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Long-term safety outcomes of ¹⁷⁷ Lu-PSMA-617 in patients with prostate cancer.

TPS294 Background: Approval of [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) for the treatment of adult patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer, previously treated with androgen receptor pathway inhibitors and taxane-based chemotherapy, was based on the results of the Phase 3 VISION study (NCT03511664). It is important to further characterize long-term safety outcomes in 177 Lu-PSMA-617–treated patients, with particular regard to potential treatment-related risks. To this end, the long-term follow-up (LTFU) safety study (NCT05803941) has been established. Findings from the LTFU study will be crucial for assessing delayed toxicities for patients with PSMA-positive metastatic prostate cancer treated with 177 Lu-PSMA-617 globally. Methods: The LTFU study is a prospective, multi-center, non-EU post-authorization safety study. Patients who received ≥1 dose of 177 Lu-PSMA-617 within one of the prospective parent studies (Table 1) are eligible. Patients may enroll in the LTFU study after fulfilling the requirements of their corresponding parent study. The primary endpoint is the number and proportion of selected adverse events (AEs), including myelosuppression, xerostomia, renal failure, xerophthalmia, and second primary malignancies (eg, myelodysplastic syndrome or acute myeloid leukemia), other serious AEs, and changes in laboratory values. The secondary endpoint is the number and proportion of deaths. Following enrollment, patients will undergo assessments at baseline, and then every 6–8 months for up to 10 years after their first dose of 177 Lu-PSMA-617 or until death. At each visit, a review of selected treatment-related AEs (xerostomia, xerophthalmia, myelosuppression), any-cause AEs (renal toxicity, new diagnoses of second primary malignancies), and treatment-related serious AEs will be conducted. Physical and laboratory assessments, as well as details on concomitant medications and interventions, including anti-cancer therapies, will be collected. Patients may receive treatment with any medical intervention. Interim analyses are planned at 2 and 5 years post-study activation. Enrollment is ongoing (n=13). Clinical trial information: NCT05803941 . Parent studies of the long-term follow-up safety study. Trial Indication Phase N (all groups) ClinicalTrials.gov ID VISION (+sub-study) Post-taxane mCRPC 3 831 (+30) NCT03511664 PSMAfore Pre-taxane mCRPC 3 469 NCT04689828 PSMAddition mHSPC 3 1144 NCT04720157 177 Lu-PSMA-617 in patients with moderately or severely impaired, or normal renal function Post-taxane mCRPC 2 20 a NCT06004661 a Planned. mCRPC, metastatic castration-resistant prostate cancer; mHSPC, metastatic hormone-sensitive prostate cancer.

Enhancing machine learning performance in cardiac surgery ICU: Hyperparameter optimization with metaheuristic algorithm

The healthcare industry is generating a massive volume of data, promising a potential goldmine of information that can be extracted through machine learning (ML) techniques. The Intensive Care Unit (ICU) stands out as a focal point within hospitals and provides a rich source of data for informative analyses. This study examines the cardiac surgery ICU, where the vital topic of patient ventilation takes center stage. In other words, ventilator-supported breathing is a fundamental need within the ICU, and the limited availability of ventilators in hospitals has become a significant issue. A crucial consideration for healthcare professionals in the ICU is prioritizing patients who require ventilators immediately. To address this issue, we developed a prediction model using four ML and deep learning (DL) models—LDA, CatBoost, Artificial Neural Networks (ANN), and XGBoost—that are combined in an ensemble model. We utilized Simulated Annealing (SA) and Genetic Algorithm (GA) to tune the hyperparameters of the ML models constructing the ensemble. The results showed that our approach enhanced the sensitivity of the tuned ensemble model to 85.84%, which are better than the results of the ensemble model without hyperparameter tuning and those achieved using AutoML model. This significant improvement in model performance underscores the effectiveness of our hybrid approach in prioritizing the need for ventilators among ICU patients.

Constitutive relationships for ultra-high-performance concrete at elevated temperatures

Comorbidity burden and effectiveness of immunotherapy in patients with metastatic renal cell carcinoma.

509 Background: Comorbidities pose a challenge in the treatment of patients with cancer and present a barrier to inclusion in clinical trials. While the effect of comorbidities on the efficacy of immunotherapy (IO) has been studied in various malignancies, it remains unclear in patients with metastatic renal cell carcinoma (mRCC) treated with IO-based combinations. Methods: Data from patients with mRCC receiving IO-based combinations (IO+IO or IO+anti-vascular endothelial growth factor (VEGF)) as first-line treatment were collected from the Dana-Farber Cancer Institute and the Tom Baker Cancer Centre-University of Calgary. The comorbidity burden was assessed at baseline using the Charlson Comorbidity Index (CCI). Patients were stratified into two groups: CCI-low (≤3) or CCI-high (>3), to predict overall survival (OS) through maximally selected rank statistics. The effect of CCI on OS and time-to-treatment failure (TTF) was assessed using multivariable Cox regression models. Results: Overall, 311 patients were included. The median age was 63 years (Q1-Q3: 58-69), and most patients had clear-cell mRCC (89.7%). A total of 167 (53.7%) and 144 (46.3%) patients were treated with IO+IO and IO+anti-VEGF, respectively. The most prevalent comorbidities were cardiovascular disease (20.2%) and diabetes (18.6%). In terms of CCI, 241 (77.5%) and 70 (22.5%) patients were categorized as CCI-low and CCI-high, respectively. Median follow-up was 40.8 months (Q1-Q3: 34.4-47.2) for OS. OS (aHR: 1.89, 95% CI: 1.16-3.06, p=0.010) and TTF (aHR: 1.56, 95% CI: 1.04-2.33, p=0.029) were worse in the CCI-high group (vs. CCI-low group) after adjusting for covariates (IMDC groups, age, Karnofsky score, histology, sarcomatoid features, sites of metastases, treatment type, and nephrectomy status). Rates of all adverse events (AEs) (66% vs. 65.5%) and immune-related AEs (42.1% vs. 35.9%) were comparable between the CCI-low and CCI-high groups, respectively. Conclusions: We report for the first time that comorbidity burden is an adverse prognostic factor in patients with mRCC undergoing IO-based combinations, highlighting the need for multidisciplinary care and tailored treatment strategies in this vulnerable patient population. Interestingly, despite the observed difference in survival outcomes, the incidence and profile of AEs were similar between the high- and low-comorbidity groups, suggesting that comorbidity burden does not substantially alter the safety profile of IO-based treatments.

Estimation of overall survival in immunotherapy-treated bladder cancer using computer vision.

862 Background: Bladder cancer (BC) is a difficult and expensive cancer to treat, as lifelong care is needed. Anti-PD-1 therapies are used as a frontline treatment for BC. However, diverse response creates a need for novel methods to identify those patients that will benefit. We developed an algorithm (MIA-IO: Microscopy Image Analysis - Immunotherapy Outcome) to infer BC patient survival under anti-PD-1 immunotherapies with H&E-stained whole slide images (WSIs). Methods: A foundation model was trained on ~100k WSIs from various sources. Next, it was fine-tuned to create MIA-PDL-1, which infers PDL-1 status from H&E WSIs ( n = 1546). It was separately fine-tuned to identify tumor, stroma, necrosis and lymphocytes (training n = 2765 patches). An open-source model (CellViT) was used to identify neoplastic, inflammatory, connective, epithelial, and dead cells (training n = 190K cells). 617 features were derived from the segmentations to measure the spatial makeup of the tissues. Finally, a random survival forest (MIA-IO) was trained combining PDL-1 status, tissue/cell features, age and sex to estimate overall survival from treatment start. To develop MIA-IO, we used 331 WSIs from BC patient treated with several immunotherapies from internal trial and commercial sources (internal dataset) and 227 from a vendor as an external test set. We also evaluated MIA-IO using only patients treated with PD-1 therapies (i.e., Pembrolizumab and Nivolumab). Log-rank test was used to determine statistical significance of inferred high-risk (HR) and low-risk (LR) event times for each model. Results: The table shows survival probabilities for inferred HR and LR patient groups as stratified based on inferred death time. Survival of LR group was significantly higher than HR group for the all-immunotherapies model and for the PD-1 only therapy model in internal and external sets. Features holding greatest inference weight included texture of tumor regions and immune distributions. Cell and tissue features were found to carry the greatest estimation weight, such as texture of the tumor regions and immune distributions. Conclusions: Routine H&E biopsies may contain information prognostic of therapeutic response to immunotherapies and further study with more samples is warranted. This method is and faster than immunohistochemistry, spares additional tissue use, and may be used to select those patients that would benefit from PD-1 therapy. Survival probabilities based on algorithm stratification. Internal A Internal PD-1 External A External PD-1 Patients Train / Test ( n ) 264 / 67 157 / 39 - / 227 - / 182 MIA-IO LR / MIA-IO HR ( n ) 38 / 29 18 / 21 33 / 194 154 / 28 Overall Survival probability (LR / HR) 6-month 0.81 / 0.5 0.95 / 0.63 0.82 / 0.78 0.84 / 0.68 12-month 0.81 / 0.37 0.95 / 0.39 0.78 / 0.58 0.64 / 0.4 24-month 0.59 / 0.3 0.75 / 0.29 0.62 / 0.37 0.45 / 0.23 Log-rank test p -value 0.008 0.004 0.050 0.0182 A All patients, PD-1 PD-1 only treated cohort.

NEXUS-01, a phase 1 study of LY4052031, an antibody-drug conjugate targeting Nectin-4 in participants with advanced or metastatic urothelial carcinoma or other solid tumors.

TPS900 Background: Nectin-4 is a cell surface antigen overexpressed in multiple tumor types including urothelial cancer. Enfortumab vedotin (EV) is a first generation anti-nectin-4 antibody-drug conjugate (ADC) comprising a fully humanized antibody conjugated to an MMAE payload with heterogeneous DAR 4 and is approved in metastatic urothelial carcinoma (mUC) both as a single agent in treatment refractory disease and as first-line treatment in combination with pembrolizumab. Persistent nectin-4 expression despite progression on EV has been demonstrated in preclinical tumor models suggesting payload mediated treatment resistance. LY4052031 is a next generation anti-nectin-4 ADC, consisting of a Fc-silent IgG1 antibody conjugated to a novel topoisomerase I (TOPO 1) inhibitor camp98 (LSN3889710) via a cleavable peptide linker with improved stability and a homogeneous drug antibody ratio (DAR) of 8. LY4052031 has demonstrated robust in vivo efficacy in tumor models across a range of nectin-4 expression levels and in MMAE-resistance. Methods: NEXUS-01 (NCT06465069) is a first-in-human, open-label, multi-center, phase 1 study of LY4052031 in patients (pts) with advanced or metastatic UC or other solid tumors known to express nectin-4. LY4052031 is administered intravenously once every 3 weeks. Eligible pts have ECOG PS 0-1 with a histologic diagnosis of advanced UC, triple-negative breast, non-small cell lung, esophageal, pancreatic, gastric (Japan only), ovarian, cervical, head and neck squamous cell carcinoma, or prostate cancer. Pts must have progressed on or be ineligible for all available standard therapies, with no limit on the number of prior therapies. The study consists of phase 1a dose escalation/dose optimization and phase 1b dose expansion. Dose escalation will utilize a Bayesian optimal interval design. Additional pts will backfill previously cleared dose levels that demonstrate therapeutically relevant exposures or direct evidence of clinical activity. Optional dose optimization will involve randomized evaluation of 2 or more dose levels selected in the dose escalation phase. Dose expansion will enroll pts with UC who are EV-naïve (cohort B1) and with prior EV treatment (cohort B2), or with non-UC solid tumors (cohort C). Primary objectives are to determine the recommended phase 2 dose (RP2D) and assess the safety of LY4052031. Key secondary objectives are to evaluate the pharmacokinetic profile, immunogenicity, and antitumor activity of LY4052031 per RECIST v1.1. Nectin-4 expression and other biomarker data will be generated and correlated with clinical activity. Clinical trial information: NCT06465069 .

Barriers and facilitators of adherence to treatment interventions for COPD amongst individuals from minority ethnic communities: Meta-ethnography

Objective Numerous studies have documented the low adherence rate to treatment interventions for Chronic Obstructive Pulmonary Disease (COPD) amongst minority ethnic communities. This systematic meta-ethnographic review was performed to identify barriers and facilitators of adherence to treatment interventions (e.g., smoking cessation and pulmonary rehabilitation) of COPD in minority ethnic communities. Method This systematic meta-ethnographic review followed the approach by Noblit and Hare. Systematic searches were performed across six databases MEDLINE (OVID), EMBASE (OVID), CINAHL (EBSCO), PsycINFO (OVID), Web of Science, and Scopus from their inception until November 2023. Quality appraisal of included studies was conducted using Critical Appraisal Skills Programme (CASP) tools. Results Out of 1,329 identified citations, seven qualitative studies were included in this meta-ethnography. Using reciprocal translation, four overarching themes were developed to represent the barriers and facilitators of adherence to treatment interventions of COPD amongst minority ethnic communities: 1) positive and negative experiences affecting a person’s motivation for their care, 2) patient attitude and beliefs, 3) being able to access and attend care, and 4) the influence of communication and culture on a person’s care. Conclusion This review highlighted the barriers and facilitators of adherence to treatment interventions for COPD amongst individuals from minority ethnic communities. The key barriers include language difficulties and the inability to comprehend and communicate effectively with healthcare professionals. This demonstrates the need for further research on the impact of linguistic and cultural characteristics on adherence to treatment interventions for COPD. Addressing ethnicity-specific barriers could inform the development of tailored protocols and strategies for optimising adherence among minority ethnic communities. (PROSPERO CRD42023476187).

Hypoxia-activated oxidative stress mediates SHP2/PI3K signaling pathway to promote hepatocellular carcinoma growth and metastasis

Contemporary post-prostatectomy radiation therapy for prostate cancer within a statewide quality consortium.

369 Background: The 2024 AUA Salvage Therapy for Prostate Cancer Guideline provides guidance at the time of suspected recurrence after radical prostatectomy (RP). Recommendations include early initiation of post-operative radiation therapy (RT), and the addition of androgen deprivation therapy (ADT) for those with high-risk features. Given that an increasing number of men receive RP for high-risk disease, we characterized RT in a prospective cohort from the Michigan Radiation Oncology Quality Consortium (MROQC) and the Michigan Urological Surgery Improvement Collaborative (MUSIC). Methods: Patients who received post-RP RT at an MROQC center from 06/09/20 – 09/18/24 were eligible. The MUSIC database provided surgical pathology variables, and MROQC prospectively collected data via patient-, physician-, and physicist-completed forms. RT was defined as adjuvant (pre-RT PSA <0.1 ng/mL), consolidative (persistently elevated PSA post-RP), or salvage. Multivariable analyses (MVA) were used to evaluate associations between ADT intent and patient and clinical features, including high risk features (pT3b/T4, pN1, grade group (GG) 4/5, pre-RT PSA >0.5 ng/mL, consolidative). Results: A total of345 patients at 26 centers received RT. The median pre-RT PSA was 0.3 ng/mL (IQR: 0.2-0.6); PET staging was done in 60%, and 34% had genomics testing. RT was adjuvant in 10% (n = 35), consolidative in 28% (n = 95), and salvage in 62% (n = 215). Median pre-RT PSA in each subgroup was 0.07 (IQR: 0.03-0.09), 0.5 (IQR: 0.3-1.5), and 0.3 (IQR: 0.2-0.5) ng/mL, respectively (p=0.005). Median time to RT post-RP was 8, 6, and 29 months, respectively. Most patients (62%) had at least one high risk feature including pT3b (24%), pN1 (5%), GG 4/5 (30%), Pre-RT PSA >0.5 ng/mL (27%), and PSA persistence (28%). Consolidative patients had worse pathologic features compared to salvage patients: pT3b (35% vs. 15%), pN1 (9.5% vs. 0.5%), GG 4/5 (42% vs. 24%), and pre-RT PSA (0.5 vs. 0.3 ng/mL), p<0.01 for all. Sixty percent (n = 204) were prescribed ADT, with an intended duration of ≤6 months in 133 men (65%) and ≥24 months in 34 (17%). On MVA, ADT use was positively associated with high-risk features including pN1 (OR 6.22 [95% CI 1.35 – 47.57]), pT3b/T4 (ref. pT2, OR 2.77 [95% CI 1.34 – 5.93]), GG 4/5 (ref. GG 1/2, OR 2.87 [95% CI 1.51 – 5.56]), pre-RT PSA ≥0.5 ng/mL (OR 2.11 (95% CI 1.17 – 3.91]). ADT was less often used with adjuvant RT (ref. salvage, OR 0.17 [95% CI 0.06 – 0.45]). Conclusions: In a contemporary statewide quality consortium, salvage RT was delivered at a PSA ≤0.5 in nearly 75% of patients, and ADT use was associated with high-risk features. Importantly, 62% of patients have at least one high-risk feature, and over 25% received consolidative RT for persistently positive PSA. Optimized treatment strategies are needed for this at-risk population that has been underrepresented on many modern trials.

Non-clear cell renal cell carcinoma in the immune checkpoint era: A retrospective study on survival and treatment approaches.

512 Background: Non-clear cell renal cell carcinoma (nccRCC) includes several molecularly distinct subtypes of renal carcinoma. Due to their rarity, nccRCC subtypes have been understudied, and treatment options are often adapted from clear cell RCC therapies. Trials investigating immune checkpoint inhibitors (ICIs) have demonstrated promising efficacy and survival benefits in certain nccRCC histologies. This report aims to present our experience with nccRCC, focusing on patient characteristics, treatment choices, and survival outcomes in the era of ICIs. Methods: A retrospective analysis was conducted on adult patients with metastatic RCC treated at the Emory Winship Cancer Institute between 2018 and 2024. nccRCC histologies were identified and confirmed through pathology reports. An objective response is defined as a complete or partial response by RECIST v1.1. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method with SAS 9.4 software to calculate survival probabilities. Results: We identified 69 patients with various nccRCC histologies, with papillary RCC (pRCC) being the most common (36.2%), followed by unclassified RCC (24.6%). The median age was 63 years. 59.4 of the patients were male, and 75.4% of the patients had an ECOG PS of 0 or 1. 53.6% of the patients were White, while 40.6% were African American or Black. Nephrectomy was performed in 44 patients (63.8%). The median follow-up time was 24 months. ICI-based treatments were used as the first-line option in 52% of patients, with 88% of unclassified RCC patients receiving ICI-based regimens as first-line. The mOS was longest in patients with chromophobe RCC at 21 months (4, NA), followed by patients with unclassified RCC at 19 months (6, NA). Among pRCC patients, there was no significant difference in mOS between African American or Black patients (12 months) and White patients (10.5 months; p=0.61). mOS was similar across ICI monotherapy, dual ICI therapy, and ICI+TKI combinations. 12-month survival rates were 50%, 57%, and 33% (p=0.21), and objective response rates (ORR) were 11%, 14%, and 11% for ICI monotherapy, dual ICI, and ICI+TKI combinations, respectively. Conclusions: Our study highlights the heterogeneity of non-clear cell RCC subtypes. The rare nature of nccRCC and the small patient cohort in our study limited its statistical power, emphasizing the importance of larger studies and expanded clinical trials to better understand and optimize treatment strategies for this understudied group of renal carcinomas. Histology n White African American or Black 12 Months OS Rate 12 Months PFS Rate ORR Papillary 25 12 12 46% (25, 64) 44% (7, 78) 12% Unclassified 17 10 6 63% (35, 81) 43% (10, 73) 35% Translocation 9 4 3 67% (21, 91) 36% (17, 56) 0% Collecting Duct 7 4 3 43% (10, 73) 0% (NA) 14% Chromophobe 6 6 - 67% (20, 90) 34% (12, 58) 0%

Socioeconomic position as a social determinant of health and its effect on cardiovascular outcomes and mortality in patients with prostate cancer: A SEER-Medicare based study.

315 Background: Socioeconomic position (SEP) is a key social determinant of health (SDOH) associated with disparities in cancer care and cardiovascular (CV) outcomes in patients with prostate cancer (PC). Understanding the impact of SEP on cardiovascular health is critical for addressing inequities in PC CV outcomes. Methods: We conducted a retrospective cohort study on the SEER-Medicare database. Multiple CV outcomes were assessed in patients ≥65 years of age with no prior CV disease and with localized or advanced PC. SEP was defined using the census-tract level Yost index where those living in first and second quintiles were considered as living in low SEP areas. A competing risk analysis using univariable and multivariable Fine-Gray Models was used for CV events (CVE), CV mortality (CVm) and PC specific mortality (PCsm). CVEs included myocardial infarction, heart failure, atrial fibrillation, ischemic stroke, and peripheral artery disease. All-cause mortality was assessed using Cox proportional hazard (PH) models. All models were adjusted for age, race, marital status, education level, PC grade, PC TNM stage, diabetes, hypertension, hyperlipidemia, chronic kidney disease, and receiving chemotherapy. A sub-group analysis was further conducted in patients who self-identified as non-Hispanic Black (NHB). Results: We included 150,647 patients of whom 102,271 had high SEP and 48,376 had low SEP. Patients with low SEP have shown higher associated risks of CVm (subdistribution hazard ratio [sHR] 1.25, 95% CI 1.19-1.32, p<0.001), PCsm (sHR: 1.20, 95% CI 1.14-1.26, p<0.001), CVE (sHR 1.07, 95% CI 1.04-1.09, p<0.001), and all-cause mortality (adjusted HR 1.17, 95% CI 1.14-1.20, p<0.001) when compared to patients with high SEP. Similarly, in the NHB subgroup analysis, patients with low SEP showed an increase of 11% in CVE, 37% in CVm, and 21% in PCsm and 20% all-cause mortality (Table). Conclusions: Adverse SEP, as a proxy for SDOH, plays an important role in patients with localized or metastatic PC by increasing associated risks for adverse cardiovascular and survival outcomes by up to 25% in the overall population and 37% in NHB individuals. Survival analysis using Fine-Gray analysis (competing risk models) and Cox PH regression for the various cardiovascular outcomes using the fully adjusted model. Overall (n=150,647) NHB (n=15,474) CVE (Competing risk = All-cause mortality)sHR (95% CI, p-value) 1.07 (1.04-1.09, p<0.001) 1.11 (1.03-1.20, p=0.007) CVm (Competing risk = All-cause mortality except CVD mortality)sHR (95% CI, p-value) 1.25 (1.19-1.32, p<0.001) 1.37 (1.15-1.64, p<0.001) PCsm (Competing risk = All-cause mortality except PCsm)sHR (95% CI, p-value) 1.20 (1.14-1.26, p<0.001) 1.21 (1.04-1.41, p=0.016) All-cause mortality (Cox)aHR (95% CI, p-value) 1.17 (1.14-1.20, p<0.001) 1.20 (1.08-1.35, p=0.001)

The impact of climate variability on agricultural employment in Mexico from 1980–2017

Employment in the agricultural sector is highly dependent on climate. Most agricultural jobs worldwide rely on predictable precipitation, in terms of both quantity and seasonality. Mexico is a largely agrarian country, with at least 20 million people directly reliant on food production for the livelihoods. However, research on the relationship between climate variability and agrarian employment is limited in the nation, complicating the development of effective adaptation strategies to drought and climate change. This study aims to address this gap, by analyzing the employment changes of farmers and livestock producers at a national level in the past five decades (1980 to 2017) and its relationship to long-term precipitation variability. We employed governmental datasets from national agrarian surveys and national precipitation, both at the annual scale and seasonally within each year. We found a negative relationship between agricultural employment and total annual precipitation. In particular, employment in the livestock sector showed a negative correlation with current-year precipitation (p = 0.06, cor = -0.33), while employment in rainfed agriculture was linked to the previous year’s rainfall (p = 0.07, cor = -0.33). It is likely that this pattern was driven by the positive relationship of precipitation with planted cropland area (p<0.05, cor = 0.19) and agrarian income (p<0.05, cor = 0.18). We also found that as many as 10 million people left the agrarian employments each year during the dry season. Finally, as precipitation continues to pose a challenge, it may have contributed to people of ages 23 to 35 to leave in recent years, compared to 15 and 19 in the 1990s. These findings underscore the need for national policies to mitigate the impacts of dry years on livelihoods and to inform strategies for building resilience in the agricultural sector.

Tester selection for combining ability estimation of storage root yield and sweetpotato virus disease in sweetpotato breeding

Abstract General combining ability (GCA) is the major selection criterion for new sweetpotato (Ipomoea batatas) parents in a reciprocal recurrent selection (RRS) scheme. Here we aimed to estimate GCA and specific combining ability (SCA) by using 16 potential testers involved in an 8 × 8 partial diallel and propose a procedure to identify testers in sweetpotato breeding. Data on storage root yield in tons per hectare (rytha), and sweetpotato virus disease (vir2) from 64 families (1,913 clones) were collected in five trials at two locations in Uganda. The estimates of the female GCA accounted for the largest additive genetic variation for storage root yield compared to the male GCA for both traits. Mid-parent heterosis ranged from − 6.2 to 7% for rytha, and − 1.1 to 1.3% for vir2 in the progeny families. A stepwise procedure to identify testers top-ranked ‘NASPOT 7’ as a dual tester for both traits. Besides this parent, ‘Ejumula’ and ‘NASPOT 10 O’ for rytha, and ‘NASPOT 1’, ‘NK259L’, ‘SPK004’, and ‘NASPOT 11’ for vir2 are particularly suitable as respective single-trait testers. Testers are important in many plant breeding programs to enhance efficiency of RRS, and thus other crop species might benefit from the strategy and methods applied herein.

Expression of tissue factor (TF) in penile squamous cell carcinoma (PSCC) and enrichment in HPV-negative cases.

10 Background: Advanced/metastatic PSCC is an aggressive malignancy with limited treatment options. An antibody-drug conjugate (ADC) targeting TF is approved for treatment of advanced cervical cancer and may benefit patients with PSCC. We evaluated TF expression in PSCC which could support a future clinical trial of a TF-targeting agent for PSCC. Methods: We identified 33 pts with PSCC who underwent primary surgery at MD Anderson from 1999-2017 and had archived primary tumor tissue available for analysis. HPV-positive status was determined by either PCR testing or high-risk HPV in situ hybridization assay. A tissue microarray (TMA) was constructed with 3 cores per tumor. Anti-TF-1 antibody staining was performed by immunohistochemistry and mean H-scores for membrane and cytoplasm staining were assessed (range 0-300) for each tumor. Median H-scores were described and compared between HPV-positive and negative tumors. Percentage of pts with tumors staining positive for TF (≥10% of tumor cells with at least 1+ intensity in cytoplasm and/or membrane) was determined. Association of TF expression with tumor grade, presence of metastatic disease, lymphovascular invasion (LVI), perineural invasion (PNI), recurrence free survival (RFS), and overall survival (OS) was assessed. Results: 17 pts (51.5%) had HPV-positive disease; 19 pts (57.6%) had metastatic disease. 27 tumors (81.8%) stained positive for tissue factor. Median overall membrane TF H-score was 47 (range 1-232). HPV-negative tumors had significantly higher membrane expression of TF (median H-score 70, range 1-232) than HPV-positive tumors (median H-score 19, range 1-123; p=0.004). While analyses were limited by small sample size, we did not find a significant association of TF H-score with tumor grade, presence of metastatic disease, LVI, PNI, RFS, or OS. Conclusions: TF expression was highly prevalent in this PSCC pt cohort. HPV-negative tumors had significantly higher TF expression than HPV-positive tumors; this finding requires further study. These data support further investigation of TF-targeted therapy, such as an ADC, for treatment of PSCC. Variable Overall population HPV-positive(17 patients) HPV-negative(16 patients) Median (range) H-score  Membrane 47 (1-232) 19 (1-123) 70 (1-232)  Cytoplasm 29 (2-180) 18 (2-98) 59 (2-180) Positive TF expression (Percent of patients with ≥1 core having ≥10% of tumor cells with at least 1+ intensity in either cytoplasm or membrane) 27/33 (81.8%) 12/17 (70.6%) 15/16 (93.8%)

Results of AFU-GETUG-20: A randomised phase 3 trial of adjuvant androgen deprivation therapy with leuprorelin acetate after radical prostatectomy in patients with high-risk localized prostate cancer.

386 Background: After radical prostatectomy (RP), men with an undetectable PSA and specific features (extracapsular extension, seminal vesicle involvement, high Gleason score) are at risk of recurrence. No randomized prospective study has been published with LH-RH agonists in the PSA era. AFU-GETUG-20 is a phase III randomised, open, multicenter trial, designed to evaluate the benefit of adjuvant ADT with leuprorelin acetate for 24 months after radical prostatectomy in patients with high risk of recurrence. Methods: Patients with high-risk features (postoperative Gleason score > 7, or ≥ 7 with presence of high-grade Gleason patterns, or pT3b), R0, N0 or Nx, M0, and postoperative PSA < 0.1 ng/mL after RP were eligible. Patients were randomized 1:1 to leuprorelin acetate for 24 months vs observation. The primary endpoint was metastases-free survival (MFS). Secondary endpoints included overall survival, disease-specific survival, PSA recurrence-free survival, and quality of life. Originally 700 patients (350 in each arm) and 250 events were required to detect an improvement of MFS with a HR of 0.80 with a bilateral Logrank test with α= 0.05 and β= 0.20. An interim analysis was planned to test the null hypotheses at the 125th event (50% of events) but was eventually held given the low accrual rate and the accrual was stopped after 325 patients had been accrued. Results: Of 325 patients enrolled, 322 are included in the ITT population. 160 were randomized to the Leuprorelin arm and 162 to the observation arm. The median age was 64.7 years [range, 46-77 years]. The median follow-up is 96.1 months [93.6-106.1] IC95% in the leuprorelin arm and 97.2 months [91.8-101.4] IC95% in the surveillance arm. There was no statistically significant difference between arms for MFS (HR = 0.63 [0.30-1.30] 95%CI; p-= 0.204). Similar results were found for PSA relapse-free survival (HR = 0.74 [0.47-1.16]; p = 0 .187), overall survival (HR = 1.24 [0.56-2.76; p = 0.596), and specific survival (HR = 0.57 [0.10-3.17]; p = 0.512). Patients in the leuprorelin arm reported poorer HRQoD on EORTC QLQ-C30 global health scales, social function scale, and specific symptoms (fatigue, pain, dyspnoea, and insomnia). Post-hoc contrast analysis showed a difference between the groups during the treatment period. The two groups returned to comparable levels during follow-up (M36 and M48). Conclusions: Using 2 years of ADT after RP in high-risk patients with an undetectable post-operative PSA did not significantly improve MFS in AFU-GETUG-20. That the trial only accrued about half of the planned patients is the main limitation. The limited number of observed metastatic events in this population, although with a long follow-up, emphasizes the need to identify better biomarkers predicting for relapse to select candidate patients for the next generation of trials. Clinical trial information: EudraCT #:2010-022037-29 UC-0160/1003.

Peri-operative treatment patterns in real-world muscle-invasive bladder cancer patients undergoing radical cystectomy in the era of adjuvant immunotherapy.

704 Background: Muscle-invasive bladder cancer (MIBC) has traditionally been managed with radical cystectomy (RC) and pelvic lymph node dissection combined with neoadjuvant (NAD) and/or adjuvant (AD) chemotherapy in eligible patients. In late 2021, adjuvant nivolumab, was approved in the US among patients with certain high-risk of recurrence (HRR) features. Contemporary peri-operative treatment utilization patterns in MIBC patients post-RC is lacking. This study aimed to characterize demographics, clinical features, treatment patterns, and surgical outcomes, in a contemporary cohort of MIBC patients undergoing RC in the post-immunotherapy era. Methods: The US Syapse Learning Health Network Enriched Bladder Cancer Cohort, comprised of patients from community-based practices with cancer registry data supplemented and validated by chart review, was used to identify adults with clinically diagnosed MIBC (T2-T4aN0M0, T1-T4aN1M0) undergoing RC from February 19, 2021 (6-months prior to nivolumab approval) to December 31, 2023, with a minimum 6-month follow-up post-RC (except in cases of patient death). Patients with history of other primary cancer, non-bladder systemic antineoplastic therapies, prior partial cystectomy, NAD radiation, or clinical trial participation were excluded. Real-world HRR following resection was defined using a combination of NAD agent receipt and pathological staging (PS) from RC: received NAD cisplatin-based therapy and pT2-T4a or pN+; or, if patient did not receive NAD cisplatin-based therapy, pT3-4a or pN+. Pathological complete response (pCR) was defined as pT0N0. Results: Of 138 eligible patients, mean age was 66 years, and the majority were male (82%), white (83%), current/former smokers (68%), presented as de novo MIBC (97%), and had urothelial histology (91%). Overall, 49% (67/138) of patients received RC without NAD or AD treatment. Around 46% (64/138) received NAD chemotherapy; of these, one-third achieved pCR (20/61 NAD chemotherapy-treated patients with complete PS data post-RC). The most prevalent NAD regimens were cisplatin + gemcitabine (58%; 37/64) and methotrexate + vinblastine + doxorubicin + cisplatin (30%; 19/64). Only 14% (20/138) of all patients received AD treatment, with 10% (14/138) receiving AD nivolumab. Half of patients had HRR following resection (63/125 patients with complete PS data post-RC). Among the HRR subgroup, 22% (14/63) received AD treatment, with 19% (12/63) receiving nivolumab. Conclusions: In this contemporary cohort of MIBC patients undergoing RC, nearly half received NAD treatment (mainly gemcitabine and cisplatin) while there was limited use of AD treatment. Since FDA approval, AD nivolumab use was 10% among all RC-treated MIBC patients and less than a fifth among HRR patients (nivolumab eligible).

Evaluation of a home-based parenting support programme—Parenting Young Children—For parents with intellectual and developmental disabilities when there is a risk for neglect: Study protocol for a multi-centre study

Introduction Parents with intellectual and developmental disabilities (IDDs) often need parenting support, but there are few evidence-based programmes adapted to their cognitive needs. Parenting Young Children (PYC), a home-based programme for parents with IDDs, is perceived as beneficial by parents and practitioners, but it is unclear if PYC improves parenting. The purpose of the proposed mixed-methods study is therefore to evaluate the PYC programme for improved parenting in parents with IDDs. Methods and analysis The quantitative evaluation will have a multi-centre, pretest-posttest study design and include parents with IDDs (children aged 0–9) in need of adapted parenting support. Goal-attainment in parenting skills, parental self-efficacy and child mental health will be measured outcomes. Interviews will be used to explore the perspectives of parents and children on PYC. Ethics and dissemination Particpation is based on informed consent from parents and guardians of the participating children. Ethical approval was granted by the Swedish Ethical Review Authority.

Evaluating flood dynamics and effects in Nagpur city using remote sensing and Shannon’s entropy analysis

Abstract Flood is among the most disastrous natural disasters since they are responsible for massive damage to infrastructure, severe fatalities and injuries, innumerable economic losses, and social disruptions worldwide. These damages caused by floods have been worsening in recent years worldwide because of environmental degradation, climatic change, and high-speed urbanization. A rising precipitation rate increases the chances of floods in flood-vulnerable areas. A flash flood is a rapid flooding of geomorphic low-lying regions caused by remarkably high rainfall in a short duration. On September 23rd, 2023 a flooding event in the Nagpur, Maharashtra, it is directly impact on the human death and economic loss entire city. In the present study, the change in the dynamics of Nagpur city was analysed by employing remote sensing and GIS techniques to assess the change in the land use and land cover patterns. Landsat imagery of year 2000, 2010, 2020, and 2023 was used for land use and land cover classification. This analysis reveals that there is an increase in built-up area from 72.85 sq. km in year 2000 to 185.4 sq. km in year 2023. The built up land is increased this changes where directly affects the infiltration rate of rainwater into the soil. The total area covered by water bodies is reduced to 2.29 sq. km in 2023 which were 12.2 sq. km in year 2000. It is indicates the encroachment of built-up land on the water bodies. On the day of flash flood occurrence, it was observed that Nagpur city received 145 mm rainfall which is highest in the month of September, 2023. The Shannon entropy model was used to estimate the population dynamics and growth patterns of Nagpur city. Higher entropy values were obtained during the analysis which indicates the rapid transformation of city in all directions. Population dynamics of Nagpur city also indicate the inflation in population from 4,067,637 in 2000 to 4,653,570 in 2010. The SAR water index was calculated using Google Earth Engine to detect the water surges in residential areas during the flood. Precautionary measures should be taken by governing authorities to avoid such disasters. Proper city planning and improvements in drainage systems are recommended within the city. It is needed for an hour to develop a river monitoring system and early warning system, as well as preventive measures that should be implemented, like the construction of retaining walls to control the flood water.

Effectiveness and safety of first-line atezolizumab in locally advanced or metastatic urothelial cancer: The IMFLAME study.

720 Background: Urothelial cancer (UC) is the tenth most common cancer globally. Standard first-line treatment for metastatic UC (mUC) involves enfotumab-vedotin + pembrolizumab or platinum-based chemotherapies, but some patients are ineligible to standard treatment due to significant comorbidities and poor performance status. Atezolizumab, an immune checkpoint inhibitor, has shown activity in clinical trials. This study evaluates the real-world effectiveness and safety of atezolizumab as a first-line treatment in patients with locally advanced or metastatic UC ineligible for platinum-based chemotherapies. Methods: This retrospective, multicenter, observational study included 91 patients with locally advanced or mUC treated with atezolizumab monotherapy as first-line treatment in Spain. Data were extracted from medical charts, including patient demographics, clinical characteristics, treatment patterns, and outcomes. The primary endpoint was the 12-month survival rate. Secondary endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and safety profile. Results: The median age at diagnosis of mUC was 77 years, and 90.1% of patients had mUC. The population had a high burden of comorbidities, 90,1% had at least 1 comorbidity, 30% of the patients had PS ECOG ≥ 2 and 42.9% had visceral metastases. The 12-month survival rate was 41.8%, decreasing to 30.8% and 19.8% at 18 and 24 months, respectively. The ORR was 45.2%, with a median DoR of 19 months (95% CI: 9.8-28.3). The median PFS was 4.1 months, and the median OS was 9.7 months. According to multivariate COX regression analysis, PS ECOG ≥ 2 was an independent prognostic factor for worse survival. Safety analysis revealed that 26.4% of patients required treatment interruption due to treatment related adverse events (TRAEs), with immune-related adverse events (irAEs) occurring in 12.1% of patients, only 6% of patients discontinued treatment due to an irAEs. Conclusions: First-line atezolizumab monotherapy provides a clinically relevant benefit in terms of response, PFS, and OS in patients with locally advanced or metastatic UC ineligible for platinum-based chemotherapies. Despite the high burden of comorbidities and poor prognosis in this population, atezolizumab demonstrated an acceptable safety profile. These findings support the use of atezolizumab in platinum-ineligible patients and potentially in those who are not suitable for EV-Pembrolizumab under routine clinical practice conditions and highlight the need for further research to optimize patient selection and management. Outcome Measure Value 95% CI 12-month survival rate (%) 41.8 33.5-55.3 18-month survival rate (%) 30.8 23.4-44.5 24-month survival rate (%) 19.8 13.6-32.5 Overall Response Rate (%) 45.2 Median PFS (months) 4.1 Median OS (months) 9.7

Survival in advanced prostate cancer (PCa) patients with visceral metastasis: A population-based SEER study.

134 Background: Prostate cancer patients with visceral metastases at diagnosis are often treated using one-size-fits-all approach. For example, CHAARTED criteria treats any visceral metastasis as high volume. Therefore, we aimed to assess overall survival (OS) by site of visceral involvement in patients with metastatic PCa. Methods: Surveillance, Epidemiology, and End Results (SEER) database (2010-2021) was queried to obtain case listing data on metastatic PCa patients from 17 registries. The patients were categorized into three groups based on visceral metastasis at diagnosis: lung metastasis, liver metastasis, and others. Kaplan-Meier survival analysis was performed to estimate median OS with 95% confidence interval (CI). Log-rank test was conducted to assess if survival was significantly different among the groups. Cox proportional hazard regression analysis was performed to assess the magnitude of difference among the groups. P-value <0.05 established statistical significance. Results: This analysis included 21,007 metastatic PCa patients (lung: n=319; liver: n=123; brain: 107; bone: 20538). Metastatic PCa population with lung metastasis exhibited a median OS of 60 months (95% CI: 48-72) compared to 24 months (95% CI: 12-36) in population with liver metastases and to 36 months (95% CI: 36-36) in population with other metastases. The difference in OS among the groups was statistically significant (p < 0.001). Compared to population with lung metastasis, those with liver (HR: 1.91; 95% CI: 1.41-2.57) but not those with other metastases (1.16; 0.97-1.39) had significantly worse OS adjusting for Gleason score, PSA and race (Table). Conclusions: In metastatic PCa, patients with lung-only metastasis have significantly better overall survival and should be considered differently in prognostication to liver metastases. Consideration of site of visceral metastasis is critical for treatment intensification decisions. Limitations of this analysis include lack of accounting for confounding relationships at individual patient level. Variable Hazard Ratio (95% CI) Metastases (Lung) REFERENCE Metastases (Liver) 1.91 (1.41-2.57) Metastases (Other) 1.16 (0.97-1.39) Gleason score≥8 REFERENCE Gleason score <8 0.68 (0.64 -0.72) PSA - ng/dL 1.01 (1.00 – 1.01) Race (White) REFERENCE Race (Black) 0.99 (0.94 – 1.05) Race (Asian or Pacific Islander) 0.70 (0.64 – 0.76)