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ESM1 promote proliferation, invasion and angiogenesis via Akt/mTOR and Ras pathway in kidney renal clear cell carcinoma

Time burden and healthcare costs associated with docetaxel in patients with metastatic castration-sensitive prostate cancer (mCSPC) initiating an androgen receptor pathway inhibitor (ARPI) –based regimen.

58 Background: Prior to ARPIs, chemotherapy was used to treat mCSPC. Recently, intensifying mCSPC treatment with a triplet combination of chemotherapy, ARPI and androgen deprivation therapy (ADT) has been a recommended approach. Few recent studies explore time burden and costs associated with chemotherapy-containing regimens (CCR) relative to non-chemotherapy containing regimens (NCR). This study compared the additive burden of docetaxel to ADT and ARPI combination by assessing the number of days needed to manage prostate cancer (PC) care and healthcare costs among patients with mCSPC receiving CCR or NCR in the US. Methods: Clinical data from community urology practices (PPS Analytics) linked with the Komodo Research Database (1/1/2016-12/31/2023) were used to identify patients initiating a CCR or NCR. The index date was earliest of ARPI or docetaxel initiation. Patients were followed from index until earliest of 12 months, ARPI discontinuation, start of new ARPI, chemotherapy initiation (NCR cohort only), or end of insurance/data availability. Outcomes reported per-patient-per-month (PPPM) included time spent managing mCSPC (total days with PC-related resource utilization [inpatient admissions, outpatient, emergency room, and other PC-related visits]) or PC management care (imaging, biopsy, chemotherapy management [iron/blood transfusions, erythropoiesis-stimulating agents, granulocyte colony-stimulating factor], testing), and all-cause and PC-related healthcare costs ($2023 US dollars). Cohorts were balanced on baseline covariates using overlap weighting. Outcomes were compared using weighted multivariable Poisson and linear regression models. Results: A total of 126 CCR and 837 NCR patients were identified (mean age 64.7 years, 52.6% White, 14.4% Black, and 33.7% had visceral metastasis in both cohorts). Patients were followed for a mean of 6.3 (CCR) and 6.8 (NCR) months. For the CCR cohort, a mean of 4.0 docetaxel infusions were observed per patient (mean time 22.0 days between infusions). The CCR cohort spent a mean of 4.1 days PPPM managing mCSPC, compared to 3.3 days PPPM in the NCR cohort (rate ratio: 1.18; 95% confidence interval [CI]; 1.03, 1.34). Mean all-cause medical and pharmacy costs were $17,833 PPPM in the CCR cohort and $11,527 PPPM in the NCR cohort (weighted adjusted cost difference [CD]: $6,184; 95% CI: 3,515, 8,517). Mean all-cause medical costs were $6,592 PPPM in the CCR cohort and $4,240 PPPM in the NCR cohort (CD [95% CI]: $2,060 [865, 3,369]). Conclusions: In this real world study, patients initiating a CCR experienced greater time toxicity managing mCSPC and higher healthcare costs than those initiating an NCR. Counseling expressing these differences in burden should be included in decision-making conversations when selecting treatment for mCSPC.

Validation of a 15-gene prognostic signature in metastatic clear cell renal cell carcinoma.

578 Background: Our group previously developed and validated a 15-gene prognostic signature (15G score) in localized clear cell renal cell carcinoma (ccRCC). Giving its ability to differentiate aggressive and indolent disease in the localized setting, we sought to apply the 15G score to patients with metastatic ccRCC to evaluate the 15G score’s prognostic performance across different treatments. Methods: We analyzed 2,121 patients from four major metastatic ccRCC trial datasets: IMmotion 150 (IMM150), Immotion 151 (IMM151), Javelin Renal 101 (JR101), and Checkmate 009, 010, and 025 (CM009/010/025). Treatment and control arms from all trials were included and grouped within treatment groups which included atezolizumab, atezolizumab plus bevacizumab, sunitinib, avelumab plus axitinib, nivolumab, and everolimus. The 15G score, originally derived and established to be prognostic in localized ccRCC, was calculated using z-score transformed RNA-seq data from each arm of the included trials to classify patients into high-risk versus low-risk using a previously derived threshold. We tested the association of 15G score high-risk with progression free survival (PFS) in each treatment group using Cox proportional hazards analyses with and without controlling for MSKCC risk. Results: On univariable Cox analysis, a 15G high-risk score was associated with significantly worse PFS in five of the seven treatment groups (Table). Worse PFS was observed for atezolizumab, atezolizumab plus bevacizumab, sunitinib, and everolimus (HR [95% CI]: 2.8 [1.6-4.9],1.7 [1.4-2.2], 1.7 [1.4-2.0], and 1.5 [1.1-2.2]. Within IMM151 and CM009/010/025, where risk group data were available, 15G score high-risk was independently associated with worse PFS while controlling for MSKCC risk group for atezolizumab plus bevacizumab, sunitinib, and everolimus (HR [95% CI]: 1.5 [1.2-2.0], 1.7 [1.4-2.2], 1.6 [2.3], p<0.05). Within CM009/010/025, where overall survival (OS) data were available, 15G score high-risk was associated with worse OS for everolimus (HR [95% CI]: 1.5 [1.0-2.2]) but did not reach significance for nivolumab (HR [95% CI]: 1.4 [0.9-2.0]). Conclusions: The 15G score was independently prognostic in metastatic ccRCC among a diverse cohort of patients receiving different systemic therapy regimens. PFS associated with 15G score high-risk compared to low-risk from univariable Cox analysis within each treatment group. Treatment Group Trials 15G scoreLow-risk (n) 15G scoreHigh-risk (n) p-value PFS HR (95% CI) Immunotherapy Atezolizumab IMM150 45 41 <0.001 2.8(1.6, 4.9) Nivolumab CM009/010/025 74 106 0.06 1.4(1.0, 1.9) Combination Atezolizumab+Bevacizumab IMM151/150 218 277 <0.001 1.7(1.4, 2.2) Avelumab+Axitinib JR101 152 202 0.09 1.3(1.0, 1.8) TKI / MTORi Sunitinib IMM150/IMM151/JR101 370 507 <0.001 1.7(1.4, 2.0) Everolimus CM009/010/025 51 78 0.03 1.5(1.1, 2.2)

Molecular evolution of HRR gene alterations in metastatic prostate cancer: A ctDNA-based study.

255 Background: Homologous recombination repair (HRR) genes, including DNA repair genes, are increasingly recognized for impacting treatment resistance and prognosis of metastatic prostate cancer (mPC). Next-generation sequencing of circulating tumor DNA (ctDNA) enables non-invasive, longitudinal monitoring of molecular alterations in patients (pts) undergoing systemic therapies. This study explores the dynamic changes in ctDNA profiles in mPC, particularly focusing on the HRR alterations. Methods: We utilized GuardantINFORM, a clinical-genomics database containing de-identified ctDNA test results and commercial payer-claims data. Eligible pts had a diagnosis of mPC and underwent ctDNA testing pre (within 3 months before initiation) and post (within 3 months of discontinuation before initiating subsequent treatment) Androgen Receptor Pathway Inhibitors (ARPi), poly ADP-ribose polymerase inhibitors (PARPi), and taxane chemotherapy. Mann-Whitney test assessed the differences in mutations. We also examined the association between ctDNA burden and overall survival (OS). Results: From a database of 21,682 pts with mPC, 145 had ctDNA collected pre/post-ARPi, 54 pre/post PARPi and 115 pre/post taxane chemotherapy. Pre-to-post-ARPI, individual HRR alterations increased from 21 to 34, with the most common (%pre/%post) genes to be altered, including ATM (5.5/7.6), BRCA2 (3/6) and CDK12 (3/2). In the PARPi group, the most prevalent (%pre/%post) genes to be altered were ATM (28/22), BRCA2 (28/20) and BRCA1 (4/6). Although overall BRCA2 prevalence declined, 11 new unique alterations were detected post-PARPi, along with an increase in unique BRCA1 (2 to 4) and BRCA2 (16 to 21) alterations. Three of 25 patients (12%) who underwent serial testing pre- and post-PARPi exhibited BRCA reversion mutations. In the taxane group, notable (%pre/%post) HRR genes to be altered included ATM (4/3), BRCA1 (1/3), and BRCA2 (1/3). Patients with higher ctDNA burden in pre-treatment samples exhibited worse OS. Conclusions: This study reveals dynamic changes in HRR gene alterations in mPC using ctDNA profiling. We observed increased unique alterations in ATM, BRCA1, and BRCA2 post-treatment, along with BRCA reversion mutations, indicating potential treatment resistance mechanisms. These findings underscore the importance of tailoring therapeutic approaches based on HRR gene profiles in mPC.

Relationship between undetectable PSA nadir and outcomes for patients with metastatic hormone-sensitive prostate cancer (mHSPC) in IRONMAN, the International Registry for Men with Advanced Prostate Cancer.

65 Background: Intensified androgen deprivation therapy (ADT) with an androgen receptor pathway inhibitor (ARPI) and/or docetaxel has led to improved outcomes for metastatic hormone-sensitive prostate cancer (mHSPC) in multiple clinical trials. Achievement of an undetectable PSA nadir has been associated with improved clinical outcomes, but real-world data across treatment regimens are limited. Methods: We evaluated PSA response and outcomes for patients with mHSPC treated with ADT monotherapy (mono), ADT + ARPI, and ADT + docetaxel in the International Registry for Men with Advanced Prostate Cancer (IRONMAN). All patients with mHSPC enrolled in IRONMAN between 2017 and August 2023 in the United States, Canada, Spain, and England were included. Patients treated with triplet therapy were excluded due to small numbers. Undetectable PSA nadir, defined as PSA <0.2 ng/mL, was evaluated at 6 and 12 months after treatment start. In this real-world study, relapse was defined as meeting one of the following criteria: PSA progression (≥25% PSA increase from nadir and absolute increase >2 ng/mL), treatment change preceded by new metastasis location, or change to a neuroendocrine prostate cancer regimen. Rates of relapse were calculated using Kaplan Meier estimates, with confidence intervals based on standard errors calculated using the Greenwood formula. Results: Among 1,377 eligible patients, treatment was most commonly ADT + ARPI (n=775) followed by ADT mono (n=375) and ADT + docetaxel (n=227). In the overall population, PSA nadir <0.2 ng/mL was achieved in 40% (n=554) at 6 months and 51% (n=702) at 12 months. Rates of PSA nadir <0.2 ng/mL at 6 months were: 51% for ADT + ARPI, 27% for ADT mono, and 26% for ADT + docetaxel. At 12 months, rates of PSA nadir <0.2 ng/mL increased to: 63% for ADT + ARPI, 38% for ADT mono, and 32% for ADT + docetaxel. During a median follow-up of 18 months, 291 patients (21%) experienced disease relapse; 19% experienced PSA progression. The percentage of patients in each treatment group with disease relapse at months 12, 24, and 36 of treatment are shown (Table); treatment groups are divided by whether patients had achieved PSA nadir <0.2 ng/mL in 6 months. Conclusions: In this non-randomized, real-world registry, patients with mHSPC who achieved a PSA nadir <0.2 ng/mL had a lower relapse rate than patients who did not, regardless of treatment. Percentage (95% CI), [number at risk] of patients with relapse at timepoint. Treatment Month 6 Month 12 Month 24 Month 36 ADT Monotherapyn=375 PSA <0.2 ng/mL 0%(0, 0)[60] 1.7%(0, 5.0)[31] 11%(0, 24)[15] PSA ≥0.2 ng/mL 18%(11, 24)[80] 41%(30, 51)[38] 45%(33, 55)[19] ADT + ARPIn=775 PSA <0.2 ng/mL 2.2%(0.6, 3.8)[288] 9.7%(5.9, 13)[166] 18%(12, 24)[76] PSA ≥0.2 ng/mL 21%(16, 26)[178] 42%(35, 49)[81] 50%(42, 58)[37] ADT + Docetaxeln=227 PSA <0.2 ng/mL 8.2%(0.2, 16)[44] 22%(8.9, 33)[29] 36%(18, 50)[14] PSA ≥0.2 ng/mL 34%(25, 43)[69] 62%(50, 72)[21] 73%(59, 82)[12]

Thermal processing to modulate surface chemistry and bulk charge distribution in nickel-rich layered lithium positive electrodes

Robust pose estimation for non-cooperative space objects based on multichannel matching method

Differences in health-related quality of life between rural and urban bladder cancer patients following radical cystectomy.

766 Background: Bladder cancer (BC) patients from rural areas (RA) may have more difficult access to health care with potentially detrimental impact on oncological outcome following radical cystectomy (RC). However, little is known on differences in health-related quality of life (HRQOL) between rural- and urban residents treated with RC for BC. We therefore aimed to assess these differences between rural and urban BC-patients by providing HRQOL data from a large prospective cohort of patients undergoing RC with a systematic follow-up of up to 10 yrs. Methods: n=1514 consecutive patients [n=576 from urban areas (UA), n=938 from rural areas (RA)] who underwent RC at a large tertiary care center were included. Exclusion criteria encompassed age <30 yr and RC due to benign diseases. HRQOL was assessed preoperatively, at 3 months, then annually until a maximum follow-up of 120 months, applying the validated EORTC QLQ-C30- as well as the bladder cancer-specific QLQ-BLM30- and FACT-BL-questionnaires. Separate modeling of longitudinal HRQOL for rural- and urban patients was performed. Spearman’s rank correlation was applied to identify residential-specific factors influencing HRQOL. Results: At baseline rural- and urban residents showed no significant difference in general HRQOL assessed by the global health status domain (GHS) (p=.983). In line no differences regarding symptom-related subscales were observed between both cohorts (p-range: .189 - .907). Postoperatively and in longitudinal analysis, rural residents reported significantly better general HRQOL up to 96 months after RC (p-range: .001 - .037). At 12 months, a significant correlation between physical-, emotional functioning or urinary continence and better general HRQOL was observed for both, rural- and urban residents (each p< .001). No significant correlation was found between sexual functioning and increased general HRQOL. While a significant correlation between Social/Family wellbeing and increased general HRQOL was found for rural residents (p=.042), no correlation was found for urban residents (p=.594). Conclusions: The current study provides prospective data from a contemporary cohort of BC-patients, which display residential-specific differences in the natural course of HRQOL following RC. Those results are important to guide individualized treatment decision-making for patients with BC.

Comprehensive modalities of kidney-sparing treatment in a carefully selected cohort of localized high-risk upper tract urothelial carcinoma: A potential paradigm shift.

794 Background: This study aims to assess the efficacy and safety of comprehensive modalities of kidney-sparing treatment in a carefully selected cohort of patients with localized high-risk upper tract urothelial carcinoma (UTUC). Methods: This study was initiated in January 2019 and is ongoing. Selected localized high-risk UTUC patients, characterized by conditions such as solitary kidney, bilateral tumors, impending renal insufficiency or patient refusal/ineligibility for radical nephroureterectomy (RNU), were included. Systemic therapy regimens were tailored to patient characteristics, tumor pathology and biomarkers, and included platinum-based chemotherapy, Disitamab Vedotin, and immune checkpoint inhibitors (ICIs). After endoscopic biopsy and attempted laser ablation, patients received four cycles of systemic induction therapy, followed by maximal endoscopic laser ablation or segmental ureterectomy. Postoperatively, a one-year course of immunotherapy maintenance was administered. The co-primary endpoints were disease-free survival (DFS) and conversion-free survival (CFS). Secondary endpoints included metastasis-free survival (MFS), renal function changes, ureteral stricture and treatment safety. Results: 68 patients were enrolled, with a follow-up of 18 months. 54 patients underwent endoscopic thulium laser tumor ablation, while 14 underwent segmental ureterectomy. The induction therapy comprised Disitamab Vedotin for 32 patients, platinum-based chemotherapy for 9, and immunotherapy for 37. Urothelial tract recurrence was observed in 28 patients with a 1-yr DFS rate was 58.82%, who subsequently underwent repeat endoscopic laser ablation. Salvage RNU was performed in 9 patients, yielding a 1-yr CFS rate of 93.7% and a 2-yr CFS rate of 88.9%. No distal metastasis was reported. Postoperative renal function impairment was noted in 15 patients (22.06%). Mean eGFR improvements were observed at various time points: 3.15 ml/min/1.73m 2 at 1 months, 5.07 ml/min/1.73m 2 at 3 months, 2.41 ml/min/1.73m 2 at 6 months, and 3.97 ml/min/1.73m 2 at 12 months. Ureteral stricture on the affected side was a common complication, which was more likely to occur in patients who underwent 3 or more times of ureteroscopy (9/27). Notably, no grade 3 or higher systemic toxicities were observed. Conclusions: Preliminary findings indicate that our comprehensive modalities of kidney-sparing treatment demonstrated promising tumor control and satisfactory renal function preservation in a carefully selected cohort of localized high-risk UTUC. Its definite application strategy and value should be further evaluated in future clinical practice.

Impact of deferred cytoreductive nephrectomy in the era of the immunotherapy in metastatic renal cell carcinoma: A multicenter retrospective study.

502 Background: Deferred cytoreductive nephrectomy (dCN) is an emerging, strategy in the management of metastatic renal cell carcinoma (mRCC), applied selectively to patients who demonstrate a favorable response to initial systemic therapy. This study aimed to assess the clinical impact of dCN within the context of sequential treatment management. Methods: A multi-institutional retrospective evaluation. The descriptive analysis was performed to examine the demographic and clinical characteristics. Progression-free survival (PFS) and overall survival (OS) were analyzed by the Kaplan-Meier method. A level of p < 0.05 was considered significant. Results: With a median follow-up of 19 months (1-174 months), 50 patients were divided into three groups: 46% received IO+TKI, 24% received IO+IO, and 30% received TKI. Of the cohort, 66% were male, with median age of 60.6 years. All had clear cell histology, and 76% were intermediate IMDC risk. The most common metastatic sites were lungs (50%), lymph nodes (36%), and bone (32%). The median time from systemic therapy to cytoreductive nephrectomy (CN) was 6 months. Notably, 26% did not restart treatment post-CN, and 6% discontinued pre-CN (two due to toxicity, one due to progression). Median PFS was 36 months, with a 5-year PFS rate of 40%. Analysis by IMDC risk and type of treatment showed no significant differences. However, patients with a Karnofsky score (KS) ≤80% had a lower risk of progression than those with KS >80% [HR: 0.31, 95% CI (0.13-0.75), p=0.01] and those achieving complete response had a significantly lower risk of progression [HR: 8.59, 95% CI (1.1-67), p=0.042]. Median OS was 91 months, with no significant differences between groups. Conclusions: This study demonstrates that dCN can offer a therapeutic advantage especially in selected patients who achieve favorable responses to upfront systemic therapy. Careful patient selection is crucial to maximize the potential benefits of delayed surgery, reduce perioperative risks and improve oncological outcomes. Larger patient cohorts and well-designed prospective clinical trials are essential to solidify these findings and establish evidence-based guidelines.

Assessing the impact of PTEN loss on outcomes in high-/very high-risk, advanced hormone-sensitive prostate cancer patients: Institutional retrospective study.

260 Background: Inactivation of tumor suppressor gene, PTEN (Phosphatase and tensin homolog) by deletion or mutation occurs in between 15-20% of localized prostate cancers and up to 50% of castration-resistant prostate cancers. The series of studies has shown a robust correlation between the genomic loss of PTEN and its protein as assessed by immunohistochemistry (IHC). Dysregulation of PI3K/AKT/mTOR signaling pathway has been linked with adverse pathological features and poor oncological outcomes such as the development of disease recurrence, metastasis, and castrate-resistant prostate cancer (CRPC). Here, we aim to study the prognostic and predictive role of PTEN in relation to treatment outcomes in a newly developed retrospective institutional research cohort. Methods: The cases with genomic PTEN loss (FoundationOne CDx, n=190) and protein loss by IHC (BenchMark Ultra, Roche Diagnostics, n=273) were pooled together. A total of 311 patients (PTEN loss=84, PTEN intact=227) that had available clinical and pathological information, including follow-up, were used for downstream statistical analysis. Kaplan-Meier analyses and univariate and multivariate Cox proportional hazard models were used to assess the benefit of RP over definitive RT with or without androgen deprivation therapy (ADT) for high-risk localized cohort as well as the benefit of primary ADT with or without intensification in the patients experiencing the loss of PTEN. Results: Patients with PTEN loss were more likely to present with advanced-stage disease (Stage IV: 33% vs. 19%) and more frequently received RT+ADT (43% vs. 34%) in high-risk patients. In contrast, those with intact PTEN were more likely to undergo radical prostatectomy (34% vs. 28%). Although overall survival (OS) did not differ significantly between all groups (log-rank p=0.51), mortality was higher in the PTEN loss group (32% vs. 22%). There was also a trend toward earlier development of castration-resistant prostate cancer (CRPC) in patients with PTEN loss (log-rank p=0.16). Conclusions: PTEN loss in prostate cancer is linked to more aggressive disease, higher mortality, and earlier CRPC development, consistent with existing literature. Our findings suggest that high-risk/very high patients with PTEN loss may benefit from definitive RT-based treatment over surgery. The study is limited by its retrospective, smaller sample size and single-institution design.

Simultaneous profiling of chromatin-associated RNA at targeted DNA loci and RNA-RNA Interactions through TaDRIM-seq

Impact of public versus non public insurance on hispanic kidney transplant outcomes using UNOS database

Prognostic impact of first-line (1L) chemotherapy cycles in patients with metastatic urothelial carcinoma receiving avelumab 1L maintenance.

725 Background: First-line chemotherapy with 4-6 cycles followed by avelumab 1L maintenance therapy is the standard of care in patients with metastatic urothelial carcinoma (mUC). However, a non-negligible number of patients received less than four cycles of chemotherapy due to adverse events, or pre-existing severe comorbidities in our daily practice. Thus, we examined the prognostic impact of the number of first-line chemotherapy cycles in mUC patients treated with avelumab. Methods: In this multi-institutional study, we collected data of 91 patients with mUC who received avelumab maintenance therapy following 1 st -line chemotherapy. Patients were divided into those who received less than four cycles and those more than four cycles. Kaplan-Meier curve and Cox regression model were used to assess the association of chemotherapy cycles with overall (OS), cancer-specific (CSS), and progression-free survival (PFS). Logistic regression analyses were used to assess factors predicting initial progressive disease (PD). Results: Of the patients, 17 (19%) underwent less than four cycles of chemotherapy. Baseline characteristics, including chemotherapy regimen and best response to 1L chemotherapy, were comparable between the groups. Kaplan-Meier curve showed that patients receiving less than four cycles of chemotherapy were significantly associated with shorter OS ( p =0.032). On multivariable analyses controlling for the effects of confounding factors, the number of cycles (< 4) remained associated with worse OS, CSS, and PFS (HR 2.83; 95%CI 1.32-6.08; p=0.008, HR 3.37; 95%CI 1.52-7.47; p=0.003, and HR 2.11; 95%CI 1.09-4.07; p=0.03, respectively). In addition, the number of cycles was associated with an increased risk of initial PD (OR 3.26; 95%CI 1.08-9.79; p =0.035) for avelumab maintenance therapy. Conclusions: The inadequate number of 1L chemotherapy cycles was associated with poor survival outcomes and was at an increased risk of initial PD in patients receiving avelumab maintenance therapy. More than four cycles of 1L chemotherapy should be given to ensure the efficacy of avelumab maintenance therapy in patients with mUC. 　 OS CSS PFS Predicting PD Multivariable Multivariable Multivariable 　 Multivariate 　 　 HR (95% CI) P value 　 HR (95% CI) P value 　 HR (95% CI) P value 　 OR (95% CI) P value Age (ref. < 70) 1.2 0.54-2.70 0.66 1.09 0.48-2.49 0.84 1.21 0.46-3.23 0.70 1.54 0.48-4.96 0.47 ECOG-PS≥2 (ref.≤1) 7.01 1.67-29.9 0.008 10.3 2.27-46.9 0.003 2.63 0.29-23.7 0.39 1.07 0.10-11.3 0.96 Severe AE (ref. < G3) 0.96 0.47-1.94 0.9 0.80 0.38-1.66 0.55 1.86 0.83-4.15 0.13 Visceral metastasis 2.20 1.05-4.60 0.037 2.43 1.11-5.29 0.026 2.23 1.01-4.91 0.046 eGFR (ref. < 60) 0.81 0.34-1.89 0.62 0.70 0.28-1.75 0.44 0.62 0.22-1.77 0.38 1st-line chemotherapy cycle (ref. ≥ 4) 　 2.83 1.32-6.08 0.008 　 3.37 1.52-7.47 0.003 　 2.11 1.09-4.07 0.03 　 3.26 1.08-9.79 0.035

Identification of potential immune evasion mechanisms in aggressive small renal cell carcinomas through single-cell and bulk RNA sequencing.

574 Background: Small renal cell carcinoma (RCC) is generally nonaggressive but in some cases, small RCCs exhibit distant metastasis. The biology and biomarker of small aggressive RCCs remain unclear, necessitating appropriate evaluation to avoid undertreatment. Previous biomarker studies via genetic profiling of tumor tissues were hindered by RCC heterogeneity. We utilized bulk RNA sequencing and single-cell RNA sequencing (scRNA-seq) of blood samples to identify genetic biomarkers and characterize the tumor immune microenvironment in patients with aggressive small RCC. Methods: We identified four T1a (≤4 cm) clear cell RCCs (ccRCC) with synchronous distant metastasis as aggressive, and four age-, sex-, and tumor size-matched ccRCC patients without metastasis as non-aggressive, from a prospective cohort (ClinicalTrials.gov Identifier: NCT03694912). Two healthy kidney donors served as controls. Using the 10X Genomics platform, we performed scRNA-seq and bulk analysis on ten peripheral blood mononuclear cell (PBMC) samples. Samples were demultiplexed with Souporcell, and sequencing reads were normalized and analyzed using R/Seurat. Cellular components were identified with marker genes, and bulk analysis included differential gene expression and pathway enrichment. Results: The mean tumor size and age of the eight ccRCC patients were 2.5 cm and 63 years, respectively. Among the four aggressive ccRCCs, two had lung metastasis and two had bone metastasis. We analyzed 32,417 cells, identifying 41 subpopulations. Single-cell analysis revealed variations in T and natural killer (NK) cell proportions among aggressive, non-aggressive, and normal groups, with significant differences. The aggressive group showed increased MYOM2, OVCH1-AS1, and HLA-DQA2 expression. Despite an increased proportion of CD4+ cytotoxic T lymphocytes (CTLs) with disease severity, key cytotoxic and immune regulatory genes like GNLY, CD247, CCL4, NKG7, and TGFB1 were decreased, suggesting compromised antitumor function in aggressive states. Conclusions: This study offers insights into the molecular and cellular characteristics of aggressive small RCCs via PBMC analysis using single-cell and bulk RNA sequencing. The increased proportion of CD4+ CTLs with decreased expression of critical cytotoxic and immune regulatory genes in aggressive RCCs suggests a mechanism for immune evasion. These findings enhance our understanding of aggressive small RCC biology and highlight potential biomarkers and therapeutic targets for adjuvant treatment. Clinical trial information: NCT03694912 .

Role of circulating tumor DNA (ctDNA) in locally advanced (LA) and metastatic urothelial cancer (mUC).

685 Background: The role of ctDNA is emerging as an adjunctive prognostic tool for survival in the laUC setting, but its role is evolving in mUC. We aimed to analyze ctDNA in the real-world setting and correlate its trend with available clinical, radiographic, and next generation sequencing (NGS) data. Methods: Patients with a diagnosis of laUC and mUC were included in the analysis of an IRB-approved protocol. Clinical/pathologic stage, systemic therapy received, NGS (TEMPUS) results, and tumor-informed detection and quantification (Signatera, Natera, Inc) was analyzed with baseline ctDNA data (positive + vs. negative -). Mean tumor molecules (MTM) levels were obtained and time to radiographic progression (TTrP), radiographic progression-free survival (rPFS) and overall survival (OS) evaluated. If baseline ctDNA was negative (ctDNA-), time to initial ctDNA+ was recorded. Analyses of time in days (d) from ctDNA- to ctDNA+ with regard to radiographic progression and OS was analyzed using Kaplan-Meier method and between group comparison by Log-rank test. Descriptive statistics were used to evaluate ctDNA trends in patients receiving various systemic therapies. Results: 47 patients (n=24 laUC; n=23 mUC) were included in analyses; 34 Male, 14 Female. The median rPFS in patients with baseline ctDNA+ was 189d. Higher baseline levels did not significantly affect rPFS (p=0.0518, HR=1.007) or TTrP (p=0.2718, HR=1.004). The median rPFS in baseline ctDNA- level was 553d. The overall TTrP was worse in mUC baseline ctDNA+ vs baseline ctDNA- (log-rank p=0.037). Median OS in baseline ctDNA+ was 266d and ctDNA- was not evaluable. Patients who received immunotherapy-based treatment or antibody-drug-conjugate based therapy had a decline in baseline ctDNA at 1 month follow up. Lack of response or clearance of ctDNA served as predictor of mortality. Of the mUC patients who had baseline ctDNA +, mortality was as high as 70% at the time of follow up. No correlation with specific NGS findings were seen. Conclusions: The use of ctDNA allowed for identification of earlier disease relapse than radiographic imaging alone which allows for earlier switch in therapeutic management. Obtaining a baseline positive ctDNA result without conversion to a negative value portends a poor prognosis in mUC.

Efficacy and safety of fexagratinib (Fexa) in combination with tislelizumab (T) in a phase II study of patients (pts) with locally advanced or metastatic urothelial carcinoma (mUC) harboring FGFR alterations (FGFRa).

789 Background: A significant proportion of pts with mUC are intolerant to platinum-based chemotherapy, highlighting the urgent need for alternatives. Fexagratinib(former AZD4547)is a potent and selective inhibitor of FGFR and had showed promising anti-tumor activity in mUC pts with FGFRa. This Phase II study (NCT05775874) aimed to evaluate efficacy of Fexa plus T combination treatment (Tx) in mUC pts harboring FGFRa who were 1st-line platinum-ineligible or rejected chemotherapy. Methods: FGFR3 mRNA overexpression were detected by in situ hybridization (RNAscope). FGFR3 activating mutations or fusions were detected by NGS. Eligible pts received continuous oral Fexa 80mg BID plus T 200 mg infusion on day 1 of a 21-day cycle. Primary objectives were objective response rate (ORR) by Independent Review Committee (IRC) per RECIST 1.1. Results: As of data cut off (10 Aug 2024), 26 pts received combination Tx with the majority being treatment-naïve. Of those, 57.7% were male with median age of 68.5 years and 86% had an ECOG of 1. Nine pts had confirmed FGFR3 mutation or fusion and 24 pts were overexpression. In 22 pts with available PD-L1 expression status, 86.4% were negative (CPS<10). Among 24 IRC evaluable pts, 9 (37.5%) partial responses (PRs) were confirmed. The median duration of response was 5.9 months. The median progression free survival mPFS was 5.3 months (95%CI 2.7-8.2) with 4 pts were still on Tx. Among the evaluable pts with FGFR3 overexpression but without mutation/fusion, ORR was37.5%,(6/16)pts.Most common treatment-related adverse events (TRAEs) were stomatitis (42%), anemia (38.5%), AST/ALT increased (27%). Grade ≥3 TRAEs occurred in 12 (46.2%) pts, incidence >10% events included stomatitis (n=3, 12%), hand-foot syndrome(n=3, 12%). Immune-related AEs occurred in 23.0% of pts. The majority of TRAEs were reversible. Conclusions: 1st-line Tx with Fexa plus T were tolerable with a safety profile consistent with previously reported for both agents. The toxicity was overall manageable. Encouraging efficacy was observed in pts with FGFR3 overexpression, regardless of PD-L1 expression or FGFR3 mutations/fusions.Further exploration of these findings is warranted. Clinical trial information: NCT05775874 .

Visualization of chromosomal reorganization induced by heterologous fusions in the mammalian nucleus

Small-world networks propensity in spontaneous speech signals of Alzheimer’s disease: visibility graph analysis

The analysis of active surveillance for Japanese young early-stage prostate cancer patients: From the PRIAS-JAPAN study.

351 Background: The current status of active surveillance (AS) for early-stage young Japanese patients is unknown. We examined it from the data of PRIAS-JAPAN, a multicenter prospective collaborative study of AS in Japan. Methods: Initially, low-risk patients with a PSA density (PSAD) <0.2 and 2 or fewer positive cores were eligible. The eligibility criteria have since been revised accordingly, and from 2021, when MRI imaging was performed, the inclusion criteria allowed a PSAD of up to 0.25, no upper limit on the number of positive cores for Gleason score (GS) 3+3 cases, and up to half of the total number of positive cores for intermediate-risk GS 3+4 cases. PSA test every 3 months, rectal examination every 6 months, biopsy at 1, 4, 7, and 10 years, and every 5 years after that, and recommendation for secondary treatment after confirming pathological deterioration. The AS results and clinical outcomes were compared between the patients aged 60 years and younger (Young group: Y-group, n=165) and those over 60 years old (elderly group: E-group; n=1,109). Results: In the Y-group, the median age was 57 years, the median PSA at diagnosis was 4.8 ng/ml, the median prostate volume was 33.4 cm3, the median PSAD was 0.15 ng/ml/c m3,T1c was 149. At diagnosis, the Y-group had significantly smaller prostate volumes and a higher proportion of GS 3+3 cases than the E-group. The biopsy acceptance rate decreased with increasing (1 st , 2 nd , 3 rd, and 4th year: 81.8%, 70.3%, 34.4%, and 13.3%). The reclassification rate increased over time (1 st , 2 nd , 3 rd and 4th year: 28.7%, 30.8%, 27.3%, and 50.0%). The persistence rate of the Y-group decreased over time, with a 10-year persistence rate of 19.2%, with no significant difference between the two groups. The 10-year metastasis-free survival (MFS), 10-year overall survival (VS), and 10-year cancer-specific survival (CSS) rates of the Y-group were 98.8%, 98.9%, and 100%, respectively. Although OS was lower in the Y-group (p=0.051, HR=2.29. 95%CI 1.004-5.21), MFS and CSS did not significantly differ between the two groups. The Y-group was more likely than the E-group to choose prostatectomy (38.3%) as the next treatment, while they did not want hormone therapy (4,7%) or watchful waiting (6.5%). Conclusions: Although the Y-group was superior to the E-group in OS, there was no significant difference in MFS and CSS between the two groups. AS persistence rate Metastasis-free survival 　 3 year 5 year 10 year 13 year 　 3 year 5 year 10 year 13 year ≤60y.o 55.7% 39.9% 19.2% 17.1% ≤60y.o 100% 100% 99% 99% 60y.o< 58.2% 38.5% 16.3% 12.0% 60y.o< 100% 100% 99% 98% Overall survival Cancer-specific survival 　 3 year 5 year 10 year 13 year 　 3 year 5 year 10 year 13 year ≤60y.o 100.0% 100.0% 98.9% 95.3% ≤60y.o 100.0% 100.0% 100.0% 100.0% 60y.o< 97.9% 97.0% 92.2% 88.7% 60y.o< 99.9% 99.9% 99.9% 99.9%