Citations

PURPOSE The continuous development of new imaging approaches, molecular phenotyping, genetic subtypes, prognosis assessments, and effective therapies across a range of disease states has created a need to redefine terminology and best practices for clinical trial conduct in patients with advanced prostate cancer. Methods We convened an international expert committee of diverse working groups, the Prostate Cancer Working Group 4 (PCWG4), between 2016 and 2025. Our objective was to formulate updated criteria based on emerging evidence and clinical trial data in a biomarker context to provide guidance for clinical trial design, eligibility, and end point assessments for patients with advanced prostate cancer. RESULTS PCWG4 redefines terminology around the disease state and previous therapies in a patient-centric context and terminology focused on androgen pathway modulation. We consider imaging, with a particular focus on positron emission tomography (PET)–defined disease. New recommendations are provided for disease state terminology, defining eligibility criteria, response and delay/prevent end points, intervals for reassessments including imaging, and patient-reported outcome determination. We provide recommendations in a biomarker-based context of use for the intended indication, reflective of patient benefit for specific interventions. We emphasize the need for development of validated PET imaging and molecular and phenotypic criteria as well as trial designs to appropriately risk stratify patients, predict and assess benefit, and measure post-treatment outcomes reliably in a trial framework. CONCLUSION PCWG4 updates recommendations on patient and tumor characterization, therapy development, and imaging criteria and extends guidance into earlier androgen pathway modulator–naïve/sensitive disease states to reflect an evolving, heterogeneous, and diverse patient population to optimize treatment benefits for all patients.

Abstract Background: Triple-negative breast cancer (TNBC) is an aggressive yet immunogenic subtype of breast cancer (BC) and the only one with FDA-approved immune checkpoint inhibitor (ICI) - pembrolizumab. Currently, PD-L1 (22C3) is the companion biomarker for predicting pembrolizumab benefit, but its utility is limited by spatial/temporal heterogeneity, assay variability, and modest correlation with treatment response. Chemokines such as CXCL9, CXCL10, and CCL5 recruit CD8+ T cells into the tumor microenvironment and have been associated with improved response to ICI, but their predictive value alongside PD-L1 remains unclear. Here, we examined the relationship between these chemokines, PD-L1, and pembrolizumab efficacy in TNBC. Methods: We analyzed 3662 TNBC tumors profiled by NGS (592, NextSeq; WES/WTS, NovaSeq; Caris Life Sciences). Immune cells were estimated using WTS deconvolution (Quantiseq). PD-L1 positivity was defined as >10% CPS (PharmDx 22C3). CXCL9/CXCL10/CCL5-high (H) and -low (L) TNBC were classified by RNA expression above or below 50th percentile. Real-world median overall survival (mOS) was derived from insurance claims and calculated from start of pembrolizumab to last contact using Kaplan-Meier. Statistical significance was assessed by chi-square and Mann-Whitney U with multiple comparison adjustments (q<0.05). Results: TNBC expressed higher levels of CXCL9, CXCL10, and CCL5 (N = 3662, median TPM: 5.3, 14.8, and 15.1) compared to HER2+ (N = 1344; 4.8, 10.1, 10.6) and HR+HER2- BC (N = 6097; 2.7, 6.6, 9.4), all q<0.05. Moderate correlations were observed between PD-L1 CPS and each chemokine (r = 0.41, p<.01). PD-L1-positive tumors had better mOS (24.3 months (m) vs 18.6 m, HR 0.75, 95% CI 0.6-0.92, p=0.007) compared to PD-L1-negative TNBC post-pembrolizumab. Among PD-L1-negative tumors, those with CXCL9-H had better mOS (26.9 m vs 15.8 m for CXCL9-L, HR 0.61, 95% CI 0.45-0.82, p=0.001) post-pembrolizumab. Among PD-L1-positive tumors, CXCL10-H and CCL5-H was associated with improved mOS (CXCL10-H: 25.7 m vs. 20.7 m for CXC10-L, p = 0.03; CCL5-H: 26.7 vs. 18.5 m for CCL5-L, p = 0.03) post-pembrolizumab. PD-L1 negative CXCL9-H, PD-L1 positive CXCL10-H and PD-L1 positive CCL5-H groups showed higher infiltration of CD8+ T cell, B cells, M1/M2 macrophages, Tregs. They also exhibited higher T cell inflamed score, IFNy score and MAPK activation score vs. CXCL9-L, CXCL10-L and CCL5-L groups (Table). Conclusions: In TNBC, a chemokine signature comprising CXCL9, CXCL10 and CCL5 refines PD-L1 based prediction of pembrolizumab benefit. Specifically, high CXCL10 or CCL5 expression in PD-L1-positive tumors, and high CXCL9 expression in PD-L1-negative tumors, were associated with improved survival post pembrolizumab and immune-rich microenvironment. These findings support the use of chemokine profiling to complement PD-L1 and enhance patient selection for ICI therapy in TNBC. Citation Format: S. Gandhi, S. Deshmukh, S. Wu, J. Xiu, G. Sledge Jr., D. Trapani, J. Leone, S. Chumsri, M. Lustberg, C. Hong, S. Yao, K. Takabe, M. Ernstoff, M. Opyrchal, P. Chalasani, C. Paulos, G. Lesinski, A. Madabhushi, S. Badve, K. Kalinsky, P. Kalinski. Chemokine signatures improve PD-L1-based prediction of pembrolizumab response in triple-negative breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-08-14.

Abstract Response Assessment in Pediatric Neuro-Oncology (RAPNO) is an international working group dedicated to developing standardized recommendations for response assessment in children with central nervous system tumors enrolled on clinical trials. This standardization facilitates easier and more reliable comparison of responses across trials. Since the first RAPNO publication in 2013, response guidelines have been issued for medulloblastoma (MB), low-grade glioma (LGG), high-grade glioma (HGG), diffuse intrinsic pontine glioma, ependymoma, and craniopharyngioma. Many of these guidelines have already been incorporated into clinical trials to evaluate their effectiveness and accuracy. RAPNO has always been predicated on the idea that these consensus recommendations will require updates over time as they are applied in practice given technological advancements, evolving treatment approaches, and growing knowledge of disease pathology. A half-day RAPNO symposium sponsored by the Society of Neuro-Oncology was held in San Diego, California, United States, on May 15, 2025. This event coincided with the 8th Biennial Pediatric Society of Neuro-Oncology meeting. The main objectives were to identify ongoing RAPNO challenges, discuss potential updates, and plan future initiatives across 3 specific groups: (1) LGG/Craniopharyngioma, (2) HGG/diffuse midline glioma (DMG)/Ependymoma, and (3) MB and other seeding tumors. This manuscript reviews the symposium proceedings and highlights key topics and challenges discussed, as well as outlining future RAPNO initiatives.

Purpose: The ASPiration to Improve Renal Calculi Removal Effectiveness study showed steerable ureteroscopic renal evacuation (SURE) with CVAC that significantly reduced residual stone volume at 30 days vs standard ureteroscopy (URS). This report presents 2-year health care consumption and stone events (SE) and their link to residual stone volume and other variables ( n = 101 at primary end point; n = 93 at 2 years). Materials and Methods: Logistic regression identified predictors of health care consumption events (HCEs), that is, emergency department visits, hospitalization, surgical retreatment, and SE across the study population. Incidence was compared between the treatment groups with Kaplan–Meier survival analysis. Results: At 2 years, residual stone volume was significantly associated with both HCEs and SE. For every 100 mm 3 increase in residual stone volume, the HCE risk increased by 50% to 54%, and the SE risk increased by 70%. Stone-free rate, the number of residual fragments (RFs), and RF total stone burden (based on diameter) were not predictors. Significantly fewer HCEs occurred in the SURE group (3 vs 20 events, p = 0.0004). Survival analysis confirmed this (4.3% vs 20%, log-rank p = 0.02), with a 73% risk reduction (hazard ratio 0.27, 95% Cl 0.09–0.80, p = 0.02). Fewer SE occurred in the SURE group, although not statistically significant. These subjects also had longer event-free survival. Conclusion: High-quality volumetric analysis supports evaluation of stone removal therapies, as residual stone volume predicts HCEs and SE. SURE significantly reduces the downstream incidence and risk of HCEs compared with standard URS.

Abstract Glioblastoma (GBM) remains the most aggressive primary adult brain cancer with limited therapeutic options. Our prior research demonstrated that androgen receptor antagonists (ARAs) enhance survival in GBM mouse models by preferentially suppressing glioma stem cells. This study investigates the potential of ARAs as radiosensitizers in combination with radiotherapy (RT). Combined effects of ARAs and RT were evaluated using an orthotopic GBM mouse model. RNA-Seq and TCGA analyses delineated AR-associated regulatory networks, while integrated cellular and molecular approaches utilizing human and mouse GBM cell lines, as well as in patient-derived primary high-grade glioma cultures, interrogated signaling and immune paradigms. ARA treatment induced G2/M cell cycle arrest, apoptosis, and downregulated DNA repair genes, with AR expression correlating with the DNA repair and TGF-β pathway. In both immortalized GBM cell lines and primary high-grade glioma cultured cells, ARAs in combination with RT showed only a modest enhancement of radiosensitivity. However, in an orthotopic GBM mouse model, ARA + RT demonstrated a strong synergy, achieving 100% long-term survival, compared to less than 50% with ARA alone and 0% with RT alone. Mechanistically, ARA modulated the TGF-β pathway, durably switching from Smad3 linker to c-terminal phosphorylation (pSmad3C) and inhibiting LIF/STAT3 axis. Distinct TGF-βs ligand expression patterns were observed in ARA-treated GBM cells. A protein–protein interaction noted between AR and Smad3, which was disrupted following ARA treatment, leading to elevated protein levels and nuclear localization of pSmad3C (S423/425), indicating normalization/activation of the TGF-β/pSmad3C-dependent anti-tumorigenic cascade. Comprehensive analyses in GBM cell lines and mouse model tissues demonstrated pathway reprogramming characterized by elevated TGF-β2 and increased pSmad3C. Tissue analysis revealed immune activation in the tumor microenvironment, while peripheral blood and spleen showed systemic immune responses following ARA + RT. Our study provides novel insights into how ARAs enhance RT efficacy through immunomodulation involving TGF-β/pSmad3C cascade, offering therapeutic implications in GBM.

Background: Studies have suggested that administering antithrombotics—oral anticoagulants (OACs) and antiplatelets (APLT)—after acute ischemic stroke(AIS) with hemorrhagic transformation (HT) is safe and can reduce ischemic recurrence. However, the safety of their early initiation after HT remains unclear. Method: This study utilized data from nine centers across several countries. The study population included patients with AIS who subsequently experienced HT. Patients with a specific HT type—hemorrhagic infarction(HI) or parenchymal hematoma(PH)—were categorized based on the time between HT and antithrombotic initiation, and their outcomes were compared. Outcomes included 30-day HT exacerbation and composite outcomes of recurrent stroke and systemic emboli, as well as 90-day vascular death and functional outcome. Results: Of 748 patients,496 received APLT, and 252 were prescribed OACs after HT. The median HT-to-APLT time was significantly shorter among HI patients than PH patients(1[IQR:0-2] vs. 3[IQR:1-5] days,p<0.001). The rates of 30-day HT exacerbation and composite outcomes, as well as 90-day vascular death and unfavorable functional outcomes, did not significantly differ between patients who received same-day, early (HI:<1day;PH:<3days), or late (HI:>1day;PH:>3days) APLTs after either HI or PH. Among patients who received OACs, those with HI had a significantly shorter median HT-to-OAC time than PH (7[IQR:2-15] vs. 15[IQR:7-32] days,p<0.001). However, 30-day HT exacerbation rates were comparable between early (HI:<7days;PH:<15days) and late (HI:>7days;PH:>15days) OAC initiation among patients with either HI or PH, late initiation among patients with PH was associated with higher rates of 30-day composite outcomes than early initiation(20.7% vs. 3%,p=0.044). Based on regression models adjusted for NIHSS and stroke severity, early initiation of APLTs or OACs was not associated with increased risk of HT exacerbation. Conclusion: Findings suggest that the same-day initiation of APLTs after HI or PH-1, and within 1-3days following PH-2, might not be associated with HT exacerbation or worsening outcomes. Similarly, OACs initiated 2-7days after HI and 7-15days after PH may not be associated with worsened patients' outcomes, whereas delays beyond these timeframes can be associated with higher thromboembolic risk.

Background The role of dose escalation of radiotherapy (RT) in unresectable stage III NSCLC followed by immunotherapy is unclear. The objective of the current study is to investigate if intermediate dose escalation (IDE) is beneficial in stage III NSCLC patients who receive definitive concurrent chemoradiation (dcCRT) followed by immunotherapy. Materials and methods The study used data from the National Cancer database. Multivariable Cox regression analysis was used to assess the all-cause mortality of patients who received standard RT dose (SD) (60 Gy ± 10%) and IDE (64–74 Gy). Results 47,315 patients were diagnosed in the era before immunotherapy and received dcCRT only, while 4,947 patients were treated with dcCRT and immunotherapy. In the cohort with dcCRT only, patients who received SD had statistically significant worse mortality but clinically minimal difference compared to patients with IDE (HR: 1.09, 95% CI: 1.07-1.12; p&lt;0.0001). In the era of immunotherapy, SD was still associated with worse mortality compared to IDE (HR: 1.17, 95% CI: 1.03-1.33; p=0.02). However, the survival benefit associated with IDE was only restricted to patients who started immunotherapy within six weeks after RT completion (HR: 1.26, 95% CI: 1.05-1.6; p=0.01). There was no difference in mortality between SD and IDE among patients who started immunotherapy between 7–10 weeks (HR: 1.13, 95% CI: 0.88-1.45; p=0.35) or &gt;10 weeks after RT completion (HR: 0.74, 95% CI: 0.51-1.07; p=0.11). Conclusion IDE of RT is not needed for patients diagnosed with stage III unresectable NSCLC who receive immunotherapy &gt; six weeks after dcCRT.

BACKGROUND: TRPC6 (transient receptor potential canonical 6) channels, encoded by the TRPC6 gene, are widely expressed in cardiomyocytes and play a critical role in maintaining intracellular Ca 2 + homeostasis. Variants in TRPC6 are associated with chemotherapy-related cardiomyopathy. Specifically, the TRPC6 A404V polymorphism, with a minor (404 V) allele frequency of 12% in the general population, has been identified in patients undergoing anthracycline therapy. However, the underlying mechanisms remain largely unexplored. METHODS: Using patch-clamp recordings, Ca 2 + imaging, computational analysis, and molecular biology techniques, we assessed the effects of doxorubicin and its metabolite, doxorubicinol, on regulating TRPC6 alanine (A) at position 404 replaced by valine (V; A404V) channel expression and function in a heterologous expression system and native cardiac cells. RESULTS: Both additive and recessive models demonstrated a significant association between the TRPC6 A404V variant and doxorubicin-related cardiomyopathy. The TRPC6 A404V channel exhibited higher membrane expression levels compared with the wild type (WT) control. Patch-clamp recordings showed that both TRPC6 WT and A404V channels remained mostly inactive at baseline. Application of 50 μmol/L 1-oleoyl acetyl-sn-glycerol (OAG), a TRPC6 activator, significantly increased the inward- and outward-current densities of WT and A404V channels. Furthermore, a 24-hour treatment with 0.5 μmol/L doxorubicin enhanced TRPC6 mRNA expression and potentiated the OAG effects on both WT and A404V channels, with a more pronounced response in A404V channels. Treatment with 0.5 μmol/L doxorubicinol had no effect on OAG-induced current densities in either WT or A404V channels. Doxorubicin effects on intracellular Ca 2 + levels were confirmed by Ca 2 + imaging in native cardiac cells. Computational modeling revealed that the A404V mutation induces a conformational change in the OAG-binding pocket, enhancing its interaction with OAG in the A404V protein compared with the WT control. CONCLUSIONS: The TRPC6 A404V is a gain-of-function variant that exhibits enhanced activity in the presence of doxorubicin. Therefore, the TRPC6 A404V variant represents a risk factor for anthracycline-induced cardiotoxicity in patients with cancer.

Abstract Management of scapholunate advanced collapse (SLAC) wrist arthritis remains challenging in physically high-demand patients with primarily salvage options described for advanced SLAC wrist. Microfracture resurfacing of the scaphoid fossa may be a potential option for this condition. A case of a physically active farmer with advanced SLAC wrist arthritis underwent arthroscopic dorsal capsulodesis of the scapholunate interval, microfracture of the scaphoid fossa chondral defect, and application of cartilage allograft is reported. At 1-year follow-up, there is continued resolution of his wrist pain, and function had improved with increased grip strength and wrist range of motion. Radioscaphoid microfracture and dorsal capsulodesis for SLAC wrist can be a potential dual-pronged reconstructive strategy for the physically high-demand patient that may obviate the need for salvage procedures.

ABSTRACT Gain-of-function mutations in the transient receptor potential 6 (TRPC6) channel have recently been recognized as risk factors for both doxorubicin (DOX)-induced cardiomyopathy. Functional evaluation of TRPC6 missense variants is therefore important for cancer patients undergoing anthracycline treatment. However, traditional electrophysiological methods are labor-intensive and time-consuming. In this study, we compared the functional responses of TRPC6 missense variants to 1-oleoyl-2-acetyl-sn-glycerol (OAG), a TRPC6 agonist, using molecular docking and patch clamp recording techniques. For the wild-type (WT) TRPC6 structure (PDB ID: 6UZ8), OAG exhibited a binding energy of -4.49 kcal/mol and a dissociation constant (Kd) of 0.511 mM. Twenty TRPC6 missense variants were identified from cancer patients in the Mayo Clinic database. Of these, fifteen variants had resolvable structures, nine of which displayed increased Kd values and six decreased Kd values compared to WT in molecular docking analysis. Patch clamp recordings revealed that TRPC6 WT and mutant channels were inactive at baseline but were activated upon 50 μM OAG stimulation, except two loss-of-function variants. Moreover, a 24-h treatment with 0.5 μM DOX significantly enhanced OAG-induced channel activation. All three variants identified in patients with heart failure demonstrated gain-of-function properties in both electrophysiological measurements and in-silico predictions. Importantly, the results obtained from molecular docking and patch clamp recordings were strongly correlated, showing an 82% concordance, higher than the predictions from AlphaMissense. These findings indicate that our computational analysis provides a rapid and reliable method for predicting the functional impact of TRPC6 missense variants, which may aid clinical decision-making in cancer patients receiving chemotherapy.