. The group analysis was conducted based on the alterations in PSA levels during abiraterone therapy. Kaplan-Meier survival curves and Cox proportional hazards regression analysis were used to evaluate the association between the trend and duration of PSA decline and treatment outcomes, which include PSA progression-free survival (PSA-PFS), radiographic progression-free survival (rPFS), and overall survival (OS). Results: Among the 153 patients treated, 85 exhibited a minimum PSA level of less than 0.2 ng/ml, 48 had a minimum PSA level ranging from 0.2 to 0.4 ng/ml, and 20 presented with a minimum PSA level exceeding 4 ng/ml.During abiraterone treatment, the lowest PSA level of <0.2 ng/ml was significantly associated with improved mPSA-PFS (51.0 vs. 18.5 vs. 6.9 months, P < 0.0001), mrPFS (52.0 vs. 24.3 vs. 10.3 months, P < 0.0001), and mOS (NR vs. 48.5 vs. 28.1 months, P < 0.0001). A reduction in PSA levels exceeding 90% was correlated with enhanced patient survival outcomes; additionally, a baseline PSA level of <80 ng/ml at the initiation of abiraterone therapy significantly improved patients' mPSA-PFS (43 .1 vs .26 .0 months, P=0 .01), mrPFS (46 .8 vs .27 .5 months, P=0 .01), and mOS (NR vs .43 .8 months, P=0.03).In the cohort with the lowest PSA levels (PSA < 0.2 ng/ml), achieving a PSA level of less than 0.2 ng/ml within six months and maintaining this level for over ten months significantly enhanced clinical outcomes, as evidenced by mPSA-PFS (NR vs. 26.9 months, P < 0.0001), mrPFS (NR vs. 27.5 months, P < 0.0001), and mOS (NR vs. 44.4 months, P < 0.0001). Cox regression analysis indicated that achieving a PSA level of less than 0.2 ng/ml within six months, sustaining this level for more than ten months, along with age and initial PSA at diagnosis were independent prognostic factors. Conclusions: In mHSPC patients undergoing first-line abiraterone treatment, a sustained improvement in PSA levels serves as an indicator of therapeutic response, while the rate and depth of PSA decline, along with its duration, are critical prognostic determinants.

Identification of metabolism-related subtypes and feature genes of pre-eclampsia

Chronic obstructive pulmonary disease mortality risk in renal cell carcinoma: A population-based study from 1992-2021.

450 Background: Renal Cell Carcinoma (RCC) is one of the most common malignancies in the United States, with about 82000 new cases and 15000 deaths each year. Over the years, RCC mortality rates have been on a downward trend, and this is attributable to cutting-edge research and treatment modalities; however, non-cancer deaths continue to have an increasing trend. Chronic Obstructive Pulmonary Disease (COPD) plays a significant role in this trend. We holistically evaluated the COPD mortality risk in patients with RCC. Methods: We utilized the Surveillance, Epidemiology, and End Results (SEER) database to retrieve cases of RCC with mortality secondary to COPD from 1992 to 2021. The histologic code for RCC in the SEER database is 8312/3, which is part of the International Classification of Diseases for Oncology, Third Edition (ICD-O-3). We then obtained the standardized mortality rates (SMR) and absolute excess risk (AER). Results: We compared the COPD mortality risk of each group to the general US population and noted significantly increased COPD SMRs. Patients with non-COPD causes of death and patients with unknown age, race and cancer stage were excluded. Regarding race, Non-Hispanic American Indians had the highest risk of COPD mortality (SMR 15.30, CI 3.16-44.71, AER 1029.25), followed by Non-Hispanic Asian/Pacific Islanders (SMR 8.67, CI 5.22-13.55, AER 1781.62), then Hispanics (SMR 3.67, CI 2.63-4.97 994.43), Non-Hispanic Whites (SMR 2.69, CI 2.44-2.95, AER 788.19), Non-Hispanic Blacks (SMR 2.33, CI 1.67-3.16, AER 648.94). Based on cancer stage, distant had the highest risk of COPD mortality (SMR 16.65, CI 9.70-26.65, AER 3985.35) while regional had relatively the lowest risk (SMR 3.62, CI 2.18-5.65, AER 1174.61) with localized (SMR 4.00 CI 3.37-4.72, AER 1572.98). In terms of age, patients aged 40-59 years had an SMR of 5.33 (CI 4.28-6.56, AER 619.66), 60-79 years had an SMR of 2.73 (CI 2.45-3.03, AER 838.76), while 80 years and above had an SMR of 2.00 (CI 1.63-2.43, p<0.05, AER 1261.89). Conclusions: We evaluated the extent of the risk of COPD-related deaths in RCC patients. Compared to the general United States population, patients with RCC have a higher risk of COPD mortality. Therefore, there is a need to improve primary and secondary preventive modalities and modify risk factors in this subset of patients to reduce morbidity and mortality.

Determining lung cancer screening eligibility in a surgically treated urothelial carcinoma population: Making the case for linking bladder cancer screening to lung cancer screening.

875 Background: Bladder cancer is the 10th most common cancer globally, with 573,278 cases reported in 2020. Tobacco consumption is a major risk factor; smokers have a 3x higher risk of bladder cancer compared to non-smokers. Tobacco consumption is also a risk factor for lung cancer, and current guidelines recommend screening high risk patients. While screening for bladder cancer in the general population is not recommended, screening high-risk bladder cancer populations may be beneficial. We hypothesize that linking bladder cancer screening to lung cancer screening may have higher yield than general population screening and enable earlier bladder cancer diagnosis. Methods: We performed a retrospective review of patients at a single-institution that underwent surgical treatment for urothelial carcinoma (TURBT, ureteroscopy, ureterectomy, nephroureterectomy, or cystectomy) by a single urologic-oncologist from October 2022 to June 2024. Patients were initially referred for microscopic/gross hematuria, badder/upper tract mass, or known urothelial cancer. We collected patient demographics, smoking history and imaging/surgical pathology. We aimed to determine the eligibility of these patients for lung cancer screening programs. Secondary outcomes included rates of lung cancer screening and lung cancer diagnosis. Results: We identified 76 patients with a urothelial carcinoma diagnosis. 87% had bladder cancer and 13% had UTUC. 48 (63%) patients were either current or former smokers, and the mean pack year history was 24 pack years. Of those patients, 14 (29%) met the criteria for lung cancer screening guidelines (ages 50-80, at least a 20 pack year smoking history, and current smoker or quit within 15 years); only 1 patient (7%) had received a screening low-dose CT Chest for lung cancer screening. Out of these 14 patients, 11 (79%) had a concerning finding on CTU. Conclusions: Our analysis highlights that lung cancer screening uptake remains low. In our cohort, 29% met lung cancer screening guidelines at the time of diagnosis. In this high risk population, 79% had concerning findings on CTU. While our results are promising and establish a potential rationale for linking bladder cancer screening to lung cancer screening due to their higher inherent risk, future prospective studies are needed to demonstrate utility and benefit. Patient demographic information. No Smoking History (N = 28) Smoking History (N = 48) Overall (N = 76) Age, Mean (SD) 72.5 (12.2) 72 (9.9) 72.2 (10) Sex (%) Male 20 (71.4%) 35 (72.9%) 55 (72.4%) Female 8 (28.6%) 13 (27.1%) 21 (27.6%) Gross Hematuria Upon Presentation 12 (42.9%) 36 (75.0%) 48 (63.2%) Concerning CTU Findings 14 (50.0%) 31 (64.5%) 45 (59.2%) Taking Blood Thinners 11 (39.2%) 18 (37.5%) 29 (38.2%) CAD/Afibb/Stroke/PE 13 (46.4%) 19 (39.6%) 32 (42.1%) HTN/DM 17 (61%) 25 (52%) 42 (55.2%)

NSD2 inhibition as a therapeutic approach for treatment-induced neuroendocrine prostate cancer.

198 Background: Trans-differentiation from adenocarcinoma to neuroendocrine histology is a major treatment-induced resistance mechanism against androgen receptor pathway inhibitors (ARPI) in castration-resistant prostate cancer (CRPC). With increased use of ARPI in the clinic, neuroendocrine prostate cancer (NEPC) constitutes 15~20% of CRPC. The histone H3 K36 di-methyltransferase NSD2 has recently been shown to be a driver of the adeno-to-neuroendocrine trans-differentiation. The level of NSD2 expression is markedly increased in AR(-) NEPC compared to AR(+) CRPC and correlates with a poor disease outcome. Furthermore, genetic depletion of NSD2 has been shown to reverse AR(-) NEPC to an AR(+) adenocarcinoma phenotype and re-sensitize the prostate cancer cells to enzalutamide treatment. Methods: K36 Therapeutics has developed a selective NSD2 inhibitor KTX1001 that is currently undergoing clinical evaluation in multiple myeloma (NCT05651932). Dose proportional pharmacokinetics and on-target pharmacodynamics of KTX1001 have been observed as well as an excellent safety profile in patients. Here we have investigated whether pharmacological inhibition of NSD2 reverses AR(-) NEPC to AR(+) adenocarcinoma in preclinical models. Results: In the NEPC cell line NCI-H660, KTX1001 treatment led to a significant change in the epigenome landscape, resulting in reduced expression of neuroendocrine markers SYP, CHGA and FOXA2 and concomitant upregulation of the adenocarcinoma markers AR, NKX3.1 and KLK3. These observations are consistent with a lineage change from AR(-) NEPC to AR(+) adenocarcinoma. We further investigate this in vivo using a NEPC patient-derived xenograft model. Indeed, treatment with our selective NSD2 inhibitor resulted in pronounced upregulation of the Hallmark Androgen Response gene signature, suggesting restoration of the AR-signaling pathway. Moreover, Hallmark E2F and Myc signatures, which are known to be elevated in NEPC cells, were markedly downregulated after NSD2 inhibitor treatment. These observations suggest a significant change in NEPC lineage identity towards AR(+) adenocarcinoma. Conclusions: These data support our hypothesis that NSD2 inhibition can reverse NEPC to AR(+) adenocarcinoma lineage and restore sensitivity to standard-of-care ARPI. Given these mechanistic insights and the safety profile observed with our NSD2 inhibitor in the clinic, evaluation of NSD2 inhibition in NEPC patients is warranted.

Establishing reproductive seasons for the conservation of the critically endangered Kashmir red deer Cervus Hanglu

Survival outcomes of testicular cancer (TC) in Hispanic men based on analyses from the National Cancer Database (NCDB).

622 Background: The incidence of TC among Hispanic men has been rising, as reported in our analysis of patients in the United States (Yu et al., JCO 2024 42 (4):503). We sought to determine the survival outcomes in Hispanic men based on data obtained from the National Cancer Database (NCDB). Methods: We extracted patient-level data from the NCDB and identified the incidence, demographics, treatment patterns, and outcomes in Hispanic men with TC diagnoses (non-seminoma, NS; seminoma, S) from 2004 to 2020. Results: There were a total of 89550 patients (pts) in the database. Median age at diagnosis was 37 years and 29 years for S and NS pts, respectively. There were 11005 (12.3%) TC pts designated as Hispanic (H), of whom 5396 and 5609 had S and NS TCs, respectively. In contrast, there were a total number of 74350 non-Hispanic (NH) patients with TC; n = 43629 with S, n = 30721 with NS. The majority of H pts had a Charlson-Deyo score of 0 (94.2%). Less than half of H pts had private insurance (48.8%) compared to three-quarters of NH patients (75.1%). 19.6% of H pts were diagnosed with stage II & III TC (compared to 15.8% in NH pts). Pts were treated at academic/research centers in 6.6% of H pts versus 10.8% in NH pts. For S pts, radiation was utilized in 19.4% of H pts vs 25.8% in NH pts, chemotherapy utilized in 28.3% H pts vs 24.4% in NH pts, whereas chemotherapy for NS pts was utilized in 60.1% in H pts vs 53.4% in NH pts. Overall Survival (OS) was not significantly different in S pts for H pts vs NH pts (Log-rank p = 0.066), but among NS pts, H patients did worse compared to NH pts (Log-rank p < 0.001) although OS differences were seen in pooled analyses of S and NS pts (log-rank p < 0.001). Conclusions: Our analysis reports on the treatment patterns and survival of Hispanic men with TC. Survival appears to be worse for Hispanic patients with non-seminoma compared to non-Hispanic patients, but outcomes for seminoma are similar. We also noted slight differences in patterns of treatment receipt for seminoma versus non-seminoma in Hispanic men which may have to do with stage at diagnosis and access to care.

Analyses on impact of tumor burden at progression and changes in IMDC from baseline in patients (pts) with advanced renal cell carcinoma (aRCC) treated with lenvatinib + pembrolizumab (L+P) in the phase 3 CLEAR trial.

531 Background: L+P significantly improved efficacy vs sunitinib in treatment-naïve pts with aRCC in the CLEAR trial (Motzer 2021). We report data from further analyses on the impact of tumor burden at the time of progression and shifts in IMDC scores in the L+P arm of the CLEAR study. Methods: Study design has been reported (Motzer 2021). Data cutoff for analyses was July 31, 2022 (median follow-up: ~4 years; Motzer 2024). Data herein are limited to the L+P arm of CLEAR. Medians for survival from either progression or randomization (i.e., overall survival) were estimated by Kaplan-Meier method, and 95% CIs were estimated via generalized Brookmeyer and Crowley method. Survival was assessed according to percent changes from baseline in target lesion diameters of pts at progression (on L+P) by tertiles (T1: ≤-61%; T2: >-61%-≤-34%; T3: >-34%-≤51%). Changes in IMDC score from baseline were reported at 6 months to assess treatment impact on prognosis. Results: Pts with a larger percentage decrease in sums of target lesion diameters at progression had longer median survival (months [95% CI]) from time of progression vs pts with smaller percentage decreases in tumor size (T1 [n=59], 35.6 [28.4-39.2]; T2 [n=58], 24.4 [15.5-34.5]; T3 [n=59], 20.2 [16.4-26.9]). Similar trends were observed with overall survival (from randomization; T1, not estimable [49.9-NE]; T2, 43.0 [33.0-NE]; T3, 31.5 [22.4-34.4]). Most pts, irrespective of tumor shrinkage at progression, received subsequent systemic anticancer medication during survival follow-up (T1: 63%; T2: 59%; T3: 71%). Pts received an anti-VEGF therapy (46%; 45%; 59%) as their first subsequent medication more frequently than any other medications. The most frequently used anti-VEGF therapies were cabozantinib (22%; 29%; 29%), sunitinib (12%; 3%; 20%), and axitinib (7%; 3%; 8%). At 6 months, IMDC score stayed the same or decreased from baseline in most pts; ≤10% of pts had increases in IMDC score, regardless of score at baseline (Table). Conclusions: Pts in the L+P arm with lower disease burden at progression showed improved prognosis, highlighting the importance of deep tumor response when considering treatment sequence. IMDC risk scores were typically constant or improved in pts treated with L+P; data are limited by missing pts. Clinical trial information: NCT02811861 . L+P arm IMDC score at 6 months, n (%) Baseline IMDC score a Decreased by ≥1 points Remained constant Increased by 1 point Increased by ≥2 points Missing b 0 (n=110) NA 84 (76) 9 (8) 2 (2) 15 (14) 1 (n=137) 25 (18) 82 (60) 8 (6) 2 (1) 20 (15) 2 (n=72) 34 (47) 18 (25) 5 (7) 1 (1) 14 (19) 3 (n=26) 18 (69) 0 0 0 8 (31) 4 (n=5) 4 (80) 0 0 0 1 (20) 5 (n=1) 1 (100) 0 0 0 0 Total (n=355) 84 (24) 186 (52) 22 (6) 5 (1) 58 (16) a 4 pts had a missing score at baseline. b IMDC prognostic score was derived based on total risk score from 6 prognostic factors at baseline and month 6 (+/- 2 weeks).

A prospective phase II study to evaluate olaparib plus abiraterone and prednisone combination therapy in metastatic hormone sensitive prostate cancer patients with HRR gene mutation: Updated analysis of PROact.

TPS292 Background: Approximately 10% - 15% of patients with metastatic hormone sensitive prostate cancer (mHSPC) harbor loss-of-function mutations in homologous recombination repair (HRR) genes. Although olaparib plus abiraterone and prednisone has significantly prolonged radiographic progression-free survival (rPFS) in metastatic castration resistant prostate cancer patients, there is a lack of evidence regarding the efficacy of this combination therapy in patients with mHSPC. Here, we report the updated analysis of PROact study, the first phase II trial to evaluate the effects of olaparib plus abiraterone and prednisone in mHSPC patients with HRR gene mutation. Methods: This was a single center, single arm, phase II trial (NCT05167175) conducted in male patients with mHSPC who had at least one HRR gene mutation ( BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD 51C, RAD51D and RAD54L ) as determined by tissue-NGS. Patients were administered olaparib 300 mg BID plus abiraterone 1000 mg QD and prednisone 5 mg QD. Previous treatment with new hormonal agent (NHA) was not allowed. The primary endpoint was 1-year radiographic progression-free survival (rPFS) rate per PCWG3-modified RECIST 1.1 by investigator assessment. The secondary endpoint included prostate-specific antigen (PSA) response rate, objective response rate (ORR), and adverse events. Safety and efficacy data with a median follow-up of 9.5 months have been reported. Here, we present the updated efficacy data categorized by gene. Results: Thirty patients were enrolled, all of whom had de novo mHSPC, consisting of 30% (9/30) with low-volume and 70% (21/30) with high-volume disease. As of the data cut-off (September 6, 2024), the median follow-up duration was 14.0 months. 13 patients had measurable disease; the confirmed ORR was 84.6% (11/13). One patient with ATM mutation achieved complete response. Ten patients obtained partial response, including four with BRCA2 , two with ATM , two with CDK12 , one with RAD51B mutations and one with co-mutation of three pathogenic genes. Furthermore, two patients harboring BRCA2 mutation experienced progressive disease (Table). Clinical trial information: NCT05167175 . Gene by gene efficacy evaluation. HRR mutation Totally number RECIST assessment CR PR PD BRCA2 11 6 0 4 2 CDK12 7 2 0 2 0 ATM 6 3 1 2 0 PALB2 2 0 - - - CHEK2 1 0 - - - RAD51B 1 1 0 1 0 RAD51D 1 0 - - - CDK12, CHEK2, RAD51B 1 1 0 1 0