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World-wide oligometastatic prostate cancer (omPC) meta-analysis leveraging individual patient data (IPD) from randomized trials (WOLVERINE): An analysis from the X-MET collaboration.

15 Background: Metastasis-directed therapy (MDT) for omPC has demonstrated progression-free survival (PFS) benefit in multiple phase 2 randomized clinical trials (RCTs) yet has fallen short of demonstrating benefit for later endpoints. The X-MET collaboration amalgamates IPD from RCTs investigating oligometastatic cancers, incorporating new trials when published. Within X-MET, WOLVERINE combined IPD from all published omPC MDT RCTs. Methods: Trial search identified 5 omPC RCTs of MDT and standard of care (SOC) vs. SOC alone: STOMP (NCT01558427), ORIOLE (NCT02680587), ARTO (NCT03449719), SABR-COMET (NCT01446744), and EXTEND (continuous and intermittent androgen deprivation therapy [ADT] baskets; NCT03599765). IPD were retrieved for all trials. PFS was defined as biochemical or radiographic (RECIST 1.1) progression or death. Castration-resistance free survival (CRFS) was analyzed in castration-sensitive prostate cancer (CSPC) patients and was defined as development of castration-resistant prostate cancer (CRPC) or death. Meta-analyses were conducted using fixed- and random-effects models to calculate pooled hazard ratios (HRs). As a complementary approach, HRs were computed utilizing Cox regression stratified by trial. The analysis plan was archived in Prospero: CRD4203479078. Results: This analysis included 472 patients, 224 randomized to SOC and 248 randomized to MDT+SOC, with a median follow-up of 41 mo. The majority were CSPC (58%), treated with ADT (74%) +/- androgen receptor pathway inhibitors (ARPI; 54%), and had a previously treated primary prostate (82%). For both analyses, MDT significantly improved PFS, radiographic PFS (rPFS), and CRFS (Table). Meta-analysis utilizing fixed- and random-effects yielded similar results. Overall survival (OS) was excellent in both arms (3- and 4-year OS: MDT+SOC 92% and 87% vs. SOC 86% and 75%) and exhibited near-significant association with MDT. The benefit of MDT for PFS persisted across most subgroups including castration status, prior primary treatment, staging imaging, and ADT/ARPI use (all HR < 0.52, all P < 0.05, all P[interaction] > 0.05). Conclusions: Leveraging IPD from all published omPC RCTs, WOLVERINE demonstrated for the first time a significant benefit of MDT for longer term endpoints including rPFS and CRFS, in addition to a near-significant association with OS. Furthermore, MDT benefit persisted across the entire omPC disease spectrum ranging from de novo to metachronous and CSPC to CRPC. Association between MDT and outcomes. Cox regression: HR (95% CI) Random-effects model: HR (95% CI) PFS 0.45 (0.35-0.58), P<0.0001 0.44 (0.35-0.57), P<0.0001 rPFS 0.59 (0.46-0.76), P<0.0001 0.60 (0.43-0.85), P=0.0039 CRFS 0.58 (0.37-0.91), P=0.020 0.58 (0.37-0.92), P=0.019 OS 0.64 (0.40-1.01), P=0.057 0.63 (0.39-1.004), P=0.051

A neuronal code for object representation and memory in the human amygdala and hippocampus

Abstract How the brain encodes, recognizes, and memorizes general visual objects is a fundamental question in neuroscience. Here, we investigated the neural processes underlying visual object perception and memory by recording from 3173 single neurons in the human amygdala and hippocampus across four experiments. We employed both passive-viewing and recognition memory tasks involving a diverse range of naturalistic object stimuli. Our findings reveal a region-based feature code for general objects, where neurons exhibit receptive fields in the high-level visual feature space. This code can be validated by independent new stimuli and replicated across all experiments, including fixation-based analyses with large natural scenes. This region code explains the long-standing visual category selectivity, preferentially enhances memory of encoded stimuli, predicts memory performance, encodes image memorability, and exhibits intricate interplay with memory contexts. Together, region-based feature coding provides an important mechanism for visual object processing in the human brain.

Self-supervision advances morphological profiling by unlocking powerful image representations

Characterization, treatment and survival outcomes of penile cancer: Over a decade in a tertiary Mexican center.

5 Background: Penile cancer, as a rare disease worldwide, represents 4.1% of urological cancers in Mexico. Despite the need for multimodal treatments, delayed diagnoses and poor follow-up adherence impact survival outcomes. This study aims to characterize the patient population diagnosed with penile cancer at a tertiary center in Mexico and evaluate treatment and survival outcomes. Methods: This cross-sectional retrospective cohort study analyzed patients diagnosed with penile cancer at the medical oncology and urology services of Centro Médico Nacional 20 de Noviembre from January 2005 to January 2024. Statistical analyses included Kaplan-Meier survival analysis and subgroup analyses by age, surgical treatment type and radiotherapy. Results: Of the 54 patients analyzed, the median age was 64 years (34-84) with a median time symptoms to diagnosis of 12 months. Clinical stages at diagnosis were stage I (9.2%), II (40.7%), III (29.6%) and IV (20.3%). Human papillomavirus (HPV) was positive in 17 patients (31.4%), negative in 2 (3.7%) and undetermined in 35 (64.8%). HIV status was undetermined in 88.8% of cases. Additionally, 22 patients (40.7%) were smokers. Tumor anatomical locations were glans (64.8%), prepuce (25.9%), body of the penis (7.4%) and scrotum (1.8%). Histologically, all cases were squamous cell carcinoma. Most common sites of metastasis were lymph nodes (79.6%), lungs (7.4%) and liver (5.5%). Systemic therapy was administered to 38.8% and radiotherapy to 55.5% with a median overall survival of 44.8 months. Surgical treatment was required in most cases (88.8%), with total penectomy and bilateral inguinal dissection predominating in 21 patients (38.9%), followed by total penectomy alone in 8 (14.8%), partial penectomy with bilateral inguinal dissection in 6 (11.1%) and partial penectomy in 8 (14.8%). Tumor resection alone was performed in 5 (9%). Subgroup analysis based on age, surgical technique and radiotherapy indicated that overall survival was not significantly affected by age when comparing patients <60 years to those >60 years (p=0.1). However, patients undergoing partial penectomy had significantly higher survival rates (12 months vs 7 months; p=0.04), regardless of clinical stage. There was no significant difference in overall survival between patients who received radiotherapy and those who did not (p=0.7). Conclusions: Despite advanced stage at diagnosis, the results suggest that surgical intervention is associated with improved survival rates. However, neither age nor radiotherapy significantly impacted overall survival outcomes, likely due to the homogeneity of clinical stages and surgical approaches. These findings underscore the importance of early detection and comprehensive management strategies to improve survival in this patients.

Prostate Cancer Supportive Care (PCSC) program: An alternative to consolidated framework for implementation research (CFIR) model.

346 Background: The CFIR model is one approach to implementing supportive care services. It requires extensive resources, staff training, and reliance on infrastructure. In contrast, the PCSC Program grew organically based on knowledge of patient-expressed needs. Rather than tailoring services to individuals, the PCSC Program offers a menu of services that the patient can choose from with the help of a program coordinator. Methods: We compared the implementation considerations for CFIR (1) to those of the PCSC Program. Results: Patient Needs Assessment & Staffing: CFIR assesses needs at diagnosis using specific tools in the EHR and recommends a care plan formulated by a multidisciplinary team. In contrast, PCSC empowers patients to self-select services from eight modules (see table below) based on their needs after registration, whether at diagnosis or beyond. This flexibility allows the program to operate efficiently, freeing up clinician time for delivering group education sessions and clinic appointments. Resource Management and follow-up: CFIR identifies community resources with a multidisciplinary team. This may require referrals and clinic-specific communication. This approach may lead to inconsistencies and variation in patient experience. In contrast, PCSC provides all services at a single site that is familiar to many patients as it is across from the urology clinic. Clinic visits are in person or virtual, allowing access to all patients across the province. This model eliminates the need for extensive documentation, and the quality of the services is controlled centrally. Since there is transparency on available services from the outset, patients may return as needed, negating the need for individualized formal follow-up assessments. Sustainability and Impact: While CFIR is process-driven, PCSC’s model has supported over 5,288 patients and their families, free of charge, with $3.25 million in philanthropic support over 11 years in addition to grants and government funding, underscoring the community's trust in the program's efficacy and value. Conclusions: CFIR is a structured and resource-intensive approach that focuses on the individual patient. The PCSC Program presents patients with a menu of services known to be of importance to this population and offers a flexible, patient-driven approach. The longevity of the PCSC Program and the patient satisfaction responses suggest that this is an alternative model for delivering supportive care. 1. Stout et al JCO Oncol Pract 20:1173-1181. Attendance for 5288 registrants from 2013 to 09/2024. Modules Attendees 2013-9/2024, n Introduction to PC and Primary Treatment Options 1994 Managing Sexual Function and Intimacy 2461 Management of side effects of ADT 809 Pelvic Floor Physiotherapy for Incontinence 1890 Counselling 852 Metastatic Disease Management 162 Nutrition 1527 Exercise 1336

Implementation and preliminary validity of the Functional Assessment of Cancer Therapy – Radionuclide Therapy (FACT-RNT) in patients receiving radionuclide therapy for prostate cancer.

118 Background: The Functional Assessment of Cancer Therapy-Radionuclide Therapy (FACT-RNT) is used in trials and clinical practice to monitor patient-reported RNT-relevant symptoms and toxicities in advanced metastatic castrate-resistant prostate cancer (mCRPC) patients receiving RNT. This study examined FACT-RNT feasibility and preliminary validity for U.S. patients receiving RNT. Methods: Patients scheduled to start 177Lu-PSMA-617 for advanced mCRPC at Moffitt Cancer Center from October 2023 – March 2024 completed patient-reported outcome (PRO) measures before each cycle. PROs included previously validated measures of prostate cancer specific-symptoms (NFPSI-17) and physical function (Scored Patient-Generated Subjective Global Assessment; PG-SGA) and the FACT-RNT, a 15-item measure of symptoms/toxicities with higher total scores (range: 0-60) indicating less symptom burden. Correlations between the FACT-RNT and other PROs were calculated. Results: Patients (N=17) were, on average, 69 years old (SD=11, range=43-90) at RNT cycle 1 and mostly non-Hispanic (76%) and White (82%). Gleason scores at diagnosis were 7-8 (30%) or 9-10 (71%). Patients had previously undergone surgery (35%), chemotherapy (94%), radiation (71%), hormone therapy (94%), targeted therapy (88%), and immunotherapy (29%). Fifteen patients (88%) received ≥2 RNT infusions; of these, 1 (6%) died and 1 (6%) discontinued RNT prior to cycle 2. Thirteen (87% of those with ≥2 infusions) completed the FACT-RNT at ≥2 cycles. Cycle 1 FACT-RNT total scores ranged from 31-58 (M=46.5, SD=8). The FACT-RNT was positively associated with symptoms as assessed by NFPSI-17 at cycles 1-3 ( p s≤.03) and negatively associated with physical function at cycles 1-2 ( p s≤.05). Conclusions: Preliminary results support FACT-RNT validity due to associations with validated PRO measures and the feasibility of FACT-RNT implementation in the U.S. The FACT-RNT may be helpful in clinical management and decision-making with RNT recipients. Future research will replicate and extend these findings in a larger longitudinal sample and examine validity with clinician-rated outcomes and RNT dosimetry.

Comparative survival outcomes of non-clear cell and clear cell renal cell carcinomas with indications for adjuvant pembrolizumab.

515 Background: While immunotherapy has become first-line treatment for metastatic renal cell carcinoma in both clear cell (ccRCC) and non-clear cell (nccRCC) histologies, there has been limited investigation into adjuvant therapies for nccRCC in the context of high-risk localized RCC. As adjuvant Pembrolizumab is being more commonly employed for high-risk non-metastatic ccRCC, its application in nccRCC remains less understood. This study aims to compare survival outcomes between patients with high-risk localized ccRCC and nccRCC, focusing on cancer-specific survival (CSS) and overall survival (OS). Methods: Prospectively collected data from a multicenter database, including University of California San Diego Health (USA), IRCCS San Raffaele Hospital (Italy), Emory University Hospital (USA) and Tokyo Medical and Dental University (Japan), were retrospectively analyzed. Non-metastatic patients treated with surgery were included. The cohort was divided between nccRCC and ccRCC groups for descriptive and survival analyses, with the aim of comparing survival of the two groups according to subgrouping factors, specifically high-grade disease (G3-G4 or sarcomatoid features) at final pathology (HG) and locally advanced disease (pathological stage T3). Kaplan-Meier analyses (KMA) and Cox regression multivariable analyses (COX) were conducted to evaluate for cancer-specific survival (CSS) and overall survival (OS) and predictors of cancer-specific (CSM) and all-cause mortality (ACM). Results: With median follow-up of 58 months, a total of 5968 patients were analyzed. 4724 (79%) patients had a ccRCC while 1244 (21%) had a nccRCC. The nccRCC cohort comprised 923 (74%) papillary, 240 (19%) chromophobe and 81 (7%) variant histology patients. KMA comparing nccRCC high-grade (G3-G4; HG) tumors and ccRCC high-grade (HG) tumors showed no difference in 5-year CSS rates (nccRCC-HG 91% vs ccRCC-HG 88%, p=0.08) and 5-year OS (nccRCC-HG 79% vs ccRCC-HG, p=0.1). Comparing T3 stage tumors between nccRCC and ccRCC, KMA also showed similar 5-year CSS (nccRCC-T3 83% vs. ccRCC-T3 84%, p=0.05) and 5-year OS (nccRCC-T3 73% vs ccRCC-T3 73%, p=0.2). Cox regression for predictors of mortality showed that histology was not an independent predictor of CSM (p=0.17) and ACM (p=0.11). Conclusions: Although focus of most RCC adjuvant therapy clinical trials has been on ccRCC, aggressive features in nccRCC patients yield similar 5-year cancer-specific and overall survival rates. This study highlights the need for further clinical trials to evaluate efficacy of adjuvant systemic therapy in the setting of unfavorable groups of non-clear cell RCC.

Self-optimized contact in air-robust thermoelectric junction towards long-lasting heat harvesting

Health related quality of life and its influencing factors in Chinese patients with ocular tumors

Impact of BRCA status in patients with castrate-resistant prostate cancer undergoing abiraterone +/- stereotactic body radiotherapy: ARTO trial.

397 Background: ARTO (NCT03449719) was a multicenter randomized phase II trial exploring the benefit of concomitant Abiraterone acetate and stereotactic body radiotherapy (SBRT) administration in oligometastatic castrate resistant prostate cancer patients (omCRPC). Both biochemical response and biochemical progression free survival (bPFS) were improved by the addition of SBRT in the experimental arm if compared to abiraterone alone. Here is presented a secondary analysis focusing on prognostic impact of BRCA alterations in enrolled patients. Methods: Patients affected by omCRPC (< 3 non-visceral metastatic lesions) were randomized 1:1 to receive either Abiraterone alone (ARM A) or associated with concomitant SBRT on all sites of disease (ARM B). Subgroup analysis focusing on BRCA positive, negative or BRCA untested patients were conducted. Results: Overall population consisted of 157 patients, 89 patients were tested for BRCA 1 and BRCA 2 alterations, of whom 80 and 9 patients resulted negative and positive, respectively. Sixty eight patients were untested. In the BRCA negative population, bPFS events were registered in 43 patients (72.1 and 32.4% of population included in ARM A and B, respectively). Six bPFS events were registered in BRCA positive population (80 and 50% of patients included in ARM A and B, respectively). In the BRCA untested population, 26 bPFS events were detected (52.9 and 23.5% of patients included in ARM A and B, respectively). No significant difference in terms of bPFS was detected between BRCA positive and negative patients (HR 0.93, p=0.86). Conversely, BRCA untested patients had a significant lower risk of biochemical progression (HR 0.58, p=0.02). Benefit of SBRT in the experimental arm was confirmed both in the BRCA negative and BRCA untested populations in terms of bPFS, with HR of 0.37 (95% CI 0.19-0.73) and 0.50 (95% CI 0.14-0.76), respectively. In BRCA positive patients, results were inconclusive due to limited sample size (HR 0.5, 95% CI 0.09-2.89). Conclusions: In a well selected cohort of omCRPC included in a prospective trial, benefit of SBRT was confirmed in BRCA negative and untested patients. Larger cohorts of BRCA positive omCRPC patients undergoing SBRT are needed to confirm these results in this scenario. Clinical trial information: NCT03449719 . Biochemical progression free survival (BPFS) results in the two trial arms according to BRCA status. BRCA negative BRCA positive(vs negative) BRCA untested(vs negative) N Events N Events HR (95%CI), p N Events HR (95%CI), p BPFS 80 43 9 6 0,93(0,39-2,19)p=0,863 68 26 0,58(0,35-0,94)p=0,028 arm A 43 31 5 4 0,86(0,30-2,44)p=0,773 34 18 1,07(0,24-4,85)p=0,926 arm B 37 12 4 2 0,64(0,36-1,15)p=0,135 34 8 0,56(0,23-1,38)p=0,207

Real-world epidemiology and clinical outcomes of bladder cancer patients in Spain: BLARWE multicenter study.

702 Background: Bladder cancer (BC) is one of the most prevalent oncologic diseases in the world, and its incidence in Spain is among the highest in Europe. The optimal management of patients with muscle-invasive bladder cancer (MIBC) and non-MIBC (NMIBC) remains challenging. Currently, there are clinical trials ongoing that have the potential to change the management of early BC and its standard of care. The aim of this study is to provide a comprehensive description of the epidemiology of BC in Spain, and to generate robust evidence on the clinical characteristics, treatment patterns and clinical outcomes of these patients in routine clinical practice. Methods: This multicenter observational study collected adult patients diagnosed with primary or recurrent BC between Jan 1, 2018, and Dec 31, 2018. Patients with histopathological confirmation were included from 16 participating sites, and real-world data was retrospectively collected from medical records. Three cohorts were included: Cohort 1: all cases of BC; cohort 2: high risk NMIBC patients; cohort 3: MIBC patients. The data from cohort 1 presented here includes the incidence of newly diagnosed BC (primary objective) and recurrent or progressive cases (secondary objective) at all stages (NMIBC, MIBC and mBC). Results: 2071 patients were included, with the information available up to the data cutoff on Sep 13, 2024. The median age was 72 years and 84.9% of patients were male. 66,1% of patients were newly diagnosed, while 33.9% were recurrences/progressions. Most patients had NMIBC (80.8%), while the remaining patients had MIBC (16.5%) and mBC (2.7%), respectively. Patient characteristics at diagnosis according to type of BC are presented in the table. 2.8% of patients received their first treatment within a clinical trial after de novo or recurrent disease. Results from cohorts 2 and 3 are scheduled to be presented in the third quarter of 2025. Conclusions: This is the first study of this size to present real-world data on the incidence of all stages of BC (NMIBC, MIBC and mBC) including newly diagnosed/relapsed cases, in Spain. Most patients (4/5) had NMIBC and almost 2/3 were newly diagnosed. By 2025, the final results of the study are anticipated to provide robust evidence on the clinical characteristics, treatment patterns, and clinical outcomes of these patients in routine clinical practice. Patient characteristics at index date (2018). NMIBC MIBC mBC Median age, years (range) 72.0 (20.0-102.0) 73.0 (37.0-101.0) 72.0 (46.0-95.0) Age <=70, N (%) 763 (45.6) 144 (42.1) 23 (41.8) Age >70, N (%) 910 (54.4) 198 (57.9) 32 (58.2) Gender (Male), N (%) 1410 (84.3) 296(87.1) 49 (89.1) New cases, N (%) 1072 (64.0) 264 (77.2) 33 (60.0) Recurrences/progressions, N (%) 602 (36.0) 78 (22.8) 22 (40.0) Enrolled in a clinical trial to receive first treatment after the index date N (%) 30 (1.8) 19 (5.6) 8 (14.5)

The prognostic significance of circulating tumor DNA in prostate cancer: A systematic review and meta-analysis.

214 Background: Circulating tumor DNA (ctDNA) has attracted increasing interest as a biomarker in multiple cancers. This study aimed to perform a systematic review and meta-analysis to evaluate the prognostic value of ctDNA in prostate cancer (PCa). Methods: An electronic search of PubMed, Embase, and the Cochrane library was conducted to identify eligible studies. Hazard ratios (HRs) and corresponding 95% confidence intervals (95%CIs) for progression-free survival (PFS) and overall survival (OS) were extracted for pooled analysis. Data were pooled using a fixed-effects or random-effects models based on the study heterogeneity. Subgroup analyses were performed according to disease status, study design, treatment regimen, and sequencing method. R software (version 4.2.2) was used for statistical analysis. Results: A total of 13 studies comprising 1946 patients with PCa were included. The pooled analysis showed that higher baseline ctDNA levels were associated with shorter PFS (HR 2.88, 95%CI 1.98-4.19, P<0.001) and OS (HR 2.57, 95%CI 1.66-3.97, P<0.001) in overall PCa patients. Subgroup analysis further indicated that the prognostic value of ctDNA levels remained consistent across different study designs, systemic treatment regimens, and sequencing methods. Additionally, elevated ctDNA levels were significantly correlated with shorter PFS (HR 2.56, 95%CI 1.69-3.87, P<0.001) and OS (HR 2.76, 95%CI 1.76-4.33, P<0.001) in the metastatic castration-resistant prostate cancer (mCRPC) setting. Conclusions: Our systematic review and meta-analysis demonstrated that higher ctDNA levels were associated with poorer survival outcomes in patients with PCa, suggesting that ctDNA may serve as a valuable prognostic biomarker in PCa.

Five-year follow-up of prostate specific membrane antigen PET/CT-guided salvage radiotherapy following radical prostatectomy: A single center retrospective analysis.

336 Background: Salvage radiation therapy (sRT) is standard of care for biochemically recurrent prostate cancer following radical prostatectomy (RP). In this setting, prostate specific membrane antigen (PSMA) PET/CT has superior sensitivity and specificity for identifying recurrent disease, especially at low prostate specific antigen (PSA) levels, and can guide target volume delineation for sRT. We set out to identify how PSMA PET/CT guidance impacts long term clinical outcomes following sRT. Methods: We retrospectively screened five prospective PSMA PET/CT studies conducted at the University of California, Los Angeles between 2016 and 2021 for patients who had a prior RP, were restaged with a PSMA PET/CT at their first biochemical recurrence (PSA >0.2 ng/mL), subsequently received sRT, and had at least 24 months of follow up from the start of sRT. Progression-free survival (PFS), freedom from distant progression, and overall survival (OS) were calculated from the start of sRT using the Kaplan-Meier method. Cox regression was used to calculate adjusted hazard ratios (aHRs) for PFS, adjusting for androgen deprivation therapy (ADT), age, pre-sRT PSA level, and use of whole pelvis radiotherapy (WPRT). Results: 113 patients who received sRT between December 2016 and March 2021 met inclusion criteria. Median PSA at PSMA PET/CT was 0.4 ng/mL (IQR, 0.3-1). Median time from RP was 19.9 mo. (IQR, 5.6-51.8 mo). On PSMA PET/CT, 19 patients (17%) were staged TrN0M0, 35 (31%) N1/M1a, 13 (12%) M1b-c, and 46 (41%) T0N0M0 (no visible disease). 76 (67%) received ADT and 70 (62%) received WPRT. Median follow-up was 59.4 mo. (interquartile range [IQR], 47.4-69.5 mo.). 57 (50%) had documented progression. Median PFS was 49.2 mo. (95% confidence interval [CI], 24.1-74.3 mo.). Median freedom from distant progression was 76.4 mo. (95% CI, 62.9-89.9 mo.). Median OS was not reached. The five-year OS rate was 97.1% (95% CI, 94.1-100%). T0N0M0 patients had the most favorable PFS (aHR relative to M1b-c cohort, 0.25) followed by TrN0M0 and N1/M1a patients (aHR relative to M1b-c cohort, 0.39 for both). Pre-radiotherapy PSA was not associated with PFS (aHR, 1.0; p =0.98). WPRT was significantly associated with improved PFS in TrN0M0 patients (aHR, 0.12; p =0.035) but not in T0N0M0 patients (aHR, 0.87; p =0.8). Among T0 N1/M1 patients, prostate bed irradiation was significantly associated with improved PFS (aHR, 0.25; p =0.005). Among T0N0M0 and TrN0M0 patients, ADT was not associated with improved PFS ( p >0.05 for both). Among N1/M1 patients, ADT was significantly associated with improved PFS (aHR, 0.37; p =0.02). Conclusions: PSMA PET/CT-guided sRT was associated with favorable long-term clinical outcomes. Exploratory analyses suggest a benefit for WPRT following a positive PSMA PET/CT and for ADT for N1 or M1 disease. Further prospective data are needed to confirm these findings.

Mitofusin 2 displays fusion-independent roles in proteostasis surveillance

Abstract Mitochondria are essential organelles and their functional state dictates cellular proteostasis. However, little is known about the molecular gatekeepers involved, especially in absence of external stress. Here we identify a role of MFN2 in quality control independent of its function in organellar shape remodeling. MFN2 ablation alters the cellular proteome, marked for example by decreased levels of the import machinery and accumulation of the kinase PINK1. Moreover, MFN2 interacts with the proteasome and cytosolic chaperones, thereby preventing aggregation of newly translated proteins. Similarly to MFN2-KO cells, patient fibroblasts with MFN2-disease variants recapitulate excessive protein aggregation defects. Restoring MFN2 levels re-establishes proteostasis in MFN2-KO cells and rescues fusion defects of MFN1-KO cells. In contrast, MFN1 loss or mitochondrial shape alterations do not alter protein aggregation, consistent with a fusion-independent role of MFN2 in cellular homeostasis. In sum, our findings open new possibilities for therapeutic strategies by modulation of MFN2 levels.

RETRACTED ARTICLE: Saudi calcium bentonite: a novel modifier for enhanced foamed underbalanced drilling performance

Barriers to and facilitators of first-line treatment intensification (TI) in metastatic castration-sensitive prostate cancer (mCSPC) by practice setting and intensification frequency: A sub-analysis of IMPLEMENT.

48 Background: First-line TI (i.e., androgen-deprivation therapy + chemotherapy, androgen receptor pathway inhibitors, or both) is recommended for mCSPC but is underutilized. Phase 1 of IMPLEMENT identified barriers to and facilitators of TI. Phase 2 prioritized these factors and identified resources to increase TI. This sub-analysis describes the results in academic and nonacademic settings, and among high and low intensifiers (physicians who use first-line TI in >50% vs ≤50% of patients, respectively). Methods: Phase 1: Semi-structured virtual interviews with 18 oncologists and 18 urologists, using an implementation science approach based on the Theoretical Domains Framework to analyze themes by setting and intensification frequency. Phase 2: Discrete choice experiment with 302 physicians who reviewed descriptions of potential resources across 12 scenarios and selected the most helpful for increasing TI. We used a mixed-effects logistic regression model to calculate a coefficient of helpfulness for each resource to identify those with the strongest impact on TI decisions. Results: Phase 1:Low intensifiers and nonacademic physicians more frequently reported barriers to TI. Low intensifiers had gaps in clinical trial knowledge, tended to reserve TI for later, and had low-intensifier peers; nonacademic physicians had concerns about side effects, cost, and impact on quality of life. High intensifiers and academic physicians more frequently reported facilitators such as good clinical support and anticipated regret about missing the best chance at improving survival. Phase 2: Significant differences were noted between high and low intensifiers in the utility of decision support and clinical trial summaries (Table). Conclusions: Decision support tools and databases of post-treatment options may help address barriers to TI and improve guideline-concordant care. Resource, mean COH (±SD) Academicn = 81 Nonacademicn = 221 High intensifiersn = 184 Low intensifiersn = 118 Database of post-treatment options 1.89(0.38) 1.80(0.38) 1.94(0.39) 1.65(0.36) Decision support tool linking patient characteristics to first-line treatment options 1.60(0.53) 1.75(0.53) 1.45*(0.52) 2.12*(0.51) Summaries of key clinical trial data 1.39(0.40) 1.25(0.44) 1.55*(0.44) 0.88*(0.37) Cross-specialty treatment guidelines 0.57(0.26) 0.59(0.25) 0.48(0.22) 0.75(0.30) Information comparing clinical outcomes of first-line vs later TI 0.41(0.21) 0.37(0.18) 0.40(0.19) 0.36(0.19) Tools to reduce administrative burden 0.13(0.06) 0.23(0.11) 0.18(0.10) 0.25(0.11) COH, coefficient of helpfulness (scaled to have average value of 1, i.e., >1: above average utility; <1: below average utility). * P < 0.05 from bootstrap testing of subgroup averages.

LEEP: A randomised, window of opportunity, neoadjuvant trial examining the pharmacodynamic effects of ribociclib prior to radical prostatectomy for high-risk, localised prostate cancer.

392 Background: Prostate cancer (PCa) remains the second leading cause of cancer death in men. Neoadjuvant pharmacodynamic studies facilitate rational decisions about which therapies should progress to phase 2/3 trials. CDK4/6 inhibitors are effective in breast cancer, but have not demonstrated the same efficacy in metastatic PCa. LEEP assessed the pharmacodynamic effects of ribociclib, a highly selective oral CDK4/6 inhibitor, in hormone-naïve, high-risk, localised PCa. Methods: This open-label, window of opportunity trial randomised participants at 3 Australian sites in a 4:1 ratio to an experimental or control group. Participants in the experimental group were to be treated with ribociclib 400mg daily for 21 days prior to radical prostatectomy (RP). The primary endpoint was a 50% reduction in Ki-67 expression from the pre-treatment biopsy compared to the RP. Immune cell changes in peripheral blood and tissue were also examined. Results: Between November 2018 and October 2022,33 patients were randomised to either ribociclib or control. 17 participants in the ribociclib group and 7 in the control group were evaluable for response (9 not evaluable due to surgical delays (including COVID shutdowns) or insufficient cancer in the biopsy). When examining a random selection of cancer areas, 10/17 (58%) participants had a greater than 50% reduction in Ki-67, compared to only 2/7 (29%) in the control group. When examining hot spot areas of cancer (i.e. areas with the highest proportion of positive cells on low power estimation), only 5/17 (29%) participants had a greater than 50% reduction in Ki-67, compared to 0/7 (0%) in the control group. In peripheral blood, there were reductions in CD1c and CD141 dendritic cells and myeloid derived suppressor cells over 4 times points in the ribociclib (p>0.05, 0.05 and 0.05 respectively) vs. control groups (p=0.46, 0.14 and 0.14). In patients treated with ribociclib, there was no difference in circulating regulatory T cells (p=0.67). Within the PCa tissue, there was a reduction in regulatory T cells in the ribociclib group compared to controls (p=0.07), but no change in adjacent non-cancerous tissue (p=0.701). There was no difference in M1 or M2 macrophages between the ribociclib and control groups (M1: tumour p=0.307, adjacent non-cancer p=0.334; M2: tumour p=0.168, adjacent non-cancer p=0.130). Conclusions: Following neoadjuvant treatment with ribociclib, >50% reductions in Ki-67 were more frequent among those treated with ribociclib than controls. Reductions in Ki-67 were uncommon in more proliferative areas. Changes in the immune environment were consistent with breast cancer studies. We hypothesise that the more proliferative areas of cancer are less responsive to CDK4/6 inhibitors and this may in part explain the lower observed efficacy in mCRPC than metastatic breast cancer. Clinical trial information: ACTRN12618000354280 .

Association between post-orchiectomy systemic inflammatory indexes and tumor characteristics in clinical stage I germ cell tumours.

643 Background: Approximately 25-30% of clinical stage I (CSI) GCT patients will experience disease relapse after orchiectomy. Adding adjuvant treatment will decrease relapse rate, however, on the contrary leads to over-treatment. Prognostic biomarkers such as lymph-vascular invasion (LVI) and/or embryonal carcinoma (EC) in non-seminoma (NSGCT) and rete testis invasion (RTI) and/or primary tumor size (PTS) in seminoma (SGCT) add limited value in treatment decision making. The aim of this study is to assess systemic inflammatory (SI) indexes and lactate-dehydrogenase (LDH) with clinico-pathological findings along with their prognostic impact. Methods: This is retrospective study, which included 159 diagnosed CSI GCT patients, who underwent active surveillance (AS) from June 2004 to November 2023. Medical records and pathology reports were collected retrospectively. Blood drawn must have been done less than 3 months since orchiectomy had been done. For survival analysis we used dichotomized values of studied biomarkers to “low” and “high” based on median value. Results: Median follow-up was 61 months (ranging from 1-230 months), with 2-years relapse free survival (RFS) 81.3% and 69.0% in SGCT and NSGCT respectively. We confirm inferior RFS among LVI presence compared to LVI absence in NSGCT ([HR]= 2.59, 95%CI (0.74-9.07), p=0.04). Trend to inferior RFS in NSGCT patients with EC predominance (≥50%) was observed as well ([HR]= 2.59, 95%CI (0.98-6.85), p=0.06). Prognostic impact of RTI and PTS(>4cm) in SGCT was not observed, p=0.24 and p=0.51, respectively. SI indexes were assessed among population, where higher neutrophil to lymphocyte ratio (NLR) value was associated with LVI presence and with advanced tumor stage in NSGCT. In SGCT, higher systemic inflammatory index (SII) level was associated with LVI presence as well as with advanced pathological stage. PTS (>4cm) was associated with higher LDH level among cohort of all studied patients, without significance among SGCT nor among NSGCT. Higher LDH value in NSGCT was also associated with EC predominance (≥50%). Conclusions: Our study for the first-time revealed associations of post-orchiectomy systemic inflammatory indexes and/or LDH in CSI GCT. Those new associations deserve further evaluation on larger cohort of CSI GCT to elucidate, whether, its associations in certain histology subgroups will improve stratification of risky population.

Assessing racial disparities in testicular cancer survival: Evidence from a nationwide cohort.

621 Background: Testicular cancer is one of the most common and curable malignancies in young men, with a 5 year survival rate of 95%. Limited research has explored long-term survival outcomes among Black men, given rarity of disease among this demographic. Our study aims to assess potential racial differences in overall survival (OS) and cancer-specific mortality (CSM) among testicular cancer patients using a large, equal access nationwide Veterans Affairs (VA) database, focusing on self-identified Black and White race. Methods: This retrospective study analyzed Black and White testicular cancer patients from the VA database utilizing Veterans Informatics and Computing Infrastructure (VINCI). Self-identified race was obtained from the VA Cancer Registry, with OS and CSM as the primary outcomes. CSM was identified using the National Death Index (NDI). NDI data is available through 12/31/2020, after which date all patients with continued follow-up were censored. Cox proportional hazard models were applied to examine the associations of race on OS and CSM, adjusting for relevant clinical factors such as cancer staging, Charlson Comorbidity Index (CCI), and receipt of adjuvant chemotherapy or radiation. All time to event analyses were done from time of testicular cancer diagnosis to outcome of interest. Results: We compared 1799 White patients to 118 Black patients. A total of 431 (22.49%) patients died, of whom 405 were White and 26 were Black. There was no statistically significant difference in survival at 10 years between Black and White individuals (80.4% vs 81.6%, p = 0.68). The multivariable cox-regression analysis showed no statistically significant difference between Black and White men. Of the 431 deaths, 72 were identified as CSM (71 White, 1 Black). There was no significant difference in 10-year cumulative incidence of CSM in Black and White individuals (0% vs 4.1%, p=0.12). Similarly, no significant differences were found for CSM between Black and White men in the multivariable analysis. Conclusions: Our study found no significant racial disparities in OS or CSM between Black and White testicular cancer patients in the VA healthcare system. As the VA represents an equal access to care setting, these findings may not be generalizable to the broader U.S. population, where disparities in care are more notable. Conversely, access to care may overcome known sociodemographic disparities that drive worse clinical outcomes. The analysis is limited by the small number of patients experiencing the event of interest. Future research should be conducted to validate the association between self-identified race and survival outcomes in more diverse healthcare settings.

Mechanisms of urate transport and uricosuric drugs inhibition in human URAT1

Abstract High urate levels in circulation lead to the accumulation of urate crystals in joints and ultimately inflammation and gout. The reabsorption process of urate in the kidney by the urate transporter URAT1 plays a pivotal role in controlling serum urate levels. Pharmacological inhibition of URAT1 by uricosuric drugs is a valid strategy for gout management. Despite the clinical significance of URAT1, its structural mechanism and dynamics remain incompletely understood. Here, we report the structures of human URAT1 (hURAT1) in complex with substrate urate or inhibitors benzbromarone and verinurad at resolution ranges from 3.0 to 3.3 Å. We observe urate in the central substrate-binding site of hURAT1 in the outward-facing conformation and urate is wrapped in the center of hURAT1 by five phenylalanines and coordinated by two positively charged residues on each side. Uricosuric compounds benzbromarone and verinurad occupy the urate-binding site of hURAT1 in the inward-facing conformation. Structural comparison between different conformations of hURAT1 reveals the rocker-switch-like mechanism for urate transport. Benzbromarone and verinurad exert their inhibitory effect by blocking not only the binding of urate but also the structural isomerization of hURAT1.