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Possibilities of using biosorbents and synthetic sorbents in monitoring heavy metal pollution of surface waters

Low-dose radiation ameliorates doxorubicin-induced renal injury via reducing oxidative stress and protecting mitochondrial function

Doxorubicin (DOX) is a well-established chemotherapy drug, but its clinical application is restricted due to significant tissue toxicity, of which nephrotoxicity is a serious adverse reaction. Low-dose radiation (LDR) exerts effects through stimulating diverse cell and molecular mechanisms, which has been shown to have anti-inflammatory and alter immune adaptation effects. This study aims to investigate how LDR protects against DOX-induced nephrotoxicity and to explore the underlying mechanism involved. Sixty mice were randomly divided into control (CTR), LDR, DOX, and combination (COM) group. Nephrotoxicity was induced by injecting a single dose of DOX (7.5 mg/kg) in mice abdominal cavity, and LDR was performed 72 h before DOX treatment. Histological analysis, immunohistochemical analysis, immunofluorescence analysis and western-blotting were used to detect the related indicators. Research data was showed as mean ±SD and tested by One-way ANOVA. The results showed that compared with DOX group, the contents of serum UREA, UA, and the expression level of Bax and caspase 9 were significantly reduced in COM group (P<0.05). Western-blotting and immunohistochemical analysis showed that the expression level of MDA and Nrf2 in COM group were significantly lower than that in DOX group (P<0.05). In addition, the activity of complex Ⅰ, ATP, NDUFA1 and CYC1 were enhanced in COM group compared with DOX group (P<0.05). All the results suggested that LDR pretreatment prevented excessive accumulation of peroxides, restored antioxidants activity (SOD, GSH, CAT), activated Nrf2/HO-1/NQO1 signaling pathway, attenuated damage to the mitochondrial respiratory chain, and protected kidney cells from DOX attack. This study demonstrated that LDR could effectively and safely inhibit the progression of DOX-induced nephrotoxicity. Future studies should further investigate the mechanism of LDR protecting tissues from DOX-induced damage and find an optimal radiation dose for humans.

Nitrogen-enriched carbon nanotube supported palladium as a catalyst for desulfurization of dibenzothiophene and reduction of nitroarenes

Global natural history infrastructure requires international solidarity, support, and investment in local capacity

Amid global challenges like climate change, extinctions, and disease epidemics, science and society require nuanced, international solutions that are grounded in robust, interdisciplinary perspectives and datasets that span deep time. Natural history collections, from modern biological specimens to the archaeological and fossil records, are crucial tools for understanding cultural and biological processes that shape our modern world. At the same time, natural history collections in low and middle-income countries are at-risk and underresourced, imperiling efforts to build the infrastructure and scientific capacity necessary to tackle critical challenges. The case of Mongolia exemplifies the unique challenges of preserving natural history collections in a country with limited financial resources under the thumb of scientific colonialism. Specifically, the lack of biorepository infrastructure throughout Mongolia stymies efforts to study or respond to large-scale environmental changes of the modern era. Investment in museum capacity and training to develop locally-accessible collections that characterize natural communities over time and space must be a key priority for a future where understanding climate scenarios, predicting, and responding to zoonotic disease, making informed conservation choices, or adapting to agricultural challenges, will be all but impossible without relevant and accessible collections.

Fractal perspective of superquadratic functions with generalized probability estimations

This study introduces for the first time a class of generalized superquadratic functions specifically on fractal sets and explores their unique features. The research develops several generalized inequalities, including Jensen’s, converse Jensen’s, Mercer Jensen’s and Hermite-Hadamard’s inequalities based on the properties of generalized superquadratic functions. The findings are confirmed through reduced results, numerical calculations and graphical depictions, ensuring the robustness and accuracy of the proposed inequalities by taking into account several appropriate examples. A detailed comparative analysis between inequalities derived from generalized superquadratic functions and those from generalized convex functions, highlighting the greater refinement provided by the generalized superquadratic functions. The study enhances its findings with practical applications in probability expectations and special means in fractal space, demonstrating the applicability and relevance of the new results in these domains. The new results presented in this work provide significant extensions and improvements over existing literature, showcasing advancements and potential for further research in the field.

First next-generation sequencing (NGS) testing at the end of life in patients with metastatic prostate cancer.

90 Background: Poly(ADP) ribose polymerase inhibitors and pembrolizumab are approved for patients with metastatic prostate cancer (mPC) with susceptible genomic alterations based on NGS testing. We recently reported that the rate of NGS testing in mPC remains low at 29.3% in the United States (1). Herein, we investigated the rates of NGS testing at the end of life in a real-world patient population. Methods: This study utilized the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. Eligibility: diagnosis of mPC, with information on receipt of NGS testing (blood/tissue) and recorded date of death. The time between each patient’s first NGS testing result date and date of death was measured and categorized into 3 groups: NGS test results delivered more than 3 months (mo) before death, within 3 mo of death, and delivered after death. Frequencies and percentages of these 3 categories were reported, also by the year of death. Results: Out of 24,105 patients with mPC in the database, 3,397 had both a recorded date of death and underwent NGS testing and were eligible and included. The median age was 74 (IQR 67–80), 70% were White non-Hispanic, and 83% were treated in a community-based practice. In these patients, 2,901 (85.4%) NGS results were reported more than 3 mo before death, 457 (13.5%) within 3 mo of death, and 39 (1.1%) after death. From 2015 to 2024, the percentage of patients receiving their result more than 3 mo before death increased from 27% to 91%, while those receiving it within 3 mo before death decreased from 55% to 8.5%, and the percentage of NGS results reported after death declined from 18% to 0.6%. Baseline characteristics (including race-ethnicity, insurance plan, practice type [academic vs. community]) in these categories will be presented at the meeting. Conclusions: Despite the availability of life-prolonging targeted therapies based on NGS testing results for patients with mPC, in ∼14% of patients, the first NGS testing results were reported within 3 mo before death or after death. The lack of timely NGS testing limits patients' access to life-prolonging personalized treatments in earlier settings, resulting in missed opportunities for improved outcomes. 1. Hage Chehade, Swami, JAMA Network Open, 2024.

Hydroxychloroquine effects on tumor suppressor PAR-4 levels in patients with oligometastatic prostate cancer: Results from a phase-2 trial.

233 Background: In oligometastatic prostate cancer (OMPC), delaying time to initiation of androgen deprivation therapy (ADT) may have oncologic and quality of life benefits. Additionally, there is an emerging role for metastatic/primary tumor site-directed therapy for patients with OMPC. Prostate apoptosis response-4 (PAR-4) is a potent tumor suppressor, facilitating apoptosis in prostate cancer cells. Hydroxychloroquine (HCQ) has been identified to be a potent inducer of PAR-4 secretion and downstream tumor inhibition in preclinical models and Phase I trials. We present a single institution Phase II trial assessing induction of PAR-4 levels in the plasma of patients in response to HCQ administration in combination with radiation therapy (RT) for OMPC. Methods: Men with OMPC (≤5 synchronous metastatic lesions) following primary tumor treatment were eligible. Patients received 400 mg HCQ daily for 2 weeks prior to metastatic site-directed RT and 400 mg HCQ daily for 90 days post-radiation. Plasma samples were collected on Day 0, 14, 30, 60, and 90. The primary endpoint was induction of ≥50% serum PAR-4 expression above baseline level within 90 days of treatment initiation. We hypothesized that over half of patients would exhibit ≥50% induction of serum PAR-4 expression. Results: Nineteen participants met inclusion criteria and were treated with 90 days of HCQ and RT to oligometastatic lesions. Median age was 68 years (range 55-77), the majority of patients were Caucasian (94%) and the median baseline PSA was 6.30 ng/ml (range 0.99 to 27.80). Prior primary tumor treatment included radiation therapy in 26%, radical prostatectomy in 32%, and radical prostatectomy with radiation in 42%. Eleven patients (58%) showed ≥50% increase in plasma PAR-4 above baseline levels (p=0.0006). This was associated with a concomitant PSA decline at 6-months (mean -0.98 ng/ml, 95% CI -6.61 to 4.65) and 12-months (mean -7.21 ng/ml, 95% CI -12.45 to -1.97). At 12-month follow-up, seven patients (37%) were free from ADT and median progression-free survival was 9.3 months (95% CI 6.4 to N/A). Twelve patients (63%) reported at least one adverse event, with 2 patients (11%) experiencing grade 3 toxicity. Conclusions: Oral administration of HCQ is well tolerated and effectively induces plasma expression of the potent tumor suppressor PAR-4 in patients with OMPC. Given the promising findings, further investigation into possible radiosensitizing and anti-tumor benefits of HQC in a larger cohort of OMPC is necessary. Clinical trial information: NCT04011410 .

Severity of bleomycin-induced lung toxicity in Indian patients with intermediate and poor-risk non-seminomatous germ cell tumors (NSGCT): A clinical perspective.

635 Background: Bleomycin, etoposide and cisplatin (BEP) chemotherapy is the standard of care in advanced NSGCT due to its extremely high efficacy. The incidence of bleomycin-induced lung toxicity ranges between 5-40%. Risk factors include older patients, smokers, pre-existing lung diseases, cumulative dose > 300 units and previous radiation to thorax. Methods: This was a retrospective analysis of a prospectively collected dataset of intermediate and poor risk NSGCT patients treated with BEP at a comprehensive cancer care centre in India. Adolescent and adult males with an eastern co-operative oncology group (ECOG) performance status (PS) 0-2 who developed bleomycin-induced lung toxicity were included. Descriptive analyses were performed and Kaplan-Meier method was used for estimation of survival using SPSS version 29.0. Results: A total of 223 patients with intermediate and poor risk NSGCT received BEP, of which 30 (13%) developed bleomycin induced lung toxicity and were included in this analysis. The median age was 31.5 years (IQR: 25.75 - 34.5 years) (Table). Twenty-eight (93.3%) were non-smokers while 14 (46.7%) did not have lung metastases. Six (20%) had baseline serum creatinine > 1.3mg/dL. Twelve (40%) required granulocyte colony stimulating factor (G-CSF). The median baseline forced vital capacity (FVC) was 3.88 L while diffusing capacity of lung for carbon monoxide (DLCO) was 90%. Post BEP, the median FVC was 2.76 L while DLCO was 68% among those who had lung toxicity. Seventeen (56.7%) were symptomatic for lung toxicity while 13 (43.3%) had grade 1 pneumonitis. Eighteen (60%) received 4 cycles of BEP, 8 (26.7%) received 3 cycles while 4 (13.3%) received 2 cycles prior to developing lung toxicity. Seven (23.3%) required hospitalization of which 6 (20%) had hospital stay for more than 10 days, 5 (16.7%) required ambulatory oxygen and 4 (13.3%) required intensive care. Nineteen (63.3%) required steroids. Five (16.7%) died due to bleomycin-induced lung toxicity. With a median follow-up of 81 months, the 5-year and 10-year OS were 61.6% and 55.5% respectively. Conclusions: The potential of bleomycin to cause lung toxicity necessitates careful patient selection, monitoring and optimal management. Patient characteristics. Characteristics All patients(n = 30) Age group Less than 35 years 23 (76.7%) More than or equal to 35 years 7 (23.3%) Primary site Testis 28 (93.4%) Retro-peritoneum 1 (3.3%) Mediastinum 1 (3.3%) Risk stratification Intermediate 15 (50%) Poor 15 (50%) Lung metastases None 14 (46.7%) Unilateral 3 (10%) Bilateral 13 (43.3%) Grade of pneumonitis (CTCAE v5.0) Grade I 13 (43.3%) Grade II 10 (33.3%) Grade III 2 (6.7%) Grade IV 0 Grade V 5 (16.7%) CT chest findings Air-space consolidation 1 (3.3%) Ground glass or nodular opacities 10 (33.3%) Reticular interstitial thickening 14 (46.7%) Fibrotic changes 5 (16.7%)

Long-term outcomes of neoadjuvant chemotherapy (NAC) before bladder-sparing chemoradiotherapy (CRT) for patients with nonmetastatic muscle-invasive bladder cancer (MIBC).

819 Background: Neoadjuvant cisplatin-based combination chemotherapy followed by concurrent chemoradiation is an emerging approach in carefully selected MIBC patients who opt for bladder sparing however, long-term data on its efficacy and tolerability remains lacking. We evaluated long-term outcomes in MIBC patients treated with this approach. Methods: We conducted a retrospective chart review of patients treated with NAC followed by CRT bladder sparing approaches between 2008 and 2017 at the Princess Margaret Cancer Centre and Lakeridge Health Cancer Centers. We initially published the feasibility of this approach and early outcome data in 2018. In this analysis, we updated long-term disease free survival (DFS), bladder intact disease free survival (BI-DFS) and overall survival (OS). Results: In total 57 patients were treated with NAC + CRT. Most were male with a median age of 72 (range 45-87), and an Eastern Cooperative Oncology Group performance status of 0 (60%) or 1 (40%). Patients with stage II (65%), and stage III disease (25%), as well as regional nodal metastases (11%), carcinoma in situ (28%) and hydronephrosis (25%) were included. The majority of patients completed planned NAC (95%). All patients completed external-beam radiotherapy, and 84% completed at least 60% of the planned concurrent weekly cisplatin doses. Median follow up for this population was 74.4 months (9.7-142.1). At the time of this updated analysis, 23/57 (40%) recurred, local recurrence occurred in 11/57 patients (19%), and 9/57 patients (16%) required salvage cystectomy. Distant recurrence occurred in 12/57 (21%) patients, all of whom died as a result of bladder cancer. The median DFS for the study population was 56.7 months (95% CI 25.3-99.1), and 5-year DFS rate was 49%. The median BI-DFS was 40.1 months (95% CI 23.3-85.4) and 5-year BI-DFS rate was 45%. The median OS was 104.9 months (95% CI 60.8-119.2) with a 5-year OS rate of 65% (95% CI 50.7-75.5). Conclusions: NAC+CRT is a safe and effective approach for selected patients with MIBC with encouraging long-term outcomes. This data supports evaluating neoadjuvant and adjuvant systemic therapies along with bladder preservation strategies in prospective clinical trials.

Metastasis-directed radiotherapy in oligometastatic bladder and upper tract cancer: A single institution retrospective experience.

799 Background: Metastasis-directed therapy (MDT) for oligometastatic cancer is a concept utilized for prostate and kidney cancer. Clinical research in MDT for oligometastatic urothelial carcinoma (UC) remains sparse especially in the modern era where systemic therapy advancements have substantially improved patient’s outcomes overall. We explored our institutional experience of patients with oligometastatic carcinoma of the bladder and upper tract undergoing MDT utilizing radiotherapy (RT). Methods: Patients were retrospectively identified with oligometastatic bladder or upper tract cancer from January 2016 to July 2024 with five or less sites of metastases. Those with equivalent dose of RT (EQD2 10 ) ≥ 45Gy to metastases were included. Progression free survival (PFS) and overall survival (OS) were evaluated using Kaplan Meier from time of diagnosis to metastatic disease. Cox proportional hazards analysis was conducted to determine covariates associated with survival endpoints. Results: 60 patients with oligometastasis were included with 8 patients excluded due to a RT dose EQD2 10 < 45Gy. 52 patients were in final analysis. Most were men (67%) with a median age 68 years (range, 35-91). Most had bladder primary (79%) with the remaining including upper tract. Majority had pure UC (85%) and the remainder were UC subtypes with variant histology including small cell (8%), squamous (6%), sarcomatoid (2%). Median number of metastases was 1 site, while 23% had 3+ sites. Bony metastases (27%) were most common site, then retroperitoneal nodes (18%) and lung (17%). Most received ≥2 systemic therapy cycles before MDT (62%) with 8% without any therapy prior to MDT. Most commonly used therapy included ddMVAC (21%), Gem/Cis (20%), pembrolizumab (15%), and EV (12%). MDT was delivered to all metastases in 71%, while the remaining had MDT to select sites. Most common MDT dose was 30Gy in 3 fractions (21%) followed by 50Gy in 4 fractions (17%). Median follow up from metastatic diagnosis was 19 months (range, 3-106 months). Median PFS and OS was 21 months (95% CI 8-33 months), and 39 months (95% CI, 14-64 months), respectively. At last follow up, 31 patients were alive (60%). Most common first recurrence was distant from site of MDT (96%) while 2 patients had in-field recurrence in pelvic bones. On univariate analysis, those with 1 vs 2+ sites had improved PFS with MDT (p=0.03, 95% CI 1.1-6.0). Univariate showed no association with MDT to all sites vs select, age, or # lines of systemic therapy. Conclusions: As systemic therapy has improved for patients with bladder and upper tract cancers, MDT may serve as an effective adjunct to improve cancer control. Baseline characteristics. Characteristic (n=52) No % Median Age (yrs) 68 Histology UC 44 85% UC subtype with variant histology 7 15% Site of Primary Bladder 41 79% Upper Tract 11 21% Lines of therapy before MDT 0 4 8% 1 17 33% 2+ 31 60%

Clinicopathological features and prognosis of MED15-TFE3 rearrangement renal cell carcinoma: An updated report.

492 Background: TFE3-rearranged renal cell carcinoma (rRCC) is uncommon, and demonstrates unique heterogenous morphological features and distinct immune characteristics. MED15-TFE3 is a rare gene fusion that usually present as an extensive cystic mass with low malignant potential and is more susceptible to immune check point inhibitor. Identifying the clinical characteristics is crucial for the treatment. Methods: All samples were collected retrospectively from West China Hospital between 8/2011 and 5/2024. Diagnosis of MED15-TFE3 gene fusion was confirmed by RNA sequencing and fluorescence in situ hybridization. Both clinicopathological features and follow-up prognosis information were collected for further analysis. Results: The detailed information of 16 cases were described in the table. The median age was 47.5 years (range, 22 to 70 years). Majority of the cases were female (12/16). All patientes were surgically treated (radical nephrecomy: 8; partial nephrectomy: 7; cytoreductive surgery: 1). At initial diagnosis, most cases (14/16) were localized disease, while two patients had positive regional lymph nodes metastasis, and one patient had distant metastasis. For the patients without distant metastasis (n=15), two patients developed metastasis with disease-free survival of 11.4 and 29.0 months, respectively. As for the pathological features, 14 (87.5%) of the casess presented cystic morphologically, and other two (12.5%) were papillary. Except for one patient with diatant metastasis at initial diagnosis, all patients (15/16) were in G2 by ISUP score. For metastatic patients, 3 received first-line therapy (1 axitinib, 1 axitinib + sintilimab, 1 sunitinib), 2 received second-line therapy (1 axitinib + sintilimab, 1 axitinib + toripalimab), 1 received third-line therapy (axitinib + toripalimab and combined with everolimus). They are still under follow-up. Conclusions: MED15-TFE3rRCC mainly present low-grade cystic renal neoplasm with favorable prognosis. For metastatic MED15-TFE3 rRCC, there is no standard therapy currently. Clinicopathological characteristics and prognosis of 16 MED15-TFE3 rRCC cases. Characteristics Cases Age, median (range), years 47.5 (22, 70) Gender Male 4 Female 12 Morphology Cystic 2 Papillary 14 Tumor size, median (range), cm 5.6 (3.3, 14.0) Nephrectomy Radical 8 Partial 7 Cytoreductive 1 T stage T1 10 T2 3 T3 3 N stage N0 14 N1 2 M stage M0 15 M1 1 ISUP grade 2 15 3 1 Distant metastasis Synchronous 2 Metachronous 2 No 12 Survival status Alive 15 Dead 1

Association of high ctDNA tumor fraction (TF) and detection of clinically significant copy number (CN) losses in liquid biopsies (LBx) from patients with advanced prostate cancer (PCa).

53 Background: Detection of somatic genomic alterations (GA) in LBx is dependent upon the amount of tumor DNA shed, inferred by ctDNA TF. Many clinically actionable GA in PCa are homozygous copy number (CN) losses, which present distinct detection challenges relative to short variant (SV) alterations. BRCA2 CN loss in PCa has been associated with prolonged benefit from PARP inhibitors (PARPi), possibly due to the inability to develop resistance-associated BRCA2 reversion mutations. Methods: Tissue-based FoundationOne CDx (TBx) or blood-based FoundationOneLiquid CDx (LBx) comprehensive genomic profiling (CGP) data from PCa patients was interrogated. We compared GA detection rates in TBx, all LBx (any ctDNA TF), and high-TF (ctDNA TF≥20%) LBx for pathogenic/likely pathogenic SVs and CN losses in 5 clinically relevant genes: BRCA1 , BRCA2 , PTEN , RB1 , and TP53 . We used logistic regression on data from the nationwide de-identified Flatiron Health-Foundation Medicine Clinico-Genomic Database (~280 US cancer clinics, ~800 sites of care) to identify clinical factors predicting high ctDNA TF for optimal CN loss detection. Results: 24,888 TBx and 13,604 LBx were available from patients with predominantly advanced/recurrent PCa. The prevalence of CN losses and SVs in the 5 genes, as detected by TBx, are shown in the Table. >30% of all GA in BRCA2 (36%), PTEN (72%) and RB1 (48%) were CN losses, while losses were rare for BRCA1 (6%) and TP53 (7%). Across all LBx, CN loss rates were lower than in TBx ( BRCA1 0.01 vs 0.05%, BRCA2 1.0 vs 3.0%, PTEN 7.4 vs 24%, RB1 1.4 vs 2.7%, TP53 0.7 vs 2.6%), while SV rates were similar to TBx (not shown). However, high-TF LBx and TBx had similar or higher CN loss rates ( BRCA1 0.06 vs 0.05%, BRCA2 3.3 vs 3.0%, PTEN 28 vs 24%, RB1 5.4 vs 2.7%, TP53 2.9 vs 2.6%), suggesting that high ctDNA TF enables optimal CN detection. Logistic regression linked high alkaline phosphatase, high PSA, and blood draw within 60 days prior to a new therapy with greater likelihood of ctDNA TF≥20% (all P <0.01). Conclusions: Detection of SVs requires only modest ctDNA TF, while CN losses require higher ctDNA TF. High alkaline phosphatase and PSA levels are associated with greater likelihood of ctDNA TF sufficient for CN loss detection. About one-third of men with PCa harboring BRCA2 GA have CN loss, which confers prolonged benefit from PARPi. A validated ctDNA TF is a critical quality indicator, and when low, should prompt consideration of confirmatory TBx to ensure that actionable CN losses are not missed. Gene Rate of homozygous CN loss detection (TBx, %, 95CI) Rate of SV detection (TBx, %) Proportion of all GA due to CN loss (TBx, %) BRCA1 0.05 [0.03-0.09] 0.76 [0.65-0.87] 6.5 [3.5-11] BRCA2 3.0 [2.8-3.2] 5.2 [5.0-5.5] 36 [34-39] PTEN 24 [23-25] 9.0 [8.6-9.4] 72 [71-73] RB1 2.7 [2.5-2.9] 2.9 [2.7-3.1] 48 [45-51] TP53 2.6 [2.4-2.8] 36 [35-37] 6.7 [6.2-7.2]

Complications after transurethral resection of bladder tumor: Findings from the 2022 ACS NSQIP database.

742 Background: Transurethral resection of bladder tumor (TURBT) is a widely utilized procedure for the diagnosis and treatment of bladder cancer (BC). Despite its well-established role, TURBT is associated with a relatively high rate of postprocedural complications. This study aimed to provide an update on the most prevalent complications following TURBT, using data from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) 2022 database. Methods: The ACS NSQIP 2022 database was queried for all patients who underwent TURBT. Current Procedure Terminology (CPT) codes 52234, 52235, and 52240 were used to identify size-specific TURBTs. Standard statistical analysis using R version 4.4.1 was performed to determine complications. Results: A total of 9,448 TURBTs were included in our analysis. Median age was 73 years old (IQR: 58-88), 2,315 females and 7132 males that received a TURBT within the cohort. Patients with concurrent procedures were removed from the final analyses, but those who received intravesical chemotherapy or underwent concurrent ureteroscopy were retained. The overall complication rate of TURBT was 8.04% in 2022. Postprocedural urinary tract infection (UTI) - within 30 days after TURBT - was the most common complication, accounting for 4.5% of total complications. 160 patients or 1.7% were found with more than one complication. There were no significant differences in complications by age or sex (p = 0.129 and p = 0.124); however larger tumors were related to higher likelihood of post-operative complications. Conclusions: Serious adverse complications after TURBT are rare and TURBTs are generally a safe procedure. However, the ACS NSQIP database suggests that postprocedural UTI are the most common but the rate may be marginally higher than previously reported in TURBT patients. The key limitation of this study was the inability to report the most serious complications of TURBT – i.e. bladder perforation and TUR syndrome – due to NSQIP database’s inability to capture detailed case-specific data. More detailed studies assessing patient-reported outcomes may provide a better method to evaluate the types of complications following TURBT. 30-day complications after TURBT in 2022. 30-day Complications Frequency Percentage Acute Renal Failure 4 0.043% Cardiac Arrest Requiring CPR 10 0.108% Still in Hospital after 30 days 15 0.161% Stroke/CVA 22 0.237% Pneumonia 31 0.333% DVT/PE/Thrombophlebitis 48 0.508% Transfusions Required 122 1.312% Progressive Renal Insufficiency 135 1.452% Related Reoperations within 30 days 148 1.592% Urinary Tract infections 430 4.603% Total 760 8.044%

Racial differences in active surveillance intensity and overtreatment in men with prostate cancer.

316 Background: Marginalized communities in cancer care are often characterized by lower healthcare utilization. In prostate cancer, however, utilization may have mixed effects on quality, particularly in the Medicare population where non-cancer health risks are more prevalent. In this context, we examined racial differences in active surveillance intensity (i.e. confirmatory testing) and potential overtreatment, two key measures of prostate cancer care quality. Methods: Using a 20% national sample of Traditional Medicare beneficiaries, we identified men with newly diagnosed prostate cancer from 2014 to 2019. We used multivariable logistic regression to evaluate the association between race (White, Black, or other) and receipt of a confirmatory test (prostate biopsy, magnetic resonance imaging, or genomic testing) within one year of diagnosis among men on active surveillance. We created a subset of patients with significant comorbidities to assess potential overtreatment (i.e., treatment among patients with >50% estimated non-cancer mortality in five years). Results: We identified 41,092 men meeting inclusion criteria. On adjusted analysis, Black men (OR=0.75; 95%CI: 0.62-0.92, p=0.01) had lower odds of receiving a confirmatory test compared to White men. Among men at risk of overtreatment, Black men (OR=0.86; 95%CI: 0.77-0.97, p=0.01) were less likely to receive treatment compared to White men. Further, all patients, regardless of race, had a predicted probability <50% of receiving a confirmatory test within one year of diagnosis (Table). Conclusions: Our study highlights racial differences in two measures of prostate cancer care, receipt of a confirmatory test and overtreatment. We demonstrated that Black men have lower odds of receiving a confirmatory test. This stands to disproportionately affect Black men, given that they present with higher risk tumors compared to other racial groups. Conversely, Black men have lower odds of being overtreated when compared with White men, suggesting that lower utilization may shield them from potential overtreatment and its related morbidity. As a result, policy efforts aiming to reduce disparities may be most impactful by prioritizing clinical contexts where utilization and access are tightly aligned with care quality. Predicted probabilities for confirmatory testing and overtreatment. White Black Other Confirmatory Testing 43% 37%* 46% Overtreatment 50% 43%* 46%* Adjusted for socioeconomic status tertile, Charlson Comorbidity Index, age, rurality, and year of diagnosis. *Indicates p<0.05.

A phase 2 study of cabozantinib and nivolumab in metastatic castration resistant prostate cancer (CANOPY).

TPS302 Background: Advanced metastatic-castration-resistant prostate cancer (mCRPC) remains a lethal disease with limited treatment options. Cabozantinib is a tyrosine kinase inhibitor (TKI) that targets VEGF, MET and AXL that has demonstrated activity in patients with mCRPC, particularly in individuals with bone and liver metastases. Studies have demonstrated anti-tumor activity of cabozantinib combined with atezolizumab, a programmed death ligand 1 targeting agent. In this study, we will investigate the efficacy of cabozantinib in combination with nivolumab, a programmed death 1 (PD-1) targeting agent, in patients with mCRPC. Methods: This is a prospective, multi-center, single arm, two-stage open label phase II study of cabozantinib combined with nivolumab in the treatment of patients with mCRPC. Eligible patients include those with histologically or cytologic evidence of prostate adenocarcinoma or mixed adenocarcinoma/neuroendocrine tumors, progressive mCRPC disease defined by PCWG3 criteria, exposure to one prior androgen receptor pathway inhibitor (ARPI), and one prior taxane chemotherapy (in hormone sensitive or castration resistant setting). Exclusion criteria include pure small cell carcinoma, received prior immune checkpoint inhibitor, received prior cabozantinib, and received >1 line of chemotherapy (including both hormone sensitive and castration resistant settings). Prior to treatment initiation, patients will receive a mandatory baseline biopsy. Eligible patients will receive treatment with cabozantinib (orally 40 mg daily) and nivolumab (intravenous 480 mg every 4 weeks). An on-treatment biopsy will be performed during cycle 2. Patients will continue on treatment until disease progression, unacceptable toxicity, death, or other reason (e.g., subject withdrawal). The primary endpoint is radiographic progression-free survival (rPFS) at 6 months by RECIST 1.1 for soft tissue and PCWG3 for bone metastasis. Secondary endpoints include PSA response per PCWG3, overall response rate (ORR), and overall survival (OS). For statistical analysis, a Simon’s two-stage MiniMax design will be used with 80% power and one-sided significance level of 5%, hypothesizing that the true 6-month rPFS rate is >30% and assuming the observed rate is 47%. Stage I of the trial will accrue 32 patients and the trial will proceed to stage II if > 9 patients are progression-free and living at 6 months. Stage II of the trial will accrue 18 more patients, and we will conclude that the study treatment is associated with a 6-month PFS rate > 30% if ≥ 21 subjects among 50 enrolled subjects are progression-free and alive at 6 months. This trial is conducted through the Hoosier Cancer Research Network and is actively accruing patients at the University of California San Diego, UT Southwestern, University of Chicago, and University of Wisconsin. Clinical trial information: NCT05502315 .

The estrogen response pathway as a putative predictive biomarker of neoadjuvant pembrolizumab benefit in patients with muscle-invasive bladder carcinoma (MIBC).

843 Background: Sex-specific differences in incidence, stage, and prognosis of have raised interest in the role of sex steroid hormones in pathogenesis and treatment response of MIBC. Emerging evidence supports the involvement of both androgen and estrogen pathways in MIBC. We have previously identified the androgen receptor pathway as a negative predictive biomarker for neoadjuvant immunotherapy (Tateo et al. GU-ASCO24). However, little is known about the role of the estrogen receptor (ER) pathway. Methods: In this unplanned post-hoc analysis of PURE-01 study, we evaluated transcriptome-wide expression with the Decipher assay in 102 transurethral resection of the bladder (TURB) samples of cT2-4N0M0 MIBC patients (pts) treated with neoadjuvant pembrolizumab and radical cystectomy (RC). Here, we focused on ER gene expression and estrogen response signatures (ERS-early and ERS-late), assessing the expression of 200 estrogen pathway-related genes (PMID: 26771021). Moreover, we analyzed the correlation between Immune-190 signature (PMID: 28740126) and ERS-early and -late scores. Pts and tumor characteristics were compared using Wilcoxon rank-sum tests, and Kaplan-Meier analysis assessed the impact of gene expression and signature scores on relapse-free survival (RFS), defined as the time from the first pembrolizumab dose to relapse. Results: From 2017 to 2022, 87 (85.3%) males and 15 (14.7%) females received pembrolizumab and RC. Of note, we did not find significant differences in tumor-based ER gene expression or signature scores between females and males. ER gene expression did not vary across principal molecular subtyping models (TCGA, Consensus, and GSC classifications) although ERS–early and –late pathway activity scores were consistently elevated in luminal tumors. Only ERS-late score differed significantly according to the response to neoadjuvant therapy, showing significantly lower levels in patients who achieved a pathological complete response (p = 0.019). There were no significant differences in RFS based on ER gene expression, while low ERS–early and -late pathway activity scores were significantly associated with better RFS (p = 0.039 and p = 0.009, respectively). Scatter plots revealed a significant, moderate negative correlation between the Immune-190 signature and both ERS-early (cor = -0.64, p = < 0.001) and ERS-late (cor = -0.6, p < 0.001) scores. Conclusions: Estrogen response pathway emerged to be a putative biomarker of immunotherapy benefit in MIBC, with particularly higher scores observed for luminal molecular subtypes, which are related to worse outcomes following neoadjuvant checkpoint inhibition. These findings require further validation in prospective studies and underscore the importance of molecular subtype-driven approaches, potentially facilitating novel combination therapies in MIBC.

Mechanism of action and translation to the clinic of detalimogene voraplasmid (EG-70): A novel, investigational, non-viral immunotherapy for non-muscle-invasive bladder cancer (NMIBC).

826 Background: Detalimogene voraplasmid (EG-70) is a novel, investigational, non-integrating, non-viral gene therapy designed to elicit local stimulation of anti-tumor immune response in the bladder while mitigating the risk of systemic toxicities from immune stimulation. It is administered by intravesical instillation (IVI) to eligible patients with NMIBC to drive bladder-localized expression of innate (RIG-I agonists) and adaptive (IL-12) immune regulators and remodel the tumor microenvironment. LEGEND is an ongoing Phase 1/2 study (NCT04752722) investigating the safety and efficacy of detalimogene voraplasmid in bacillus Calmette Guerin (BCG)-unresponsive NMIBC. We present preclinical data supporting the mechanism of action of detalimogene voraplasmid, which involves immune cell recruitment, tumor microenvironment remodeling and immune training on neoantigens and tumor clearance. Methods: Preclinical evaluation of detalimogene voraplasmid was conducted in vitro in relevant cell lines and in vivo in an orthotopic syngeneic model of bladder cancer in immunocompetent C57BL/6 mice. Luciferase-expressing MB49 cells were instilled in the bladder on Day 1; following confirmation of tumor engraftment by in vivo bioluminescence imaging on Day 9, mice received two weekly IVIs of mEG-70 (a murine surrogate of EG-70) on Days 10&17. Efficacy of mEG-70 was assessed post-dosing by flow cytometry, MSD immunoassays, immunohistochemistry, bioluminescence in vivo imaging, and overall survival. Animal experimentation was approved by the Institutional Animal Care Committee (IACC) and conducted in accordance with Canadian Council on Animal Care (CCAC) guidelines. The Phase 1 component of the LEGEND study evaluated detalimogene voraplasmid in patients with high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS). Results: Immune profiling revealed remodeling of the tumor microenvironment from an immunosuppressive phenotype to a pro-inflammatory milieu supportive of tumor clearance. Accordingly, administration of mEG-70 was associated with marked reduction in tumor burden and improvement in survival in mice. As demonstrated by either bladder or flank tumor cell rechallenge, the anti-tumor immune response in surviving tumor-free mice resulted in durable protection against subsequent tumor re-challenge, and systemic immune memory. In the Phase 1 part of the LEGEND study, detalimogene voraplasmid was generally well tolerated, with an overall complete response rate of 73% in patients with NMIBC with CIS. Conclusions: These preclinical findings demonstrate that detalimogene voraplasmid delivers genetically encoded immunostimulatory payloads locally to the bladder. The mechanism of action described preclinically has been translated into the clinic in the Phase 1 part of the LEGEND study.

Heterogeneity in subgroup reporting across clinical trials assessing systemic therapies in metastatic castration resistant prostate cancer: A report from a living systematic review.

270 Background: Inconsistent reporting of subgroup data across clinical trials makes interpretation and application of the evidence from trials challenging. We conducted a living systematic review to summarize evidence for American Society of Clinical Oncology (ASCO) guidelines for management of metastatic castration resistant prostate cancer (mCRPC). Here, we provide an overview of reporting patterns of subgroup data across mCRPC trials. Methods: MEDLINE and EMBASE were systematically searched from each database's inception through September 20 th , 2024, to identify phase II/III/IV randomized clinical trials assessing the efficacy and safety of treatment options in mCRPC. For outcomes of overall survival (OS) and progression free survival (PFS), data from the subgroup analyses was collected and compared across trials to assess heterogeneity in the reporting of subgroups. Results: This analysis included 141 trials (phase II: 83; phase III: 56; phase IV: 2). OS was reported by 113 (80%) trials; 32 (28%) reported OS by any subgroups with 95 unique subgroup categories. PFS was reported by 110 (78%) trials; 23 (21%) reported PFS by any subgroups with 63 unique subgroup categories. Even among consistently reported subgroups, such as age, ECOG performance status, race, geographical area, and Gleason score, considerable heterogeneity in different subgroup levels/thresholds was observed across trials. Top ten most commonly reported subgroups are summarized (Table). Conclusions: Lack of consistent reporting for subgroup analysis in mCRPC trials preclude meaningful conclusions about clinically relevant subgroup and synthesizing evidence for clinical guidelines. A standardized framework for consistent reporting of subgroup data across trials can help inform clinical practice and clinical practice guidelines. OS PFS Number of trials 113 110 Reporting subgroup analysis – N (%) 32 (28) 23 (21) Commonly reported subgroups – (N) Age (26)ECOG-PS (26)LDH (21)PSA (18)Geographic area (15)Alkaline phosphatase (14)Visceral disease (14)Gleason score (9)Race (9)Brief pain inventory level (8) Age (21) ECOG-PS (19)PSA (18)LDH (14)Geographic area (13)Visceral disease (11)Gleason score (10)Alkaline phosphatase (9)Bone metastasis (9)Disease location (9) Age – (N) <65 (14); ≥65 (9); ≤68 (1); ≥69 (1); <70 (5); ≥70 (5); ≤74 (4); 65-75 (5); ≤ 71 (1); >71 (1); ≥75 (11); >Median (1); <Median (1) <65 (12); 65-74 (6); ≥65 (6); <70 (5); ≥70 (5); <75 (4); ≥75 (10); 76-80 (1); >80 (1) ECOG-PS – (N) 0 (15); 0-1 (11), 1 (11); 1-2 (5); 2 (12) 0 (15); 0-1 (5), 1 (12); 1-2 (2); 2 (6) Race – (N) White (9)Non-white (6)African American/black (2)Asian (2) White (8)Non-white (5)African American/black (2)Asian (4) Geographic Area – (N) Europe (8)North America (14)United States (1)Australia (1)Asia (2) Europe (11)North America (13)United States (1)Australia (1)Asia (2)North and South America (2) Gleason Score – (N) 2-6 (1); 7 (1); 8 (1); <8 (8); ≥ 8 (8); 9-10 (1) <8 (10); ≥ 8 (10)

Clinicopathological variations between early and late recurrence in bladder cancer post-radical cystectomy.

874 Background: Over 50% of patients diagnosed with muscle-invasive bladder cancer are estimated to experience urothelial cell carcinoma (UCC) recurrence following radical cystectomy (RC). Current studies have found clinicopathological factors associated with overall UCC recurrence; however, there is a lack of data on variations between patients with early versus late recurrence. This study examines the clinicopathological differences of these cohorts. Methods: Within our single institutional IRB-approved cystectomy database, we reviewed 1,050 patients from 1971 - 2023 who underwent RC with intent to cure for primary UCC and experienced recurrence at the University of Southern California. Patients included had documented recurrence via biopsy or imaging. Patients with distant metastasis at RC were excluded. Clinicopathological factors were chosen based on significance in prior studies. Early recurrence (ER) was defined as within two years of cystectomy, the most common time frame for UCC, and late recurrence was beyond two years. Cox regression and chi-squared tests were utilized to compare the groups. Results: Among 1,050 patients, the median age was 68. Of the 928 open cystectomies, 73.2% had ER, compared to 87.7% of the 122 robotic cystectomies. ER rates were 71.9% for the 588 orthotopic diversions, 69.9% for the 143 continent diversions, and 82.5% for the 319 incontinent diversions. Factors predictive of ER included older age (OR = 1.582, p = 0.0017), higher Charlson Comorbidity scores (OR = 1.460, p = 0.0112), higher ASA scores (OR = 1.900, p = 0.001), hydronephrosis prior to RC (OR = 1.944, p = <0.0001), lymphovascular invasion (OR = 1.472, p = 0.0383), lymph node involvement at RC (OR = 2.770, p = <0.0001), neoadjuvant chemotherapy (OR = 3.457, p = <0.0001), incontinent urinary diversions (OR = 1.832, p = 0.0008), greater than pT3 pathological staging (p = <0.0001), and variant histology (OR = 1.782, p = 0.0006). Conclusions: This study identifies clinicopathological risk factors significantly associated with ER. By describing these factors, this study aims to improve predictions of UCC recurrence patterns and inform personalized treatment. Further research is needed to validate our findings and optimize surveillance protocols for at risk patients. Multivariate analysis of variables predictive of early recurrence. Variable Hazard ratio p-value Age > 70 1.464 (1.054 - 2.042) 0.0238 Pre-operative Albumin 0.990 (0.981 - 0.999) 0.0227 Neoadjuvant Chemotherapy 3.527 (2.187 - 5.930) <0.0001 Pathological Staging Organ - Confined Extravesical Lymph Node Positive Ref4.511 (2.955 - 7.024)7.553 (5.000 - 11.636) <0.0001 Urinary Diversion Orthotopic Diversion Continent Diversion Incontinent Diversion Ref0.807 (0.513 - 1.281)1.459 (1.003 - 2.139) 0.0531 Adjuvant Chemotherapy 0.568 (0.372 - 0.863) 0.0083

Association between neutrophil and tumor-infiltrating lymphocyte count and bladder cancer stage and treatment response in BCG-treated mice models.

823 Background: Although Bacillus Calmette-Guérin (BCG) is widely used to treat bladder cancer, its mechanism is still not fully understood. Tumor-infiltrating lymphocytes (TIL) have been postulated to have prognostic value in bladder cancer, where presence of TIL signifies favorable outcomes. TILs play an important role in the tumor immune microenvironment, mediating its response to tumorigenesis and immunotherapeutic drugs. Neutrophils are also key players in the initiation, development and progression of bladder cancer. This study features BCG-treated mice, demonstrating that TIL and neutrophil count in bladder stroma correlates with tumor stage and response to treatment. Methods: Specific pathogen-free C57BL/6 mice were obtained. BBN acquired from TCI America was administered at 0.05% in water, provided ad libitum to half of the cages, while the other half received regular water. BBN administration began at 8-10 weeks of age and continued for 12 weeks. Subsequently, mice received regular water until study completion. Tumors were evaluated via ultrasonography starting at week 14. Upon detecting intravesical tumors, intravesical BCG treatment was given weekly, up to 6 weeks. Bladders were harvested for histopathological analysis, H&E stains were obtained. BCG-treated bladder tumors collected from 85 patients via transurethral resection were similarly analyzed. Results: TILs showed significant association with tumor stage and BCG-treatment response. In BCG-treated mice, mean TIL counts for stages T0 to T4 were 96±13.2 (T0), 11.1±15.1 (T1), 15±4.2 (T2), and 4.1 (T4). Neutrophil count also showed a significant association with tumor stage progression. In BCG-treated mice, the mean neutrophil counts for stages T0 to T4 were 30.25±11.6 (T0), 37.7±18 (T1), 46±34 (T2), 48±25.5 (T3), and 75.5±44 (T4) (p<0.01). We further analyzed the neutrophil to lymphocyte Ratio (NLR) to predict tumor response. Using an optimal threshold of 1.93, NLR was calculated as the ratio of neutrophils to total lymphocytes in the stroma. ROC analysis for predicting poor response to BCG (defined as ≥ T2) yielded an AUC of 0.72, demonstrating a reasonably good predictive ability. Sensitivity was 81.25%, specificity was 87.50%, and overall accuracy was 83.33%. Tumor-infiltrating neutrophil (TIN) count in humans showed a significant association to tumor recurrence, with an OR of 1.25 (p=0.03). Conclusions: In conclusion, this study demonstrates that in a BCG-treated murine bladder cancer model, both the neutrophil count and the NLR are positively correlated with tumor stage. Using NLR to predict poor response to BCG, ROC curve yielded an AUC of 0.72, with a sensitivity of 81.25% and specificity of 87.50%. Additionally, TIL counts were significantly associated with response to BCG treatment. Validation in humans showed a significant association between TIN count and tumor recurrence.