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Predictive value of neoadjuvant therapy combined with VI-RADS re-scoring in bladder preservation for muscle-invasive bladder cancer.

688 Background: Radical cystectomy (RC) is standard treatment for muscle-invasive bladder cancer (MIBC). However, many patients are unwilling or unable to undergo. Therefore, trimodality treatment (TMT) containing TURBT and chemoradiotherapy is an option for MIBC. However, TMT may not fully assess the effectiveness of maximal tumor resection, which is considered an important factor affecting outcomes. Additionally, neoadjuvant chemotherapy is thought to have limited effectiveness in TMT. The study aims to assess the predictive value of mpMRI VI-RADS’s re-scoring following neoadjuvant therapy in TMT. Methods: The study prospectively selected MIBC patients from January 2021 to August 2023. Inclusion criteria: 1) pathologically confirmed muscle-invasive urothelial carcinoma; 2) age <80 years tolerable cisplatin-based chemotherapy; 3) tumor size unrestricted; 4) initial VI-RADS score of 4-5; 5) no metastasis tested by CT or MRI. Exclusion criteria: 1) anterior urethra invasion; 2) dysfunction bladder; 3) lymph node and/or distant metastasis; 4) postoperative hydronephrosis not improved; 5) absolute contraindications to chemoradiotherapy. Patients underwent maximal TURBT before or after neoadjuvant therapy with gemcitabine plus cisplatin (GC) +/- toripalimab (PD-1) or RC48 plus PD-1, following VI-RADS re-scoring, then approached concurrent bladder radiotherapy (50-64Gy) with low-dose paclitaxel (50 mg/m2, D1/week) plus cisplatin (20 mg/m2, D1-2/week). Bladder recurrence and metastasis were assessed, with follow-up until August 2024 or death. Results: The study included 14 males (82.4%) and 3 females (17.6%); median age 65 (44–76) years, median follow-up 19 (8–40) months. 12 cases were cT2N0 (70.6%), 5 cases were cT3N0 (29.4%). NAC more than 2 cycles were 11 cases (64.6%), combined with PD-1 were 3 cases (17.7%), and RC48 plus PD-1 in 4 cycles were 3 cases (17.7%). Second TURBT after above neoadjuvant therapy were 11 cases (64.6%), whose VI-RADS re-scoring were all 0 points but 3 cases with residue after (3/11, 27.3%). Neoadjuvant therapy following maximal TURBT were 6 cases (35.4%), whose re-scoring was 5 points in 2 cases (11.8%), both cPR and pathological T2; re-scoring of 4 points were 2 cases (11.8%), 2 points and 1 point was respective 1 case (5.9%), who were all cPR and pathological downstaging to T1. 3 cases recurred: 2 cases whose re-scoring were 5 points recurred at the 20 and 31 months and had salvage RC (11.8%, 2/17) ; 1 case recurred at 10 months with T1 stage (1/17), whose re-scoring was 0 points, suffering reTURBT. The 1-year disease-free survival rate for all patients was 94.1% (16/17), no metastasis and death case. Conclusions: The VI-RADS re-scoring after neoadjuvant therapy for MIBC has concordance with postoperative pathology, offer a predictive value for achieving maximal tumor resection, and provide clinical reference for bladder preservation. Clinical trial information: 2000029504.

Use of urinary cell-free DNA fragmentomics in urothelial carcinoma diagnosis.

846 Background: Traditional diagnostic procedures for urothelial carcinoma (UC) are often limited by patient burden and reduced sensitivity, impacting diagnostic accuracy. Liquid biopsy-based molecular detection, particularly through fragmentomics analysis, offers a promising supplement to clinical applications. Fragmentomics, which examines the unique fragmentation patterns of tumor DNA, can provide crucial insights into tumor origin and behavior. This study aims to leverage urinary cell-free DNA (ucfDNA) fragmentomics patterns to enhance the diagnostic capabilities for urothelial carcinoma. Methods: We conducted a case-control study to investigate cfDNA fragment size distributions in urine samples. The study included patients diagnosed with malignant UC (cases) and individuals with benign conditions (controls). High-throughput sequencing was used to identify distinct fragmentomics patterns, including variations in fragment size, end motifs, and genomic coverage at transcription factor binding sites. Diagnostic performance was evaluated using sensitivity, precision, and the area under the curve (AUC). Results: UC patients exhibited distinct fragmentation patterns, characterized by a shift towards shorter cfDNA fragments compared to controls. Analysis of fragment size and genomic coverage provided additional diagnostic insights when combined with methylation data, significantly improving early-stage UC detection. Fragmentomics combined with methylation markers achieved an AUC of 86.25%, with a sensitivity of 89.3% and a precision of 75.76%, demonstrating substantial improvements in diagnostic accuracy. Conclusions: Urinary cfDNA fragmentomics provides valuable complementary information to traditional molecular markers for detecting urothelial carcinoma. This innovative approach enhances diagnostic precision and shows potential for improving early detection strategies, with promising applications in non-invasive cancer screening and monitoring.

DeepKymoTracker: A tool for accurate construction of cell lineage trees for highly motile cells

Time-lapse microscopy has long been used to record cell lineage trees. Successful construction of a lineage tree requires tracking and preserving the identity of multiple cells across many images. If a single cell is misidentified the identity of all its progeny will be corrupted and inferences about heritability may be incorrect. Successfully avoiding such identity errors is challenging, however, when studying highly-motile cells such as T lymphocytes which readily change shape from one image to the next. To address this problem, we developed DeepKymoTracker, a pipeline for combined tracking and segmentation. Central to DeepKymoTracker is the use of a seed, a marker for each cell which transmits information about cell position and identity between sets of images during tracking, as well as between tracking and segmentation steps. The seed allows a 3D convolutional neural network (CNN) to detect and associate cells across several consecutive images in an integrated way, reducing the risk of a single poor image corrupting cell identity. DeepKymoTracker was trained extensively on synthetic and experimental T lymphocyte images. It was benchmarked against five publicly available, automatic analysis tools and outperformed them in almost all respects. The software is written in pure Python and is freely available. We suggest this tool is particularly suited to the tracking of cells in suspension, whose fast motion makes lineage assembly particularly difficult.

Randomized controlled trial of bromelain and alpha-lipoic acid in breast conservative surgery

Head-to-head comparison of micro-ultrasound, mpMRI, and PSMA PET/CT with a wholemount histopathology as gold standard in the detection and T staging of prostate cancer.

338 Background: Micro-Ultrasound (MicroUS) is a new imaging modality capable of identifying prostate cancer (PCa). Prior evaluation of MicroUS and multiparametric MRI (MRI) have demonstrated comparable accuracy but are limited by relying on biopsy pathology for ground truth. There are no available studies that comprehensively evaluate the diagnostic accuracy and extraprostatic extension (EPE) of MicroUS, MRI, and PSMA PET/CT (PSMA) against wholemount histopathology (WMHP) as the reference. Methods: Patients with PCa who underwent MicroUS and MRI before radical prostatectomy were included. Among the included patients, a subgroup analysis was performed in patients with a PSMA scan. Imaging scans and WMHP findings were translated into involvement on a standardized 36 sector map. Accuracy in determining the PCa, csPCa (GG≥2) and EPE was assessed using receiver-operating-characteristic curve analysis (AUC). Results: The final analysis included 25 patients, 19 of whom underwent PSMA scan. The lesion-level PCa and csPCa detection rates were 55% and 72%, 57% and 75%, 53% and 70% for Micro-US, MRI and PSMA, respectively (Table). For the sector-level analysis, the AUCs of MRI were higher than that of MicroUS and PSMA in identifying PCa, and csPCa (P<0.05). MicroUS and PSMA had comparable sector-level PCa and csPCa AUCs. The AUCs of MRI and PSMA were higher than MicroUS for sector-level EPE (P<0.05). The AUCs for prediction of patient-level EPE were 0.68, 0.69 and 0.54 for MicroUS, MRI and PSMA, respectively (p = NS). Patient level PCa, csPCa, and for specific pathologic features was similar among imaging modalities. Conclusions: MicroUS showed good reliability in identifying csPCa and patient-level EPE. At the patient level, its performance is comparable to that of MRI. MRI performs better at the sector-level. Diagnostic accuracy and EPE staging for MicroUS, MRI, and PSMA PET/CT. N = 25 MicroUS Multiparametric MRI PSMA PET CT P-Value PCa Sector-Level AUC 0.67 (0.64, 0.71) 0.71 (0.68, 0.75) - 0.03 csPCa Sector-Level AUC 0.69 (0.65, 0.72) 0.74 (0.70, 0.77) - 0.01 EPE Patient-Level AUC 0.68 (0.47, 0.88) 0.69 (0.51, 0.87) - 0.93 EPE Sector Level AUC 0.57 (0.47, 0.67) 0.79 (0.65, 0.93) - <0.01 N = 19 PCa Sector-Level AUC 0.66 (0.61, 0.71) 0.62 (0.57, 0.68) 0.62 (0.57, 0.68) 0.03*, <0.01** csPCa Sector-Level AUC 0.67 (0.63, 0.71) 0.71 (0.67, 0.75) 0.64 (0.60, 0.67) 0.06*, <0.01** EPE Patient-Level AUC 0.69 (0.51, 0.87) 0.72 (0.51, 0.94) 0.54 (0.30, 0.78) 0.32*, 0.28** EPE Sector Level AUC 0.54 (0.45, 0.62) 0.78 (0.63, 0.92) 0.73 (0.58, 0.87) 0.01* , 0.50** Pathologic Feature Detection Rates for MicroUS, mpMRI, and PSMA PET CT MicroUS Multiparametric MRI PSMA PET CT P-Value PCa (%) 55.3 57.4 52.8 0.81 csPCa (%) 72.2 75.0 70.4 0.78 Index Lesion (%) 96.0 92.0 84.2 0.26 Cribiform/IDC (%) 94.1 100 83.3 0.08 EPE (%) 44.4 66.7 62.5 0.17 *MicroUS vs. PSMA PET/CT. **mpMRI vs PSMA PET/CT.

Comparison of IO-TKI vs IO-IO combinations in IMDC poor-risk metastatic renal cell carcinoma (mRCC) patients (Meet-URO 33 analysis).

495 Background: Immune-combinations have become the cornerstone of the mRCC treatment landscape, but head-to-head comparisons between the different first-line treatment strategies are lacking and few real-world data are available in this setting. In this context, little evidence is available, especially for IMDC poor-risk patients, who have the worst prognosis and lowest response to standard treatments. Methods: The Meet-URO 33 study is an Italian retrospective/prospective registry of the first-line setting of mRCC patients from January 2021 (Trial registration: CESC IOV 2023-78, PMID: 38914928) with the aim to answer as many clinical questions as possible. This analysis focused on assessing the different performance of IO-TKI and IO-IO combinations in terms of survival and response outcomes and the differential baseline clinical characteristics in the two treatment groups. Results: Among 892 patients enrolled from 40 Italian centres, 772 patients (87%) were evaluable for survival analyses; 160 patients (21%) had IMDC poor risk: 42 (26%) received IO-IO, 105 (66%) IO-TKI and 13 (8%) TKI. Comparing the baseline clinical characteristics of patients included in the two immune-combinations, poor-risk patients receiving IO-IO were older (mean age: 68 vs 64, p=0.03), had more cardiovascular comorbidities (74% vs 56%, p=0.048) and lower frequency of bone metastases (29% vs 57%, p=0.002). After a mFUP of 6.9 months (mo), the mOS of all poor-risk patients was 11.3 months, higher with IO-IO than with IO-TKI [20.6 vs 11 mo, HR 1.65 (0.97-2.82); p=0.067]. After multivariable analysis (age, comorbidities, ECOG, bone metastases) the difference between IO-TKI and IO-IO was not statistically significant [HR 1.37 (0.78-2.40); p=0.27]. The overall mPFS was 6.4 mo, higher with IO-IO compared with IO-TKI [11 vs 5.8 mo, HR 1.70 (1.05-2.75); p=0.031]. After the multivariable analysis, the difference between the two treatment groups lost statistical significance [HR 1.58 (0.95-2.63); p=0.078]. The general ORR was 46%, higher with IO-TKI than with IO-IO [71% vs 29%, OR 0.70 (0.21-1.56); p=0.38]. Conclusions: These preliminary analyses of the ongoing Meet-URO 33 study show no clear survival advantage in using an IO-TKI combinations instead of an IO-IO combination in IMDC poor-risk patients. These results are in line with the well-known smaller benefit of TKI in poor-risk patients (more immunogenic / less angiogenic patterns and results of the COSMIC-313 study). A longer follow-up is needed to examine in depth the different performance of immune-combinations in IMDC poor-risk patients. Clinical trial information: CESC IOV 2023-78 .

Transdermal oestradiol (tE2) patches as androgen deprivation therapy (ADT): Efficacy and safety of combining with androgen receptor pathway inhibitors (ARPIs) in metastatic (M1) prostate cancer—Randomised comparison from the STAMPEDE trial platform.

21 Background: Recent phase III data (n=1360) has shown that starting ADT with tE2 patches is non-inferior in terms of metastasis-free survival (with similar overall survival) to luteinising hormone releasing hormone analogues (LHRHa) for locally advanced (M0) prostate cancer. For both M0 and M1 patients, tE2 has advantages in terms of reported quality of life, bone mineral density, hot flushes and metabolic outcomes compared to LHRHa, with no excess of thromboembolic events. However, there is currently no data on the use of androgen receptor pathway inhibitors (ARPIs) (abiraterone, enzalutamide or apalutamide) with tE2. Methods: STAMPEDE [NCT00268476] is a multi-arm, multi-stage platform trial. This embedded phase 2 randomised study assessed efficacy and toxicity in participants (pts) randomly allocated (1:1) to tE2 patches (releasing 100mcg/24hrs, 3 patches changed twice weekly once testosterone ≤1.7ng/ml) or LHRHa (standard doses) and scheduled to receive ARPIs. Primary outcome measure was the proportion of pts reaching a PSA nadir of ≤0.2ng/ml during the first 6 months. Other PSA parameters, testosterone ≤1.7ng/ml at 12 weeks with tE2, and adverse events within the first 12 months (including hypertension, hot flushes and gynaecomastia) were assessed. Results: Between Oct-2020 and Mar-2023, 79 pts with histologically confirmed M1 prostate cancer (median (IQR) age 69 (65-75), median (IQR) baseline PSA 43.3 (11.5-296.2)) received either LHRHa+ARPI (n=41) or tE2+ARPI (n=38). Baseline characteristics were similar between the 2 groups. The proportion of pts achieving PSA ≤0.2ng/ml was LHRHa+ARPI 25/41 (61%) and tE2+ARPI 23/38 (61%). LHRHa v tE2: PSA90 (93% v 95%) and PSA50 (100% v 100%). 31/34 (91%) men treated with tE2 had testosterone ≤1.7ng/ml at 12 weeks. Hot flushes: LHRHa (grade 1: 32%, grade 2: 20%) v tE2 (grade 1: 24%, grade 2: 5%). Gynaecomastia: LHRHa (grade 1: 10%, grade 2: 0%) v tE2 (grade 1: 35%, grade 2: 8%) and any grade hypertension LHRHa v tE2 17% versus 5%. Conclusions: PSA responses were similar in pts treated with tE2+ARPI or LHRHa+ARPI further supporting the use of tE2 patches for ADT in prostate cancer management. tE2 patches provide patients with ADT choices about expected toxicity profiles, including reduced hot flushes (and subsequent impact on quality of life), and mode of administration. Clinical trial information: NCT00268476 .

OCTOPUS: A retrospective, multicenter study of real-world cabozantinib treatment of patients with advanced renal cell carcinoma in France—Subgroup analyses of treatment sequences and optimization.

472 Background: Cabozantinib is an established therapy for advanced renal cell carcinoma (aRCC) in France. We evaluated real-world data from the OCTOPUS study to assess treatment sequences and explore strategies for therapeutic optimization. Methods: OCTOPUS was a real-world, retrospective, non-comparative, non-interventional study of 252 patients receiving second-line (2L) cabozantinib therapy at 26 centers in France between 2018 and 2021 (NCT05444933). Exploratory analyses of treatment sequences and endpoints including duration of treatment (DoT), progression-free survival (PFS), overall survival (OS) and disease control rate (DCR) were performed for subgroups of patients based on cabozantinib dose modifications, local treatment (radiotherapy or surgery) and receipt of third-line (3L) treatment. Results: In total, 252 patients (median age, 63.0 years; lung metastases, 63%; bone metastases, 52%) were included; 61% had prior tyrosine kinase inhibitor (TKI) therapy, and 37% received prior immunotherapy (IO). Patients who underwent local treatment or cabozantinib dose modifications exhibited longer 2L DoT and PFS than those without these interventions (Table). In total, 157 patients (62%) received 3L therapy post cabozantinib (55% nivolumab, 26% TKI), and 14 patients were still on cabozantinib at study end. Dose modification rates were higher among patients who received 3L therapy (≥1 reduction, 67% vs 55%; ≥1 interruption, 69% vs 56%). Those receiving 3L therapy demonstrated improved outcomes (Table); the median OS from 2L cabozantinib initiation in patients who received 3L treatment was 20.5 months (95% CI, 18.0–22.6). Conclusions: Cabozantinib outcomes may be enhanced with dose modifications and local treatment. These strategies may delay the need for 3L therapy in patients with oligoprogressive disease, potentially improving long-term disease control. Clinical trial information: NCT05444933 . Subgroup N (%) Median (95% CI) DoT for 2L cabo, months Median (95% CI) PFS from 2L cabo start, months DCR for 2L cabo, % (n/n) Overall population 252 (100) 7.4 (6.1–8.5) 6.9 (5.7–8.2) 76.9 (160/208) Dose modificationsNoYes 58 (23)194 (77) 2.5 (1.6–3.5)8.6 (7.6–9.9) 3.5 (2.2–5.7)7.6 (6.5–8.7) 62.5 (20/32)79.5 (140/176) Local treatment a,b NoSurgery or focal treatment c Radiotherapy 153 (61)25 (10)52 (21) 6.0 (4.6–7.6)9.6 (4.4–15.0)9.3 (7.6–13.3) 6.2 (5.3–8.2)8.0 (4.4–9.5)7.2 (5.2–10.1) 78.0 (96/123)90.1 (20/22)78.3 (36/46) 3L treatmentNoYes 95 d (38)157 (62) 4.3 (3.2–6.9)8.2 (6.9–9.6) 5.1 (3.1–7.3)8.0 (6.2–9.1) 69.7 (46/66)80.3 (114/142) a Patients may receive surgery and radiotherapy; b 41 patients had a surgery not related to aRCC; c Only surgeries or focal treatments related to aRCC are presented; d 14 patients were receiving 2L cabozantinib at study end.

Explore the possible influence of Sjogren’s syndrome on thyroid cancer: A literature data mining and meta-analysis

Objectives To explore the potential influence of Sjogren’s syndrome (SS) on thyroid cancer (TC). Methods First, a literature data mining (LDM) approach was used to reconstruct functional pathways connecting SS and TC. A meta-analysis was then performed to examine the expression changes of genes mediated by SS using 16 TC case/control expression datasets, with results validated through the TCGA/GTEx dataset. Finally, gene set enrichment analysis (GSEA) and survival analysis using GEPIA2 were conducted on the significant genes. Results Our findings indicate that SS may increase the risk of TC by activating 14 TC promoters (PDCD1, NTRK1, LGALS3, CD274, FOXP3, BCL2, CYP1A1, HMGB1, TGFB1, CCL2, PLA2G7, TFF3, LCN2, and CLDN1) and suppressing three TC inhibitors (MIR145, MIR30C1, and EP300). Four molecules (PLA2G7, TFF3, LCN2, and CLDN1) exhibited significant expression changes in TC patients (LFC > 1 or < -1; p < 2.07E-04), which were confirmed in TCGA/GTEx expression analysis. These results highlight three possible mechanisms—the SS-PLA2G7-CCL2-TC pathway, the SS-LCN2-LGALS3-TC pathway, and the SS-CLDN1-BCL2-TC pathway—that may explain how SS contributes to TC development. Enrichment analysis suggests that SS may affect TC prognosis by regulating leukocytes and tolerance induction. Survival analysis indicates that SS may enhance TC survival through the regulation of the CLDN1 and EGF pathways. Conclusion LDM-based pathway analysis highlighted three genetic pathways through which SS may adversely affect TC progression, while SS may enhance TC survival via the CLDN1 and EGF pathways, highlighting the need for further research.

Efficacy of ossiculoplasty in patients with chronic otitis media with severe to profound hearing loss

Implementing Indiana regimen salvage high-dose chemotherapy in relapsed germ cell tumors in Slovakia.

642 Background: Salvage chemotherapy for relapsed testicular germ cell tumors (GCT) remains controversial, however, large retrospective series show higher cure rates with high-dose chemotherapy (HDCT) and peripheral blood stem cell transplant (PBSCT) compared to conventional dose chemotherapy (CDCT). Successful implementation of HDCT salvage treatment in high-volume centers is an important step towards achieving optimal cure rates in relapsed GCTs. Methods: 22 relapsed GCT patients were treated at National Cancer Institute in Slovakia with first (41%), second (54%) and third line (5%) salvage HDCT between 2014 and 2024. Median age at 1 st HDCT cycle was 33 years (range 21-55). Of the 22 patients, 3 (14%) had pure seminoma, 3 (14%) had primary mediastinal non-seminoma (PMNSGCT), 10 (45%) patients had cisplatin resistant disease, 7 (32%) and 15 (68%) of patients received 1 and 2 cycles of HDCT, respectively, 5 (23%) received maintenance oral etoposide and 6 (27%) had post-HDCT surgery. Indiana regimen consisted of 750mg/m2 etoposide and 700mg/m2 of carboplatin given on days -5,-4,-3 followed by PBSCT on day 0. Of 22 patients, 3 have received single dose CarboPEC (carboplatin, etoposide, cyclophosphamide) regimen in 2014 and 2015. Results: Median time between two cycles was 43 days (range 26-89) showing decreasing trend over the last years. 2-year PFS and OS were 40% (95% CI 0.19-0.61) and 34% (95% CI 0.13-0.55) and 5-year PFS and OS were 32% (95% CI 0.1-0.54) and 27% (0.06-0.48). Kaplan-Meier analysis produced inaccurate outcomes due to small sample size, currently 32% of patients is alive and disease-free. Predictors of unfavorable outcome were non-seminoma, NPMGCT, 1 cycle of HDCT, CarboPEC regimen and platinum resistant disease. Patients who underwent post-HDCT surgical resection had longer OS compared to patients unable to undergo surgery HR 4,85 (95% CI 1,69-13,9), p = 0.01 Patients receiving pre-HDCT bridging CDCT regimens had significantly worse OS compared to patients going directly to HDCT, HR 0 (95% CI 0-0), 5 year OS 19% vs 100%, p = 0.05. 10% of patients with cisplatin resistant disease is surviving beyond 5 years. There was one (4.5%) treatment-related death due to septic shock. Conclusions: HDCT is an effective salvage option in heavily pretreated relapsed GCTs. Our study suffers from weakness associated with small number of patients and selection biases. However, increasing expertise and timely delivery of HDCT results in cures in relapsed GCTs including cisplatin resistant subgroup.

Receipt of poly(ADP) ribose polymerase inhibitors (PARPi) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) harboring <i>BRCA1/2</i> alterations.

108 Background: PARPi are approved for the treatment of pts with mCRPC either as single agents or as a combination with an androgen receptor pathway inhibitor (ARPI) [PMID: 37442702]. In a US Food and Drug Administration (FDA) pooled analysis, the benefit from PARPi appeared greatest for pts harboring BRCA1/2 alterations [PMID: 38484203]. However, real-world uptake of PARPi in pts with mCRPC with BRCA1/2 alterations is unknown. Herein, our objective was to assess the usage of PARPi in real-world pts with mCRPC harboring BRCA1/2 alterations. Methods: A de-identified nationwide Flatiron Health electronic health record (EHR)-derived database was used to extract pt-level data. Eligibility criteria: pts with mCRPC harboring alterations in BRCA1 or BRCA2 or both and alive after 8/15/2020 (i.e., 3 months following the approval of the first PARPi, rucaparib, in mCRPC) with available treatment information. The data cutoff date was 5/31/2024. Pts were categorized into two cohorts based on the receipt of any PARPi or not. Baseline characteristics at the time of mCRPC diagnosis, including age, race-ethnicity, and insurance plan, were collected in both cohorts. Results: Of the overall cohort of 24,105 pts with metastatic prostate cancer, 443 pts had mCRPC with BRCA1/2 alterations and were eligible and included in this analysis. 227 (51.2%) received a PARPi, while 216 did not (48.8%). Among the 227 pts who received a PARPi, 166 received it as a single agent (73.1%), 40 received it in combination with an ARPI (17.6%), and 21 received it in combination with other agents (9.3%). The median age was 72 in both cohorts (IQR 65 – 79 in patients receiving a PARPi and 66 – 78 in patients who did not). Other baseline characteristics in both groups are shown (Table). Conclusions: Despite PARPi demonstrating survival improvement in pts with mCRPC with BRCA1/2 alterations, a significant proportion of pts do not receive them. Our findings highlight the need to improve education among clinicians of level 1 evidence and improve access to life-prolonging therapies in pts with mCRPC. Baseline characteristics of pts with mCRPC who received vs. did not receive a PARPi. Characteristic Subgroup Pts who received a PARPiN = 227 Pts who did not receive a PARPiN = 216 Race-ethnicity, n (%) Asian 9 (4) 1 (0.5) Black 22 (9.7) 30 (13.9) Hispanic-Latino 10 (4.4) 10 (4.6) White 149 (65.6) 124 (57.4) Other and unknown 37 (16.3) 51 (23.6) Insurance, n (%) Commercial health plan 192 (84.5) 182 (84.3) Medicare-other government programs 31 (13.7) 18 (8.3) Medicaid 1 (0.4) 3 (1.4) Others and unknown 3 (1.3) 13 (6)

Concurrent pembrozulimab and radiation treatments in the management of locally advanced bladder cancer in cisplatin-ineligible patients.

817 Background: Pembrolizumab (P) is commonly used to treat cisplatin-ineligible patients with locally advanced bladder cancer. We previously reported a potential synergistic effect of concurrent radiation and immunotherapy, https://doi.org/10.1200JCO.2020.38.15_suppl.e17020. Here, we present our updated experience with this combination. Methods: After transurethral resection of bladder tumor (TURBT), patients received Pembrolizumab 200 mg IV every 3 weeks and radiation treatments, starting 1 week after Pembrolizumab initiation. A total of 64-65 Gy was delivered to the bladder and pelvis. Pembrolizumab was continued for 1 year. Response was assessed by follow-up cystoscopies and serial imaging studies. Results: Between October 2021 and May 2023, 14 patients with locally advanced bladder cancer (cT2-T4 or LN+ve) were treated. Median age was 74 years (range 62-91), with a male-to-female ratio of 9:5. ECOG performance status was 0-1 in 5 patients, 2 in 7 patients, and 3 in 2 patients. All patients completed radiation treatments, while 10 patients completed 1 year of Pembrolizumab, 3 patients completed 6-12 months, and 1 patient received less than 6 months. Follow-up cystoscopy was performed in 12 patients, with 7 (58.3%) showing a complete clinical response. Grade 3/4 immune-related adverse events (irAEs) occurred in 1 patient. At a median follow-up of 16 months (range 6-23 months), 9/14 patients (64.2%) remained without evidence of distant disease, 3/14 patients (21.4%) had oligometastatic disease treated with stereotactic body radiation therapy (SBRT) and are now without distant disease, and 2/14 patients (14.4%) developed multiple distant metastases. Conclusions: Concurrent radiation and immunotherapy is an effective option with a favorable side-effect profile for cisplatin-ineligible patients with locally advanced bladder cancer. Incorporating other non-chemotherapeutic agents, such as antibody-drug conjugates, into concurrent radiation-immunotherapy combinations warrants further investigation.

Cabozantinib in patients (pts) with non-locally pretreated brain metastases (BM) from renal cell carcinoma (RCC): Results of the multicenter CABRAMET phase II trial (NCT03967522).

533 Background: Despite dramatic progress in metastatic RCC treatments, pts with BM remain with poor outcome and were mostly excluded from clinical trials. Local treatments on BM are standard today. Methods: Adult pts with histologically proven RCC and BM ≥ 5 mm (or &gt; 8 mm if solitary) including at least one non-locally pretreated, &lt; 3 prior systemic treatments excluding cabozantinib, ECOG PS 0 or 1 and steroids &lt; 40 mg/day were included. Primary endpoint was BM progression free survival rate at 6 months (6m-BM-PFS) according to modified RANO-BM criteria by central review. Secondary endpoints were BM response and response duration, extracranial response, PFS, overall survival and safety. 25 evaluable pts were required to evaluate the main endpoint. Results: 26 pts were included, 25 were evaluable for the primary endpoint and median follow up time was 39.8 months [5.9-49.7]. The 6m-BM-PFS was 56.0% [unilateral 95%CI 37.9-] (14/25 pts). BM response was partial response (PR) for 61.5% (16/26) pts and median duration of response was not reached, 66.7% pts being event-free 24 months after BM response. Extracranial response was PR for 38.5% (10/26). Median PFS was 8.1 months [95%CI 4-11.9], and median BM PFS 8.4 months [95%CI 5.4-NR]. Median overall survival was 15.8 months [95%CI 9.7-35.0]. No new safety signals were observed. Conclusions: This is the first prospective trial assessing cabozantinib in RCC pts with non-locally pretreated BM. These results confirm the efficacy of cabozantinib on BM previously reported in retrospective series. Clinical trial information: NCT03967522 . Pts characteristics. Pts number N = 26 Median age (years) [range] 67 [44-86] Gender: F / M, n 5 / 21 ECOG PS: 0 / 1,n 10 / 16 RCC: non-clear cell / clear cell, n 2 / 24 Prior nephrectomy : n 16 Number of BM: 1 / 2 / &gt;3, n 9 / 7 / 10 Prior BM treatments: Overall/ Surgery/ Radiation, n 10 / 3 / 10 Prior systemic treatment: 0 / 1 / &gt;2, n 7 / 15 / 4 IMDC: Favorable / Intermediate / Poor, n 7 / 10 / 9

Implementation research to develop an optimized delivery model for effective implementation of evidence-based interventions to reduce stillbirth in India: A study protocol

Background Stillbirth remains a public health concern in India, despite a decrease in reported rates. Inconsistent data collection hampers clear understanding the burden of stillbirth, and interventions for its reduction are scattered across various national programs. This research aims to explore effective strategies to improve the delivery and uptake of high-quality antenatal and intrapartum care services which have the potential to reduce stillbirth rates in various states of India. Methods This mixed-method, multi-site study in India will be conducted in three phases: Phase 1: Formative Phase; Phase 2: Development of a Comprehensive Package for Stillbirth Reduction and Optimization of the implementation model and Phase 3: Scale-up of comprehensive package and monitoring of optimized strategy/model. Participants will include pregnant women, women who have recently delivered, family members, respectable community members, healthcare workers and staff, state and district health authorities. The effectiveness of intervention package and optimized implementation model in reducing stillbirth will be evaluated using a pre-post quasi-experimental design. The burden of stillbirth will be estimated through community survey, recording pregnancy outcomes for women who have delivered within the past one year. Various methods including semi-structured questionnaires, verbal autopsies, and in-depth qualitative interview guides, review of clinical case sheets will be used to assess the causes of stillbirth. Additionally, government health facilities will be assessed and strengthened over study period. This study will utilize implementation science theories, models, and frameworks (TMF), including the Consolidated Framework for Implementation Research (CFIR) to identify barriers and facilitators, and the evaluative TMF of RE-AIM (Reach Effectiveness Adoption Implementation and maintenance) to monitor the optimized model. The primary outcome is the development of a scalable, sustainable model of intervention package and delivery strategies to reduce stillbirths. The secondary outcome includes a robust estimation of burden, timing, and risk factors of stillbirths across all study sites. Certain sites will conduct an economic evaluation to assess the incremental cost of implementing comprehensive packages using the optimized implementation model. Discussion This innovative study addresses a critical public health gap in context of stillbirth reduction in India. Integrating proven interventions with real-world implementation challenges across diverse regions, this project aims to develop a comprehensive and replicable model. If successful, this model can significantly improve stillbirth prevention in low-resource settings. Trial registration ClinicalTrials.gov CTRI-2024/07/069796.

A geospatial and statistical analysis of land surface temperature in response to land use land cover changes and urban heat island dynamics

Efficacy of systemic treatments for advanced non-clear cell renal cell carcinoma: A single-arm systematic review and meta-analysis.

550 Background: Non-clear cell renal cell carcinoma (nccRCC) represents a genetically and histologically diverse subset of renal cancers, accounting for 15–30% of all renal malignancies. Patients with nccRCC generally face poorer prognoses compared to those with clear cell renal cell carcinoma (ccRCC). While many therapies, such as tyrosine kinase inhibitors (TKI), mammalian target of rapamycin (mTOR) inhibitors, and immune checkpoint inhibitors (ICI), have broadened treatment options for nccRCC, high-quality randomized controlled trials (RCTs) assessing these treatments remain scarce. Consequently, RCT-based reviews provide an incomplete understanding of systemic therapy in nccRCC. In contrast, single-arm trials (SATs), more commonly conducted in nccRCC patients, offer additional insights into therapeutic efficacy. This study aims to synthesize evidence from both RCTs and SATs to comprehensively evaluate the efficacy of systemic treatments for nccRCC. Methods: We conducted a systematic review and meta-analysis of SATs and arms of RCTs, retrieving studies from PubMed, MEDLINE, EMBASE, and the Cochrane Library up to October 1, 2024. Primary outcome was objective response rate (ORR), and secondary outcomes were progression-free survival (PFS), and overall survival (OS). A random-effects meta-analysis was employed to pool data, and subgroup analyses were conducted based on treatment regimens. Results: Thirty-two studies encompassing 1,958 patients were included in the meta-analysis. The pooled ORR across all treatments and therapy lines for nccRCC was 20% (95% CI 15%–26%). The median PFS and OS were 5.56 months (95% CI 4.03–7.09 months) and 17.25 months (95% CI 12.48–22.01 months), respectively. Among them, the pooled ORR for TKI and ICI monotherapy was 19% (95% CI 10%–30%) and 19% (95% CI 13%–26%), respectively, while the pooled ORR for TKI and ICI combination therapy was 39% (95% CI 28%–51%). For first-line therapy, the ORR was 20% (95% CI 12%–28%). Combination therapies (e.g., TKI+ICI, TKI+mTOR and ICI+ICI) demonstrated a higher pooled ORR of 32% (95% CI 19%–46%), while monotherapies (TKI, mTOR or ICI) had an ORR of 14% (95% CI 8%–21%). In papillary RCC (pRCC), the ORR for first-line therapy was 17% (95% CI 9%–26%). Combination therapies showed an ORR of 31% (95% CI 14%–51%), and single-agent therapies had an ORR of 12% (95% CI 6%–21%). Conclusions: This meta-analysis provides evidence supporting the efficacy of existing systemic therapies, particularly combination therapies, in advanced nccRCC. However, the inherent limitations of single-arm analysis necessitate further large-scale, multicenter trials to validate these findings and guide future clinical practice.

A prospective provincial registry of PSMA PET CT for recurrent prostate cancer (PREP): Results for 4135 men.

35 Background: PREP was initiated in Ontario to provide access and characterize performance of PSMA PET CT among men with recurrent prostate cancer after primary definitive treatment (RP or RT). Methods: Between 03/18 and 09/22, 4135 men were accrued. Men were enrolled and imaged with 18F-DCFPyL at 1 of 6 participating sites within 1 of 6 clinical cohorts. Standardized reports delineated sites of recurrence and post PET management changes. Linkage to provincial databases allowed estimation of overall survival and utilization of salvage radiotherapy after PET. Results: Median follow-up was 1.8 years; key findings are in Table 1. Significant predictors of a positive PET scan on multi-variable analysis included: higher PSA at time of PET and clinical cohort (highest for cohort 4). Significant predictors of change in management were type of recurrence (highest for loco-regional) and higher PSA. Significant predictors of worse overall survival included clinical cohort (worst for cohort 4), extent and type of metastases (worst for mixed bone/lymph/visceral or extensive metastases). A change in management post PET was a significant predictor of improved survival. Conclusions: The PREP registry facilitated access to PSMA PET/CT with high rates of disease detection and impact on management. Significant factors associated with survival were extent and sites of disease detected and management change after PET. Clinical trial information: NCT03718260 . PREP registry: Key findings. Total (n=4135) Cohort 1 (n=255): BF within 3 months from RP and pN+ or PSA &gt;0.1 Cohort 2 (n=1500): BF following RP Cohort 3 (n=1040): BF post RPand adjuvant or salvage RT Cohort 4 (n=263): BF while on salvage hormone therapy Cohort 5 (n=176): BF following Therapy for Oligo-metastases on prior PET Cohort 6 (n=901): BF following primary RT Median Age at scan (IQR) 71.0 (66.0–76.0) 66.0 (61.0–70.0) 70.0 (65.0–74.0) 72.0 (67.0–76.0) 74.0 (69.0–79.0) 73.0 (66.0–77.0) 75.0 (70.0–79.0) Median PSA (IQR) at scan (ng/mL) 1.3 (0.3–4.0) 0.7 (0.2–2.5) 0.3 (0.2–1.0) 1.1 (0.5–2.7) 3.5 (1.6–7.2) 2.4 (1.0–5.3) 4.4 (3.1–7.4) PET: Negative Findings 1216 (29.4) 84 - 88 (32.9 - 34.5)* 749 (49.9) 258 (24.8) 19 (7.2) 18 - 22 (10.2 - 12.5)* 84 (9.3) PET: Locoregional Recurrence 1377 (33.3) 95 (37.3) 471 (31.4) 295 (28.4) 63 (24.0) 34 (19.3) 419 (46.5) PET: Oligo-Metastatic (≤5 metastases) 1021 (24.7) 45 (17.6) 224 (14.9) 354 (34.0) 111 (42.2) 70 (39.8) 217 (24.1) PET: Extensive Metastases 521 (12.6) 29 (11.4) 56 (3.7) 133 (12.8) 70 (26.6) 52 (29.5) 181 (20.1) Change in management post PET 2070 (50.1) 135 (52.9) 585 (39.0) 552 (53.1) 152 (57.8) 99 (56.3) 547 (60.7) Radiotherapy within 6 months 1729 (41.8) 165 (64.7) 866 (57.7) 346 (33.3) 88 (33.5) 49 (27.8) 215 (23.9) Died during follow-up period 138 (3.3) 1 - 5 (0.4 - 2.0)* 18 (1.2) 30 (2.9) 35 (13.3) 8 -12 (4.5 - 6.8)* 44 (4.9) BF: Biochemical Failure; RP: Radical Prostatectomy; RT: Radiotherapy; IQR: Interquartile Range. *Small cell size.

Time from medication order to administration of cabazitaxel (C) vs. lutetium Lu-177 vipivotide tetraxetan (Lu) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

109 Background: C and Lu are associated with overall survival benefit and approved for pts with mCRPC after prior treatment with docetaxel and an androgen receptor pathway inhibitor (ARPI). However, in real-world settings, administering Lu requires coordination across specialties and resources [PMID: 36637862], which could delay its administration. Herein, we sought to compare the time from medication order to administering the first dose of C versus Lu. Methods: This study used pt level data from the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. Inclusion criteria: availability of the date of the first order of single-agent C or Lu and the date of first administration of the drugs. The time between the first medication order to the administration of single-agent C or Lu was measured. Wilcoxon rank-sum test was used to compare the median days between medication order to administration between these 2 agents and a stratified analysis by practice type and insurance was performed. Results: Of 2,329 orders, 2,045 orders were for C between 1/1/2013 and 1/26/2024, while 284 were for Lu between 8/1/2013 and 12/6/2023. The time from medication order to administration was significantly longer with Lu (median 22 days, IQR 12-43) compared to C (median 7 days, IQR 3-14, p &lt; 0.001). Time from medication order to administration of C and Lu by practice type and insurance is summarized (Table). At the time of the first order, pts in Lu cohort, compared to C cohort, were significantly older (median age 74 vs. 72, p &lt; 0.001), more likely to be treated at an academic practice (27% vs. 15%, p &lt; 0.001), and more likely to be covered by a commercial health plan (80% vs. 73%, p &lt; 0.001). Conclusions: Our results show that it takes significantly longer to administer Lu compared to C across different practice types and most insurance plans. These results could inform healthcare policies aimed at improving access to Lu and guide treatment selection in the clinic. Time from medication order to administration of C and Lu by practice type and insurance. Category Subtype (number of orders for C/number of orders for Lu) CN = 2045 LuN = 284 p-value Practice type, mean (range) (days) Academic (315/77) 1.3 (0 – 59) 9.2 (0 – 55) &lt; 0.001 Community (1730/207) 13 (0 – 243) 44 (1 – 282) &lt; 0.001 Insurance, mean (range) (days) Commercial (1494/226) 11 (0 – 163) 32 (0 – 215) &lt; 0.001 Medicare/other government programs (266/46) 10 (0 – 120) 46 (0 – 282) &lt; 0.001 Medicaid (32/2) 9 (0 – 76) 28 (0 – 55) 0.8 Others (72/6) 12 (0 – 42) 21 (0 – 41) 0.2 Unknown (181/4) 14 (0 – 243) 76 (39 – 91) &lt; 0.001

Real-world discontinuation and efficacy data of abiraterone acetate/prednisone (AAP) plus androgen deprivation therapy and radiotherapy in localized prostate cancer.

367 Background: Data from STAMPEDE trial confirmed Overall survival benefit for patients with high-risk localized or locally advanced prostate cancer treated with Radiotherapy (RT) plus 24-month Abiraterone/prednisone (AAP) and ADT. Nevertheless, a 17% discontinuation rate in the experimental arm of the trial was reported. Here we present a cohort of patients treated with this regimen at two Institutions. Methods: We conducted a retrospective analysis of patients with localized or locally advanced prostate cancer who underwent treatment with AAP+ADT+RT with at least 18 months of follow-up. Primary endpoint was the discontinuation rate of AAP in the ITT population. Secondary endpoints included PSA decline rate, PSA nadir &lt;0.02 ng/mL and safety. Clinical data were collected from patients’ electronic records. GraphPad Prism software was used for chart design, data comparison and statistical analysis. Results: Overall, 104 patients completed RT (60 Gy in 20#) and met inclusion criteria for this analysis. Of them, 61 (58.7%) patients had N0 disease, while 43 (41.3%) had N1 disease. AAP was discontinued prior the pre-planned two years in 29/104 (27.9%) patients. Among those who discontinued, median duration of AAP was 13.5 mo [3.2-23.5], while median duration of ADT was not reached [6.1-35.9]. Reasons for AAP discontinuation included hepatotoxicity (n=8), heart concerns and oedema (n=7 and 2, respectively), brain fog (n=2), hypokalaemia (n=2), quality of life deterioration (n=5), other (n=3). In total, 73/104 patients (70.2%) reached a PSA nadir &lt;0.02 ng/mL at the 18-month analysis. No significant difference in achieving a PSA &lt; 0.02 ng/mL was seen between those stopping AAP early (20/29 - 69%) and those who didn't (53/75 - 70.7%). Conclusions: Our analysis revealed a notably high rate of early discontinuation of AAP in the real-world setting in patients treated for their localized prostate cancer when compared to what observed in the STAMPEDE trial. Nonetheless, early discontinuation did not negatively impact on short-term treatment efficacy as a possible surrogate for long-term treatment benefit. Future studies on larger populations with longer follow-up are warranted to confirm these results.