Browse Articles

Dynamic investigator initiated enterprise (DIVINE) in prostate cancer: Randomized phase II trial of stereotactic body radiotherapy with or without short-course androgen deprivation and AR pathway inhibition in oligometastatic castration-sensitive prostate cancer.

TPS283 Background: Emerging evidence suggests that metastasis-directed therapy (MDT) with stereotactic body radiotherapy (SBRT) can delay systemic therapy in oligometastatic castration-sensitive prostate cancer (omCSPC). However, the optimal timing of androgen deprivation therapy (ADT) and androgen receptor pathway inhibitor (ARPI) initiation in this setting remains undefined. While deferred ADT following MDT may preserve quality of life, early short-course ADT/ARPI may eradicate micrometastatic disease and extend progression-free survival. Extracellular vesicles (EVs) carrying PSMA-positive prostate cancer (PC) signals and circulating tumor DNA (ctDNA) may serve as real-time biomarkers of MRD and treatment response. Methods: DIVINE [NCT06378866] is an open-label, phase II, randomized trial enrolling men with omCSPC defined by 1–5 metastases (≥1 extrapelvic) on conventional imaging (CT/MRI and bone scan) and testosterone >100 ng/dL. PSMA PET may be obtained for correlative purposes but does not determine eligibility. Participants (N = 220) are randomized 1:1 to: Arm A (Early systemic): SBRT plus 6 months of ADT + ARPI. Arm B (Deferred systemic): SBRT alone with observation, reserving systemic therapy until radiographic progression not amenable to further SBRT (mrPD). SBRT is delivered per institutional standard; repeat SBRT is allowed until lesions become non-addressable. The primary endpoint, modified radiographic progression-free survival (mrPFS), is the time from randomization to death or radiographic progression not amenable to further MDT, defined by PCWG3 (bone) and modified RECIST 1.1 (soft tissue) criteria on conventional imaging. Soft-tissue progression requires ≥ 20% increase in measurable disease or a new lesion; bone progression requires ≥ 2 new confirmed lesions. Secondary endpoints include OS, biochemical PFS, time to local and distant progression, and grade 3–5 adverse events during systemic therapy. Exploratory endpoints evaluate EV and ctDNA kinetics as MRD markers, correlation of PSMA-positive EV burden with outcomes, and duration of response after short-course ADT/ARPI. Correlative analyses will longitudinally quantify PSMA-positive EVs and ctDNA at baseline, on treatment, and at progression to define MRD dynamics and resistance patterns. The trial uses Pocock–Simon dynamic allocation by EV strata and metastatic burden to ensure balance across arms. The trial is open and actively enrolling across all Mayo Clinic sites; as of October 2025, 35 of the planned 220 patients have been accrued. Clinical trial information: NCT06378866 .

Quantifying the value of tumor response and survival: Perceived monetary loss in anticancer therapy.

878 Background: The clinical benefit of anticancer therapy is usually evaluated using endpoints such as tumor response or survival. However, how healthcare professionals perceive the value of intermediate outcomes remains unclear. We conducted this study to quantify the perceived value of anticancer treatment outcomes by converting them into equivalent monetary loss. Methods: A nationwide web-based survey was conducted among 580 respondents in Japan. After excluding incorrect responses, 530 participants were eligible, including physicians, nurses, pharmaceutical staff, students, and others. Participants were asked to assign a perceived monetary loss (0–100% of one million yen) to three hypothetical scenarios: partial response (PR), stable disease (SD), and 5-yr overall survival (OS) of 50%. Treatment preference was assessed on a 5-point scale (1 = strongly efficacy-oriented, 5 = strongly adverse event–oriented). Descriptive analyses were performed across age, sex, and professional groups. Results: The median perceived loss was 20% for PR, 50% for SD, and 50% for 5-yr OS of 50%. Preference scores were skewed toward efficacy orientation (median = 2), with 53% choosing scores of 1–2. Perceived losses were consistent across subgroups and showed little association with preference scores. male respondents and those who assigned a perceived loss > 20% for PR were more likely to prioritize adverse event avoidance (preference score 4–5). Limitations include reliance on hypothetical scenarios and restriction to healthcare professionals. Conclusions: This study introduced a novel framework by translating tumor response rates into monetary perception, demonstrating how healthcare professionals value treatment outcomes.

Circulating tumor DNA analysis from the prospective pT0 study of systematic endoscopic evaluation in patients undergoing radical cystectomy for bladder cancer.

837 Background: We published a prospective trial of Systematic Endoscopic Evaluation (SEE) prior to radical cystectomy (RC) as a predictor of pT0. The results demonstrated that 26% of patients with negative SEE harbored pT≥2 disease, and the negative predictive value (NPV) of SEE to determine pT0 disease was 48.4%. Here we present a post-hoc analysis of plasma cell free DNA collected the day of surgery to determine if circulating tumor (ctDNA) improves NPV for detecting pT0 disease to better identify patients for bladder preservation. We also present survival updates. Methods: This was a prospective study of patients with muscle-invasive and non-muscle invasive bladder cancer planned to undergo RC. Plasma collected the day of surgery was processed, stored, and sent to GRAIL for extraction of cfDNA and calculation of a ctDNA-based cancer score using a proprietary tumor-naïve methylation platform. All patients underwent SEE during surgery to predict pT stage, and patients were followed for recurrence and overall survival (RFS and OS). ctDNA status with and without SEE findings were evaluated as predictors of pT stage using Bayesian logistic regression with area under the receiver operating curve (AUROC) calculation. A grid search was used to identify a post-hoc cutoff on ctDNA score (either positive or negative) that maximized the AUROC for pT stage. RFS and OS were evaluated using Kaplan–Meier survival curves and Cox proportional hazards regression. Results: 54 of 61 patients accrued to the trial had evaluable ctDNA and pT data. A model of pT stage including SEE and continuous ctDNA-based cancer score resulted in an AUROC of 0.94. Results using the post-hoc optimized ctDNA threshold with and without SEE to predict pT stage (pT=0 vs pT>) are shown in the table. Combining SEE and ctDNA only 2 patients negative by SEE and ctDNA had pT>0 disease, correlating to a NPV of 83%. One had pTis and never recurred, while the other had fatal pT2b disease. Median OS was not reached (NR) for ctDNA negative patients vs 5.7 yrs for ctDNA positive patients (p=0.011). Median RFS was NR vs 4.7 years for ctDNA negative vs positive patients, respectively (p=0.048). Conclusions: In this post-hoc, exploratory analysis of a prospective study, ctDNA at the time of surgery combined with SEE improves predictors of pT stage and is prognostic for RFS and OS. Adding ctDNA to SEE yields a NPV of 83% for pT0 disease, compared to 48.4% for SEE alone. This analysis requires validation in additional datasets, but the high NPV is encouraging and warrants further prospective study using ctDNA with SEE to identify patients confidently able to forgo RC. ctDNA and SEE to predict for pT0 disease ctDNA+VsctDNA- ctDNA + OR SEE+ vsctDNA- AND SEE- Sensitivity 0.68 (27/40) 0.95 (38/40) Specificity 0.71 (10/14) 0.71 (10/14) Positive Predictive Value 0.87 (27/31) 0.90 (38/42) Negative Predictive Value 0.43 (10/23) 0.83 (10/12)

Impact of bleomycin dose omissions on clinical outcomes in non-seminomatous germ cell tumors: A systematic review and meta-analysis.

612 Background: Non-seminomatous germ cell tumors (NSGCT) represent the most curable solid malignancies in young men with Bleomycin, Etoposide, and Cisplatin [BEP] ×3 as the cornerstone first-line regimen. Bleomycin-induced pulmonary toxicity often leads to dose omission or discontinuation, but its impact on treatment efficacy remains unclear. This study evaluates the effect of omission of one or more bleomycin doses from BEP ×3 on Clinical outcomes in patients with NSGCT. Methods: Following PRISMA guidelines, a literature search (PubMed, Google Scholar, Cochrane; through May 2025) identified 259 records, of which 3 studies met inclusion criteria. Adult NSGCT patients receiving BEP × 3 with or without ≥1 omitted bleomycin dose were analyzed. Primary outcomes were overall and relapse-free survival; secondary outcomes included salvage therapy and pulmonary toxicity. Data were pooled using a fixed-effects Mantel–Haenszel model to generate ORs with 95% CIs; heterogeneity was assessed via I². Study quality was appraised using the Newcastle–Ottawa Scale, and analyses were performed in RevMan 5.4. Results: Three studies encompassing a total of 514 patients were included in the final analysis; with 236 in intervention and 278 in comparator group. The population was predominantly male, with a median age ranging from 27 to 34 years across studies. In 2 of the studies average reduction in Bleomycin dose was about 20%. Reasons for omission of Bleomycin doses included; >25% reduction in DLCO, pulmonary symptoms, interstitial pneumonia on computed tomography without infection and an attempt at decreasing toxicity by simplifying the treatment regimen. No significant efficacy difference was reported by the included studies with omission of one or more bleomycin doses. When pooled, there was no statistically significant difference in efficacy as measured by the need for salvage therapy (OR 1.16, 95% CI: 0.80–1.68, p = 0.43; I² = 0%). In contrast, pulmonary toxicity was significantly lower among patients with omitted bleomycin doses (OR 0.33, 95% CI: 0.22–0.49, p < 0.00001; I² = 0%). These findings indicate that omitting bleomycin doses does not compromise efficacy while substantially reducing pulmonary risk. Conclusions: Bleomycin omission in BEP ×3 preserves treatment efficacy while markedly reducing pulmonary toxicity, supporting individualized chemotherapy adjustment for optimal safety and cure. While these findings are promising but data is very limited and, prospective studies are warranted to further confirm the safety and efficacy of bleomycin dose omission in NSGCT management.

Li ₃ N‐Enriched Solid Electrolyte Interphase Derived From Interfacial Catalysis Toward High‐Performance Lithium Metal Batteries

ABSTRACT The commercialization of lithium metal batteries (LMBs) is fundamentally challenged by Li dendrite growth, which originates from an unstable solid electrolyte interphase (SEI). Engineering a Li 3 N‐enriched SEI is highly desirable for achieving high conductivity and mechanical strength, but the kinetic barrier of the LiNO 3 ‐to‐Li 3 N conversion remains a major obstacle. Here, we report a catalytic approach to engineer Li 3 N‐enriched SEI layers by accelerating LiNO 3 reduction using transition metal single‐atom catalysts supported on nitrogen‐doped carbon (M/NC, M = Cr, Mn, Fe, Co, Ni, Zn). Among them, Co/NC exhibits the highest catalytic activity, leading to an SEI with significantly enhanced mechanical robustness and ionic transport. Theoretical calculations reveal that the superior performance of Co/NC stems from the minimal energy difference between its frontier molecular orbitals and those of the key LiNO intermediate, facilitating the electron transfer process. Consequently, the symmetric battery using Co/NC catalyst achieves exceptional cyclability for over 2500 h (1 mA cm −2 , 1 mAh cm −2 ). When applied in full cells, the Co/NC‐modified current collector also yields a dramatically prolonged cycle life. This work underscores the profound role of interfacial catalysis in designing high‐performance SEI for practical LMBs.

Surveillance after complete response (CR) to first-line chemotherapy (chemo) in non-seminomatous germ-cell tumor (NSGCT).

599 Background: Management of NSGCT following CR after first-line chemo remains variable across institutions. Recent data indicates that patients (pts) with teratoma and/or yolk sac tumor (YST) in their orchiectomy specimen were associated with finding teratoma or viable non-teratomatous GCT at post-chemo retroperitoneal lymph node dissection (PCRPLND) specimen. It is not clear whether this finding impacts long-term survival outcomes. We sought to evaluate long-term outcomes of surveillance after CR at Indiana University (IU) specifically in this patient population. Methods: We retrospectively reviewed the IU GCT database (January 1990-June 2024). Eligible pts were diagnosed with metastatic testicular/retroperitoneal NSGCT who achieved CR after first-line chemo defined by no residual mass >1cm in the longitudinal axis. Pts who were treated with chemo outside IU were excluded to reduce referral bias. Pts were stratified according to orchiectomy specimen into two groups: Those with teratoma and/or YST and those without either component. Primary outcomes were to estimate progression-free survival (PFS) and overall survival (OS) in these subgroups using Kaplan-Meier methodology. Results: A total of 261 pts met the inclusion criteria. Of these, 21 (8.0%) had teratoma, 50 had YST (19.2%), and 65 had both (24.9%). IGCCCG risk was good in 85.1%, intermediate in 6.1%, and poor in 8.8%. Median follow-up was 4.97 years (range, 0.01-28.80). Pre-chemo retroperitoneal lymph node size was <1 cm in 19 (7.3%), 1-3cm in 102 (39.1%), >3cm in 67 (25.7%), and unknown in 73 (28.0%). Four-year PFS for pts with teratoma or YST in their orchiectomy specimen was 92.2% vs 95.3% in pts without teratoma/YST (P=0.37). Four-year OS for pts with teratoma/YST in orchiectomy specimen was 98.0% vs 98.1% in pts without teratoma/YST (P=0.59). Late relapse occurred in 3.7% (n=5) of those with teratoma/YST and 2.4% (n=3) for those with neither (P=0.72). Of the 16 pts who relapsed, 8 underwent delayed RPLND, 3 received salvage chemo, 2 were treated with salvage chemo and RPLND, and 3 underwent resection of other metastatic sites. At last follow-up, 12 pts who relapsed were without evidence of disease, 2 were alive with disease, and 2 died of NSGCT. Conclusions: In this large cohort, most pts with NSGCT who achieved CR after first-line chemo remained disease-free on surveillance, regardless of the presence of teratoma or YST in the orchiectomy specimen. Relapses were uncommon and most pts who relapsed were salvaged successfully with surgery and/or chemo. Group Progression Count Row N % Late Relapse Count Row N % Any Teratoma (86) 7 8.1 % 3 3.5 % Any YST (115) 10 8.7 % 5 4.3 % Both Present (65) 6 9.2 % 3 4.6 % Either Present (136) 11 8.1 % 5 3.7 % Neither Present (125) 5 4.0 % 3 2.4 % P-value a 0.17 P-value a 0.72 a P -values compare “Either Present” vs “Neither Present.”

Development of a non-muscle invasive bladder cancer (NMIBC) genomic score (NGS) to predict early BCG failure.

850 Background: Although BCG is the standard of care for high-grade (HG)-NMIBC, half of patients recur and 25% progress to muscle invasive disease or require cystectomy. Given emerging intravesical therapies showing promising efficacy, better biomarkers are urgently needed to identify patients at risk for BCG failure and guide personalized therapy. Methods: We included HG-NMIBC patients treated at Memorial Sloan Kettering (MSKCC) who developed early BCG failure [HG recurrence within 6 months of complete induction (n = 24)] or long-term BCG response [no recurrence 5+ years after at least complete induction (n = 40)]. All patients were profiled using MSK-IMPACT – a targeted exome panel. Genes selected for analysis balanced effect size ( > 10% frequency difference) and biological relevance. Three machine learning algorithms (logistic regression, random forest and support vector machine) were employed for feature selection using a stratified 60:40 train-test split to maximize recurrence cases in model evaluation. Models were trained via 5-fold cross validation with AUC-ROC optimization. Random forest achieved the highest test AUC and was selected for feature identification. A normalized NMIBC Genomic Score (NGS) from 0 (low risk) to 100 (high risk) was developed using variable importance weights, with patients stratified into risk tertiles. Kaplan-Meier analysis and multivariable Cox regression adjusting for AUA risk, demographics and CIS were performed. Time-dependent ROC analysis evaluated discriminatory performance. Results: The groups had similar demographic and clinicopathologic characteristics. Random forest variable importance weights were: Mutation Count (100.0), TP53 (38.6), PIK3CA (28.7), TERT (23.2), KDM6A (17.9), FAT1 (17.4) and ERCC2 (15.1). All variables except TP53 were associated with long-term response. Patients were stratified into Intermediate/High NGS (n = 42) and Low NGS (n = 22) groups. Low NGS patients demonstrated superior high-grade recurrence-free survival (HG-RFS) compared to Intermediate/High NGS patients (median not reached, p = 0.025). In a multivariable Cox regression, Low NGS remained independently protective against early BCG failure (HR 0.32, 95% CI 0.11–0.96, p = 0.04). Time dependent ROC analysis at 12 months demonstrated that adding genomic variables to AUA risk improved discriminatory accuracy by 22% (AUA Risk AUC: 0.545, Combined: 0.666). Conclusions: This preliminary evaluation of the novel NGS, derived using data from the clinically deployed MSK-IMPACT assay, demonstrates an independent association with early BCG failure in HG-NMIBC, suggesting a role in risk stratification beyond clinical parameters. Prospective validation in a larger cohort is ongoing and will determine whether this biomarker could identify patients who may benefit from alternative therapies or early radical cystectomy.

Reply to: Blind Spots in REZILIENT-1: Does Post-Platinum Zipalertinib Address Needs in Epidermal Growth Factor Receptor ex20ins+ Non–Small Cell Lung Cancer?

Differential performance of immune-combinations (ICI-ICI vs ICI-TKI) in metastatic renal cell carcinoma (mRCC) with sarcomatoid features (sRCC) (Meet-URO 33 analysis).

449 Background: The treatment landscape of mRCC has deeply evolved with the advent of 1 st line immune-combinations (ICI-ICI, ICI-TKI), but many unmet needs still remain in clinical practice. Sarcomatoid feature is a well-established negative prognostic factor but also confers sensitivity to immunotherapy. However, there are still uncertainties regarding the choice of the ICI-combinations type, warranting large-scale ad-hoc analyses. Methods: The Meet-URO 33 is an Italian multicentric retrospective/prospective observational study enrolling mRCC patients receiving 1 st line systemic therapy according to clinical practice from January 2021. Analyses on the different response and survival performance of ICI-ICI vs ICI-TKI in intermediate/poor-risk patients with sarcomatoid component (I/P-sRCC) were performed using univariate and multivariate analyses. Univariate and multivariate analyses were conducted, including also the novel prognostic Meet-URO score (IMDC + NLR + Bone metastases). Results: Among 1695 patients enrolled from 58 centres, 184 (10.9%) had sRCC, 961 (56.7%) non-sRCC and 550 (32.5%) non-assessable. Of sRCC patients, 21 patients (11.4%) were IMDC favorable-risk, 107 (58.2%) intermediate-risk and 56 (30.4%) poor-risk. In I/P-sRCC, the choice of ICI-ICI was preferred in patients with Meet-URO groups 4-5 (p = 0.018) and the choice of ICI-TKI in patients with liver and bone metastases and Meet-URO groups 2-3 (Standardized Mean Difference – SMD > 0.35). With a median follow-up of 21.8 months (mo), overall survival (OS) was longer with ICI-ICI vs ICI-TKI, while progression-free survival (PFS) and objective response rate (ORR) were comparable, although a non-statistically significant long-term trend toward improved PFS was observed (Table 1). The superiority of ICI-ICI in OS was confirmed in the multivariate analysis adjusted for the known prognostic factors (ECOG, liver/bone metastases, IMDC and Meet-URO score, histology, stage, surgery) (HR 0.47, p = 0.014). Conclusions: In the large-scale Meet-URO 33 study, I/P-sRCC patients treated with ICI-TKI had more liver and bone metastases and belonged to the more-favorable Meet-URO groups (groups 2-3). In addition, 1 st line treatment with ICI-ICI combination was associated with better long-term outcomes compared with ICI-TKI, maintaining similar response outcomes in both terms of ORR and PD. Clinical trial information: CESC IOV 2023-78. Survival Outcomes ICI-ICI ICI-TKI HR (ICI-ICI vs ICI-TKI) (95% CI) P value OS (mo) NR 23 0.58 (0.35 – 0.97) 0.04 3y-OS (%) 55.5 25.3 3y RMST OS (mo) 25.7 21.1 PFS (mo) 18.1 12.9 0.75 (0.49 – 1.15) 0.18 2y-PFS (%) 39.1 26.1 2y RMST PFS (mo) 14.4 12.6 Response Outcomes ICI-ICI ICI-TKI OR (ICI-ICI vs ICI-TKI) (95% CI) P value ORR 49.1% 50.6% 0.94 (0.47 – 1.88) 0.86 PD 20.8% 21.5% NR not reached; RMST restricted mean survival time, CI confidence interval.

Trace Detection of Multiple Macromolecular Biomarkers in Saliva by Enzymatic Responsive Serial‐Nanofluids Strategy

ABSTRACT Saliva assay is a promising potential strategy for widespread screening and prompt surveillance of oral cancer to improve the prognosis and reduce the financial burden. But current saliva detection methods are hampered from clinical application by their restricted target diversity, complex procedures, and costly equipment. In this work, we introduce an enzymatic responsive serial‐nanofluids strategy, enabling simultaneous trace‐level detection of multiple humoral markers in saliva. Enzymatic‐responsive nanochannels were engineered respectively by modifying the outer surfaces of AAO arrays with polypeptides featuring target‐cleavage sites. Thus, the macromolecular markers in saliva could cleave corresponding polypeptide, opening the ion pathway and enhancing the ion flux of nanochannels. Upon the open of a set of nanochannel‐arrays tandemly connected, serial‐nanofluids are generated and ionic currents are coupled to enable collaborative detection of multiple targets. Employing oral cancer markers of MMP‐1 and MMP‐3 as models, we developed a mobile nanosensor that can concurrently monitor their trace variation low to 2.14 × 10 − 1 3 g/mL. Furthermore, the clinical trial indicated that our nanosensor could noninvasively, conveniently, and effectively distinguish healthy individuals from oral cancer patients, and those with lymph node metastasis. This strategy offers a robust framework for multi‐marker detection in clinical diagnostics, facilitating high‐frequency and large‐scale cancer screening through saliva test.

Demographic and socioeconomic disparities in early-onset vs. late-onset bladder cancer: A cross-sectional study in the NIH All of Us research program.

657 Background: Bladder cancer typically presents after age 60, but cases diagnosed before age 60 (early-onset) may show distinct demographic and socioeconomic profiles. Using NIH All of Us, we characterized disparities in early- vs late-onset bladder cancer. Methods: Cross-sectional analysis of 1,669 adults with incident bladder cancer in All of Us (Registered Tier) (early-onset <60, n=222; late-onset ≥60, n=1,447). We compared age at diagnosis, sex, simplified race/ethnicity (White, Hispanic, Black, Asian, Other), and neighborhood-level socioeconomic z-scores (median income, high-school completion, poverty, assisted-income reliance, uninsured rate, vacant housing, deprivation index, composite SES). Categorical variables were analyzed with χ² tests; continuous (age and SES z-scores) with Welch t-tests. Results: Early-onset patients were younger (mean age 52.3 vs. 71.4 years; p<0.001), more often female (38.3% vs. 26.7%; p = 0.0012), and more Hispanic (16.7% vs. 5.7%; p<0.001), Black (17.1% vs. 5.3%; p < 0.001), and Asian (3.2% vs. 0.7%; p<0.001), with fewer White (57.2% vs. 80.4%; p<0.001). Neighborhood deprivation (deprivation index +0.22 vs. –0.03; p<0.001), uninsurance (+0.21 vs. –0.03; p = 0.0015), and poverty (+0.17 vs. –0.03; p = 0.0074) z-scores were higher, while median income (–0.14 vs. +0.02; p = 0.024) and high-school completion (–0.20 vs. +0.03; p = 0.002) were lower. Conclusions: Early-onset bladder cancer is enriched for women and racial/ethnic minorities and clusters in disadvantaged areas. These differences implicate social determinants–limited health care access, occupational/environmental exposures, and economic hardship, may accelerate onset in vulnerable populations, underscoring targeted prevention and earlier detection. Demographic, race/ethnicity, and socioeconomic characteristics of early- vs late-onset bladder cancer, All of Us research program (N = 1,669). Category Feature Early_Onset (n = 222) Late_Onset (n = 1447) p-value Ethnicity/Race Hispanic 16.7% 5.7% < 0.001 White 57.2% 80.4% < 0.001 Other or unknown 5.9% 7.9% < 0.001 Black 17.1% 5.3% < 0.001 Asian 3.2% 0.7% < 0.001 Demographics Female 38.3% 26.7% 0.001 Other or unknown 1.30% 1.10% 0.001 Male 60.4% 72.2% 0.001 Socioeconomic No health insurance 0.21 ± 1.08 -0.03 ± 0.98 0.001 SES composite index 0.12 ± 0.63 -0.02 ± 0.61 0.001 High School education -0.20 ± 1.03 0.03 ± 0.99 0.001 Assisted income 0.19 ± 1.05 -0.03 ± 0.99 0.01 Poverty 0.17 ± 1.03 -0.03 ± 0.99 0.01 Median income -0.14 ± 0.97 0.02 ± 1.00 0.02 Vacant housing 0.14 ± 1.06 -0.02 ± 0.99 0.03 Deprivation index 0.22 ± 1.01 -0.03 ± 0.99 < 0.001 Data are column percentages unless noted; socioeconomic measures are standardized z-scores and shown as mean ± SD. p-values from χ² tests (categorical) and t tests (continuous). Early-onset < 60 years; late-onset ≥ 60 years. Abbreviations: SES, socioeconomic status.

Characteristics, treatment (tx) patterns and outcomes in patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC): A retrospective cohort study in England.

665 Background: Real-world data are needed to improve the understanding of the clinical management of la/mUC and associated outcomes. This study aimed to provide an overview of the la/mUC population, tx patterns, and overall survival (OS) in England. Methods: This retrospective cohort study used data from the national Cancer Analysis System (CAS) registry and included pts aged ≥18 years with de novo la/mUC diagnosed between 2014-2022, with follow-up through May 2024. Pts were split into 3 cohorts: systemic anticancer therapy (SACT)-untreated, SACT-treated (≤90 days post diagnosis), or delayed-SACT ( > 90 days). Descriptive statistics were used for all analyses. Median OS from diagnosis was estimated using the Kaplan-Meier method. Results: Of 15,526 eligible pts with la/mUC, 64.1% were in the SACT-untreated cohort, 21.9% in the SACT-treated, and 14.1% in the delayed-SACT. The proportion of pts receiving SACT increased from 32% diagnosed in 2014 to 40% diagnosed in 2022. Compared with SACT-treated and delayed-SACT pts, SACT-untreated pts were more likely to be older, female, more socioeconomically deprived, and have more comorbidities. Pt demographics and tumor characteristics are outlined in the Table. The median (IQR) time from la/mUC diagnosis to SACT initiation was 73 (48-132) days. Among SACT-untreated patients, 8% died in ≤30 days and 28% in ≤90 days of diagnosis, and 74.5% died overall during follow-up. Median OS in SACT-untreated pts was 6.6 months (95% CI, 3.3-6.8). In the SACT-treated cohort, 3,065 (90.4%) received first-line platinum-based chemotherapy. Of these, 1,564 (46.1%) received cisplatin/gemcitabine (split dose, 25.4%) and 1,243 (36.6%) carboplatin/gemcitabine. Only 26.8% received a second-line tx. Conclusions: A substantial number of pts ( > 78%) experienced delayed and low tx rates, despite a positive trend in tx rates over time. Measures are needed to address barriers to tx access, especially for the untreated la/mUC population in England; thus, attenuating its burden through timely tx. Cohorts Overall cohort SACT-untreated SACT-treated Delayed-SACT (N=15,526) (n=9,947) (n=3,392) (n=2,187) Age at diagnosis, y Mean (SD) 72 (10.9) 74.7 (10.5) 66.7 (10) 67.7 (9.8) Female n (%) 5,340 (34.4) 3,508 (35.3) 1,087 (32.1) 745 (34.1) Site, bladder n (%) 11123 (71.6) 7,329 (73.7) 2,499 (73.7) 1,295 (59.2) Stage IV n (%) 8,699 (56.0) 5,594 (56.2) 2,120 (62.5) 985 (45.0) Transitional cell histology n (%) 11,085 (71.4) 6,987 (70.2) 2,545 (75.0) 1,553 (71.0) Variant/mixed histology n (%) 4,441 (28.6) 2,960 (29.8) 847 (25.0) 634 (29.0) Index of multiple deprivation quintile Most deprived, n (%) 2,862 (18.4) 1,904 (19.1) 582 (17.2) 376 (17.2) … 3,193 (20.6) Least deprived, n (%) 2,012 (20.2) 734 (21.6) 447 (20.4) Charlson Comorbidity Index Mean (SD) 0.43 (1.00) 0.54 (1.12) 0.23 (0.69) 0.26 (0.69) SD, standard deviation.

Biomarker analysis from the phase 2 LITESPARK-013 study of 2 different belzutifan (bel) doses in participants (pts) with advanced clear cell renal cell carcinoma (ccRCC).

545 Background: The LITESPARK-013 study (NCT04489771) showed similar efficacy and safety between 200 mg and 120 mg (approved dose) doses of the HIF-2α inhibitor bel in pts with pretreated advanced ccRCC. We report exploratory biomarker analyses (including HIF-2α IHC, RNAseq, and WES) from this study. Methods: Pts with advanced ccRCC whose disease progressed after 1-3 prior systemic therapies (including an anti–PD-[L]1 therapy) were randomly assigned 1:1 to bel 200 mg or 120 mg QD. Treatment arms were pooled for biomarker analyses. Association of HIF-2α tumor proportion score (TPS; IHC D6T8V) and H-score (sum of each percentage multiplied by its corresponding intensity [0, 1+, 2+, 3+]) with clinical outcomes (ORR, PFS, OS) were tested at prespecified multiplicity-adjusted α = 0.05. Associations of RNAseq-based HIF-2α co-expression and HIF-2α cancer cell scores, glycolysis, angiogenesis, and other HIF-2α–related genes and signatures were tested at prespecified multiplicity-adjusted α = 0.10. Associations for molecular subtypes (Motzer et al. Cancer Cell . 2020;38:803) were tested at nominal α = 0.05. DNA mutations were evaluated by WES. Results: Of 154 pts, HIF-2α IHC was evaluable in 136, RNAseq in 109, and WES in 113 pts. HIF-2α TPS and H-score were positively associated with PFS ( P = 0.016 and 0.012, respectively), but not ORR or OS. HIF-2α cancer cell score was positively associated with ORR ( P = 0.085), but not PFS or OS. No associations with clinical outcome were observed for HIF-2α co-expression score. Glycolysis and angiogenesis were positively associated with ORR ( P = 0.036) and PFS ( P = 0.070), respectively, but these were no longer significant after adjustment of other signatures. ORR was consistent across molecular subtypes and by DNA mutation status (Table), with notably higher ORR in the BAP1 mutant vs wild-type group. Conclusions: In this first RNA and WES biomarker analysis of bel, HIF-2α TPS and H-score were potentially associated with PFS, and BAP1 mutation was potentially predictive of improved ORR in pts with RCC. Molecular subtypes, other RCC-related signatures, and VHL mutation showed no associations or trends with ORR, PFS, or OS. Prospective biomarker evaluations are needed to confirm these findings. Clinical trial information: NCT02853344 . n ORR, % (95% CI) All RNAseq evaluable 109 26.6 (18.6-35.9) Molecular subtypes Angiogenic 12 33.3 (9.9-65.1) Angiogenic/stromal 24 25.0 (9.8, 46.7) Immune/proliferative 22 27.3 (10.7-50.2) Stromal/proliferative 17 23.5 (6.8-49.9) Proliferative 17 23.5 (6.8-49.9) Other (unassignable to a subtype) 17 29.4 (10.3-56.0) VHL Mut 80 25.0 (16.0-35.9) WT 33 24.2 (11.1-42.3) PBRM1 Mut 59 23.7 (13.6-36.3) WT 54 25.9 (15.0-39.7) SETD2 Mut 48 25.0 (13.6-39.6) WT 65 24.6 (14.8-36.9) BAP1 Mut 22 45.5 (24.4-67.8) WT 91 19.8 (12.2-29.4) TP53 Mut 23 26.1 (10.2-48.4) WT 90 24.4 (16.0-34.6) Chr3p loss Yes 87 24.1 (15.6-34.5) No 25 28.0 (12.1-49.4)

Predictive value of Gleason pattern 4 length on adverse surgical pathology and oncologic outcomes.

348 Background: Gleason grade group (GG) has traditionally guided prostate cancer risk stratification. Emerging evidence suggests that Gleason pattern 4 (GP4) volume is a better predictor for biochemical recurrence (BCR), metastasis, and mortality. The relationship between biopsy GP4 and clinical outcomes has not been evaluated in high-risk populations but may have significant implications for risk stratification and management of patients across medical, radiation and surgical oncology. Thus, we assessed associations between biopsy GP4 metrics and adverse surgical pathology and BCR in a high-risk and racially diverse cohort. Methods: We retrospectively identified 301 patients who underwent radical prostatectomy (RP) from 2017-2024. Biopsy variables included total cancer length, total GP4 length (GP4-TL, mm), maximum single-core length of GP4 (GP4-MCL), and GP4 percentage (GP4%). Surgical variables included extraprostatic extension (EPE), seminal vesicle invasion (SVI), and highest pathologic GG. BCR rates after RP were also recorded. Patients with incomplete GP4 quantification or GG5 disease at biopsy were excluded. Multivariate logistic regression (adjusted for age and GG) and ROC analyses assessed associations between GP4 metrics and adverse surgical pathology (ASP = EPE/SVI). Kaplan-Meier and Cox proportional hazards models were used to assess the predictive value of GP4 metrics for BCR. Analyses were additionally stratified by race. Results: Among 301 patients (median (IQR) age 62, (57-67)), 42.5% identified as African American/Black, 38.2% as Hispanic/Latino, and 25.2% as White or Other. At biopsy, 72% of patients had GG2, 20% GG3, and 8% GG4 disease. Median (IQR) GP4-TL was 2.7mm (0.80-8.75), GP4-MCL 1.3mm (0.45-3.20), and GP4% 13% (6-34%). At RP, 39% had ASP and 11% were upgraded relative to biopsy Gleason GG. During median 2-year follow-up, 19% of patients developed BCR. In multivariate models, GP4-TL (OR 1.10 per mm, 95% CI 1.06-1.14; p<0.001) and GP4-MCL (OR 1.21 per mm, 95% CI 1.10-1.33; p<0.001) predicted ASP, whereas GP4% did not. GP4-TL remained a strong predictor across all demographic groups (p<0.01), while GP4-MCL was not statistically significant in Black and Hispanic subgroups. GP4-TL also showed the highest discriminative ability versus GG (AUC 0.71 vs 0.56, p<0.001). In survival analysis, 3-year BCR rates increased sharply from 5-10% to over 20% at the GP4-TL ≥ 5 mm threshold, with a hazard ratio of 2.0 compared to patients with < 5 mm GP4-TL. Conclusions: GP4-TL and GP4-MCL independently predicted adverse surgical pathology and BCR, outperforming biopsy GG. Three-year BCR rates rose sharply at GP4-TL ≥ 5 mm, suggesting a clinically relevant threshold. Quantifying GP4 may enhance risk stratification and guide inter-disciplinary decision making among urology, radiologic oncology, and medical oncology teams in the treatment of intermediate- and high-risk prostate cancer.

Stack of Correlated Insulating States in Bilayer Graphene Kagome Superlattice

ABSTRACT Graphene‐based systems have emerged as a rich platform for exploring emergent quantum phenomena—including superconductivity, magnetism, and correlated insulating behavior—arising from flat electronic bands that enhance many‐body interactions. Realizing such flat bands has thus far relied primarily on moiré graphene superlattices or rhombohedral stacking graphene systems, both of which face challenges in reproducibility and tunability. Here, we introduce an artificial Kagome superlattice in bilayer graphene, engineered via nanopatterning of the dielectric substrate to create a precisely defined and electrostatically tunable periodic potential. Magnetotransport measurements reveal the emergence of a stack of correlated insulating states at moderate superlattice potentials, characteristic of strong electron–electron interactions within Kagome‐induced flat bands. As temperature increases, these correlated gaps collapse, signaling the thermal suppression of interaction‐driven states. Continuum‐model calculations confirm the formation of multiple flat minibands and reproduce the observed evolution of band reconstruction. Our results establish dielectric‐patterned graphene superlattices as a robust and controllable architecture for realizing flat‐band–induced correlated phenomena beyond moiré systems.

Racial and ethnic disparities in variant histology bladder cancer: Insights from SEER 2000–2021.

651 Background: Variant histology bladder cancer (VHBC) - including squamous, plasmacytoid, neuroendocrine/small cell, sarcomatoid, and signet/adenocarcinoma subtypes - is uncommon but associated with poor outcomes. While survival disparities by race and ethnicity are well documented in urothelial carcinoma, whether these persist within VHBC, independent of subtype, stage, and socioeconomic factors, remains unclear. Methods: Using SEER 18 registries (2000–2021), we identified patients with VHBC and excluded pure urothelial carcinoma (ICD-O-3 code 8120). Histologic subtypes were grouped as squamous, micropapillary, plasmacytoid, neuroendocrine/small cell, sarcomatoid/spindle, and signet/adenocarcinoma. Race/ethnicity was categorized as non-Hispanic (NH) White (reference), NH Black, Hispanic, and NH Asian/Pacific Islander (PI). The primary endpoint was cancer-specific survival (CSS). Multivariable Cox models adjusted for histologic subtype, stage, socioeconomic quartile, rurality, and diagnosis year. Logistic regression evaluated odds of presenting with a high-risk variant (plasmacytoid, neuroendocrine/small cell, sarcomatoid, or signet/adenocarcinoma). Results: We identified 1,353 VHBC cases (NH White 79.9%, NH Black 8.0%, Hispanic 6.1%, NH Asian/PI 6.1%). On multivariable analysis, NH Black patients had worse CSS vs NH White (aHR 1.39, 95% CI 1.10–1.75, p = 0.005). Hispanic (aHR 0.77, 95% CI 0.57–1.05, p = 0.10) and NH Asian/PI (aHR 0.76, 95% CI 0.54–1.05, p = 0.10) showed a trend toward improved CSS. Compared with squamous histology, micropapillary tumors were associated with lower mortality (aHR 0.55, 95% CI 0.43–0.69, p < 0.001). In logistic regression, NH Asian/PI patients had higher odds of high-risk variant presentation (OR 1.71, 95% CI 1.08–2.71, p = 0.021), while NH Black (OR 0.67, 95% CI 0.44–1.01, p = 0.058) and Hispanic (OR 0.76, 95% CI 0.48–1.21, p = 0.24) groups did not differ significantly. Conclusions: Among patients with variant histology bladder cancer, NH Black individuals experience significantly worse cancer-specific survival despite adjustment for subtype, stage, SES, and rurality, suggesting inequities beyond tumor biology. NH Asian/PI patients more often present with aggressive variants but do not exhibit excess mortality, highlighting possible differences in access or treatment delivery. Efforts to address structural and care-related disparities remain essential for improving outcomes in this rare, high risk bladder cancer population.

Molecular Profiling for Precision Oncology: Moving Beyond Feasibility and Safety

KIM-1 levels in papillary renal cell carcinoma from the CALYPSO trial.

557 Background: Kidney Injury Molecule-1 (KIM-1) has emerged as a promising biomarker in clear cell renal cell carcinoma (RCC), but its role in papillary RCC remains unknown. Methods: Serum KIM-1 concentrations were analyzed in patients with papillary RCC (n=32) and clear cell RCC (n=123) enrolled in a prospective randomized phase II trial evaluating durvalumab plus savolitinib (D+S) for papillary RCC. Associations between KIM-1 and clinicopathologic or molecular features were evaluated. Longitudinal changes in KIM-1 with time were correlated with radiologic response, circulating tumor DNA (ctDNA) status and molecular subgroups. Results: The median KIM1 levels for patients (n=32) with papillary RCC who received D+S was 7835 pg/mL. This was significantly higher than the clear cell RCC cohort (n=123) at baseline (5470 pg/mL, p=0.05). Other comparisons between these cohorts are shown in Table 1. In the papillary cohort, higher baseline KIM-1 levels did not correlate with the IMDC score, PD-L1 or TMB, but were lower in MET-driven tumors compared to non-MET driven (4217 vs 19834 pg/mL, p=0.05). Radiological response was associated with lower baseline KIM-1 levels (3368 vs 14154 pg/mL in non-radiological responders, p=0.025). Sequential KIM-1 results (n=19) showed a 54% decrease in radiological responders vs a 7% decrease in non-radiological responders (59% vs 11% in MET vs non-MET driven tumors). ctDNA positivity correlated with higher KIM-1 concentrations (17448 vs 5226 pg/mL in ctDNA-negative), and the combination of ctDNA positivity and elevated KIM-1 identified patients with poorer outcomes. Conclusions: KIM-1 levels are raised in papillary RCC. They correlated with tumor biology, MET status and response to treatment. Clinical trial information: NCT02819596 . Baseline serum KIM-1 levels according to clinical characteristics in papillary and clear cell RCC. Papillary RCC Clear cell RCC Baseline levels (pg/mL) 7835 5470 IMDC poor risk 40127 7998 IMDC intermediate risk 5918 6045 IMDC good risk 9789 4420 No prior nephrectomy 2282 9800 Prior nephrectomy 8705 5000 Presence of liver metastases 21321 6783 Absence of liver metastases 4791 5416

Outcomes of nephrectomy in patients with pathologic complete response to immune checkpoint inhibitor therapy for renal cell carcinoma: A multicenter study.

454 Background: Immune checkpoint inhibitor (ICI)-based combination therapy has become the standard of care for advanced renal cell carcinoma (RCC). A pathologic complete response (pCR) in the primary tumor may be observed in up to one-third of patients; however, data on the outcomes of these patients remain limited. This study aimed to evaluate the clinical outcomes of patients who achieved a pCR following ICI therapy. Methods: Patients with advanced RCC who underwent nephrectomy following ICI therapy were evaluated across five high-volume U.S. academic centers between 2015 and 2023. Clinical characteristics and outcomes were compared between those with and without a pCR in the primary tumor (ypT0N0/Nx). Multivariable logistic regression models were used to identify factors associated with pCR. Recurrence-free (RFS) and overall survival (OS) rates were estimated using the Kaplan-Meier (KM) method. Results: A total of 182 patients were included (Table 1). Among all patients, downstaging to ≤ypT1N0/Nx was observed in 45 patients (25%), of whom 21 (11%) achieved a pCR. In multivariable analysis, the presence of clinical thrombus was marginally associated with a lower likelihood of achieving pCR (odds ratio [95% CI]: 0.39 [0.15–1.00], p=0.06). During a median follow-up of 25 months, 70 patients (38%) experienced recurrence, including 4 (2%) in the pCR group. Median time to recurrence was 7.5 months. KM analysis demonstrated a higher estimated 5-year RFS in the pCR group compared to those with residual disease; however, the difference was not statistically significant (68% vs. 54%, p=0.2). In addition, OS rates were comparable between the two groups. Conclusions: In our cohort, 11% of patients who underwent nephrectomy following ICI therapy for advanced RCC showed pCR, which correlated with improved oncologic outcomes. Despite the lower recurrence rates observed in the pCR group, sustained long-term surveillance remains necessary due to the continued, albeit reduced, risk of disease recurrence. Clinical characteristics of patients who underwent post-ICI nephrectomy, stratified by their pathologic complete response (pCR). Variable pCR (n=21) No pCR (n=161) p-value Median (IQR) age, year 61 (56 – 70) 64 (56 – 71) 0.46 Gender (male), n (%) 15 (71) 118 (73) 0.8 Tumor advancement, n (%) Locally advanced Metastatic 2 (10)19 (90) 36 (22)125 (78) 0.26 Risk group (for metastatic), n (%) Favorable Intermediate Poor 3 (25)6 (50)3 (25) 38 (34)59 (54)13 (12) 0.42 ICI regimen, n (%) ICI monotherapy ICI+ICI ICI+TKI 4 (19)9 (43)8 (38) 46 (28)64 (40)51 (32) 0.64 Immunotherapy cycles (>4), n (%) 8 (50) 49 (37) 0.42 Median (IQR) clinical tumor size, cm 9.3 (6.7 – 11.9) 8.4 (6.6 – 12) 0.68 Clinical nodal involvement, n (%) 8 (38) 53 (33) 0.63 Clinical thrombus, n (%) 12 (57) 60 (37) 0.1 ICI: immune checkpoint inhibitor; TKI: tyrosine kinase inhibitor.

Defect Passivation with Organic Co‐Crystal Layers for Efficient and Stable Inverted Perovskite Solar Cells: A Non‐2D‐Perovskites Strategy for Surface Treatments

ABSTRACT Surface defects caused by the wet‐chemical deposition method negatively affect the performance and stability of inverted perovskite solar cells (PSCs). It is common to post treat perovskite films with large‐sized organic ammonium salts, which allow for the formation of 2D perovskites on top of the perovskite films. However, the low‐dimensional perovskites feature a low charge carrier mobility and poor structural stability. To address these issues, we introduce an organic co‐crystal layer rather than 2D perovskites on top of the perovskite film in this work. This co‐crystal layer effectively passivates the surface defects through a reinforced hydrogen‐bonding network, suppresses non‐radiative recombination, enhances n‐type semiconductor characteristics, increases electron mobility and facilitates charge carrier transport in the perovskite films. As a result, the PSCs based on this layer achieve a champion power conversion efficiency (PCE) of 26.35% with enhanced short‐circuit current ( J SC ) and open circuit voltage ( V OC ). Furthermore, the nonencapsulated device exhibits excellent thermal and moisture‐resisted stability, manifesting in 80% initial PCE retention under heat stress of 85°C for 1392 h and 88% initial PCE retention after exposure to air with ∼50% RH for 2040 h. This work provides a novel strategy to passivate the surface defects of perovskite films beyond the formation of 2D perovskites for inverted PSCs.