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Germline correlates of clinical outcomes in aggressive prostate cancer subtypes treated with radiation therapy.

418 Background: Research on the genetic profile of cribriform pattern (CP) and intraductal carcinoma (IDC) subtypes of aggressive prostate cancer (PCa) is limited. We evaluated germline mutations in CP/IDC PCa patients receiving radiation therapy (RT) to assess the role of familial high-risk (FHR) and DNA damage repair (DDR) mutations associated with these pathologies and clinical outcomes. Methods: This multi-institutional study included CP/IDC PCa patients treated with RT who consented to germline whole exome sequencing (WES). WES data was annotated using Ensembl Variant Predictor, ClinVar, and OncoKB to identify pathogenic/oncogenic mutations. Mutational frequencies were calculated in R. Clinical data and disease progression (biochemical recurrence [BCR], local relapse [LR], distant metastases [DM]) were assessed. Gene and clinical outcome associations were evaluated using the Kaplan-Meier method and log-rank test (p < 0.05 for significance, Benjamini-Hochberg FDR of 0.1 used for multiple hypothesis testing). Results: Of 1,392 CP/IDC patients treated with RT between 2010-2024, 80 had germline sequencing, and 49 had WES data (12 CP, 24 IDC, 13 CP+IDC); 45 were localized at diagnosis (28 high-, 16 intermediate-, 1 low-risk). Median age at diagnosis was 64 years. 39 (80%) received RT post-radical prostatectomy (RP, salvage) and 10 (20%) for intact prostate (definitive). Median follow-up (FU, months) was 64.5 after diagnosis and 60.3 after RT. At last FU post-RT, 14 (29%) exhibited BCR, 12 (24%) had LR, and 9 (18%) had DM, with progression rates of 83% in CP and IDC, and 77% in CP+IDC. Five-year OS from diagnosis was 94.8% (95% CI, 80.4-98.7), and BCR-free survival (defined as no BCR post-salvage or post-definitive RT) was 69% (95% CI, 47.8-83). Of the 98 FHR and 280 DDR genes analyzed, 4 (8%) and 20 (40%) patients had confirmed mutations, respectively. Of the 24 patients with germline mutations, 20 (83%) had IDC pathology. DDR mutations associated with improved BCR-free survival, HR 0.14, 95%CI 0.03-0.70, p=0.007. Notably, 19 patients had a pathogenic MSH3 deletion, which was associated with improved BCR-free survival, HR 0.17, 95%CI 0.03-0.83, p=0.02. Additionally, 20 patients had pathogenic stop-gains/deletions, 17 (85%) of whom had IDC pathology. Five oncogene mutations were identified in DDR genes ATR, TP53 and ATM, and tumor suppressor genes SHDA and DPYS previously implicated in PCa, all in IDC samples. Conclusions: Pathogenic germline mutations, particularly DDR variants, are significantly associated with aggressive IDC pathology. Continued evaluation in non-CP/IDC patients undergoing RT is needed to examine associations between mutations, subtypes, and outcomes. Mutations in DDR genes, such as MSH3 deletion, were linked to improved BCR-free survival, highlighting the potential role of DDR alterations in therapeutic response of RT patients with aggressive PCa subtypes.

Use of integrated multi-omics profiling in renal cell carcinoma to identify molecular subtypes and associated clinical outcomes and therapeutic vulnerabilities.

588 Background: Although histologically defined subtypes exist, renal cell carcinoma (RCC) is a heterogenous disease, resulting in various treatment outcomes and prognosis. Here, we conducted comprehensive profiling of RCC with histopathologic, proteomic, phosphoproteomic, genomic, and transcriptomic analyses on tumor and paired adjacent normal tissues from 113 patients. Methods: Tumor and matched normal tissues were subjected to proteomic and phosphoproteomic analysis (N=113), whole exome sequencing (N=74), and whole transcriptomic sequencing (N=70). Results: RCC tumors are molecularly distinct from corresponding normal tissues, revealing the loss of tissue identity and de-differentiation. Various hallmarks of cancer were differentially observed at the individual patient level, highlighting the intertumoral heterogeneity of RCC. Proteomic subtyping classifies RCC tumors into four subtypes (C1-4) with distinct phosphoproteomic, genomic, and transcriptomic characteristics with prognostic and predictive implications. Among these subtypes, C1-3 were almost composed of clear cell RCC (ccRCC; 96.8%), whereas C4 was composed of non-clear cell RCC (nccRCC) or other types of cancer (100.0%). Among each subtype, C1 (N=37) exhibits the strongest angiogenesis signaling pathway activation with favorable prognosis after surgical resection. C2 (N=39) was characterized with enrichment in DNA repair pathways along with genetic alteration in BAP1 (24.0%). C3 (N=19) was characterized by chromosome 7q amplification and associated with enrichment in inflammatory response with dismal prognosis along with therapeutic resistance to tyrosine kinase inhibitors and/or immunotherapy. C4 (N=18) was exclusively enriched with nccRCC with active mitochondrial and oxidation phosphorylation. VHL had significant trans -acting effects on various protein and phosphoprotein substrates, whereas PBRM1 and SETD2 had differential cis - and trans -acting profiles. Based on the in silico and in vitro exploration, we also identified CDK5, located on chromosome 7q and highly upregulated in C3 subtype, as a valuable target which can be modulated by small molecule inhibitors. Conclusions: This study reports a large-scale multi-omics-based approach of RCC, providing insights into biologic underpinning and evidence for rational treatment selection as well as linking the multiomics-derived phenotypes to clinical outcomes of RCC.

Quantifying the impacts of volume-based procurement policy on spatial accessibility of antidepressants via generic substitution: A four-city cohort study using drug sales data

Objective To assess the spatial accessibility and inequality of antidepressants and its correlation with VBP (Volume-based procurement) policy using procurement data from four representative Chinese cities between 2018 and 2020. Methods The least-cost-path algorithm was employed to calculate travel time from each population point to the nearest medical institution. Gini coefficient and Theil index were utilized to measure accessibility and inequality. OLS (Ordinary Least Squares) and mediation analysis were used to investigate potential statistical relationships. Results Under the influence of the VBP policy, we observed varying degrees of growth in the procurement volumes of two antidepressants across different cities (Escitalopram: Beijing 30.3%, Shanghai 26.2%, Ningbo 37.4%, Harbin 25.7%; Paroxetine: Beijing 28.2%, Shanghai 1.2%, Ningbo 50.2%, Harbin 590.5%). The increase in the procurement volumes of antidepressants across cities was primarily driven by generic drugs (Escitalopram: Beijing 159.8%, Shanghai 75.0%, Ningbo 146.4%, Harbin 146.3%; Paroxetine: Beijing 67.3%, Shanghai 4.9%, Ningbo 58.0%, Harbin 15,758.3%). In the results on spatial inequality, we observed annual improvements across all cities, with more pronounced progress in economically underdeveloped regions (Escitalopram: Gini in Harbin decreased by 10.6%; Paroxetine: Gini in Harbin decreased by 32.6%). In Beijing, the substitution of generic escitalopram was found to be a partial mediating factor in the improvement of spatial inequality (ACME = -0.00, p-value = 0.01; ADE = -0.00, p-value = 0.02). In Harbin, the substitution of generic paroxetine was identified as a complete mediating factor for spatial inequality (ACME = -0.04, p-value = 0.01; ADE = 0.01, p-value = 0.14). Conclusions This study found that the spatial accessibility and inequality of antidepressant medications gradually improved under the influence of the VBP policy. These improvements can be partially attributed to the substitution of generic drugs.

Enhancing yield and nutrient dynamics of rice through long term fertilization with slag-based and commercial gypsum in Southern India

A multicenter, open-label phase 1/2 study of TYRA-300 in advanced urothelial carcinoma and other solid tumors with activating FGFR3 alterations (SURF301).

TPS904 Background: Activating FGFR3 gene alterations have been identified in up to 20% of advanced/metastatic urothelial cancers (mUC). The pan-FGFR inhibitor erdafitinib (erda) is approved for the treatment of mUC with susceptible FGFR3 genetic alterations whose disease has progressed on or after at least one line of prior systemic therapy. Since pan-FGFR inhibitors target all four isoforms of FGFR (1-4), their lack of FGFR isoform specificity can lead to off-target toxicity (e.g., hyperphosphatemia, stomatitis, ocular toxicity, skin and nail toxicity) and loss of activity due to development of on-target resistance mutations (e.g., V555M/L gatekeeper). TYRA-300 has been designed to be more selective for FGFR3 over FGFR1/2/4 to minimize off-target toxicity and to avoid interactions with known FGFR3 gatekeeper mutations. TYRA-300 is in development for the treatment of FGFR3 + mUC and other solid tumors (SURF301 - NCT05544552). Methods: SURF301 is a first-in-human, open-label, Phase 1/2 global study in several parts: dose escalation in participants with advanced malignancies, with/without FGFR3 alterations (Phase 1, Part A); dose expansion in participants with FGFR3 -activating mutations or fusions (Phase 1, Part B); and select tumor expansion cohorts with FGFR3 activating mutations or fusions (Phase 2). The purpose of Phase 1 is to evaluate the safety, tolerability, pharmacokinetics (PK), preliminary antitumor activity of TYRA-300, and identify the recommended Phase 2 dose (RP2D). Phase 2 will enroll participants in FGFR3 + mUC and other tumor types to further explore the anti-tumor activity and safety of TYRA-300. SURF301 study began enrolling patients in November 2022 and is ongoing in Australia, the United States, France, and Spain. Clinical trial information: NCT05544552 .

G-DISCO: Gemcitabine-docetaxel intravesical instillation synchronous co-administration—A phase I study.

TPS897 Background: Treatment options are notably limited for BCG-unresponsive high-risk non-muscle invasive bladder cancer (HR-NMIBC), often involving intravesical chemotherapy or radical cystectomy. If a patient is unsuitable for cystectomy, or they decline, guidelines suggest intravesical chemotherapy utilizing a combination of gemcitabine and docetaxel 1,2 . Traditionally, these drugs have been administered sequentially with no previous studies investigating synchronous intravesical instillation of gemcitabine-docetaxel. Synchronous treatment has potential resource and time-utlization advantages but has not been formally studied. Methods: G-DISCO (ANZUP 2403, ACTRN12624001188527p) is a single-arm, Phase I study designed to assess the feasibility, safety, and tolerability of synchronous intravesical instillation of gemcitabine and docetaxel. The study has Ethics approval and is currently recruiting patients with fully resected HR-NMIBC that is unresponsive or unsuitable for intravesical BCG therapy and where the patient is unwilling or unable to undergo radical cystectomy. Participants will receive synchronous intravesical administration of gemcitabine (1 g) and docetaxel (37.5 mg), both agents constituted together in 50 mL of saline. The combined solution will be administered via urinary catheter with a recommended minimum dwell time of 60 minutes, aiming for an optimal dwell time of 90 minutes. This intravesical treatment will be repeated weekly for six weeks. This study will enroll 15 patients and has a two-year recruitment strategy expected to finish recruiting in 2026. Feasibility of synchronous intravesical administration of gemcitabine and docetaxel will be assessed by the completion rates of the planned six-week course. Safety will be monitored through the recording of adverse events and tolerability will be evaluated using AUA-SI / IPSS, and NMIBC-SI. Secondary endpoints include; recurrence rates at three months post-treatment, effects of regimen on carbon footprint, pharmacokinetic impacts of combined administration, and tissue translational end-points. If successful, G-DISCO could establish a new standard for administering intravesical gemcitabine-docetaxel, offering several potential advantages including shortened treatment time for patients, improved unit time-efficiency and resource savings for healthcare facilities, and reduced exposure for staff handling these cytotoxic agents. References: 1. Holzbeierlein JM et al. Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline: 2024 Amendment. J Urol. 2024;211(4):533-8. 2. Bladder intravesical DOCEtaxel and gemcitabine 2023 [cited 2024 09 Jul]. Available from: https://www.eviq.org.au/medical-oncology/urogenital/bladder-and-urothelial/4320-bladder-intravesical-docetaxel-and-gemcitabin Clinical trial information: ACTRN12624001188527p.

Evaluating clinical and pathologic predictors for pathologic lymph node positivity (pN+) in patients with clinical T1-4N0M0 bladder cancer undergoing cystectomy.

877 Background: Occult pathological lymph node involvement at radical cystectomy (RC) in patients with clinical (cN0) bladder cancer (BC) remains a diagnostic and therapeutic challenge. We sought to evaluate clinical and pathological predictors of lymph node positivity (pN+) and its correlation with outcomes in patients with cT1-4N0M0 BC at RC. Methods: The study included patients with cT1-4N0M0 BC undergoing RC and pelvic lymph node dissection between 2004 and 2020. Patients were grouped as pN+ vs. pN0 at surgery. Baseline characteristics like age at surgery, sex, ethnicity, body mass index, concomitant carcinoma in situ (CIS) on TURBT, and lymphovascular invasion (LVI) were summarized using descriptive statistics. We performed logistic, univariable, and multivariable Cox regression models to identify independent predictors for pN+ at surgery. Kaplan Meier analysis and multivariable Cox proportional hazards model were used to analyze recurrence-free survival (RFS) and overall survival (OS). Results: 440 patients with T1-4N0M0 bladder cancer undergoing RC were evaluated, of which 359 (81.6%) were pN0 and 74 (16.8%) were pN+. Seven patients (1.6%) had incomplete information and were not included in the final analysis. Most patients were male (79.8%), White (87.7%), and had a median age of 71 years at surgery. Most patients had T2 (54.5%) disease, followed by T1 (24.8%) and T3 (5.7%) disease. On multivariable analysis, LVI [HR 3.02 (95% CI 1.21-7.54); p = 0.018] and positive surgical margins [HR 15.38 (95% CI 4.69-50.41); p < 0.001] at RC were independent predictors for lymph node positivity at surgery. Interestingly, pN+ was not significantly associated with concomitant CIS, preoperative hydronephrosis, and preoperative renal function on multivariable analysis. pN+ demonstrated significantly worse RFS [HR 7.48 (95% CI 4.89-11.42); p < 0.001] and OS (HR 7.86 (95% CI 5.20-11.89); p < 0.001]. Preoperative hydronephrosis [HR 1.76 (95% CI 1.16-2.69); p = 0.008] was an independent predictor for RFS. Preoperative hydronephrosis [HR 1.60 (95% CI 1.19-2.15); p = 0.002] and positive surgical margins [HR 2.31 (95% CI 1.26-4.25); p = 0.007] were independent predictors for OS. Conclusions: LVI and positive surgical margins were significant predictors for pN+ at surgery in patients with cT1-4N0M0 BC. These features could inform perioperative therapy considerations and bladder preservation approaches in cN0 BC.

Metastasis-directed therapy (MDT) plus androgen deprivation therapy (ADT) for oligometastatic prostate cancer (omPC): Primary results of the EXTEND continuous ADT (cADT) basket plus combined analysis with the updated intermittent ADT (iADT) basket and immune correlatives.

140 Background: In the phase II EXTEND iADT omPC basket, MDT+iADT improved progression-free survival (PFS) vs iADT. Here we present the primary results of the EXTEND cADT omPC basket. We further report a pre-specified combined analysis with updated results from the iADT basket and examine the effects of MDT on immunity. Methods: Patients with 1 to 5 omPC metastases were randomized 1:1 to MDT+cADT vs cADT (NCT03599765). MDT consisted of definitive local therapy. cADT consisted of ADT +/- second-generation anti-androgens. The primary endpoint was per-protocol PFS, defined by biochemical criteria (Prostate Cancer Working Group 3), radiologic measures (RECIST v1.1), clinical progression, or death. 87 patients were needed to show superiority at a one-sided P of 0.10 by log-rank test. CDR3 regions in rearranged T cell receptor (TCR) β-chains from pre- and post-enrollment peripheral blood were sequenced with immunoSEQ (Adaptive Biotech). TCR repertoire modulation was defined as having TCR expansion plus contraction using a false-discovery-corrected betabinomial model. TCR sequencing from the ORIOLE trial (NCT02680587) was assessed for external validation. Results: From 2018 to 2022, 87 randomized patients were treated per protocol (MDT+cADT: 45; cADT: 42). 39% had castrate resistant omPC. MDT was definitive radiotherapy in all cases. With median follow-up of 31 mo, median PFS was 47 mo after MDT+cADT vs 22 mo after cADT (HR 0.50; 95% CI 0.23 to 1.08; one-sided P = 0.036). In the combined analysis (N=174) with median follow-up of 42 mo, MDT+ADT improved PFS (HR 0.45; 95% CI 0.30 to 0.69; P < 0.001), radiologic PFS (HR 0.63; 95% CI 0.40 to 0.97; P = 0.038), and castration-resistance free-survival (HR 0.40; 95% CI 0.19 to 0.82; P = 0.013). MDT+ADT had higher odds of TCR repertoire modulation vs ADT (55% vs 15%, P < 0.001). This finding was validated in the ORIOLE trial (MDT: 57% vs observation: 19%, P = 0.03). Among the subset of patients with extreme responses, random forest modeling of 37 clinical/immune variables identified TCR repertoire modulation as the variable with highest importance; further, MDT+ADT induced TCR repertoire modulation in all patients with favorable responses (i.e. PFS > 4 years) and none with unfavorable responses (i.e. PFS < 1 year). Among all patients randomized to MDT+ADT, TCR repertoire modulation was associated with longer PFS (HR 0.21; 95% CI 0.06 to 0.76; P = 0.02). Conclusions: MDT+cADT met the PFS primary endpoint of the phase II EXTEND trial, warranting phase III testing. From the combined analysis, MDT+ADT may also improve longer term outcomes including radiologic PFS and castration-resistance-free survival. Improved outcomes may result from MDT-induced immunomodulation, with implications for future trial design. Clinical trial information: NCT03599765 .

Characterizing pre-discharge interventions to reduce length of stay for older adults: A scoping review

Background Hospital pre-discharge interventions are becoming one of the leading strategies to promote early discharge. For older adult patients, it remains unclear what these interventions are and how they affect discharge outcomes. Objective This scoping review categorizes pre-discharge interventions promoting early acute care hospital discharging or total hospital length of stay reductions among older adults, synthesizes contextual factors (e.g., cost, staffing) driving implementation, and assesses the perceived intervention’s impact. Design The review followed the five states of the Arksey and O’Malley framework and the PRISMA-ScR extension. The PubMed, Embase, and Scopus databases were searched from 1983 to 2020 for pre-discharge interventions designed or adapted to discharge older adults earlier in their stay from acute care hospitals. Potentially relevant articles were screened against eligibility criteria. Findings were extracted and collated in data charting forms followed by brief thematic analyses. Results The search yielded 5,455 articles of which 91 articles were included. Eight pre-discharge intervention categories were identified: clinical management, diagnostic/risk assessment tools, staffing enhancements, drug administration, length of stay protocols, nutrition planning, and communication improvements. Leading motivations for intervention implementation included the nationwide drive to reduce care costs and hospitals’ need to increase hospital profitability, improve quality of care, or optimize resource utilization. Discharge outcomes reported included hospitalization costs, readmission rates, mortality rates, resource utilization rates and costs, and length of stay. Mixed results were found regarding the effectiveness of early discharge interventions on discharge outcomes based on expressed author sentiment. Conclusions The drive for pre-discharge interventions that reduce older adult hospital stays and associated costs continues to stem primarily from economic and governmental policies. Follow-up studies may be required to emphasize patient perspectives and care trajectories to avoid unintentional costly and health-deteriorating consequences.

Two-mode light in optomechanical cavity with squeezed vacuum reservoir

Efficacy of selective renal tumor embolization combined with axitinib and reduced-dose toripalimab in oligometastatic clear cell renal carcinoma: A comparative analysis with axitinib combined with standard-dose toripalimab.

532 Background: Oligometastatic renal cell carcinoma (RCC) involves limited metastases (1-5) and lies between localized and metastatic disease, with lower tumor burden. Studies suggest these patients may respond well to local or systemic therapies like targeted or immunotherapy. Combining renal tumor embolization with these therapies is emerging as a promising option. However, comparative data on embolization versus non-embolization treatments remain scarce. This study compares efficacy and adverse events of these treatments in oligometastatic RCC using propensity score matching. Methods: This study included oligometastatic clear cell RCC patients treated since March 2023, divided into two groups. The experimental group received renal tumor embolization, axitinib (5 mg twice daily), and reduced-dose toripalimab (160 mg every 3 weeks). The control group received standard axitinib and toripalimab (240 mg every 3 weeks). All patients had their first follow-up three months post-treatment to assess efficacy and adverse effects. Propensity score matching (PSM) was used to balance demographics, tumor characteristics, and treatment history. The primary outcomes were disease control rate (DCR) and partial response rate (PR), with secondary outcomes being grade 3-4 adverse events. Results: 58 patients were included, 29 in each group after matching. All covariates had SMD values < 0.1, indicating good baseline balance. The experimental group had a DCR of 100% and PR of 93.1%, compared to DCR of 69.8% and PR of 56.7% in the control group (P < 0.05). In 4 patients with renal vein tumor thrombus, tumor size reduced by over 50%, and thrombus control was effective. Grade 3-4 adverse events were lower in the experimental group (10.1% vs. 38.4%, P < 0.05), mainly hypertension, hand-foot syndrome, and liver dysfunction. Conclusions: Propensity score matching showed that renal tumor embolization combined with axitinib and reduced-dose toripalimab improved efficacy and reduced grade 3-4 adverse events in oligometastatic RCC patients. Larger randomized trials are needed to confirm these findings and explore personalized treatment strategies to improve long-term survival and quality of life.

Therapeutic approaches and outcomes in patients aged 50+ with germ cell tumours.

636 Background: Testicular germ cell tumours (GCT) are the most common malignancy in young men, mainly in their 30s. While multimodal treatment leads to excellent survival in younger patients (pts), its incidence is rising in men over 50, who often have comorbidities and higher risks of chemotherapy (ChT) toxicity. Limited data on outcomes in this group highlights the need for more research. Methods: We conducted a retrospective single centre study, analysing pts diagnosed with GCT aged 50 years or older between 2014 -2023. Results: 142 pts were analysed, median age of 57 years (range 50–83). Most pts had an ECOG performance status of 0 (59%), and 26% had ≥ three comorbidities. Seminoma (S) represented 70% of diagnoses, while non-seminoma (NS) 30%. Among NS, embryonal carcinoma (62%) and yolk sac tumor (55%) were the most common. Fifty-six percent had stage I, 42% were above stage I and 2% had an unknown stage. Among stage I pts, 64 had S and 16 had NS. 38 pts (48%) received adjuvant ChT: 29 S treated with carboplatin, 8 NS with BEP, and 1 with EP. Of those given adjuvant ChT, 9 relapsed (24%; 5 S, 4 NS), while 14 on active surveillance relapsed (33%; 12 S, 2 NS). Among metastatic pts, most were classified as IGCCCG good-risk (52%), followed by intermediate (23%) and poor-risk (16%). The most used protocols were EP (32%), BEP (25%), and Carboplatin (20%). Seven stage II seminoma pts received ChT-radiotherapy, with one relapse. The response to first-line treatment was favorable in 78% (n=50) of cases (CR/PR markers negative), while 16% (n=12) had an unfavorable response. The overall 5-year relapse-free survival rate for all pts was 63%, with rates of 70% for Stage I, 79% for Stage II, and 45% for Stage III. The 10-year overall survival rate was 70%, with 80% for Stage I and 59% for advanced stages. At analysis, 78% were alive and 75% in remission. Among those who died, 54% of deaths were due to GCT. Conclusions: Our study indicates that survival outcomes for pts with late-onset GCT are considerably less favourable compared to younger cohorts. The data suggests that a higher prevalence of comorbidities, treatment delays, and dose reductions, may contribute to these differences. Moreover, the number of pts relapsing after adjuvant ChT is particularly high and raises the question of whether older age GCT are biologically different. Further research on factors affecting treatment and survival is needed, as a tailored approach could address challenges and improve outcomes. Treatment delivery and toxicity. Category Data Baseline performance status 0: 58.5%1: 14.8%2: 3.5%3: 0.7%Unknown: 22.5% Total number of ChT cycles 1-2: 51.8%3-4: 36.1%>4: 12.1% ChT related toxicity Grade 3-4: 23.6%Hematological: 15.5%Non-hematological: 19.1%Unknown: 24.5% ChT delivery Delays: 11%Dose reduction: 11% Number of additional hospital admissions 0: 52.7%1: 12.7%2: 4.5%≥3: 5.4%Unknown: 24.7% Bleomycin delivery Given: 23.9%Omitted: 76.1%Incidence of pneumonitis: 11.5%

Rates of acute GI and GU toxicities with dose-escalated intensity modulated proton therapy (IMPT) for the treatment of node-positive prostate cancer.

380 Background: Node-positive prostate cancer (PCa) poses a unique treatment challenge since bowel radiation tolerance often limits the delivery of doses of 60-70Gy or more required to control gross nodal disease. IMPT is a novel therapeutic option which utilizes beam stopping properties to achieve dose sparing of normal organs with the ability to dose escalate (DE) with potentially greater safety. However, the safety of DE-IMPT in node positive PCa has not been well described. Methods: Data were reviewed for consecutive patients treated between 9/2018-4/2024 with DE-IMPT for radiographically detected node-positive PCa. Treatment to the prostate and seminal vesicles consisted of 78Gy/39fractions; elective nodal regions received 46-48.6Gy in 1.8-2Gy/fraction, as part of whole pelvis treatment, while positive nodes were DE to a mean equivalent dose at 2 Gy/fraction (EQD2) dose of 66Gy (54-77.1Gy) in 1.8-2.5Gy/fraction, based on respecting predefined surrounding organs at risk (OAR) tolerances. Acute toxicities were assessed at baseline, weekly during treatment, and up to 3 months post-IMPT using Common Terminology Criteria for Adverse Events (CTCAE version 5). Results: The study included 58 patients presenting with a mean of 3 positive nodes (1-12). Median follow up was 19.5 months (3-67 months). Median age was 73 years (49-86). Majority were high-risk: Gleason 8-10 (67.2%), T3a-b (50%), PSA > 20 (44.8%). Median prostate gland volume was 52cc (19-157). All pts received androgen deprivation therapy (ADT) with 97% completing at least 6 months; Androgen receptor pathway inhibitors were added in 26 pts (45%). Overall mean rectal V70, V60 and V50 were 6.7%, 11.2% and 16.5% while mean bladder V70, V60 and V50 were 12%, 17.3% and 24%, respectively. Mean small bowel dose to 1 cc volume D 1cc was 50.7Gy (45.6-57Gy), while mean Dmax point dose to 0.03cc was 52.2Gy (47.8-61.8). Worst acute Genitourinary (GU) toxicities Grade 0 and 1 were 1.7% and 12%, respectively. During treatment, 18/58 patients (31%) were started on Alpha-blockers for increased urinary frequency, retention and urgency, consistent with GU Grade 2 toxicity of which 7(39%) had discontinued medication by 3 months post-treatment. Before treatment, 32/58 (55.1%) were already on Alpha-blockers. There were no GU Grade ≥ 3 toxicities observed. Acute gastrointestinal (GI) Grade 0 and 1 were 43.1% and 53.5%, respectively. Grade 2 GI toxicities were observed in 2 (3.4%) patients consisting of diarrhea and proctitis. One patient (1.7%) developed transient Grade 3 enteritis. Conclusions: This contemporary series demonstrates that DE-IMPT is a safe treatment option for node-positive PCa with acceptable rates of acute grade 1 or 2 toxicity. Acute grade 3 toxicity was rare, occurring in only one patient in this cohort.

Updated outcomes of patients with metastatic non-clear cell renal cell carcinoma (mnccRCC) treated with first-line (1L) therapies: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).

494 Background: Immuno-oncology (IO)-based combination therapy with or without anti-vascular endothelial growth factor (VE) has become a standard of care for mnccRCC. However, real-world evidence on the effectiveness of contemporary therapies over traditional targeted therapies against mnccRCC is limited. Methods: Using the IMDC, patients with mnccRCC were classified into five subgroups based on 1L therapies: IOIO, IOVE, CABO, SUN/PAZ, and mammalian target of rapamycin (mTOR). Baseline patient characteristics, clinician assessment of objective response rates (ORRs) as per RECIST 1.1, and overall survival (OS) were compared across 1L therapies. Results: Of 1551 patients with mnccRCC, 180 (11.6%), 90 (5.8%), 45 (2.9%), 1039 (70.0%), and 197 (12.7%) received IOIO, IOVE, CABO, SUN/PAZ, and mTOR, respectively. The most common histology was papillary in 725 (46.7%), followed by unclassified in 287 (18.5%), chromophobe in 200 (12.9%), and translocation in 84 (5.4%), while sarcomatoid dedifferentiation was found in 236 (15.2%). The IMDC prognostic categories (favourable/intermediate/poor) differed significantly across 1L therapies: IOIO (6.7%/52.3%/40.9%), IOVE (26.9%/44.9%/28.2%), CABO (16.1%/53.2%/30.7%), SUN/PAZ (16.1%/53.2%/30.7%), and mTOR (9.6%/51.4%/39.0%). For the papillary subtype, ORRs and median OS were better in IOIO (26.1% and 31.9 months), IOVE (31.0% and 33.2 months), and CABO (36.8% and 30.7 months) than in SUN/PAZ (12.8% and 17.2 months) and mTOR (3.4% and 13.1 months), whereas for the unclassified subtype, CABO did not appear to be as effective as IOIO and IOVE. For the chromophobe and translocation subtypes, there was no significant relationship between 1L therapies and the outcomes. IOIO was associated with the highest ORR and the longest median OS for mnccRCC with sarcomatoid dedifferentiation. Conclusions: Contemporary therapies seem to be effective against mnccRCC, although histology-specific strategies may guide personalized treatment selection. Histologic subtype IOIO IOVE CABO SUN/PAZ mTOR p-value Papillary (n = 54) (n = 31) (n = 25) (n = 499) (n = 116) ORR, n (%) 12/46 (26.1%) 9/29 (31.0%) 7/19 (36.8%) 52/407 (12.8%) 3/87 (3.4%) <0.001 Median OS (95% CI), months 31.9 (20.3–NA) 33.2 (18.6–NA) 30.7 (17.5–48.7) 17.2 (15.3–19.6) 13.1 (11.1–15.4) 0.002 Unclassified (n = 50) (n = 20) (n = 10) (n = 179) (n = 28) ORR, n (%) 14/45 (31.1%) 5/17 (29.4%) 0/7 (0%) 22/149 (14.8%) 1/22 (4.5%) 0.018 Median OS (95% CI), months 18.8 (13.8–29.0) 15.5 (11.1–NA) 7.6 (2.1–NA) 13.6 (11.0–16.7) 6.1 (3.6–9.5) <0.001 mnccRCC with sarcomatoid dedifferentiation (n = 47) (n = 12) (n = 2) (n = 141) (n = 34) ORR, n (%) 16/41 (39.0%) 2/10 (20.0%) 0/2 (0%) 16/106 (15.1%) 1/26 (3.8%) 0.003 Median OS (95% CI), months 31.9 (19.3–NA) 14.0 (2.1–NA) 14.3 (7.6–NA) 12.8 (7.0–13.9) 6.6 (3.6–12.5) <0.001

Impact of federal funding for graduate medical education on residency program size: Evidence from the Affordable Care Act

Primary care and rural physician shortages are a present and growing concern to policy makers. We assessed three Affordable Care Act (ACA) provisions that changed the maximum number of residents teaching hospitals could be reimbursed for, an element of graduate medical education (GME) funding known as the resident cap. The results show that an increase in a hospital’s resident cap of one slot under one of these ACA provisions in 2010 is associated with an increase in residency program size of approximately one full-time equivalent resident. We find important heterogeneity in the magnitude of the association between resident cap changes and program growth across ACA provisions, as well as in whether these associations are driven by changes in primary or non-primary care program growth. These results suggest that targeted changes to GME funding may be an effective tool in helping address physician shortages.

Hemodynamic effects of stenosis with varying severity in different segments of the carotid artery using computational fluid dynamics

External validation of previously reported prognostic classifications for patients treated with second-line axitinib after immuno-oncology combination therapy for advanced renal cell carcinoma: JUOG retrospective study.

482 Background: To validate the prognostic classifications previously reported for patients with advanced renal cell carcinoma who received second-line axitinib after treatment with nivolumab and ipilimumab. Methods: This study included 86 patients from 27 JUOG participating institutions. Treatment outcomes for axitinib as a second-line therapy were collected retrospectively. The prognostic classifications evaluated included the MSKCC risk model (5 factors), IMDC risk model (6 factors), JMRC risk model (4 factors [Cancer Sci. 2012]), ACL risk model (3 factors: albumin, LDH, CRP [Urol Oncol. 2019]), and ATP risk model (4 factors: metastatic disease at diagnosis, number of metastatic sites, albumin level, neutrophil lymphocyte ratio [Cancer Sci. 2020]). An external validation was conducted to evaluate the predictive accuracy for overall survival. Furthermore, risk factors associated with overall survival (OS) were examined using the Cox proportional hazards model. Variables with a p-value less than 0.05 in the univariate analysis were included in the multivariate analysis. Results: The median observation period was 17 months. The median OS and progression-free survival (PFS) for second-line axitinib treatment following immuno-oncology combination therapy were not reached (95% CI: 20-NR) months and 13 (95% CI: 8-14) months, respectively. The best overall response rates were CR 4.7% and PR 34.9%. The integrated Time-Dependent AUC for the MSKCC, IMDC, JMRC, ACL, and ATP classifications were 0.76, 0.76, 0.70, 0.78, and 0.69, respectively. In analyzing treatment prognostic factors, univariate analysis identified significant prognostic factors: less than one year from initial diagnosis, Karnofsky Performance Status <80%, hemoglobin < lower limit of normal, platelet count > upper limit of normal, neutrophil-lymphocyte ratio, albumin level, and CRP level. In the multivariate analysis, only the albumin level was identified as a significant prognostic factor (HR 1.85, 95% CI: 1.18-75.59, p=0.02). Conclusions: Pre-treatment albumin level was an independent prognostic factor for OS of the patients with second line axitinib treatment after immune-oncology combination therapy. Five prognostic models demonstrated comparable accuracy for predicting OS. It is noteworthy that the ACL risk model exhibited a good performance despite its simplicity, comprising only three factors. Comparison of trends in the area under the curve (AUC) values of time-dependent receiver operating characteristic (ROC) curves (prognostic performance) among five prognostic models for OS. Risk model 6 month 12 month 18 month 23 month Integrated ACL 0.77 0.80 0.77 0.74 0.78 IMDC 0.81 0.75 0.68 0.76 0.76 MSKCC 0.80 0.73 0.70 0.72 0.76 JMRC 0.71 0.65 0.67 0.67 0.70 ATP 0.73 0.65 0.68 0.68 0.69

Real-world outcomes in metastatic prostate cancer patients with ctDNA-detected <i>SPOP</i> mutations.

110 Background: Comprehensive genomic profiling (CGP) is recommended for patients (pts) with metastatic prostate cancer (mPC) to inform therapy. ctDNA analysis provides rapid results with high concordance to tissue-based CGP avoiding the need for invasive biopsy. SPOP mutations ( SPOP+ ) define a novel group of mPC enriched in black pts. Tissue-based data suggests a subset of pts with SPOP+ mPC have improved outcomes with hormonal therapy and may not require intensified treatments. This study examined outcomes for mPC pts following ctDNA-detected SPOP mutations by race. Methods: Real-world (rw) data was sourced from GuardantINFORM from 2014 to September 2024. GuardantINFORM is comprised of aggregated commercial payer health claims and de-identified records from pts with clinical ctDNA testing via Guardant360 (G360). Index date was defined as the first metastatic claim post-mPC diagnosis and baseline period as the six months prior to the index date. Adult mPC pts with &gt;2 mPC claims in the baseline period were analyzed. Demographics and rw first-line outcomes (rw time to next treatment (rwTTNT) and rw overall survival (rwOS), months) in both unmatched and propensity score matched and weighted SPOP + vs. SPOP- were assessed. A subgroup analysis was also conducted by stratifying by the two main racial groups, white and black. Results: SPOP mutations were observed in 2.6% of pts meeting inclusion criteria (346/13283). 346 SPOP+ mPC pts were included as cases, of which 205 (59%) were White, 90 (26%) Black, and 51 (15%) other/unknown race; 43% had prior ADT use (n=151) and the median age was 72 years (range: 45-84). A larger proportion of black pts were in the SPOP + cohort compared to SPOP - (21.8% vs. 14.9%) with other demographics similar between cohorts (age, non-Black race, line of therapy, prior ADT use). In unmatched analyses, SPOP+ had numerically similar median rwTTNT and shortened median rwOS compared to SPOP -, although not significant [rwTTNT: SPOP + 12.7 (10.1-14.3) vs. SPOP - 12.4 (11.8-13.0); p=0.86; rwOS: SPOP + 18.3 (15.2-25.8) vs. SPOP - 21.9 (20.7-22.7); p=0.33]. Upon stratifying by race in matched and weighted cohorts, SPOP + black pts had numerically improved median rwTTNT and median rwOS compared to SPOP + white pts, yet not significant [rwTTNT: Black- SPOP + 13.7 (9.2-NR) vs. White- SPOP + 12.4 (8.3-14.5); p=0.66; rwOS: Black- SPOP + 18.9 (14.7-NR) vs. White- SPOP + 17.1 (13.1-29.1); p=0.38]. Conclusions: This data supports ctDNA use for detecting S POP mutation status in mPC. SPOP + may impact rwTTNT and rwOS among black pts. Further modeling of real-world matched cohorts and additional studies in clinical cohorts are needed to continue to assess the impact of SPOP + on patient outcomes.

Prostate Cancer Real World Evidence Registry (PROCARE): Recurrent and metastatic prostate cancer.

TPS274 Background: Prostate cancer remains the most common malignancy among men and the fifth leading cause of cancer-related mortality globally. Over the past 15 years, advances in imaging techniques and therapeutic options have significantly transformed the management of recurrent, advanced, and metastatic prostate cancer. However, treatment efficacy and toxicity are highly influenced by prior therapy sequences, highlighting the need for a deeper understanding of the optimal treatment sequence. The prospective real-world evidence registry, PROCARE, addresses this gap by documenting treatment patterns, imaging exams, oncologic outcomes, and safety profiles in routine clinical practice. Methods: This study focuses on four distinct patient cohorts: biochemical recurrence after local treatment with curative intent (e.g. radical prostatectomy, radiotherapy of the prostate or combination thereof), non-metastatic castration-resistant prostate cancer (nmCRPC), metastatic hormone-sensitive prostate cancer (mHSPC), and metastatic castration-resistant prostate cancer (mCRPC). PROCARE is a comprehensive long-term follow-up registry designed to document treatment patterns and outcomes in patients receiving systemic treatment. The study aims to enroll 5,000 patients across 50 sites in Germany. Recruitment is being conducted independently for each cohort, beginning with the mHSPC and mCRPC cohorts. First patient in was in January 2024. Patients will remain in the registry from the time of enrollment until death, withdrawal of consent, or study cohort closure. Throughout the study, additional blood samples will be collected at baseline and with each treatment change, respectively, and at first routine follow-up visit thereafter for exploratory research purposes, such as assessing circulating tumor DNA and RNA, as well as genome-wide single nucleotide polymorphisms (SNPs). This approach will enable a deeper understanding of treatment distribution, sequencing, efficacy, and safety in the real-world setting, contributing valuable insights into the evolving therapeutic landscape. Furthermore, analyses from liquid biopsies might provide important insights potentially guiding future therapeutic strategies for recurrent and metastatic prostate cancer. Clinical trial information: DRKS00033411 .

Final overall survival and new ctDNA analysis in MET-driven advanced papillary renal cancer (CALYPSO).

444 Background: Phase II data from the CALYPSO study (NCT02819596) has shown activity for durvalumab (PD-L1 inhibitor) plus savolitinib (MET inhibitor) (D+S) in MET-driven advanced papillary renal cancer (aPRC), resulting in the ongoing randomised phase III study, SAMETA (NCT03091192). Here we present the final efficacy and new ctDNA analysis. Methods: The aPRC cohort was a single arm study of D+S in both untreated and previously treated disease. Efficacy endpoints include response rates (RR) as per RECIST 1.1, progression-free survival (PFS) and overall survival (OS). PD-L1, TMB and MET status were analysed. Safety was assessed via CTC criteria. FoundationOne CDx was used to profile tissue in 41 patients. Plasma was collected for ctDNA analysis (FoundationOne Tracker analysis; n=21) at baseline (pre-treatment) and sequential time points on treatment. MET mutations were also tracked using F1 Tracker following identification by the F1CDx assay. Results: At 41 months follow-up, the RR in the Intention to Treat (ITT) aPRC population (n=41) was 34% (95% CI, 20-51) and 59% (95% CI, 33-82) in MET-driven patients (n=17). The median PFS was 8.4 months (95% CI, 3.0-13.9) in the ITT population and 16.7 months (95% CI, 5.1-31.4) in MET-driven patients. The median OS was 18.3 months (95% CI, 7.3-30.6) in the ITT population and 27.4 months (95% CI, 9.3-51.6) in MET-driven patients. The hazard ratio (HR) for PFS and OS in MET-driven vs non-MET-driven in PRC cohort was 0.36 (p=0.02) and 0.76 (p=0.43), respectively. 66% of patients were PD-L1+, and 32% were both MET-driven/PD-L1+. The PD-L1 biomarker did not enrich for responders. 27% patients had tissue TMB &gt;median (2.52mut/Mb). TMB was not associated with outcome. 10/16 (63%) were ctDNA positive at baseline, which was associated with a shorter median OS of 7.3 vs 36.4 months (HR 3.91, p=0.02). The mean reduction in Variant Allele Frequency (VAF) was 43% with therapy. For patients with pre- and on-treatment ctDNA, those with CR/PR had ctDNA VAF reduction while those with SD/PD had ctDNA VAF increase (p=0.05). ctDNA clearance was associated with improved PFS (p=0.04). Only 2 patients had MET mutations tracked. ctDNA positivity did not correlate with MET alterations, PD-L1 status or the presence of visceral metastases. Conclusions: D+S continue to show impressive efficacy in MET driven tumors, supporting the ongoing SAMETA trial. ctDNA monitoring on therapy holds promise as a prognostic and potentially predictive tool in this setting. Clinical trial information: NCT02819596 .