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Prognostic impact of germline deleterious variants and variants of uncertain significance in advanced prostate cancer: A call for functional elucidation.

211 Background: Prostate cancer remains the most prevalent solid tumor in men and the third leading cause of cancer-related mortality globally. Tumor aggressiveness and poorer clinical outcomes are associated with certain germline variants. Current technological developments in genetic testing have improved the identification of variants of uncertain significance (VUS), adding complexity to the challenging process of clinical decision-making. The aim of this project was to explore the potential correlation between the identified germline variants and the clinical outcomes in patients with metastatic prostate cancer (mPC). Methods: This retrospective study was conducted at a tertiary care center and included a cohort of 57 patients with mPC who underwent germline genetic testing from January 2021 to December 2022. DNA sequencing was performed by next-generation sequencing (Miniseq, Illumina) using a custom gene panel of 72 genes, and two commercial software packages were employed for variant identification. Variant reanalysis was performed in April 2024. A descriptive and exploratory statistical analysis together with a survival analysis was conducted. Hazard ratios (HRs) with 95% confidence intervals (CIs) estimated with the Cox Proportional Hazards model and p-values for the survival curves obtained by the Kaplan-Meier estimator are presented. Results: A total of 57 patients were included in the analysis, of whom 27/57 (47.5%) had synchronous metastatic disease, while 18/57 (39.1%) had a high-volume tumor (CHAARTED criteria) and 22/57 (47.8%) had high-risk disease (LATITUDE criteria). Of all patients, 19 (33,3%) carried reportable germline variants. Of these, 5 (15.8%) were classified as pathogenic or likely pathogenic, 14 (73.68%) were classified as VUS and in two cases (10.53%) both co-occurred. The impact of the reported variants (including VUS) in homologous recombination repair (HRR) genes ( BRCA1, BRCA2, BARD1, RAD50, RAD51C, RAD51D, PALB2, ATM, CHEK2, NBN ) is summarized in the accompanying table. Conclusions: These results seem to indicate that carrying a VUS in an HRR gene could be associated with worse overall survival. This finding further emphasizes the need to report and elucidate the clinical significance of VUS through precise functional studies. A comprehensive somatic and clinical outcome analysis is ongoing. Survival analysis summary. Germline HRRreportable variants mOS* (months) mOS* (months) N(patients with reportable variants) HR 95% CI p- value Pathogenic/Likely Pathogenic vs. None (including VUS) 53.4 56.3 3 1.27[0.38 – 4.20] 0.86 Only VUS vs. None 40.4 72.0 11** 1.76[0.73 – 4.21] 0.0478 All vs. None 50.3 72.0 14 2.05[0.99 – 4.24] 0.0263 *The diagnosis of metastatic prostate cancer serves as the baseline for OS. **One patient was excluded from analysis for having both pathogenic and VUS HRR variants.

Patient satisfaction with geriatric and functional assessments and referral to frailty-related interventions among older adults presenting to the University of Colorado Urologic Oncology Multidisciplinary Clinic.

TPS273 Background: Geriatric assessments (GA) are valuable tools for determining the functional age of patients and represent the standard of care in evaluating vulnerabilities in older adults with cancer. In oncological treatment, these assessments can help refer patients to appropriate ancillary resources, such as physical therapists, registered dietitians, and social workers, while also assisting in selecting chemotherapy regimens, surgical interventions, and radiation therapy plans. GA and GA-guided management have been shown to positively impact treatment completion and reduce chemotherapy-related toxicity in two recent randomized clinical trials. However, there is minimal data assessing patient satisfaction with the interventions provided through this assessment. This study aims to evaluate patient experiences and acceptance of GA and fragility-based referrals recommended by GA, while also identifying patient-reported barriers to accessing these referred resources. Understanding patient acceptability towards geriatric and functional assessments, along with the determinants and barriers to referral completion, can provide additional information to improve oncologic care for older patients. Methods: This is a single-center feasibility study enrolling patients aged 65 and older who are diagnosed with genitourinary cancer and present to the University of Colorado Urologic Oncology multi-disciplinary conference (MDC). The primary endpoint is the patient-reported acceptability of incorporating geriatric and functional assessments. The secondary endpoint is patient-reported determinants and barriers to completing appropriate referrals based on findings from the GA. Patients will undergo a Practical Geriatric Assessment (PGA) and a Stopping Elderly Accidents, Deaths, and Injuries (STEADi) assessment. Based on their functional score, patients will be referred to Cancer Rehabilitation Medicine, physical therapy, occupational therapy, or the BfitBwell exercise program. Additionally, if the patient’s weight has decreased by more than 3 kilograms in the 3 months prior to their visit, they will be referred for nutritional support. Patients will also be referred to social services if they report significant concerns regarding their ability to manage daily living activities or if they lack adequate social support. Patient acceptability will be collected using validated acceptability of intervention surveys. Semi-structured qualitative interviews will be conducted 8 weeks after the patient’s MDC visit, focusing on patient-reported determinants and barriers to completing fragility-related referrals.

Hypofractionated radiotherapy for prostate cancer (HYDRA): An individual patient data meta-analysis of randomized trials in the MARCAP consortium.

385 Background: Trials comparing moderately hypofractionated radiotherapy (MHFRT) against conventionally-fractionated radiotherapy (CFRT) for prostate cancer have varied considerably in intent (non-inferiority vs. superiority) and MHFRT dose. Herein, we compare the efficacy and toxicity profiles of isodose MHFRT and dose-escalated MHFRT. Methods: Individual patient data were obtained from 7 phase III trials comparing MHFRT vs. CFRT: three (n=3454) with isodose and four (n=2426) with dose-escalated MHFRT. Meta-analyses were designed to compare progression-free survival (PFS), late grade ≥2 genitourinary (GU) and late grade ≥2 gastrointestinal (GI) physician-scored toxicity, and clinically-significant decrements in patient-reported urinary or bowel quality of life (QOL). Results: After a median follow-up of 5.4 years (interquartile range [IQR], 4.6-7.2) and 7.1 years (IQR 5.7-8.4) following isodose and dose-escalated MHFRT, there were no differences in PFS (hazard ratio [HR] 0.92, 95%CI 0.81-1.05 and HR 0.94, 95%CI 0.82-1.09, respectively). Neither isodose nor dose-escalated MHFRT were associated with increased odds of grade ≥2 GU toxicity (odds ratio [OR] 1.16 95CI% 0.86-1.57 and OR 1.20, 95%CI 0.95-1.51). The odds of grade ≥2 GI toxicity were higher with dose-escalated (OR 1.48, 95%CI 1.14-1.92) but not isodose MHFRT (OR 1.30, 95% 0.59-2.87). Isodose MHFRT did not show different odds of urinary (OR 1.03, 95%CI 0.51-2.09) and bowel (OR 0.76, 95%CI 0.40-1.43) QOL decrements, while dose-escalated MHFRT was associated with greater odds of bowel (OR 1.68, 95%CI 1.07-2.61), but not urinary (OR 1.57, 95%CI 0.87-2.85), QOL decrement. Conclusions: Isodose MHFRT and dose-escalated MHFRT both have similar efficacy compared with CFRT, but dose-escalated MHFRT is associated with higher physician-scored and patient-reported bowel and urinary toxicity. Isodose regimens, e.g. 60 Gy in 20 fractions, should be the standard MHFRT regimen for localized prostate cancer.

High thermal durability and thermoelectric performance with ultra-low thermal conductivity in <i>n</i>-type single-walled carbon nanotube films by controlling dopant concentration with cationic surfactant

Single-walled carbon nanotubes (SWCNTs) are promising candidates for use in thermoelectric generators (TEGs) to power Internet of Things (IoT) sensors. For practical applications, the major challenge for SWCNTs is improving the thermoelectric performance and thermal durability of n-type SWCNT films. Here, SWCNT inks were prepared using a dopant, which is a cationic surfactant of dimethyldioctadecylammonium chloride (DODMAC), by changing the mass ratio of DODMAC/SWCNT. The SWCNT films were fabricated by vacuum filtering, followed by heat treatment at 423 K. The in-plane thermoelectric properties were measured at 300 K, and the Seebeck coefficient changed from positive to negative values when the DODMAC/SWCNT was 10−2. The highest dimensionless figure-of-merit, ZT, of 1.0 × 10−2 was exhibited at a DODMAC/SWCNT of 80, which was close to saturation concentration. This ZT was achieved mainly because the thermal conductivity decreased significantly to 0.16 W/(m · K), and it is currently one of the highest values among those of n-type SWCNT films with various dopants. To demonstrate power generation, we fabricated a SWCNT-TEG consisting of n-type SWCNT films with the highest ZT. The SWCNT-TEG exhibited an output voltage of 24 mV and a maximum power of 0.9 μW at a temperature difference of 80 K. Furthermore, to investigate the thermal durability of n-type SWCNT films, thermal cycling tests were performed at temperatures ranging from 300 to 423 K. The SWCNT film with a DODMAC/SWCNT of 80 exhibited the highest durability. These findings will contribute to the widespread use of SWCNT-TEGs as power sources for IoT sensors.

Blueprint for progress: Understanding the driving forces of BIM adoption in Kingdom of Saudi Arabia (KSA) construction industry

Building information modeling (BIM) as a virtual and digital mode of representing construction activities gained significant attention and facilitated construction projects. Nevertheless, many driving forces (DFs) trigger the adoption of BIM. Different kinds of studies have been conducted regarding the DFs of BIM adoption in developed countries. However, few studies have classified the adoption of DFs of BIM technology in developing countries such as the Kingdom of Saudi Arabia (KSA). A range of previous literature identified these DFs in a different context, but there is a need to answer two main questions. First, what DFs could influence BIM adoption in the construction sector of (KSA); second, what could be the possible framework to prioritize these DFs. Therefore, Fuzzy Delphi Methodology (FDM), Interpretive structural modeling (ISM), and MICMAC were applied to answer these questions. Study results highlight that ’Reduced cycle time of the design process’ and ’Efficient construction planning and management’, are the main DFs to BIM adoption in the construction sector of (KSA). This study is the first to employ a hybrid FDM, ISM, and MICMAC approach to evaluate BIM implementation DFs in the KSA context. This study informs policymakers and industry practitioners in (KSA) to develop targeted strategies for effective BIM adoption. This study enhances collaboration and communication among construction industry stakeholders by understanding the significant DFs and their interrelationships.

Analysis of antibacterial drug use and bacterial resistance in psychiatric hospital in the epidemic

Characterizing the immune effects of enfortumab vedotin (EV) on peripheral blood mononuclear cells (PBMCs) in metastatic urothelial cancer patients (mUC).

833 Background: EV has high antitumor activity and improved survival in advanced urothelial cancer both as a single agent and in combination with pembrolizumab. We hypothesized that EV primes a systemic immune response for effective T cell mediated killing. Methods: We conducted a retrospective analysis of mUC patients treated with EV at Memorial Sloan Kettering Cancer Center to evaluate its impact on peripheral blood immune cells. PBMCs were isolated from 32 patients with mUC on C1D1 and C2D1 of EV monotherapy. A 32-color spectral flow cytometry panel was used to identify T-cell subsets, and their correlation with treatment response using Wilcoxon rank sum test. Response was determined by an independent radiologist’s assessment of the first on-treatment scan according to RECIST v1.1 criteria. Results: Of 32 patients, 75% were men with median age 73. 81.3% received prior platinum-based chemotherapy and 93.8% received prior PD-1/PD-L1 immunotherapy. Partial response (PR) was observed in 16 patients, while 16 had stable disease (SD) or progressive disease (PD). At C1D1, CD8+ T cell frequencies did not correlate with response; however, a reduction in circulating CD8+ T cells at C2D1 correlated with poor response (SD + PD, p &lt; 0.05). At baseline, high frequency of CD8+PD-1+ T cells correlated with poor response (p &lt; 0.05). Baseline high frequencies of CD8+PD-1+LAG3+ and CD8+PD-1-LAG3+ T cells were also associated with poor response (p &lt; 0.05). At C2D1, high frequency of CD8+TIM3+ (p &lt; 0.05) and CD8+LAG3+ (p &lt; 0.05) T cells correlated with non-response. Additional activation markers on CD8+ T cells at C1D1 were analyzed (Table). Within the memory CD8+ and CD4+ T cell compartments, patients with higher circulating naïve memory cells (CD45RA+CCR7+) at baseline were less likely to respond to EV (p &lt; 0.05), while those with higher frequencies of T effector memory (CD45RA-CCR7-) and effector T cells (CD45RA+CCR7-) were more likely to respond to EV (p &lt; 0.05). No significant correlations were found between memory T cells and response at C2D1. Conclusions: At baseline and on treatment, distinct immunophenotypes are detected in the peripheral blood of EV treated patients, potentially correlating with treatment response. Ongoing studies aim to further elucidate the influence of prior anti-PD-1/PD-L1 therapy and the combination of EV with pembrolizumab on these immunophenotypic profiles. Peripheral T cell phenotypes at C1D1 from mUC patients treated with EV. Peripheral Immune Cell at C1D1 Responders (PR, %CD45+) Non-Responders (SD + PD, %CD45+) p-value CD8+ 11.1 13.7 0.10 CD8+ Fold Change (C1D1/ C2D1) 1.07 0.74 0.04 Responders (PR, %CD8+) Non-Responders (SD + PD, %CD8+) p-value CD8+ ICOS+ 37.6 56.5 0.01 CD8+ PD1+ 40.9 64 0.04 CD8+ TIGIT+ 39.9 54.6 0.01 CD8+ LAG3+ 1.16 1.23 0.67 CD8+ TIM3+ 23.6 18.5 0.04

Low versus low-intermediate risk metastatic renal cell carcinoma (mRCC): Contemporary data from the International mRCC Database Consortium (IMDC).

505 Background: The IMDC model has been effectively used to predict patients’ (pts) outcomes with mRCC, significantly guiding treatment decisions in the era of immune checkpoint inhibitors (ICIs) that have improved survival. In this study, we aim to characterize the clinical outcomes between patients classified as low (L, IMDC score of 0) vs. low-intermediate (L/I, IMDC score of 1) categories. Methods: Data of pts with mRCC receiving first-line (1L) ICI-based therapies with IMDC scores 0 or 1 was collected from the IMDC. Pts with score 1 were further subdivided into 4 groups based on their individual risk factor: low hemoglobin (Hb), Karnofsky Performance Status (KPS) &lt;80, time from diagnosis (dx) to treatment &lt; 1 year, and other risk factors including elevated neutrophils, platelets, and calcium. Overall survival (OS) and time to treatment failure (TTF) were analyzed using Cox regression models. Logistic regression was used to compare an objective response rate (ORR) according to RECIST 1.1. Results: Among the 803 eligible patients, 283 were classified as L and 520 as L/I. Patients' median age was 60 years (Q1-Q3: 23-88 years). The distribution of patients across specific risk categories within the IMDC score 1 group is detailed in the table. Compared to those with an IMDC score of 0, patients with a score of 1 related specifically to low performance status was associated with a shorter TTF (HR: 2.93, p&lt;0.0001) and ORR (OR: 0.24, p=0.002). Anemia was significantly associated with decreased OS (HR: 1.61, p=0.002), shorter TTF (HR: 1.63, p=0.0002), and reduced ORR (OR: 0.65, p=0.05). Time from diagnosis to initiation of treatment within 1 year was significantly associated with shorter TTF (HR: 1.39, p=0.0015). Conclusions: Anemia and low-performance status emerged as the most informative factors differentiating prognosis between L and L/I IMDC risk groups receiving 1L ICI-based treatment. Molecular studies could further clarify these differences, aiding risk stratification and personalized treatment. Clinical outcomes of patients with mRCC based on risk factors. IMDC =0(N=283) IMDC=1 Low Hb(N=133) Time from dx to treatment &lt;1 year (N=331) KPS &lt;80 (N=21) Other risk factors (N=35) HR for OS* (95% CI) Ref. 1.61 (1.08-2.42)p-value = 0.002 1.11 (0.8-1.56)p-value = 0.55 1.9(0.819-4.408)p-value = 0.135 1.16 (0.55-2.42)p-value = 0.7 HR for TTF* (95% CI) Ref. 1.63 (1.26-2.10)p-value = 0.0002 1.39(1.13-1.7)p-value = 0.0015 2.88 (1.73-4.774)p-value &lt;0.0001 1.9 (0.73-1.91)p-value = 0.47 OR for ORR** (95% CI) Ref. 0.65 (0.42-0.99)p-value = 0.05 1.1 (0.8-1.52)p-value = 0.52 0.22 (0.05-0.66)p-value = 0.02 0.99 (0.48 – 2)p-value = 0.98 *Analysis included 781 patients for OS and 778 for TTF after excluding cases with missing data. **78 not evaluable patients were included as non-responders.

Real-world outcomes of first-line dual immunotherapy versus combination VEGF immunotherapy in intermediate-poor risk metastatic renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Data Consortium (IMDC).

477 Background: Multiple phase 3 trials have established either dual immunotherapy with ipilimumab and nivolumab (IPI-NIVO) or immunotherapy with a VEGFR inhibitor (IO-VE) as standard-of-care first-line therapy for metastatic clear cell renal cell carcinoma (mRCC). We focused this analysis on patients with IMDC intermediate or poor risk where either IPI-NIVO or IO-VE would be standard. Methods: Using the IMDC database, we performed a retrospective analysis of patients with intermediate or poor risk disease (1 or more IMDC risk factors) who received first-line therapy with IPI-NIVO or an approved IO-VE combination (avelumab-axitinib, nivolumab-cabozantinib, pembrolizumab-axitinib, or pembrolizumab-lenvatinib). Baseline characteristics, objective response rates (ORR), time to next therapy (TTNT), and overall survival (OS) were compared between IPI-NIVO and IO-VE regimens by Cox regression analyses. Results: A total of 1,523 patients were identified of whom 72.9% received IPI-NIVO and 28.2% received IO-VE. Baseline characteristics of our cohort are summarized in the table. Median follow-up was 24 months. The ORR was lower with IPI-NIVO compared with IO-VE (39.1% vs 48.0%; p = 0.004). Median TTNT was shorter in IPI-NIVO than IO-VE (10.4 months, 95% CI 9.4-11.7 vs 18.6 months, 95% CI 16.3-24.6; p &lt;0.0001). Median OS was similar between groups at 35.4 months (95% CI: 31.4-41.9) and 35.6 months (95% CI: 28.9-44.1) for IPI-NIVO and IO-VE respectively (p = 0.277), and there were no significant differences when intermediate and poor risk groups were analyzed separately. Median OS in IO-VE vs IPI-NIVO was not significantly different when adjusted by IMDC criteria, brain, bone and liver metastases (HR 0.87, 95% CI 0.71-1.06; p=0.165). Conclusions: In a real-world setting amongst patients with IMDC intermediate-poor risk disease, IPI-NIVO and IO-VE strategies show similar survival outcomes although longer follow-up will be necessary to assess the tails of these survival curves. IO-VE is associated with a greater response rate compared with IPI-NIVO. Baseline characteristics. IPI-NIVON = 1110 IO-VEN = 413 p-value Male 808 (72.8) 303 (73.4) 0.823 IMDC Intermediate/Poor Risk 730/280 (65.8/34.2) 274/139 (66.3/33.7) 0.832 Pre-existing autoimmune condition 16 (2.6) 12 (4.6) 0.133 Non-clear cell histology 139 (15.9) 57 (16.4) 0.844 Sarcomatoid 147 (21.3) 50 (17.2) 0.1437 Nephrectomy 613 (55.3) 239 (57.9) 0.374 Brain metastasis 90 (8.4) 23 (5.7) 0.084 Bone metastasis 373 (34.3) 173 (42.5) 0.003 Liver metastasis 218 (20.2) 65 (16.0) 0.063

Kidney-sparing approach for selected localized high-risk upper tract urothelial carcinoma: A pilot study combining endoscopic thulium laser ablation with perioperative disitamab vedotin and immune checkpoint inhibitors.

791 Background: Radical nephroureterectomy (RNU) is the standard treatment for localized high-risk upper tract urothelial carcinoma (UTUC). However, the predominance of UTUC in elderly populations with significant comorbidities necessitates alternative treatment strategies that prioritize functional nephron preservation. This pilot study aims to assess the efficacy and safety of a comprehensive modality of kidney-sparing approach, comprising endoscopic Thulium laser ablation and perioperative systemic therapy (Disitamab vedotin [DV] and immune checkpoint inhibitors [ICIs]), in a carefully selected cohort of localized high-risk UTUC. Methods: This ongoing study, initiated in November 2021 at West China Hospital of Sichuan University, included selected patients with localized UTUC patients (cT≤2N0M0) characterized by conditions such as solitary kidney, bilateral tumors, impending/already renal insufficiency and individual refusal/ineligibility for RNU. The treatment protocol consisted of endoscopic biopsy and initial laser ablation, followed by 3-4 cycles of DV and ICIs administered every three weeks as induction therapy. Subsequently, patients underwent maximal endoscopic laser ablation. Those exhibiting efficient response received a 6-month course of DV and a 12-month course of ICIs as maintenance therapy. Co-primary endpoints were 1-yr disease-free survival (DFS) and conversion-free survival (CFS). Secondary endpoints included clinical complete response (cCR) rate, renal function benefits, and treatment safety. Results: Thirty-two patients were enrolled, with a median follow-up of 15 months. The majority of patients (26/32, 81.25%) were diagnosed with HER2-positive in biopsy-related IHC, including 3 cases of HER2 3+ and 23 cases of HER2 2+. During the follow-up, 17 local recurrences were observed in 10 patients and the 1-yr DFS rate was 68.75%. HER2 status was a significant predictive factor for local recurrence (OR, 0.15; 95% CI, 0.03, 0.91). Salvage RNU was performed in 2 patients, yielding a 1-yr CFS rate was 93.75%. The cCR rate is 78.13% (25/32). Postoperative renal function impairment was noted in 6 patients (18.75%). Mean eGFR improvements (ml/min/1.73m2) were observed with 3.15 at 1 month, 5.07 at 3 months, 2.41 at 6 months, and 3.97 at 12 months. Notably, no grade 3 or higher systemic toxicities were observed. Conclusions: Preliminary findings indicate that the combination of endoscopic Thulium laser ablation with perioperative systemic therapy (DV and ICIs) demonstrated promising efficacy and manageable safety in selected patients with localized high-risk UTUC. These results provide a solid foundation for the ongoing phase 2 trial (WUTSUP-03) and suggest a potential paradigm shift in the management of this challenging patient population.

The electric field influence on EC-0.18 eV electron trap level in (100)-oriented β-Ga2O3 crystals grown by the Czochralski method

In this Letter, we demonstrate the application of Deep Level Transient Spectroscopy (DLTS) and Laplace DLTS (L-DLTS) techniques to unintentionally doped β-Ga2O3 crystals grown by the Czochralski method. It is clearly shown that the capacitance signal associated with the electron emission from a trap level previously identified in the literature as E14 and characterized by an activation energy of 0.18 eV is found to be a superposition of electron emissions from two closely spaced energy levels. Furthermore, we noted that the corresponding L-DLTS signal splits into two well separated components with activation energies of 196 and 209 meV, and the splitting occurs as the electric field in the space charge region of a Schottky diode exceeds 2 × 107 V/m (0.2 MV/cm). Additionally, a strong dependency of DLTS and L-DLTS signals on the electric field strength and resulting enhancement of the electron emission from these two trap states agree well with the 1D Poole–Frenkel (PF) model, suggesting donor-like behavior of both states. Finally, we found that the barrier height for thermal emission of the electrons is significantly reduced in our samples by 121 meV due to the PF effect for experimental conditions corresponding to an electric field of 3.5 × 107 V/m (0.35 MV/cm).

Implementation and first report of the Brazilian Kidney Biopsy Registry

Background Kidney biopsy registries are valuable tools for guiding clinical practice and developing health policies. In 2021, the Brazilian Society of Nephrology (SBN) created the Brazilian Kidney Biopsy Registry (BKBR). This is the first BKBR report, presenting patient data from 2021. Methods BKBR is a web-based platform hosted on the BSN website, which contains patient demographics, clinical data, frequency, and distribution of histologic diagnosis of Brazilian adult native kidney biopsies. Results Of the 1012 cases registered in 2021, 954 cases were evaluated after excluding pediatric and kidney transplant cases. Twenty-one centers enrolled patients, with representation from all Brazilian regions. There was a slight predominance of females (52.6%), a mean age of 44.7 ± 16 years, and 13.6% of patients were &gt;65 years old. The main indication for kidney biopsy was renal dysfunction (56%) and nephrotic syndrome (41.4%), respectively. At the time of the biopsy, 47.9% of the patients were hypertensive and 15.2% were diabetic. Although 66.2% of patients had eGFR ≤60ml/min/1.73m2 upon biopsy, the majority (60.2%) had mild interstitial fibrosis and tubular atrophy. The most frequent diagnosis in the BKBR was glomerular disease (74.8%). Lupus nephritis was the most frequent diagnosis of glomerular disease (22.6%), followed by IgA nephropathy (13%) and focal segmental glomerulosclerosis (12.2%). Conclusion This is the first report of a Nationwide registry of kidney biopsies in Brazil. This data provides pivotal information about the kidney disease profile in this country with continental dimensions.

Global sensitivity analysis of roof hazard factors based on information entropy and the surrogate model

Abstract The prevention and management of coal mine roof accidents remain challenging issues because it is difficult to evaluate and quantify the interaction effects of the disaster hazard factors objectively. This paper proposes a novel approach: combining information entropy and the surrogate model—and applies Sobol’s method, aiming to solve it and to obtain the hazard factors’ 1th and the global sensitivity value without human intervention. The results show that: (1) The complex logical relationships and interactions of roof hazard factors can be transformed into quantifiable numerical values by building a co-occurrence matrix of disaster factors and calculating its information entropy. (2) The sensitivity levels of roof hazard factors can be successfully distinguished and categorized into priority management and prevention or general management and prevention using the surrogate model and Sobol’s sensitivity method. The novel sensitivity analysis approach suggested in this study considers both the individual impacts of hazard factors and their interactions, offering a more thorough framework for risk assessment as well as a fresh perspective and tool for coal mine safety research.

Clinical outcomes disparities in prostate cancer in the Caribbean: Results from 504 patients from the Martinique cohort.

314 Background: Ethnic and geographic disparities in cancer care access is an issue. French West Indies has one of the world highest incidence of prostate cancer (PC) related to African ancestry in indigenous population and specific environmental carcinogens. The HOXB13 X285K germline mutation is linked to strong family risk and poor prognosis in men with PC. The HOXB13 study enrolled prospectively patients diagnosed with PC in order to determine the prevalence of HOXB13 X285K germline mutation in Martinique. We reported here clinical data from all the cohort. Methods: Patients with a history of PC were proposed to participate to this single center study. Germline HOXB13 X285K mutation screening was performed by sequencing germline DNA according to the Sanger method. We reported clinical-pathological features and outcomes from medical reports from patients enrolled. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Results: We reported a cohort from 504 patients diagnosed with PC between 1999 and 2024 in the unique institution of cancer care in Martinique. The prevalence of HOXB13 X285K germline mutation was 0.99% (5/504) in our cohort, higher than the rate of 0.01% in all comers previously reported. Median age was 63.5 years (36-91). A PC family history of 1st or 2nd degree was found in 33% (166/504). Median BMI was 25 kg/m² and was ≥30 kg/m² in 7.5 %. Risk assessment according to D’Amico was low, intermediate, and high in 11.7%, 35.3%, and 52% respectively. Out of 504 patients, 61 had d e novo metastatic PC (12.1%). The Gleason score was 6, 7, 8-10 in respectively 25%, 49.2%, and 24.2%. Concerning treatment of localized cancer, 44.2% received surgery (R1 in 34%), 47% radiotherapy, 39% hormonotherapy, 8.8% active surveillance, 5.2% brachytherapy and 0.2% HIFU. After local treatment, 34.5% relapsed with median PFS of 3.5 years. Median time between pathology results and therapy initiation was about 5 months (0-4030 days).With median follow up of 5.3 years (2 months-26 years), 42 patients were dead at the time of analyses, median OS was not reached. Conclusions: We reported data from a large homogenous cohort of PC from diversity. Indigenous population from Caribbean Island is underrepresented in clinical trials. However, this population seems to be diagnosed at a younger age, have a longer time from diagnosis to initiation of treatment, a lower access to clinical trials, and an adverse outcome than those diagnosed in the rest of mainland France addressing the disparities in cancer care access. The higher incidence of HOXB13 X285K germline mutations in this population may explain the aggressive profile. To note, this germline mutation was found 100 times higher in local population with PC than in general population (around 0.01%).

Evaluating the contribution of circulating tumor DNA (ctDNA) towards magnetic resonance imaging (MRI) in clinical staging and response assessment of patients with muscle-invasive bladder cancer (MIBC).

798 Background: In patients (pts) with MIBC, optimizing clinical staging (cT-stage) and response assessment after neoadjuvant therapies has become critical in order to envision next-generation bladder-sparing strategies. We have previously reported on the performance of bladder MRI to stage and predict the pathological response to pembrolizumab with the use of modified vesical-imaging reporting and data system (VI-RADS, PMID: 37803523). Using ctDNA yields the potential to increase the prediction of pathological stage, and improve the accuracy of the clinical complete response (cCR) definition. Methods: We report interim results from a prospective biomarker study assembling data from a platform of neoadjuvant trials testing novel perioperative therapies and radical cystectomy (RC) in pts with MIBC (NCT06341478). Pts were staged before and after neoadjuvant therapy with pelvic MRI; modified VI-RADS score consisted of the addition of VI-RADS 0 category to indicate no evidence of residual tumor. MRI images were assessed by 2 independent radiologists. ctDNA monitoring was assessed before and after neoadjuvant therapy and centralized using Signatera ctDNA Assay (Natera Inc., San Carlos, CA). Mean tumor molecules (MTM)/mL were reported. Fisher’s exact test was used for comparing groups. Results: From 07/23 to 09/24, 29 pts with available information on both MRI and ctDNA at baseline and/or after treatment, before RC, were collected. Nineteen (65.5%) had a cT2-stage, 4 received neoadjuvant nivolumab+abraxane (NCT04876313), 15 sacituzumab govitecan (SG) alone (NCT05226117) and 10 SG+pembrolizumab (NCT05535218). At baseline, 0/10 pts with VI-RADS 0-3 had detectable ctDNA vs 9/13 (69%) of VI-RADS 4-5 pts (p = 0.001). Mean baseline ctDNA count was 2.31 MTM/mL. Only 17.6% of cT2 pts revealed detectable ctDNA (mean: 2.51 MTM/mL) vs 100% cT3-4 (mean: 2.39 MTM/mL) (p &lt; 0.001). Likewise, post-neoadjuvant therapy, 0/10 pts with VI-RADS 0-3 had detectable ctDNA vs 4/7 (57%) of VI-RADS 4-5 pts with a mean count of 294.8 MTM/mL (p = 0.010). 2/3 pts with clearance of ctDNA post-therapy had VI-RADS 4-5 scores post-therapy. After neoadjuvant treatment 11/14 (78.6%) pts with VI-RADS 0-3 achieved a pathologic complete response (pCR) vs 1/9 (11.1%) with VI-RADS 4-5 (p &lt; 0.001). However, the only patient with pCR and post-neoadjuvant VI-RADS 3-4 relapsed. Post-neoadjuvant ctDNA was negative in 8/11 (72.7%) pts with pCR and in 0/5 without pCR (p = 0.023). Conclusions: Initial findings from a prospective biomarker study revealed a suboptimal association between local and systemic tumor assessment in pts with MIBC. In the effort of optimizing the definition of cCR to systemic therapy, ctDNA revealed critical limitations that would limit its use in bladder-sparing strategies. More mature data will be presented at the meeting. Clinical trial information: NCT06341478 .

Extensive necrosis as a prognostic indicator in metastatic RCC patients undergoing deferred cytoreductive nephrectomy after immunologic checkpoint inhibitor treatment.

468 Background: The role of cytoreductive nephrectomy (CN) in patients (pts) with metastatic renal cell carcinoma (mRCC) after immune checkpoint inhibitor (ICI)-based therapies remains under debate. Retrospective cohorts have reported shrinkage in the primary tumors and no residual tumor in primary specimens (pT0), however, the clinical relevance has not been explored. Assessing the pathological outcomes of CN following ICI may provide valuable information. Methods: This is a single-center retrospective analysis of metastatic/locally advanced RCC who underwent CN between May 2017 and September 2024 after ICI-based treatment. Demographic and clinicopathological were collected. The primary endpoint was the rate of patients with extensive necrosis (EN), defined as ≥ 95% of necrosis in the resected primary tumor. Progression-free survival (PFS) was calculated at two timepoints: from the date of ICI initiation (PFS1) and from the date of surgery (PFS2) until event (progression or death) or last follow-up, using the Kaplan-Meier method. Differences between groups (pts with EN in resected kidney vs not) were assed with the log-rank test and hazard ratios were calculated with Cox regression model. Correlations were made with the Fisher test between presence of EN and other categorical variables. Results: Twenty-five pts were identified, with a median age of 62 years (range, 40–83), and median follow-up of 31.5 months after initiating ICI. 84% were metastatic, with 84% receiving first-line ICI-based combinations (5 Ipi/Nivo;16 ICI-TKI), while the remaining 16% had second-line nivolumab. The median ICI exposure before surgery was 10.5 m (range, 2.1–42.7) in the entire cohort, 12.7 m (range, 2.1–28.8) in the EN subgroup and 10.3 m (range, 3.1–42.7) in the non-EN. Best overall radiological response prior to surgery included 4% CR, 68% PR and 28% SD. Pathological assessment revealed 76% clear cell, 16% unclassified and 8% papillary RCC and 16% had a sarcomatoid component. 40% of pts had ≥ 95 % necrosis, with half of these pts (20%) achieving pT0. The median PFS1 was numerically longer in pts with EN, not reached (NR) vs 27.7 m, (HR 0.33; 95% CI, 0.09 -1.26; p = 0.09). The median follow-up after surgery was 10 months, and the median PFS2 was longer in the EN subgroup, NR vs 9.7 m, (HR 0.2; 95% CI, 0.04–0.96; p &lt; 0.05). No significant correlations were found between EN and Fuhrman grade, presence of sarcomatoid differentiation, treatment duration, or radiological response. Conclusions: ICI-based regimens showed activity in primary RCC tumors, leading to EN (≥ 95% of necrosis) in a subset of pts. Those who achieved EN appear to have reduced risk of disease progression.

Cadonilimab (anti-PD-1 and CTLA-4 bispecific antibody) combined with axitinib for the first-line treatment of advanced or metastatic non-clear renal cell carcinoma: A prospective, single-arm, phase Ib/II study.

544 Background: Non-clear cell renal cell carcinoma (nccRCC) accounts for approximately 25% of all renal cell carcinoma (RCC) and lacks standards of care. More recent data suggests the efficacy of anti-PD-(L)1 plus anti-CTLA-4 and immune checkpoint inhibitors combined with tyrosine-kinase inhibitors in the RCC. Cadonilimab (AK104) is a first-in-class tetravalent bispecific antibody that targets both PD-1 and CTLA-4, showing a manageable safety profile and favorable clinical benefits. Here we explore the efficacy and safety of cadonilimab in combination with axitinib in patients with advanced or metastatic nccRCC. Methods: Eligible patients had histologically confirmed advanced or metastatic nccRCC who had not previously received systemic therapy. Patients received cadonilimab (10 or 15 mg/kg q3w in phase Ib, and 10mg/kg q3w in phase II) in combination with axitinib (5mg bid) as first-line treatment until disease progression or intolerant to treatment. The primary endpoints were safety and objective response rate (ORR; RECIST v1.1). This study is registered with ClinicalTrials.gov, NCT05808608. Results: As of October 1, 2024, 26 patients were enrolled, median follow-up was 5.1 months (0.6-10.7 months). Twenty patients were available for efficacy assessment. Confirmed ORR was 55% (11/20), and disease control rate (DCR) was 95% (19/20). The median progression-free survival (PFS) was not reached. All patients experienced treatment-related adverse events (TRAEs), grade≥3 TRAEs occurred in 12 (46.2%) patients. Conclusions: Cadonilimab combined with axitinib demonstrated promising antitumoral efficacy and manageable toxicities in patients with advanced or metastatic nccRCC. The trial is an ongoing study, and complete results are awaited after completion of the enrollment and longer follow-up. Clinical trial information: NCT05808608 .

Ferroelectric tunnel junction based on Zr0.75Hf0.25O2/Al2O3 composite barrier

Ferroelectric tunnel junction (FTJ) with tunable tunnel electroresistance is promising for emerging nonvolatile memory applications. In this work, 6 nm-thick Hf-doped ZrO2 ferroelectrics with Zr : Hf = 3 : 1 (ZHO), exhibiting a high remanent polarization of 30 μC/cm2, was prepared and further used to build Pt/ZHO/Al2O3/W FTJ devices with adding 1 nm-thick Al2O3 dielectric layer to reduce the leakage. The FTJ delivered superior performance with a tunneling electroresistance ratio of over 7000, outperforming previously reported other FTJ devices based on hafnia/zirconia ferroelectrics. Under 100 ns single-pulse writing, the FTJ exhibited multiple stable states, good retention over 104 s, and switching endurance exceeding 5 × 104 cycles. Additionally, it delivered a relatively high read current density of 8 A/cm2 at 0.2 V. The results demonstrate that the ZHO/Al2O3 composite structure can effectively alter the tunneling barrier height and increase tunneling current, resulting in a large ON/OFF ratio. The results underscore a great potential of ZHO ferroelectrics in the future development of high-performance nonvolatile memory technologies.

Olympic combat sports and mental health in children and adolescents with disability: A protocol paper for systematic review

Introduction Mental health is important for children and adolescents, particularly those with disabilities. While the mental health advantages of sports participation are well-documented, the specific type of sport may have heightened relevance for children and adolescents with disabilities. The objective of this systematic review protocol is to outline the rationale and methodology for investigating how participation in Olympic combat sports influences the mental health outcomes of this unique population, which is more susceptible to developing mental health issues than their neurotypical counterparts. Methods and analysis A comprehensive search will be conducted across academic databases, including the Cochrane Library, ERIC, PsycINFO, PubMed, Scopus, SPORTDiscus, and Web of Science. The focus will be on identifying randomized and non-randomized controlled trials (RCTs and non-RCTs, respectively), and observational studies with control groups that explore the impact of Olympic combat sports on the mental health of children and adolescents with disabilities. To assess the risk of bias, the Rob 2.0 tool will be employed for RCTs, and the ROBINS-I tool for CTs. For longitudinal and cross-sectional studies, the National Institute of Health’s Study Quality Assessment Tool for Observational Cohort and Cross-sectional Studies will be used. The review process will be conducted using Covidence, possibly utilizing JASP software for meta-analysis if the retrieved studies exhibit sufficient homogeneity. Data that cannot be included in the meta-analysis will be synthesized using the Synthesis without Meta-Analysis (SWiM) tool. Furthermore, the Consolidated Framework for Implementation Research (CFIR) will provide a framework consisting of five broad domains: intervention characteristics, outer setting, inner setting, characteristics of individuals, and the process of implementation.

Ecological complexity of zoonotic malaria in macaque natural hosts