Browse Articles

Molecular pathways of immune checkpoint inhibitor–induced hepatitis.

2573 Background: Immune checkpoint inhibitor (ICI) related hepatitis is a clinically significant immune-related adverse event (irAE) and a common cause of treatment interruption. It occurs in roughly 5 to 10 percent of patients receiving anti PD-(L)1 monotherapy and in up to one third of those treated with combination ICI therapy. Despite increasing clinical recognition, the molecular mechanisms and predictive factors underlying ICI hepatitis remain poorly defined. The Montreal Immune-Related Adverse Events (MIRAE)-led hepatitis project aims to characterize the immune cell populations and underlying transcriptional programs associated with ICI-hepatitis pathogenesis. Methods: This translational study is conducted within the MIRAE biobank, a prospective multicenter cohort of ICI-treated patients with and without irAEs. The hepatitis cohort includes patients with longitudinal plasma samples collected at baseline, on treatment, and at irAE onset. Ongoing immune profiling efforts include plasma-based cytokine and chemokine analysis, high-throughput plasma proteomics, and single cell RNA sequencing of PBMCs. Preliminary analysis focused on plasma proteomics. Five patients with high-grade ICI-hepatitis and five ICI-treated controls without irAEs were selected and matched by age, sex, and primary tumor. Plasma samples were analyzed using the SomaScan 11K assay to identify differentially expressed proteins and enriched immune pathways. Results: ICI-related hepatitis was clinically severe, requiring systemic corticosteroids in all cases and additional immunosuppressive therapies in most patients. ICI-hepatitis cases showed significantly higher plasma levels of liver injury markers, including ALT and AST, compared with matched controls. Widespread alterations were observed in the circulating proteome, with strong upregulation of liver-enriched proteins and inflammatory mediators. Gene set enrichment analyses revealed enrichment of liver-associated pathways including xenobiotic and bile acid metabolism, as well as IL-12 signaling, interferon-α and γ, neutrophil-associated pathways, and liver-resident macrophage signatures. Pathway analysis of single cell data revealed enhanced cytotoxic activity of CD8 T cells during ICI hepatitis, as exemplified by upregulation of the CTL and IL-6 pathways. Conclusions: ICI-hepatitis was associated with circulating immune signature characterized by liver injury markers, inflammatory mediators, and enrichment of innate immune pathways. These findings provide molecular insight into the immunopathogenesis of ICI hepatitis and inform future biomarker discovery, druggable pathways, and risk stratification.

Accumulation of cholesterol, cortisol, and glutathione in mitochondria as a marker of metabolic adaptation in serous and clear cell endometrial carcinoma.

5617 Background: Aggressive endometrial carcinoma subtypes, such as serous (USC) and clear cell (CCC) carcinomas, are characterized by distinct cellular metabolism and dysregulation. Altered homeostasis of metabolites and hormones within mitochondria serves as a molecular driver of metabolic reprogramming in cancer cells. Excess mitochondrial cholesterol can induce oxidative stress, whereas glutathione provides antioxidant defense. Cortisol levels are capable of modulating organelle function. The aim of this study was to evaluate the levels of cholesterol, cortisol, and glutathione in mitochondria isolated from serous and clear cell endometrial carcinomas to characterize the metabolic profile of tumor cells. Methods: The study was conducted on mitochondria isolated from tumor tissue of 41 patients with USC (n=21) and CCC (n=20), stage III–IV, histological grade G3; the mean patient age was 59.6±6.7 years. Mitochondria isolated from normal endometrium (n=20) obtained during hysterectomies for uterine leiomyoma (mean age 57.8±8.2 years) served as controls. Cortisol, cholesterol, and glutathione concentrations in the mitochondrial fraction were determined by enzyme-linked immunosorbent assay (ELISA). Statistical analysis was performed using parametric and nonparametric tests with adjustments for multiple comparisons. Results: A significant increase in cholesterol levels was observed in mitochondria from these rare endometrial carcinoma subtypes: 2.1-fold in USC and 1.9-fold in CCC compared with normal endometrium. Cortisol content was elevated by 2.1- and 2.5-fold, respectively. Mitochondrial glutathione concentration was also increased: 2.4-fold in USC and 1.9-fold in CCC. Conclusions: The data reveal a universal mechanism of metabolic adaptation in serous and clear cell endometrial carcinomas, characterized by a unified mitochondrial metabolic profile featuring co-accumulation of cholesterol, cortisol, and glutathione. Elevated cholesterol generates a pro-apoptotic signal, which is counterbalanced by increased glutathione levels to maintain redox homeostasis. The concurrent rise in cortisol indicates the engagement of mitochondrial stress-response pathways. This constellation of alterations reflects fundamental reprogramming of cellular homeostasis in aggressive endometrial cancers and may be considered a potential target for mitochondrial-directed therapy.

Experimental modeling of soft tissue sarcomas with invasion into bone structures.

e23541 Background: This study aimed to establish and characterize PDX models of STS with bone invasion, evaluating their growth kinetics and verifying histologic fidelity to the primary patient tumors. Methods: The development of an orthotopic STS model with bone invasion was accomplished using two methods. To create an orthotopic PDX model of sarcoma with bone invasion, a fragment of a human tumor was implanted into the femoral bone of Balb/c Nude mice. For this purpose, the distal part of the mouse limb was preliminarily amputated to create a bed for the graft. The tumor material was fixed within the bone bed using a suture. The orthotopic PDX model of STS with invasion into a flat bone was created by implanting human tumor material into a surgically created defect in the pubic bone of immunodeficient Balb/c Nude mice under general anesthesia. Tumor nodule dimensions were measured weekly using a caliper, starting from day 7 post-implantation, over a period of 4 months with a frequency of twice per week. For histological examination, tumor nodules were fixed in 10% neutral buffered formalin for 24 hours, followed by the preparation of paraffin blocks. Results: Tumor samples from 13 patients with confirmed bone invasion were used to create two PDX models. A technique for orthotopic implantation into both long (tubular) and flat bones was established and optimized in Balb/c Nude mice. By day 35 post-implantation, invasion into long bones was confirmed in 12 out of 13 models, and into flat bones in 7 models. To verify stable growth and increase the biomass of tumor material, a second passage of the tumors was performed. This second passage yielded 6 stable xenografts with invasion into long bone and 3 with invasion into flat bone. Histological analysis revealed a predominance of pleomorphic undifferentiated sarcomas (50% of models). All xenografts retained the histological characteristics and infiltrative growth pattern of the original patient tumors. The successful engraftment rate of the orthotopic xenografts demonstrated a dependence on the bone tissue type. For long bones, characterized by richer vascularization and a specific microenvironment, the engraftment rate was 46.2% (6 out of 13), which is twice the result for flat bones (23.1%; 3 out of 13). The stable exponential growth of the six second-passage PDX models indicates successful adaptation of the xenografts to the long bone microenvironment. The range of final volumes (100.8–170.4 mm³) and the significant variability in growth rates (CV=22.4%) reflect the inherent biological heterogeneity of sarcomas. Conclusions: The obtained data demonstrate that the enhanced vascularization and unique microenvironment of long bones are critical for adequate tumor sustenance and for faithfully recapitulating the process of bone invasion in the established model.

Hospital volume, travel burden, and survival disparities in stage IV melanoma: A U.S. national cohort.

e21597 Background: Advances in immunotherapy and selective surgical resection have improved outcomes for stage IV melanoma, yet access to high-quality multidisciplinary care might not be possible for all patients. High-volume centers (HVCs) may deliver more guideline-concordant treatment but often require long-distance travel, raising concerns about socioeconomic and racial inequities. We evaluated the association of hospital volume and travel distance with treatment patterns, survival, and equity in stage IV melanoma. Methods: Patients with AJCC stage IV melanoma diagnosed between 2014–2022 were identified from the National Cancer Database. Hospitals were categorized by annual invasive melanoma volume as low (< 35/year), medium (35–91/year), or high ( > 91/year). Patients in the lowest travel-distance quartile treated at low-volume centers (Local-LVC) were compared with those in the highest travel-distance quartile treated at HVCs (Travel-HVC). Overall survival (OS) was analyzed using Kaplan–Meier methods and multivariable Cox regression adjusting for demographics, insurance, comorbidity, metastatic site, facility characteristics, and treatment. Results: Median travel distance ranged from 4.9–9.9 miles for Local-LVC patients versus 25.3–64 miles for Travel-HVC patients, varying by region. Travel-HVC patients were more likely to be White, privately insured, and treated at academic centers, and more frequently received first-line immunotherapy (75.9% vs 63.5%) and immunotherapy followed by surgery (44% vs 32%) (all p < 0.001). On multivariable analysis, treatment at a Travel-HVC was independently associated with improved OS compared with Local-LVC care (HR 0.80, 95% CI 0.67–0.95; p = 0.012). Immunotherapy alone (HR 0.72, 95% CI 0.62–0.82) and immunotherapy plus surgery (HR 0.48, 95% CI 0.42–0.56) were associated with superior OS compared with surgery alone (both p < 0.001). Brain metastases (HR 2.02), lung metastases (HR 1.42), and metastases to > 1 site (HR 2.66) were associated with worse survival (all p ≤0.05), yet the survival benefit of Travel-HVC care persisted across metastatic patterns and treatment strategies. Lack of insurance (HR 1.34) and Medicaid/government insurance (HR 1.37) were independently associated with worse OS, while racial disparities observed on unadjusted analysis were attenuated after adjustment for insurance and care delivery factors. Conclusions: Access to high-volume centers was independently associated with improved survival for patients with stage IV melanoma, even after accounting for treatment modality, disease burden, and socioeconomic factors. These findings suggest that structural access to high-quality multidisciplinary care—rather than race alone—drives much of the observed survival disparity and support regional referral pathways and shared-care models to promote equity in advanced melanoma care.

Development and evaluation of a dark kinase–based transcriptional score in acute myeloid leukemia.

e22641 Background: Dark kinases regulate cellular stress responses and transcriptional plasticity but remain largely unexplored in acute myeloid leukemia (AML). We hypothesized that coordinated dark kinase overexpression defines a high-risk transcriptional state and that a composite Dark Kinase Stress Score (DKSS) provides prognostic information beyond global transcriptomic variation. Methods: RNA-sequencing expression data and clinical annotations were obtained from The Cancer Genome Atlas (TCGA) AML cohort. Patients were stratified by cytogenetic risk. Dark kinases associated with overall survival (OS) on univariable Cox analysis were retained. DKSS was calculated as the mean of z-score–standardized expression values. Associations between DKSS and OS were assessed using Cox proportional hazards models adjusted for age. DKSS was analyzed per standard deviation (SD) increase and by quartiles. Model discrimination was evaluated using Harrell’s concordance index (C-index). Robustness was assessed using leave-one-out analyses. Independence from proliferation and global transcriptional programs was evaluated by adjustment for MKI67 expression and the first principal component (PC1). Results: In the full AML cohort (n = 140), cytogenetic risk was strongly prognostic, with intermediate/normal risk (HR 2.88; p = 0.003) and poor risk (HR 4.81; p < 0.001) compared with favorable risk. DKSS showed evidence of effect modification, with amplified risk in poor-risk AML (HR 1.95, 95% CI 0.88–4.30; p = 0.098). Primary analyses focused on poor-risk AML, where 32 patients with complete data were included (23 deaths, 71.9%). In age-adjusted models, DKSS was strongly associated with inferior OS (HR 2.27, 95% CI 1.41–3.65; p < 0.001), while age remained independently prognostic (HR 1.01 per year, 95% CI 1.01–1.02; p = 0.032). Model discrimination was high (C-index 0.738). Compared with the lowest DKSS quartile, the highest quartile had a markedly increased risk of death (HR 12.18, 95% CI 2.82–52.62; p < 0.001), with progressive risk escalation across quartiles (C-index 0.745). DKSS remained independently prognostic after adjustment for proliferation (HR 2.27; p < 0.001), whereas MKI67 was not associated with survival (p = 0.953). Adjustment for PC1 yielded similar effect sizes (HR 2.20, 95% CI 0.92–5.29; p = 0.078). Leave-one-out analyses confirmed score stability. CDK11B was the strongest individual kinase (HR 2.74, 95% CI 1.66–4.52; p < 0.001). Conclusions: DKSS identifies a high-risk transcriptional state in AML that is independently associated with inferior survival, with preferential amplification in cytogenetically poor-risk disease. Coordinated dark kinase activation captures aggressive biology beyond proliferation and global transcriptional variation, supporting DKSS as a novel prognostic framework and a rationale for dark kinase–directed therapeutic strategies in high-risk AML.

Outcomes of patients with glioblastoma multiforme (GBM) with lymphopenia.

e14053 Background: Lymphopenia has been associated with adverse survival outcomes in multiple solid tumors; however, its prognostic significance in glioblastoma (GBM) has limited and conflicting data. Given the immunomodulatory effects of temozolomide (TMZ), understanding the relationship between treatment-related lymphopenia and survival outcomes may inform prognosis and therapeutic decisions. This study evaluates the association between lymphopenia and progression-free survival (PFS) and overall survival (OS) in patients with GBM treated with TMZ. Methods: We performed a retrospective chart review of adult patients (≥18 years) with biopsy-proven GBM diagnosed between January 1, 2019, and December 31, 2023, at a single institution. All eligible patients had received at least 1 dose of TMZ. Patients with pre-existing lymphopenia, prior radiation therapy, or comorbid conditions known to cause lymphopenia were excluded. Lymphopenia was defined as an absolute lymphocyte count <1.0 × 10⁹/L. Cox proportional hazards regression analyses were used to assess associations with OS and PFS. Statistical significance was defined as p < 0.05. Multivariate analysis adjusted for MGMT promoter methylation, maintenance therapy use, ECOG status and smoking status. Results: A total of 27 patients were included. The cohort was 48% female, 96% White, and 74% never smokers; 85% had an ECOG status of 0–1 and 44% had MGMT promoter methylation. Treatment-related lymphopenia was associated with hazard ratios (HR) of 0.22 for OS and 0.75 for PFS; however, these findings were not statistically significant. Receipt of maintenance TMZ showed statistically significant association with improved OS (HR 0.22) and PFS (HR 0.25). MGMT promoter methylation was associated with improved PFS (HR 0.67) but not OS (HR 2.47), without statistical significance. Conclusions: In this single-institution retrospective analysis, treatment-related lymphopenia was not significantly associated with PFS or OS in patients with GBM treated with TMZ. In contrast, receipt of maintenance TMZ emerged as a strong independent predictor of improved survival outcomes, reinforcing its continued importance within standard-of-care management. Although limited by sample size, these findings suggest that treatment-related lymphopenia alone may not represent a reliable prognostic biomarker in GBM and may provide clinical reassurance that lymphopenia observed during standard temozolomide-based therapy does not independently confer worse survival outcomes. Larger, prospective studies are warranted to further define immune-related predictors of outcome and to inform risk-adapted, biomarker-driven therapeutic strategies. Multivariate Cox analysis for OS and PFS. PFS HR PFS P-value OS HR OS P-Value Lymphopenia 0.75 0.77 0.22 0.16 Maintenance therapy recipients 0.25 0.02 0.22 0.02 MGMT methylation 0.67 0.40 2.47 0.10

Comparison of talquetamab vs teclistamab in relapsed refractory multiple myeloma.

e19502 Background: Talquetamab (TQ) and Teclistamab (TC) are both FDA approved bispecific antibodies used in the treatment of relapsed/refractory multiple myeloma. Here we report real world data comparing both the bispecfic t-cell engagers (BiTe). Methods: A retrospective study was performed using TriNetX, a global research de-identified database with data from 172 health care organizations as of January 2026. ICD-10 codes were used for associated diagnosis and medications. The database was queried to identify MM patients who had received either TC or TQ. These treatments were set as the index event for outcome analysis. Demographics and prevalence of comorbidities were extracted. Outcome analysis queried for Overall Survival (OS), MM in remission, cytokine release syndrome (CRS), and use of tocilizumab (toci). Propensity Score Matching (PSM) was done for age, race, gender, diabetes mellitus, hypertension, chronic kidney disease, autoimmune conditions, obesity, use of CD38 antagonist and receipt of either CAR-T therapy or autologous stem cell transplant. The Measure of Association Analysis was used to calculate Risk Ratio (RR), Odds ratio (OR), Kaplan Meier (KM) curves were generated for OS and Log-Rank (LR) test. Results: 1941 cases were identified, out of whom 27.82% cases received TQ (n=540). Cases in TQ group were younger (mean age 65. Vs 69.8, p<0.0001), more often unknown race (12% vs 9%, p=0.045), and less often African Americans (17% vs 22%, p=0.0101), with no significant difference in gender. 22% of cases in TQ group received CAR-T, while only 7% received it in TC group (p<0.0001). After PSM, both groups had 465 cases. The median follow up period was 188 days in TQ group and 284 days in TC group. TQ group had higher risk for developing CRS (RR 1.91 (1.34, 2.72), p<0.0001) and use of Toci (RR 1.80 (1.39, 2.34), p<0.0001). Cases achieving remission were similar in both groups (OR 0.93 (0.55, 1.57), p=0.783) while survival probability at 5 years was significantly more in TQ group (65.33% vs 57.88%, LR - p=0.017, HR 0.72 (0.55, 0.94)). Conclusions: Our study determines that patients receiving TQ have higher odds of developing CRS, but also has better OS, even after matching covariates including the CAR-T receipt. Further studies are needed to determine if there is any difference in pharmacodynamics of B-cell maturation antigen (BCMA) or G protein-coupled receptor, family C group 5 member D (GPCR5D) bites.

Fluorescence-guided surgery with 5-aminolevulinic acid (5-ALA) in ovarian, fallopian tube, and primary peritoneal cancers: Efficacy and safety results from the GINGA study.

5582 Background: Administration of 5-aminolevulinic acid (5-ALA) results in tumor-selective accumulation of protoporphyrin IX, enabling visualization of malignant lesions as red fluorescence under blue light illumination. Although 5-ALA–based photodynamic diagnosis (ALA-PDD) is well established for non-muscle invasive bladder cancer, its role in gynecologic malignancies remains insufficiently characterized. We conducted an investigator-initiated clinical study to evaluate the efficacy and safety of ALA-PDD in ovarian, fallopian tube, and primary peritoneal cancers. Methods: From October 2024 to May 2025, patients scheduled for cytoreductive surgery or exploratory laparotomy were enrolled. After exclusion of one patient due to a change in treatment strategy, 22 patients received oral 5-ALA hydrochloride (20 mg/kg) 3–8 hours prior to surgery. Diagnostic performance for detecting peritoneal dissemination under blue light (BL) was compared with that under conventional white light (WL), assessing sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Statistical tests were performed using McNemar’s-test (sensitivity and specificity) or Chi-square test (PPV and NPV). Safety was evaluated based on the incidence and severity of adverse events. Results: Overall sensitivity was comparable between BL and WL (88.8% vs 80.9%), whereas BL demonstrated significantly higher specificity (67.3% vs 51.9%, p = 0.0229), indicating fewer false-positive findings. Notably, in patients undergoing interval debulking surgery (IDS; n = 9), BL significantly outperformed WL across all diagnostic metrics, including sensitivity, specificity, PPV, and NPV (all p < 0.05). These findings suggest that ALA-PDD enables more accurate intraoperative discrimination between malignant and non-malignant lesions following neoadjuvant chemotherapy. All patients experienced adverse events, predominantly Grade ≤2. One case of postoperative ileus was reported; however, no causal relationship with 5-ALA was identified, and no clinically relevant safety signals emerged. Conclusions: ALA-PDD appears to enhance intraoperative diagnostic accuracy compared with conventional white light inspection and demonstrates an acceptable safety profile in ovarian, fallopian tube, and primary peritoneal cancers. In IDS patients, ALA-PDD may serve as a clinically meaningful adjunct to achieve precise cytoreduction and support surgical decision-making in the neoadjuvant chemotherapy setting. Clinical trial information: jRCTs031240345.

Expression of Concern: Genetic Mapping of QTLs Controlling Fatty Acids Provided Insights into the Genetic Control of Fatty Acid Synthesis Pathway in Peanut (Arachis hypogaea L.)

Evaluation of formulation, stability and thermophysical characterization of PVP-stabilized MgO-water nanofluid for thermal management applications

A Panoramic Review on Intercalation‐Based Electrochemical Lithium Extraction From Salt Lakes: Mechanisms, Challenges, and Optimization Strategies

ABSTRACT Electrochemical lithium extraction from salt‐lake brines integrates electrochemistry and hydrometallurgy by leveraging the selective intercalation mechanisms of lithium‐ion battery electrode materials, offering a transformative approach to lithium recovery from complex brine resources. It provides a unique paradigm for achieving high efficiency, low energy consumption, and sustainable lithium recovery. Accordingly, the evolution of the field has been systematically examined—from early ion‐pump concepts to continuous rocking‐chair configurations—while establishing a theoretical framework that links material structure, interfacial dynamics, and electrochemical pathways. In addition, the contradiction between laboratory metrics and industrial applicability has been analyzed, with emphasis on three core challenges: selective extraction of lithium from salt lakes with high‐impurity content and low lithium concentration, long‐term cycling stability, and industrially feasible current density. To bridge this gap, this review summarizes emerging optimization strategies spanning from electrode modification (e.g., electrode bulk‐phase and interface modification) to system‐level engineering (e.g., potential, temperature control, and thick electrode design). Ultimately, this work aims to provide a forward‐looking roadmap to accelerate the transition of electrochemical lithium extraction from laboratory research to industrial‐scale application, thereby reshaping the future landscape of sustainable lithium supply.

DeCGAN: a diversity-enhanced CycleGAN for unpaired image-to-image translation

Disease associated missense substitutions disrupt structural stability and catalytic function of 4-hydroxyphenylpyruvate dioxygenase

Prognostic impact of TP53 co-mutation and interleukin gene expression in EGFR-mutant advanced lung cancer.

e20674 Background: EGFR-mutant non–small cell lung cancer (NSCLC) demonstrates marked biological heterogeneity despite targeted therapy. Co-occurring TP53 mutations are among the most frequent concurrent genomic alterations and are associated with aggressive tumor biology, early resistance, and inferior progression-free survival (PFS). Inflammatory signaling mediated by interleukins may further influence tumor behavior and therapeutic outcomes. However, the combined prognostic impact of TP53 co-mutation and interleukin expression in EGFR-mutant advanced lung cancer remains insufficiently defined. Methods: This prospective study enrolled 100 treatment-naïve stage IV NSCLC patients and 10 healthy controls. Among these, 38 patients had EGFR-mutant disease and received standard-of-care third-generation EGFR tyrosine kinase inhibitors. Peripheral blood RNA was extracted and reverse-transcribed to cDNA. Expression of IL1β, IL6, IL8, and IL10 was quantified using SYBR Green–based real-time PCR, with GAPDH as the housekeeping gene. Relative expression was calculated using the 2⁻ΔΔCt method. Interleukin levels were categorized as underexpressed or overexpressed based on predefined cut-offs. TP53 mutation status was determined by molecular profiling. PFS was analyzed using the Kaplan–Meier method and compared across molecular and inflammatory subgroups. Results: Among 38 EGFR-mutant patients, 14 harbored concurrent TP53 mutations, while 24 had EGFR mutation alone. The median age was 57 years, with 26 males and 12 females. Patients with EGFR + TP53 co-mutation had significantly shorter median PFS compared to EGFR-only patients (6 vs 13 months; p = 0.002). Within the co-mutated subgroup, overexpression of IL6 and IL8 was associated with the poorest outcomes (IL6: 4 vs 8 months, p = 0.01; IL8: 5 vs 9 months, p = 0.03). EGFR-only patients with underexpressed interleukins demonstrated the most favorable PFS. Conclusions: TP53 co-mutation significantly compromises PFS in EGFR-mutant advanced lung cancer treated with third-generation EGFR TKIs. This adverse prognostic effect is further accentuated by overexpression of pro-inflammatory interleukins, particularly IL6 and IL8. Integrated molecular and inflammatory profiling may enhance risk stratification and identify patients at high risk for early treatment failure.

Phase I trial to evaluate the safety and tolerability of fb-PMT in patients with recurrent glioblastoma.

2070 Background: Proliferative, pro-angiogenesis, and pro-inflammatory actions mediated by L-thyroxine in glioblastoma (GBM) are initiated at cell surface thyrointegrin αvβ3 receptors for thyroid hormone, located on the extracellular domain of αvβ3 integrin. Thyrointegrin αvβ3 receptors are over-expressed in cancer and rapidly dividing endothelial cells. fb-PMT (NP751) is a macromolecule in which fluorobenzyl is conjugated to monodisperse polyethylene glycol via mono-triazole tetraiodo thyroacetic acid, with high affinity and specificity for thyrointegrin αvβ3 receptors. In pre-clinical murine xenograft models, fb-PMT resulted in a dose-dependent suppression of GBM tumor growth and viability, and histopathological analysis revealed loss of the vascularity along with extensive tumor necrosis and apoptosis. Genomic micro-array studies suggested multiple growth pathways in GBM are modulated by fb-PMT. Based on this promising pre-clinical data, we conducted a first-in-human Phase 1 study of fb-PMT in patients with recurrent GBM. Methods: Patients with first or second recurrence of GBM were enrolled to receive fb-PMT via subcutaneous injection once daily for 28-day cycles, following a 3+3 design. Predefined dose levels were 0.08, 0.24, 0.48, 0.96, and 1.44 mg/kg/day, respectively. The study objectives were to evaluate the safety and tolerability of daily administration of fb-PMT, and establish the recommended phase 2 dose (RP2D) of fb-PMT. Exploratory objectives included pharmacokinetic profiling of fb-PMT, expression of αvβ3 integrin, fb-PMT, and other proteins in available tumor samples, and estimating preliminary efficacy of fb-PMT. Results: As of January 2026, accrual has been completed, with 22 patients enrolled and 20 patients completing at least one treatment cycle. Treatment with fb-PMT was well tolerated across the 5 dose levels examined. No serious adverse events (SAEs) related to fb-PMT and no dose-limiting toxicities occurred; the RP2D is 0.96 mg/kg/day. PK analysis demonstrated a dose-dependent increase in systemic drug exposure with escalating doses. Immunohistochemical evaluation of integrin αvβ3 expression in available tumor samples detected target expression, with variable levels of integrin αvβ3 expression and predominant localization to tumor-associated vasculature and regions of necrosis and hemorrhage. Preliminary efficacy evaluation is ongoing, with two patients in Cohort 4 (0.96 mg/kg/day) having partial response and remaining on study (cycle 35+ and cycle 26+, respectively). Conclusions: This Phase 1 study demonstrated that treatment of recurrent glioblastoma with fb-PMT was safe and well tolerated, with a predictable pharmacokinetic profile. Two patients remain on therapy beyond 24 months. Future studies are planned. Clinical trial information: NCT05226494 .

Analysis of healthcare professional management of CDK4/6 inhibitor adverse events and variance with expert recommendations.

e13103 Background: CDK4/6 inhibitors (CDK4/6is) are a mainstay of treatment for hormone receptor–positive breast cancer but can cause adverse events that require prompt recognition and management to maintain adherence by patients. We developed an online Interactive Decision Support Tool (www.clinicaloptions.com/CDK46AEtool) for healthcare professionals (HCPs) with case-specific recommendations for managing adverse events associated with CDK4/6i therapy. Methods: To use the online tool, HCPs entered the type of adverse event, symptom grade/severity, and their planned management strategy. The tool showed the management recommendation for that adverse event based on the prescription information and expert guidance and then asked if the recommendation changed HCPs’ intended management approach. Results: From April 2025 to January 2026, 80 HCPs entered 90 case scenarios into the tool; 76% treated > 10 patients with breast cancer/month, and 36% of HCPs practiced in the United States or Europe. Among the 90 cases, 41% were scenarios associated with ribociclib use, 40% with abemaciclib use, and 17% with palbociclib use. The most common adverse events entered regardless of specific CDK4/6i were cytopenias (39%), gastrointestinal toxicity (22%), and hepatotoxicity (18%). The predominant adverse events entered by HCPs varied with the specific CDK4/6i: abemaciclib, gastrointestinal toxicity (47%) and cytopenias (33%); palbociclib, cytopenias (71%); and ribociclib, hepatobiliary toxicity (35%) and cytopenias (30%). HCPs self-reported uncertainty or a difference in adverse event management strategy compared with recommendations based on the prescribing information and expert guidance for grade 1-3 ANC decrease/neutropenia (38%, n = 39); grade 2 diarrhea (38%, n = 13); grade 3 hepatotoxicity (67%, n = 12), and QTcF > 480 ms to ≤500 ms (83%, n = 6). Conclusions: These data suggest that some HCPs are challenged to optimally manage select adverse events associated with CDK4/6is and may not be managing their patients in concordance with consensus recommendations based on prescribing information and expert guidance. A detailed analysis of HCP CDK4/6i adverse event management vs recommendations, including by type of adverse event and severity, will be presented.

Outcomes in patients with metastatic renal cell carcinoma (mRCC) who complete 18 months of first-line IO-TKI therapy: A conditional survival analysis from the IMDC.

e16528 Background: Immuno-oncology and tyrosine kinase inhibitor (IO-TKI) combinations are standard first-line (1L) treatments for mRCC. The characteristics and long-term outcomes of patients who successfully complete a defined treatment period are not well described. Methods: Using the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC), we identified patients treated with 1L IO–TKI combinations (Pembrolizumab Axitinib, Pembrolizumab Lenvatinib, Nivolumab Cabozantinib, and Avelumab Axitinib). We compared baseline characteristics between patients who were still on IO treatment at 18-months and those who were not. Conditional survival was calculated as the probability of subsequent survival from 18-months onward. Overall survival (OS) and time to next treatment (TTNT) were analyzed. Patients with ongoing treatment for less than 18-months were excluded. Results: Of 953 patients treated with 1L IO-TKI, 424 (44.5%) were still on treatment at 18-months. Patients in the 18-month landmark group in univariable analysis were more likely to be younger (p < 0.001), have favorable IMDC risk (37.7% vs 22.0%, p < 0.001), better performance status (PS) (PS 0: 66.8% vs. 45.6%, p < 0.001), have undergone nephrectomy (77.2% vs. 59.2%, p < 0.001), and less likely to have liver metastasis (14.0% vs 21.3%, p = 0.005) and bone metastasis (28.7% vs 36.7%, p = 0.012). In multivariable analysis, better PS (PS 1 vs 0: OR 0.62, p = 0.06; PS ≥2 vs 0: OR 0.19, p = 0.01) and nephrectomy (OR 2.27, p = 0.007) were independently associated with a higher likelihood of completion. For patients who reached 18-months, the median subsequent OS from that landmark was an additional 73.1 months (95% CI 69.2-NR), and the median subsequent TTNT was an additional 30.3 months (95% CI 24.0-40.9). In contrast, the median OS from treatment initiation for patients who did not reach the 18-month landmark was 20.9 months. A similar pronounced survival advantage was observed for patients who reached a 24-month treatment landmark. Conclusions: In this real-world cohort, almost half of mRCC patients treated with 1L IO-TKI reached an 18-month IO treatment landmark. This group had more favorable baseline characteristics, with good PS, and prior nephrectomy being clinical predictors of completion. The conditional survival analysis demonstrates that patients who were under treatment for more than 18-months enjoyed an exceptionally favorable long-term prognosis, which is important for prognostication and patient counseling. Conditional Survival; Probabilities are calculated using landmark as time 0. Probability of surviving additional year(s) from landmark Treatment duration >= 18m Treatment duration >= 24m OS probability at 1 year 93% 95% 2 years 82% 82% 3 years 72% 73% 4 years 64% 70% 5 years 60% 68% TTNT probability at 1 year 76% 76% 2 years 56% 59% 3 years 44% 47% 4 years 36% 38%

Multimodal modeling of CCI, CCI, FaceAge, thymic health, and OS among older adults with early-stage NSCLC undergoing SBRT.

e20006 Background: Lung cancer disproportionately affects older adults, who have diverse care needs and inferior clinical outcomes. While pre-treatment geriatric assessment can address these challenges, existing tools remain limited. AI-based metrics of biological aging and thymic health have shown prognostic utility for toxicity, locoregional recurrence, and survival, but have not been explored together or in geriatric populations. We thus sought to assess whether a multimodal model incorporating Charlson Comorbidity Index (CCI), FaceAge, and thymic health was associated with all-cause mortality in older adults undergoing SBRT for early-stage NSCLC. Methods: We retrospectively reviewed the records of 708 patients ≥65 years old with stage I-II NSCLC treated with SBRT at our institution between June 1, 2009, to March 31, 2023. We abstracted demographics, functional status (Eastern Cooperative Oncology Group [ECOG] score), CCI, oncologic history, SBRT details, and time-to-death. Using validated deep learning systems, biological FaceAge was calculated from SBRT simulation photographs, and thymic health scores (range 0-1, with higher scores indicating better health) were calculated from pre-treatment CT scans. We examined associations between a model incorporating CCI, FaceAge, and thymic health and all-cause mortality, using Cox models adjusted for age, sex, stage, ECOG, and covariates significant to p<.10 in univariate analyses. Results: Overall, patients (median age 76.2 years; 60.7% female; median stage IA) had high multimorbidity (median CCI 7; IQR 6-8), elevated biological FaceAge (median 2.6 years above chronological age), and low thymic health (median 0.14; IQR 0.07-0.23). In the adjusted Cox regression model, worse performance on all 3 geriatric vulnerability measures was independently associated with higher all-cause mortality (hazard ratio [HR] CCI =1.09, 95% confidence interval [CI] CCI 1.01-1.19, P<.044; HR FaceAge =1.04, 95% CI FaceAge 1.02-1.06, P=.003; HR thymic =0.21, CI thymic 0.06-0.79, P=0.021). Conclusions: The use of an AI-based multimodal tool using CCI, FaceAge, and thymic health may offer prognostic information in older adults with NSCLC. Associations between geriatric measures and all-cause mortality. Characteristic Univariate AnalysisHR/OR (95% CI) Univariate AnalysisP-value Multivariate AnalysisHR/OR (95% CI) Multivariate AnalysisP-value Female sex 0.63 (0.50-0.78) <0.001 0.61 (0.46-0.80) <0.001 Age 1.03 (1.01-1.04) <0.001 0.99 (0.97-1.01) 0.564 Stage IB 0.76 (0.47-1.22) 0.259 0.67 (0.39-1.14) 0.141 Stage II 2.41 (1.38-4.20) 0.002 1.97 (1.09-3.57) 0.024 ECOG 1 1.90 (1.32-2.74) 0.001 1.87 (1.18-2.95) 0.007 ECOG 2+ 4.38 (3.04-6.31) <0.001 4.39 (2.76-6.97) <0.001 CCI 1.19 (1.13-1.26) <0.001 1.08 (1.02-1.17) <0.001 FaceAge 1.03 (1.02-1.05) <0.001 1.04 (1.02-1.06) 0.002 Thymic Health 0.19 (0.06-0.59) 0.004 0.30 (0.10-0.92) 0.036

TRUCE-11: An open-label, single-arm, multicenter phase II study of tislelizumab combined with nab-paclitaxel for muscle-invasive urothelial bladder carcinoma.

4618 Background: Neoadjuvant tislelizumab plus nab-paclitaxel may enhance pathologic response in muscle-invasive bladder cancer (MIBC), and TRUCE-11 evaluates its efficacy and safety prior to radical cystectomy (RC). Methods: TRUCE-11 is a multicenter phase II neoadjuvant study for eligible MIBC pts who had pure or mixed urothelial carcinoma of the bladder (cT2–4aNxM0). Pts received nab-paclitaxel 125 mg/m² IV on day 1, followed 2 h later by tislelizumab 200 mg IV (Q3W) for 2–3 cycles, then underwent RC with pathologic assessment. Imaging and urine cytology were performed at baseline and post-treatment. The primary endpoint was pathologic complete response (pCR). Secondary endpoints included pathologic downstaging rate (PaIR, ≤pT1), adverse events (AEs), and overall survival (OS). Exploratory analyses evaluated radiomics features (bladder MRI, PET/CT, and contrast-enhanced ultrasound) and serum biomarkers, including peripheral blood tumor whole-genome chromosomal aberration assay (PB-TWGCA). Transcriptomic biomarker discovery further highlighted GRHL1 using bulk RNA-seq and paired baseline/RC tumor scRNA-seq. Results: Between March 2024 and January 2026, 27 pts were enrolled; 21 underwent RC after neoadjuvant therapy. Among RC pts (n=21), 11 pts achieved pCR (52%) and 13 achieved PaIR (≤pT1, 62%). The most common grade 1–2 AEs were alopecia (86%), fatigue (76%), rash (43%), decreased appetite (38%), and fever (14%). No grade 3–4 AEs (CTCAE) were observed. After a median follow-up of 247 days (range, 65–677), all pts were alive. Among pts achieving pCR, pre-cystectomy MRI (DWI/ADC) showed no residual diffusion restriction and/or PET/CT showed no malignant findings, concordant with pathology. In 6 pCR pts with contrast-enhanced ultrasound, 5 (83%) demonstrated marked reduction or disappearance of tumor hypervascularity during treatment. In 5 pts, PB-TWGCA r-score was consistent with tumor burden. Transcriptomic analyses further suggested that tumor-cell GRHL1 expression might be underlying markers that predict adverse outcomes for the pCR and non-pCR pts cohorts in this crew. Conclusions: Neoadjuvant tislelizumab plus nab-paclitaxel achieved a high pCR and downstaging rate with no grade 3–4 AEs in pts with MIBC undergoing RC. Multimodal imaging and circulating/transcriptomic biomarkers (PB-TWGCA r-score and tumor-cell GRHL1) may aid response evaluation and require confirmation in larger cohorts. Clinical trial information: NCT05328336 .

Oral estrogen receptor (ER) degraders compared to standard endocrine therapy (ET) in ER-positive, human epidermal growth factor receptor 2 (HER2)–negative metastatic breast cancer (MBC): A systematic review and meta-analysis.

1087 Background: Treatment with ER-positive HER2-negative (ER+HER2-) MBC has evolved during the past decade. Several novel oral ER degraders have shown to modestly improve progression free survival (PFS) compared to standard ET, with significant results specifically in patients carrying activating ESR1 mutations. However, whether overall survival (OS) is also improved is unknown. Methods: This was a PRISMA guided meta-analysis. We identified all randomized controlled trials (RCTs) comparing ER degraders to standard ET in patients with ER+HER2- MBC. Efficacy outcomes included PFS and OS for the intention to treat (ITT) population, as well as for patients with ESR1 mutation, and for patients with wildtype ESR1 . Hazard ratios (HRs) and 95% confidence intervals (CI) for PFS and OS were extracted, and pooled into meta-analysis using RevMan Version 9.18.0. Statistical tests were two-sided, and statistical significance was defined as p<0.05. Subgroup analyses comparing outcomes based on ESR1 mutation were also performed. In trials with multiple investigational arms, the monotherapy ER degrader arm (EMBER-3) and the dose selected for further development (SERENA-2) were include. Results: Seven RCTs comprising 3926 patients were analyzed. Compared to standard ET, ER degraders were associated with statistically significant improvement in OS in the ITT population, HR 0.74, 95% CI 0.62-0.89, p=0.001. Analysis by ESR1 status demonstrated that ER degraders were associated with significant improvement in OS for patients with ESR1 mutation (HR 0.60, 95% CI 0.47-0.77, p<0.001), but not for patients with ESR1 wild type (HR 0.87, 95% CI 0.66-1.15, p=0.33), p=0.05 for the subgroup difference. ER degraders were associated with significant improvement in PFS in the ITT population, HR 0.80, 95% CI 0.66-0.98, p=0.03. Analysis based on ESR1 status demonstrated significant improvement is PFS for patients with ESR1 mutation (HR 0.54, 95% CI 0.43-0.68, p<0.0001), but not for patients with ESR1 wild type (HR 0.95, 95% CI 0.82-1.09, p=0.46), p=0.001 for the subgroup difference. Conclusions: Compared to standard ET, ER degraders were associated with statistically significant improvement of OS and PFS. While this impact was notable in the ITT population, subgroups analyses confirmed the statistically significant benefit is limited to patients with ESR1 mutations.