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Cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in previously untreated advanced renal cell carcinoma (aRCC): Final results of COSMIC-313.

438 Background: In the randomized, double-blind, phase 3 COSMIC-313 study (NCT03937219), C+N+I significantly improved PFS compared with N+I in first-line intermediate or poor risk aRCC, meeting the primary endpoint (Choueiri et al. N Engl J Med 2023). Here, we present the secondary endpoint of OS, updated efficacy and safety results, and biomarker analyses. Methods: Patients (pts) with previously untreated, IMDC intermediate or poor risk aRCC were randomized to receive C 40 mg QD or placebo (P). Both groups received N (3 mg/kg IV Q3W) + I (1 mg/kg IV Q3W) for 4 cycles, followed by N (480 mg IV Q4W) for up to 2 y. The primary endpoint was PFS by blinded independent central review per RECIST 1.1 in the first 550 randomized pts (previously reported). The secondary endpoint was OS in all randomized pts. A random forest model was used to identify immune subsets (deconvoluted from RNA-Seq data) associated with improved OS with C+N+I vs P+N+I. Results: A total of 855 pts were randomized to C+N+I (n=428) or P+N+I (n=427); IMDC risk was intermediate for 75% and poor for 25%. At a median follow-up of 45.0 months, an improvement in PFS with C+N+I was maintained (Table). OS was not significantly different between C+N+I and P+N+I in the ITT population or by IMDC risk group. ORR was higher with C+N+I, with a lower incidence of PD as best response. Grade 3/4 treatment-emergent AEs (TEAEs) occurred in 81% (C+N+I) vs 62% (P+N+I); most common grade 3/4 TEAEs were increased ALT (27% vs 6%) and increased AST (20% vs 5%). Grade 5 treatment-related AEs (TRAEs) occurred in 1% of pts in each group. No significant differences in OS outcomes were observed based on baseline c-Met or PD-L1 levels. Exploratory biomarker analyses showed that higher M2 macrophage abundance was associated with improved OS with C+N+I (HR, 0.51; 95% CI, 0.31–0.86), poor risk (per IMDC), high baseline sum of target lesions, and the presence of visceral metastasis. Biomarker analysis of angiogenic and immune signatures is ongoing. Conclusions: First-line treatment with C+N+I continued to demonstrate PFS and ORR benefit over P+N+I for pts with intermediate or poor risk aRCC. OS was comparable between the two arms, and no new safety signals emerged.Pts whose tumors have high M2 macrophage abundance had improved OS with C+N+I treatment. Clinical trial information: NCT03937219 . C+N+I (n=428) P+N+I (n=427) Median OS (95% CI), mo 41.9 (34.8–47.9) 42.0 (34.9–53.1) HR (95% CI); P- value 1.02 (0.85–1.23); P= 0.84 Median PFS (95% CI), mo 16.6 (14.0–22.6) 11.2 (9.3–14.0) HR (95% CI) 0.82 (0.69–0.98) ORR (95% CI), % 46 (41–51) 37 (32–41) Complete response, % 4 3 Partial response, % 42 33 Stable disease, % 40 36 Progressive disease, % 8 20

Tumor necrosis factor alpha signaling activity and NCCN risk, adverse pathology, and progression during active surveillance in prostate cancer.

415 Background: Elevated serum levels of tumor necrosis factor alpha (TNF-α) are characteristic of chronic inflammatory conditions and advanced prostate cancer (PCa). Local and systemic inflammation associated with TNF-α may enhance oncogenicity in the prostate. This study investigates the association between intra-tumoral TNF-α levels, NCCN risk, adverse pathology (AP) at radical prostatectomy (RP), and progression on active surveillance (AS). Methods: Intra-tumoral TNF-α pathway expression levels were assessed through TNF-α signaling via the NF-kB pathway. Transcriptomic profiles from 82,470 prospectively collected biopsy samples with the Decipher prostate genomic classifier (Veracyte, San Diego, CA) retrieved from the Decipher GRID registry (NCT02609269) were used to compare TNF-α levels by quartile across NCCN risk groups, Decipher score, and basal-luminal prostate subtype classifier (PSC). Transcriptomic data from a retrospective study of 647 patients with low or favorable intermediate risk (FIR) disease treated with RP were used in logistic regression to examine TNF-α levels with AP (any of Gleason grade group ≥3, SVI or LNI). A cohort of 28 favorable disease patients prospectively tested (2019-2024) with Decipher and managed with AS compared TNF-α levels with Wilcoxon for the binary endpoint of progression on AS. For progression, data from a retrospective study at a single academic center (2019-2024) were classified based on progression status (n=17 progressed, n=11 did not) following Decipher analysis of their initial biopsy specimens. Results: Among 82,470 PCa patients, the proportion of highest quartile TNF-α signature increased across NCCN low to very high risk prostate cancer and the lowest quartile decreased with increased NCCN risk group (Fisher’s exact test p < 2.2e-16). Median Decipher score was 0.57 (IQR 0.38-0.78) in the highest quartile TNF-α compared to 0.38 (IQR 0.24-0.58) for the lowest. The majority of samples with the highest TNF-α were PSC basal (73%) whereas the lowest were PSC luminal (76%) subtypes. Among 647 FIR disease patients treated with RP, higher TNF-α levels were significantly associated with AP (univariable OR 3.41, p=0.02; multivariate OR 2.93, p=0.05). In the AS cohort, elevated TNF-α signature correlated with a higher likelihood of progression. Conclusions: Increased TNF-α signaling levels are associated with increasingNCCN and Decipher risk groups and basal subtype. Elevated TNF-α levels in patients with FIR disease tumors had higher risk of AP at RP. In AS, higher TNF-α signaling was associated with progression and it may serve as a tool to guide treatment counseling. Uni- and multivariable analysis for pT3b+, GG 3-5, or LNI+. Univariable OR (95% CI) P-value Multivariable OR (95% CI) P-value TNF-α 3.41 (1.21 – 9.12) 0.02* 2.93 (1.01 – 8.02) 0.05* CAPRA - - 1.43 (1.08 – 1.91) 0.01* *p < 0.05 denotes significance.

Influence of gut microbiome composition on treatment efficacy and toxicity in bladder cancer: A comprehensive meta-analysis.

768 Background: The gut microbiome has emerged as a critical factor influencing the efficacy and toxicity of cancer treatments. In bladder cancer, variations in microbiome composition may affect patient responses to therapy, including immunotherapy and chemotherapy. This meta-analysis aims to comprehensively evaluate the impact of gut microbiome composition on treatment outcomes in bladder cancer. Methods: The PubMed, Embase, Scopus and Cochrane databases were systematically searched from inception until June 2024 using relevant keywords. The pooled data were presented as Odds Ratio (OR) with 95% confidence intervals (CI) using Random Effects model in OpenMeta (version 5.3). The I 2 and X 2 statistics were used to evaluate inter-study heterogeneity. An I 2 value of >50% was considered significant heterogeneity. The subgroup analyses were conducted to identify specific microbiome profiles associated with different treatment responses. Results: A total of 20 studies comprising 2,500 bladder cancer patients were included in the meta-analysis. Patients with a higher abundance of beneficial bacteria such as Bifidobacterium and Lactobacillus had significantly better treatment responses (OR: 2.5, 95% CI: 1.8-3.4) and lower toxicity rates (OR: 0.6, 95% CI: 0.4-0.9). Conversely, an increased presence of pathogenic bacteria like Clostridium and Escherichia coli was associated with poorer outcomes (OR: 0.5, 95% CI: 0.3-0.8) and higher toxicity (OR: 1.9, 95% CI: 1.3-2.7). Conclusions: This meta-analysis highlights the significant influence of gut microbiome composition on the efficacy and toxicity of bladder cancer treatments. Identifying specific bacterial profiles associated with positive and negative outcomes could guide personalized treatment strategies and improve patient care. Further research is needed to understand the mechanisms underlying these associations and to develop microbiome-targeted therapies.

Gene signature predictor of dose-response to prostate radiation: Validation of PORTOS in phase III trials.

308 Background: NRG/RTOG 0126 and SAKK 09/10 were phase III randomized trials examining whether higher dose resulted in better response/outcomes in PCa patients following definitive and post-operative RT, respectively. RTOG 0126 showed a benefit for RT dose escalation (DE) from 70.2Gy to 79.2Gy though SAKK 09/10 did not show a benefit from 64Gy to 70Gy. We hypothesized that a previously developed 24-gene prostate cancer RT gene expression score (PORTOS) could distinguish patients who benefited from RT DE in both trials. Methods: PORTOS scores were calculated on biopsy samples in RTOG 0126 and prostatectomy samples in SAKK 09/10 as published. Since the original PORTOS cutoffs were in the post-op setting, we utilized tertile score groups in RTOG 0126, whereas the published PORTOS cutoffs were used for SAKK 09/10. The primary objective was to evaluate PORTOS as a predictive biomarker for the benefit of RT DE on biochemical failure (BF) via the Phoenix criteria in RTOG 0126 (N=215) and clinical progression-free survival (CFPS) in SAKK 09/10 (n=226). In addition, we also investigated clinical and molecular correlates of PORTOS in large real-world datasets of 31,107 prostate biopsy samples and 42,407 radical prostatectomy samples. Results: In RTOG 0126, in patients with lower tertile PORTOS scores, there was no difference in Phoenix BF (sHR 1.14 [0.54-2.40], P=0.73). However, for patients in the middle and higher tertile PORTOS score range, there was a significant benefit for RT DE for Phoenix BF (middle PORTOS: sHR 0.45 [0.22-0.90], P=0.02; higher PORTOS: sHR 0.30 [0.12-0.75], P=0.009). An interaction test indicated a significant difference in benefit for DE between higher and lower PORTOS groups (P=0.048). Similarly in the post-op SAKK 09/10 trial, only patients in the higher PORTOS score group benefited from RT DE (CPFS HR 0.19 [0.05-0.70]; P=0.01), with a significant biomarker-treatment interaction between lower vs. higher PORTOS and treatment arm (P=0.003). Interestingly, PORTOS was not consistently associated with clinicopathologic variables in either trial or in the large real-world biopsy or prostatectomy datasets. Biologically, in the real-world datasets, PORTOS was modestly associated with hypoxia signatures consistent with its role in radio-resistance, and strongly associated with immune signatures and molecular subtypes. Conclusions: In two phase III randomized trials, we have validated that PORTOS can identify patients who benefit as well as those that do not benefit from RT DE for localized PCa and provides the first randomized evidence for any biomarker to be able to predict RT dose response. PORTOS could be used to personalize radiation dose for patients with prostate cancer clinically, and allow selection of patients most likely to benefit from RT DE while sparing others from the potential increased risk of toxicity.

Digital assessment of walking ability: Validity and reliability of the automated figure-of-eight walk test in older adults

Background The Figure-of-Eight Walk Test (F8WT) can assess straight- and curved-path walking ability, but the validity and reliability of automated measurement of the F8WT using digital device has not yet been studied. The aim of this study was to verify the validity (method comparison) and test-retest reliability of the automated FW8T (aFW8T) using a digital device based on image analysis by comparing the results of the aF8WT with those of the manual F8WT (mF8WT). Methods Community-dwelling older adults underwent the mF8WT performed by a physiotherapist and the aF8WT using the Digital Senior Fitness Test system. To verify the test-retest reliability, the aF8WT was administered again to a randomly selected group of participants one week after the baseline test. The intraclass correlation coefficient (ICC) and Pearson’s correlation analysis were used to verify the degree of agreement between the results of and correlation between the mF8WT and aF8WT, respectively. The 95% confidence interval (CI) of the limits of agreement (LoA) was obtained using Bland–Altman analysis. Results The analysis included 83 participants (mean age 71.6 ± 4.7 years). The participants’ mF8WT and aF8WT results were 29.1 ± 4.9 and 29.8 ± 4.9 seconds, respectively. Pearson’s correlation analysis showed a very strong correlation between the mF8WT and aF8WT results with r = 0.91 (p < 0.001), and the ICC between the mF8WT and aF8WT results was 0.95 (0.91–0.97), showing excellent agreement. The 95% CI of the LoA was ˗0.7 (˗4.8 to 3.3) seconds in the Bland–Altman analysis. In an analysis of the test-retest reliability of the aF8WT, participants’ aF8WT results were 30.9 ± 4.7 seconds (baseline) and 29.6 ± 4.9 seconds (retest), with an ICC of 0.94 (0.81–0.98, p < 0.001), indicating excellent reliability. Conclusion Automated measurement of the F8WT using a digital device showed excellent validity and reliability. The aF8WT can be used to assess and monitor the walking ability of community-dwelling older adults.

Potassium KCa3.1 channel overexpression deteriorates functionality and availability of channels at the outer cellular membrane

Postoperative adjuvant treatment of HER2 overexpression in upper urinary tract urothelial carcinoma with the combination of disitamab vedotin and toripalimab: A real-world retrospective study.

673 Background: Radical nephroureterectomy (RNU) bears a high recurrence risk. Thus, postoperative treatment is necessary for upper urinary tract urothelial carcinoma (UTUC) patients. The CheckMate-274 study proved the feasibility of immunotherapy after surgery for urothelial carcinoma (UC), but showing no significant efficacy difference compared to placebo in UTUC. Disitamab vedotin is an antibody-drug conjugate (ADC) composed of an anti-HER2 antibody disitamab and MMAE payload. Clinical studies have showed that combining Disitamab vedotin with Toripalimab is an efficacious regimen for advanced urothelial carcinoma. Thus, we are investigating whether this combination therapy following RNU can offer improved survival outcomes. Methods: A retrospective analysis was conducted on data from patients who underwent RNU at Nanjing Drum Tower Hospital between April 2022 and April 2024. The study included patients pathologically diagnosed with cT 2-4a N 0 M 0 UTUC and HER2 positive status (HER2 IHC2+ or HER2 IHC3+). Patients received 26 cycles of Toripalimab (240mg, IV, Day 1, q2w) combined with 8 cycles of Disitamab vedotin (2mg/kg, IV, Day 1,q2w). CT scans of the chest and abdomen were performed every three months. The primary endpoint was the 12-month disease-free survival (DFS) rate. Results: The study included 36 cases of UTUC patients after RNU. Among them, 12 cases received treatment with Disitamab vedotin combined with Toripalimab, while 24 cases did not receive postoperative adjuvant therapy. In the treatment group, the 12-month DFS rate was 91.7% (1/12), compared to 62.5% (9/24) in the non-adjuvant therapy group. The most common treatment-related adverse events (TRAEs) in the treatment group were abnormal liver function (41.6%), decreased appetite (50%), and peripheral sensory neuropathy (33.3%), with no Grade 3 or higher adverse events observed. Conclusions: Disitamab vedotin combined with Toripalimab demonstrated efficacy as adjuvant therapy following radical nephroureterectomy for UTUC. Based on the one-year DFS outcomes, this combination could be considered as an adjuvant therapy option post-surgery.

NEO-BLAST: Neoadjuvant therapy for bladder cancer followed by active surveillance vs treatment.

TPS890 Background: Neoadjuvant therapy (NAT) followed by radical cystectomy (RC) is the standard of care for muscle-invasive bladder cancer (MIBC). Approximately 35-40% of patients have no residual cancer at the time of surgery, suggesting that these patients could potentially avoid definitive bladder treatments (DBT), including RC or trimodal therapy (TMT). However, the current clinical tools used to detect residual disease prior to cystectomy are inadequate. The question remains whether patients with complete response (CR) require DBT or if active surveillance (AS) could be a safe alternative. The NEO-BLAST trial investigates whether a combination of bladder MRI, circulating tumor DNA (ctDNA), urinary tumor DNA (utDNA) and transurethral bladder tumor resection (TURBT) can accurately identify MIBC patients with a clinical CR (cCR) following NAT, and whether AS is non-inferior to standard of care (SOC) in those who achieved cCR. Methods: This is a multicenter, phase II/III, non-inferiority open-label clinical trial that will randomize patients with MIBC who achieve cCR after NAT to AS versus SOC DBT, including either RC or trimodal therapy (TMT) (NCT06537154). The primary endpoint is feasibility of randomization for the phase II pilot-RCT, and metastasis-free survival (MFS) at two years for the phase III. Eligible patients will be adults with non-metastatic MIBC (≥T2, N0M0) who are candidates to SOC NAT followed by DBT as per the current practice. After enrolment, ctDNA and utDNA will be collected. Only participants who complete SOC NAT will then undergo a comprehensive clinical restaging process, including repeat ctDNA and utDNA, bladder mpMRI, urine cytology, and TURBT with template biopsies. Participants meeting criteria for cCR, defined as negative ctDNA, utDNA, MRI, and TURBT, will be randomized to either AS-arm or DBT-arm, while those without cCR will receive SOC. Participants will be monitored with cystoscopy and urine cytology (if bladder in situ) every three months for 2 years, along with ctDNA and imaging at 3, 6, 12, 18, and 24 months. The pilot-RCT will plan to enrol 72 patients, and if 25% is found to have cCR and accept to be randomized, the trial will be considered feasible. Assuming a 5% event rate at 2 years (MFS) in both groups and a type I error of 5% (1-sided), 78 per group will provide 80% power to reject the hypothesis of inferiority. We anticipate enrolling 688 patients for the phase 3 to have a total of 172 patients with cCR randomized, assuming 10% lost to follow-up. An independent Data Monitoring Committee will oversee safety and efficacy throughout the trial. Clinical trial information: NCT06537154 .

Evaluating the spectrum of disease within Gleason grade group 3: Results from a large institutional cohort.

361 Background: A biopsy diagnosis of Gleason Grade Group (GG) 3 prostate cancer (PCa), also known as Gleason 4+3, automatically risk stratifies patients into at least unfavorable intermediate-risk by major guidelines including the AUA and NCCN, for which definitive treatment such as surgery or radiation is warranted. We hypothesized that GG3 prostate cancers represent a spectrum of disease, and that there may be GG3 PCa patients with lower risk of disease that may benefit from more conservative management. Methods: The Urologic Outcomes Database (UODB) at the University of California San Francisco (UCSF) was queried for men with localized, non-metastatic PCa diagnosed after 2000 who underwent radical prostatectomy (RP). Pre-biopsy clinicodemographic factors and biopsy and surgical pathology data were obtained, and Cancer of the Prostate Risk Assessment (CAPRA) and post-surgical CAPRA (CAPRA-S) scores were calculated. Outcomes were recurrence after surgery, defined as either biochemical failure (two PSA ≥0.2 ng/ml) or second treatment, and development of new metastasis. Multivariable Cox proportional hazards regression models were used to calculate associations with risk of recurrence and development of metastases, adjusting for year of diagnosis, age at diagnosis, percentage of positive biopsy cores (PPC), PSA density (PSAD), PSA before RP, Gleason pattern 4 histology, genomic risk score, prostate MRI findings, with or without CAPRA-S. Results: 5262 men from the UODB database who underwent RP were included in the study. Of these, 904 (17%) men were diagnosed with GG3 on diagnostic biopsy. The number of GG3 diagnoses over time increased from 8.5% between 2000-2004 to 27% between 2020-2023. Among patients with initial diagnoses of GG3, pathologic GG after RP showed an increasing proportion of patients with upgrade to ≥GG4 and a decreasing proportion of patients with downgrade to <GG3 over time. Post-RP CAPRA-S scores overall increased over time, but remained broadly distributed. On multivariable analysis, favorable biopsy Gleason pattern 4 histology was strongest pre-operative factor associated with decreased recurrence after RP (HR 0.54, 95% CI 0.35-0.85, p<0.01). Increased PPC was the only factor associated with risk of metastasis after RP (HR 1.13, 95% CI 1.00-1.27, p=0.04). Conclusions: Patients with GG3 on diagnostic biopsy are a heterogenous group, with post-surgical grade and risk scores both broadly distributed and increasing over time. These data suggest that certain GG3 patients, such as those with favorable biopsy histology and lower PPC, may not be as unfavorable as guidelines suggest and may benefit from more conservative management.

Impact of gene expression signatures of immune infiltration on response to sequential intravesical gemcitabine and docetaxel versus bacillus Calmette-Guerin in high-risk non-muscle-invasive bladder cancer.

832 Background: Intravesical Bacillus Calmette-Guerin (BCG) is the guideline-recommended therapy for high-risk non-muscle invasive bladder cancer (HR-NMIBC). However, alternative therapies for HR-NMIBC are currently under investigation due to persistent global BCG shortages. Sequential intravesical gemcitabine and docetaxel (Gem/Doce) has demonstrated similar efficacy to BCG in this setting, and a large, randomized trial versus BCG is underway. As such, biomarkers for treatment selection are an unmet clinical need. Methods: We performed a retrospective analysis of a matched cohort study (McElree et al. JAMA Netw Open. 2023) of 143 patients with treatment-naïve HR-NMIBC treated at the University of Iowa with either BCG (n=92) or Gem/Doce (n=51). Gene expression data from archived bladder tumor specimens were generated using Decipher Bladder Genomic Subtyping Classifier (GSC, Veracyte, San Diego, CA), a clinical-grade, transcriptome-wide assay. Molecular subtypes were classified using the GSC and Consensus subtyping models. ESTIMATE (Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data) scores were used to stratify patients into higher (>median) and lower (<median) ESTIMATE immune scores. The primary endpoint was high-grade recurrence-free survival (HG-RFS). Associations between molecular subgroups and HG-RFS were evaluated using Cox-regression and Kaplan-Meier analyses. Results: Of the cohort, 34% were Ta, 64% T1, and 2% T is alone; overall 30% of patients had concomitant CIS. Median patient age, clinical tumor stage, presence of CIS and molecular subtype distributions did not differ significantly between BCG and Gem/Doce treated patients (all p>0.5). Median follow-up was 49 months for patients who received BCG and 22 months for patients who received Gem/Doce. HG disease recurrence was observed in 36% of BCG treated patients and in 16% of Gem/Doce treated patients. In total, 85% were classified as GSC luminal and 71% as Consensus luminal papillary subtypes and median ESTIMATE immune score was 556 (IQR: 126-1410). Patients with higher immune scores had superior HG-RFS (hazard ratio [HR], 0.25; 95% CI; 0.07-0.85; P=0.02) with Gem/Doce as compared to BCG. At 2 years, those with higher immune scores had better HG-RFS with Gem/Doce versus BCG (90% versus 63%, HR 0.25; 95% CI; 0.07-0.85; P=0.02), whereas HG-RFS was similar in those with lower scores (86% versus 72%, HR 0.71; 95% CI; 0.26-1.95; P=0.50). Conclusions: This study represents the first molecular comparison of treatment-naïve HR-NMIBC treated with Gem/Doce versus BCG. While this HR-NMIBC cohort is predominately luminal molecular subtype, immune signature scores at diagnosis show substantial variation. Patients with high immune scores at diagnosis have particularly suboptimal response to BCG and may derive greater benefit from Gem/Doce. These findings require validation.

Quantitative research on aesthetic value of the world heritage karst based on UGC data: A case study of Huangguoshu Scenic Area

The World Natural Heritage is a rare and irreplaceable natural landscape recognized by all mankind, with outstanding significance and universal value. Among them, the World Heritage Karst sites(WHKs) holds an important position due to its special natural beauty and aesthetic value. In the field of landscape evaluation, interdisciplinary and interdisciplinary cooperation using different methods has always been a research focus. However, there is still a gap in the evaluation of natural landscape aesthetic value based on UGC(User Generated Content) data and deep learning models. This article is based on a public perspective, using social media UGC data, crawling images and texts as data sources, and combining SegFormer deep learning models, ArcGIS spatial analysis, natural Language Processing Technology (NLP) and other methods to conduct quantitative research on aesthetic value. Research has found that: (1) Huangguoshu Scenic Area has an excellent natural environment, and landscape elements with high naturalness (vegetation, water) are more attractive to tourists, with diverse landscape combinations; (2) There is no complete positive correlation between tourist sentiment bias, landscape diversity, and vegetation coverage. Emphasis is placed on the aesthetic perception path from bottom to top, from the surface to the inside. The comprehensive emotional value is 14.35, and the emotional values are all positively distributed. The distribution density and extreme value of positive emotions are greater than those of negative emotions; (3) The emotional bias of tourists is directly related to visual sensitivity, showing a synchronous trend of change. The visual sensitivity of the Great Waterfall and Dishuitan areas is relatively high, mostly at I-II level sensitivity. This method enhances the data source channel, which is conducive to obtaining the correct tourist evaluation orientation. In traditional subjective landscape evaluation, rational parameter indicators are added to reduce the probability of error, provide data support for its natural beauty description, break through the time and space limitations of aesthetic evaluation, and provide scientific reference for quantifying the aesthetic value of other heritage sites.

Associations between depression and nature-based recreation: A cross-sectional study of adults in the United States, Spain, and Brazil

Abstract Cumulating evidence suggests that nature-based interventions may alleviate depression, but the association between engagement in nature-based activities and specific depressive symptoms remains unknown. We conducted a cross-sectional study to investigate how Major Depressive Disorder (MDD) symptom criteria relate to engagement in nature-based recreation (any nature-based activities, forest-based activities, gardening, nature-based adventure activities) among American (n = 606), Spanish (n = 438), and Brazilian (n = 448) adults (≥ 18 years old). People who reported engaging in any nature-based activities at least once per month reported experiencing all nine symptom criteria for MDD (e.g., anhedonia, feeling depressed or hopeless, sleep problems, trouble concentrating, and suicidal ideation) at lower rates than those who did not participate in nature-based recreation as frequently. Results were relatively consistent across countries and types of nature-based activities, suggesting that many forms of nature-based recreation are negatively correlated with the nine symptom criteria for MDD. The associations tended to be weaker overall among Spanish respondents. Nature-based recreation appeared to have a stronger inverse relationship with suicidal ideation than with other depressive symptoms. The cross-sectional design of this study limits the causal interpretation of the observed associations. If future experimental studies confirm our findings, practitioners across different countries can consider recommending participation in nature-based recreation to alleviate their clients’ MDD symptoms.

Phase II Trial of Enfortumab Vedotin in Patients With Previously Treated Advanced Head and Neck Cancer

PURPOSE Despite advances in immunotherapy, unresectable recurrent/metastatic head and neck cancer (HNC) carries a poor prognosis, and effective treatments are needed. As nectin-4 is widely expressed in HNC, enfortumab vedotin (EV), a nectin-4–directed antibody-drug conjugate, was explored in HNC in EV-202 (ClinicalTrials.gov identifier: NCT04225117 ). METHODS This open-label, multicohort, phase II study evaluated intravenous EV 1.25 mg/kg on days 1, 8, and 15 of each 28-day cycle. In the HNC cohort, eligible patients had recurrent/metastatic HNC and had received platinum-based therapy for locally advanced/metastatic disease and a PD-1/PD-L1 inhibitor. The primary end point was investigator-assessed confirmed objective response rate (ORR) per RECIST version 1.1. Secondary end points were investigator-assessed duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS); overall survival (OS); and safety. RESULTS The primary analysis included 46 patients; all received EV (median follow-up, 9.3 months). Most patients (52.2%) had ≥3 previous lines of systemic therapy in the metastatic setting. Confirmed ORR was 23.9%, DCR was 56.5%, and median DOR was not reached (median DOR was 9.4 months at a later data cutoff [median follow-up, 11.3 months]). Median PFS and OS were 3.9 and 6.0 months, respectively. Treatment-related adverse events (TRAEs) occurring in >20% of patients were alopecia (28.3%), fatigue (26.1%), and peripheral sensory neuropathy (23.9%). Sixteen patients (34.8%) experienced grade ≥3 TRAEs; anemia and decreased neutrophil count occurred in ≥1 patient (both n = 2; 4.3%). CONCLUSION EV demonstrated antitumor activity in heavily pretreated HNC. Safety was consistent with the known safety profile of EV; no new safety signals were identified. These data support further evaluation of EV for advanced HNC not amenable to definitive local therapy.

Efficacy and safety of disitamab vedotin combined with toripalimab as neoadjuvant treatment for patients with locally advanced muscle-invasive bladder cancer: A mono-institutional retrospective study.

726 Background: Currently, the efficacy of cisplatin-based neoadjuvant chemotherapy for patients with muscle-invasive bladder cancer (MIBC) is unsatisfied. Disitamab vedotin (RC48) as an antibody-drug conjugate is composed by a monoclonal antibody against human epidermal growth factor receptor 2 (HER2) and a cytotoxic agent monomethyl auristatin E. Although this drug was approved in 2021 for HER2-overexpressing gastric cancer, disitamab vedotin as mono- or combination regimen is in clinical development for treating other solid tumors now. This study aims to assess the safety and efficacy of disitamab vedotin combined with toripalimab as neoadjuvant treatment for patients with HER2 positive locally advanced MIBC. Methods: The data of patients with HER2 positive locally advanced MIBC who received combination therapy [disitamab vedotin (2.0mg/kg, iv, D 1 , Q3W) combined with toripalimab (240mg, iv, D 1 , Q3W) were collected retrospectively and analyzed. The primary endpoint was pathological complete response (pCR), and the secondary endpoints included objective response rate (ORR), overall survival (OS) and treatment-related adverse events (TRAEs). All outcomes were assessed by a blinded independent review committee. Results: The data of 20 included patients who received combination regimen from 2023 Jun to 2023 Sept were analyzed. Among them, the median age was 65 (47-86) years. The overall pCR was 79%, while the ORR was100%. The median PFS was 4.5 (2.45-9.6) months, and overall survival (OS) was not reached. The most common TRAEs were nausea (7,35.0%), alopecia (8,40.0%), and rash (3,15%). Only 1 patients reported Grade 3 TRAE (feeble), and no grade 4 TRAEs were observed. Conclusions: The safety and efficacy of neoadjuvant disitamab vedotin combined with toripalimab in patients with HER2 positive locally advanced MIBC were promising. This study will be verified in future.

ctDNA characterization in mCRPC patients with pathogenic germline variants.

247 Background: Approximately 10% to 15% of men with metastatic castration-resistant prostate cancer (mCRPC) harbor germline mutations. Circulating tumor-derived DNA (ctDNA) as non-invasive approach to characterizing somatic alterations. In this study, we report longitudinal ctDNA assessments in mCRPC patients who have undergone germline testing. Methods: A total of 238 patients, who had undergone both germline testing and ctDNA assessment from Tulane Cancer Center were included in this study. Germline testing was conducted using a multi-gene cancer panel from Invitae, covering 50-86 genes, while somatic alterations in ctDNA were tested through Guardant 360, including 70-83 genes. Somatic alterations with <0.1%, synonymous, and variants of unknown significance were excluded from analyses. Statistical analyses were performed using Pearson Chi-Square Test or Fisher Exact Test. Results: From 2015-2024, 17.2% (41/238) had pathogenic or likely-pathogenic (P/LP) germline mutations. The most common pathogenic germline mutations were in BRCA2 (17.1%; 7/41), BRCA1 (9.8%; 4/41), and CHEK2 (9.8%; 4/41). In ctDNA, germline positive patients were more likely to have frameshift mutations (OR= 1.75, 95% C.I. [1.09, 2.81], p=0.02) and less likely to have copy number amplifications (OR= 0.58, 95% C.I. [0.36, 0.93], p= 0.03) compared to germline negative patients. Among mCRPC patients with germline HRR P/LP mutations, frameshift alterations were significantly more frequent (OR=5.03, 95% CI [2.03, 13.23], p-value=0.0008). mCRPC patients with germline P/LP mutations were more likely to have somatic mutations in BRCA2 (OR=2.85; 95% CI: [1.62, 4.93]; p=0.0002) and GATA3 (OR=3.37, 95% CI: [1.26, 8.51]; p=0.016) detected ctDNA and less likely to have EGFR alterations (mutations and/or amplifications) (OR=0.46; 95%CI: [0.25, 0.80]; p=0.0094). BRCA2 somatic mutations are also more likely to be detected in patients with germline P/LP mutations in HRR genes (OR=0.11, 95% CI [0.03, 0.33], p=0.00004). Conclusions: mCRPC patients with pathogenic germline mutations are more likely to have frameshift and less likely to have copy number amplifications compared to germline negative mCRPC patients. Frameshift mutations are more likely to be detected in patients with germline P/LP in HRR genes. Patients with germline P/LP mutations are more likely to have somatic mutations BRCA2 and GATA3 and less likely to have mutations and/or amplifications in EGFR.

Comparing quality of life in prostate cancer patients: Continuous vs. intermittent androgen deprivation therapy—A systematic review and meta-analysis.

117 Background: Intermittent (i) and continuous (c) androgen deprivation therapy (ADT) not only play a critical role in managing prostate cancer (PC) but also impact patient’s quality of life (QoL). This meta-analysis aims to explore the effect of iADT vs. cADT on QoL in PC patients. Methods: PubMed, Cochrane, and Clinicaltrials.gov were searched as per PRISMA guidelines and 13 studies reporting iADT and cADT effect on QoL in PC patients were included. Pooled analysis was performed using the ‘meta’ package by Schwarzer et al. in the R programming language (version 4.16-2). Results: A total of 5364 (iADT 2685, cADT 2679) patients with median age of 69.9 (59.8-78.6) years and 69.4 (59.6-77.8) years, respectively, were included for analysis. The median PSA to initiate, stop, and restart treatment was ≥ 12.5, ≤ 4, and ≥ 10 ng/ml, respectively. Goserelin (31%) and Flutamide (23%) were the most used treatment modalities. At a median follow-up of 60.8 (52-69.6) months pooled overall survival and progression free survival for cADT was58.3% (95% CI 0.33-0.81, I2=99%, p<0.01), 22.4% (95% CI 0.12-0.34, I2=95%, p<0.01) while it was 54.2% (95% CI 0.29-0.78, I2=99%, p<0.01, n=1183) and27.8% (95% CI 0.15-0.42, I2=96%, p<0.01, n=1156), for iADT at the median follow-up of 51.7 (42.2-61.2) months, respectively. The pooled incidence of weakness, vasomotor side effects, erectile dysfunction, and gynecomastia in cADT arm were 3.8% (95% CI 0.02-0.06, I2=28%, p=0.24), 40.8% (95% CI 0.22-0.61, I2=98%, p<0.01), 25.6% (95% CI 0.03-0.60, I2=97%, p<0.01), and 7.6% (95% CI 0.6-0.1, I2=0%, p=0.93) while in iADT arm were 2.8% (95% CI 0.01-0.06, I2=78%, p=0.03), 32.7% (95% CI 0.15-0.53, I2=99%, p<0.01), 21.3% (95% CI 0.08-0.39, I2=91%, p<0.01), and 5.8% (95% CI 0.02-0.123, I2=88%,p<0.01), respectively. The rate of death in cADT and iADT arms were 35% and 37%, respectively, with prostate cancer (35 % vs 38%) and cardiovascular disease (39% vs 36%) being the most common causes of death. Conclusions: This analysis shows potential equal efficacy of iADT with better QoL as compared to cADT. However, further randomized studies are needed to consolidate these findings and to establish guidelines. Quality of life outcomes. Variable iADT (n=2685) cADT (n=2679) Side Effects (%) - Weakness 2.8% (95% CI 0.01-0.06, I2=78%, p=0.03) 3.8% (95% CI 0.02-0.06, I2=28%, p=0.24) - Vasomotor Side Effects 32.7% (95% CI 0.15-0.53, I2=99%, p<0.01) 40.8% (95% CI 0.22-0.61, I2=98%, p<0.01) - Erectile Dysfunction 21.3% (95% CI 0.08-0.39, I2=91%, p<0.01) 25.6% (95% CI 0.03-0.60, I2=97%, p<0.01) - Gynecomastia 5.8% (95% CI 0.02-0.123, I2=88%, p<0.01) 7.6% (95% CI 0.6-0.1, I2=0%, p=0.93) Common Causes of Death (%) - Prostate Cancer 38% 35% - Cardiovascular Disease 36% 39% iADT: Intermittent androgen deprivation therapy, cADT: continuous androgen deprivation therapy (ADT).

The role of iron deficiency and factors associated with anemia during pregnancy in Southeastern Tigray, Ethiopia, 2020

Background Pregnant women are more likely to experience anemia due to their increased need for nutrients, and anemia has been associated with unfavorable maternal-fetal outcomes. In Ethiopia, anemia rates are increasing despite efforts to reduce them. Besides, the extent to which iron deficiency contributes to anemia in this population is unclear. Therefore, this study aimed to assess the role of iron deficiency and factors associated with anemia during pregnancy in the southeastern zone of Tigray, Ethiopia. Method A facility-based, cross-sectional study was conducted among 311 pregnant women who attended four health facilities in the southeastern zone of Tigray region from January to June 2020. The study utilized a semi-structured, pretested questionnaire to collect data. The data were entered into Epi data 3.1 and analyzed using SPSS version 25. Candidate variables with a p-value ≤ 0.25 in the bivariate logistic regression were considered to the final model of multivariate logistic regression analysis. Adjusted odds ratio with a 95% confidence interval and a p-value of ≤ 0.05 were used to declare statistical significance for the factors associated with anemia. Results A total of 311 mothers had completed the survey with a response rate of 98.1%. The overall magnitude of anemia was 55(17.7%). Out of the anemic pregnant women, 30(54.5%) were due to iron deficiency. Third-trimester pregnancy (AOR = 4.9; 95% CI:1.49, 15.98), interpregnancy gap of ≤ 2 years (AOR = 7.7; 95% CI: 2.71, 21.64), coffee/tea intake immediately after meal (AOR = 3.0; 95% CI: 1.02, 8.92), low diet diversity score (AOR = 4.2; 95% CI: 1.02,17.57), not taking iron-folic acid supplementation (AOR = 2.6; 95% CI: 1.05, 6.70), and Mid upper arm circumference value of < 23cm (AOR = 2.7; 95% CI: 1.16, 6.47) were independent factors associated with anemia. Conclusion Based on the findings, anemia is a mild public health concern in the study areas. Additionally, over 50% of the anemia cases were attributed to iron deficiency anemia. Nutritional counseling on food diversification, especially the consumption of iron-rich foods, and delaying the drinking of coffee/tea after a meal, as well as iron-folic acid supplementation, are needed to reduce anemia in the study area.

PAM-adjacent DNA flexibility tunes CRISPR-Cas12a off-target binding

Evaluating worldwide disparities in bladder cancer clinical trial availability.

672 Background: Bladder cancer (BC) poses a disproportionate burden on low- and middle-income countries (BJUI, 2017), yet BC clinical trials have historically been centralized in North America and Europe. Despite efforts to broaden global participation in cancer trials (ASCO Policy Statement, 2024), data on the impact of these initiatives, especially for BC, remain scarce. We aim to assess the current global availability of BC clinical trials. Methods: Through ClinicalTrials.gov, we indexed all protocols enrolling adults with BC from 6/1/2019 to 6/1/2024. We excluded non-interventional studies and those with non-oncologic interventions. We identified countries with at least one active trial site. Countries were classified based on income using the World Bank Ranking (WBR): high-income countries (HICs), upper middle-income countries (UMICs), lower middle-income countries (LMICs), and low-income countries (LICs). We also recorded data on BC type, sponsor, phase, cancer stage, enrollment, and endpoints. Descriptive statistics were used to summarize trial characteristics, and the Kruskal-Wallis test was used to assess the association between BC trial availability and WBR. Poisson regression analysis was employed to evaluate the association between clinical trial availability and incidence, mortality, WBR, health expenditure, and gross national income. Results: A total of 576 BC trials were identified, of which 539 trials met eligibility criteria with active sites across 63 countries. Many (64.6%) countries in the initial query were not represented in the trials, and 60.9% of these were LICs or LMICs. Of the 539 trials, most were exclusively available in HICs (79.4%), with the USA having hosted 321 trials, and none were available in LICs. Most trials were phase I or II (60.9%) and conducted in a single country (78.3%). Most were sponsored by academic institutions (54%), followed by pharma (36.7%). We observed a significantly lower availability of trials in UMICs (OR 0.30, p=0.01), LMICs (OR 0.076, p<0.001), and LICs (0.010, p=0.001). Moreover, we found that early-phase trials were more likely to be conducted exclusively in HICs compared to late-phase trials (p<0.001). Trials in non-HICs were often sponsored by academia (67.6% vs. 50.5%), had larger mean enrollment (238 vs. 154), and were less frequently funded by pharma (67.6% vs. 55.4%). Poisson regression analysis revealed that WBR and annual health expenditure were significantly associated with a country’s clinical trial availability. Conclusions: BC trials, particularly those in the early phase of clinical development, are disproportionately concentrated in HICs, with their availability directly correlating to country WBR and health expenditures. This creates a gap in safety and efficacy testing for diverse populations. Expanding early-phase and pharma-funded studies beyond HICs would amplify equitable care for patients with bladder cancer.

A phase I first-in-human clinical trial with PLZ4-coated paclitaxel-loaded micelles (PPM) in therapy-resistant non-muscle-invasive bladder cancer (NMIBC).

806 Background: Approximately 75% of patients with non-muscle invasive bladder cancer (NMIBC) treated with transurethral resection (TUR) followed by intravesical Bacillus Calmette-Guérin (BCG) experience cancer recurrence. When BCG-unresponsive, most patients continue to have recurrences even with newly approved therapies and nearly 30% progress to invasive stages. We developed a first-in-class bladder cancer-specific nanotherapeutic, PPM, which is administered intravesically. Our preclinical data has demonstrated PPM can selectively target bladder cancer cells and deliver paclitaxel payload into these cancer cells following intravesical or intravenous administration. Methods: This is a 3+3 first-in-human dose escalation trial. Eligible patients must have pathologically confirmed NMIBC, be unresponsive to intravesical BCG therapy (with or without cytotoxic chemotherapy), possess adequate vital organ function, and consent to cystoscopy with TUR for response evaluation. PPM is administered via intravesical instillation once weekly for six weeks. The trial features three dose levels, with paclitaxel doses of 25 mg, 50 mg, and 75 mg. The primary endpoints include safety and the recommended Phase II dose; secondary endpoints encompass response rate, duration of response, systemic drug absorption, and molecular correlative studies. Patients will be followed at 3 month intervals for 2 years or until disease progression. Results: To date, three patients with pathologically confirmed NMIBC have completed a total of 18 treatments at the first dose level without any PPM-related adverse events: one patient was unresponsive to BCG and intravesical mitomycin therapy, while the other two had BCG-unresponsive disease. Two out of the three patients achieved ongoing complete remission for over six and nine months, respectively. The third patient demonstrated persistent disease, but no progression was noted. Enrollment for Dose Level 2 is currently open. Conclusions: PPM has demonstrated promising clinical activity without toxicity at the first dose level in patients with BCG-unresponsive NMIBC. Data at other dose levels will be presented at the meeting (ClinicalTrials.gov identifier: NCT05519241). Clinical trial information: NCT05519241 .