Citations

Abstract Background: Despite efficacy in metastatic clear cell renal cell carcinoma (ccRCC), immunotherapy currently has no role in the neoadjuvant setting. Suppressive tumor-associated macrophages (TAMs) are known to mediate resistance to immune checkpoint blockade (ICB) in ccRCC. In preclinical studies, IL-1β blockade reprograms TAMs toward an anti-tumor phenotype and promotes T cell activation, creating a tumor microenvironment (TME) more sensitive to ICB. To test this in patients, we conducted a correlative-rich neoadjuvant trial of IL-1β + PD-1 inhibition in localized ccRCC. Methods: SPARC-1 is a single-center, phase 1b study assessing the safety and feasibility of neoadjuvant canakinumab (αIL-1β) and spartalizumab (αPD-1) in patients with localized ccRCC (T1b-T4NanyM0 or TanyN1M0). All patients received 2 doses of canakinumab (300mg IV, Q4w) and spartalizumab (400mg IV, Q4w), 6 weeks (±7 days) prior to nephrectomy. The primary endpoint was safety and feasibility. Key secondary and exploratory endpoints included 12-month metastasis-free survival rate, pathologic response rate, and quantification of immune cell infiltration. To characterize immunologic reprogramming, fresh tumor specimens were collected at nephrectomy for single-cell RNA sequencing (scRNAseq) and multiparametric flow cytometry. Tissue from a treatment naïve cohort was collected for comparative analysis (n=16). Results: From August 15th, 2018, to January 30th, 2025, 14 patients were enrolled. There were no severe treatment-related adverse events (Grade ≥ 3) attributed to canakinumab or spartalizumab. At a median follow-up of 12.0 months (range, 6.3-12.0 months), the 12-month metastasis-free survival was 100%. Based on the ASSURE nomogram, the mean predicted 12-month recurrence risk was 16.7% (range, 4.7-46.5%). ScRNAseq revealed that treatment with αIL-1β + αPD-1 increased the frequency of TREM2+APOE+ TAMs (p=0.035), a population typically associated with immune suppression. However, these TAMs exhibited a phenotypic shift toward a less immunosuppressive state, with reduced IL-1β expression and increased CXCL9:SPP1 ratio, consistent with anti-tumor TAM polarization. Immune profiling revealed an increased CD8/CD4 T cell ratio (p=0.042) with modest enrichment of activated CD8+ T cells after treatment, supporting a more pro-inflammatory TME. Conclusions: The neoadjuvant combination of canakinumab (αIL-1β) and spartalizumab (αPD-1) is well-tolerated, feasible, and demonstrated promising clinical activity with no progression of disease observed in a localized ccRCC population at high risk of recurrence. Correlative analyses demonstrated that combined IL-1β and PD-1 blockade reprograms immunosuppressive TAMs, providing evidence that dual IL-1β and PD-1 inhibition can overcome myeloid-driven resistance in ccRCC. Clinical Trial Information: NCT04028245 Citation Format: Patrick J. McCann, Aleksandar Obradovic, Casey R. Ager, David H. Aggen, Catherine S. Spina, Chelsea L. Rahiman, Kaitlyn R. Campbell, Caroline Laplaca, Peyton C. Johnston, Amanda Kim, Katherine Gomez, Kriti Bagri Manjrekar, Mark N. Stein, Charles G. Drake, Karie Runcie, Matthew Dallos. Neoadjuvant IL-1β and PD-1 inhibition in localized clear-cell renal cell carcinoma: Clinical and correlative analyses of the phase 1b SPARC-1 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT017.

Abstract Introduction: Epigenetic modulators may sensitize platinum-resistant ovarian cancer (PROC) to immune checkpoint inhibition by reprogramming the tumor microenvironment. Methods: We report clinical and translational findings from a phase II non-randomized study of pembrolizumab and oral azacitidine in 34 women with PROC (NCT02900560). Key eligibility criteria included age ≥ 18 years, ECOG performance status of 0-1, measurable disease and platinum-resistant, histologically confirmed epithelial ovarian cancer, fallopian tube carcinoma or primary peritoneal carcinoma. Primary endpoints included safety, tolerability, overall response rate (ORR), and disease control rate (DCR). Secondary endpoints included CA-125 response. The effect of combined epigenetic modulation and immunotherapy was evaluated by transcriptomic analyses of 72 serially biopsied tumors. Target gene expression analyses were used to identify differentially expressed genes and pathways, and bulk RNA sequencing was used for gene set enrichment analyses (GSEA) and to infer T cell receptor (TCR) assemblies. Results: The combination of azacitidine and pembrolizumab was moderately well tolerated, and the most common grade 3-4 adverse events were gastrointestinal side effects and anemia. ORR was 2.9% and DCR was 50%; with 3 of the 27 evaluable patients attaining a CA-125 response. Differential gene expression analyses revealed an upregulation of inflammatory and cytolytic genes (FDR-adjusted p=0.005) and co-inhibitory checkpoints (p=0.005) 6 weeks on-therapy. Upregulation of interferon signaling (p=0.006), antigen presentation (p=0.003), costimulatory signaling (p=0.002), and immune cell adhesion and migration (p=0.005) pathways were prominent on-therapy, together with an increase in CD8+ T-cell density (p=0.05). GSEA analyses were concordant with these findings, showing enrichment of immune and inflammatory gene sets on-therapy and upregulation of gene sets linked to IFN-γ response, natural killer cell-mediated cytotoxicity, and immunoregulatory interactions (p < 10e-13). Findings were not confounded by histological subtype. TCR abundance analyses evaluating significant TCR clonotypic expansions and regressions showed that intra-tumoral TCR repertoires were reshaped on-therapy. Furthermore, patients with a CA-125 and/or clinical response showed enrichment of hallmark inflammatory gene sets at baseline (p < 10e-10) and of adaptive and conserved immune response gene sets on therapy (p < 10e-09). Conclusions: Our findings highlight the potential of epigenetic modulators to reshape the tumor microenvironment of PROC toward a more inflammatory phenotype and may point to approaches to augment immunotherapy response. Citation Format: Blair V. Landon, Julia L. Boland, Andrea E. Wahner Hendrickson, Deborah K. Armstrong, Boris Winterhoff, Jaime Wehr, Akshaya V. Annapragada, Christopher Cherry, Archana Balan, Guneet Kaleka, Victor E. Velculescu, Stephen B. Baylin, Cynthia A. Zahnow, Dennis J. Slamon, Gottfried E. Konecny, John A. Glaspy, Valsamo (Elsa) Anagnostou. Pembrolizumab and epigenetic modification with azacitidine reprogram the tumor microenvironment of platinum-resistant epithelial ovarian cancer: clinical and translational findings from a phase II study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT260.

Abstract T cell exhaustion is commonly viewed as a terminal differentiation state marked by irreversible loss of effector function during chronic infection and cancer. However, the rapid restoration of cytotoxic activity following PD-1 checkpoint blockade challenges this view, revealing a central paradox: T cells that appear functionally inert can regain effector function on timescales incompatible with de novo differentiation or extensive epigenetic reprogramming. To resolve this contradiction, we present a mathematical framework that explicitly decouples latent effector capacity from active effector output. We define latent effector capacity as a slow, history-dependent state variable representing preserved epigenetic accessibility and regulatory readiness at effector loci, distinct from instantaneous transcriptional activity. Within this framework, PD-1 signaling functions as a reversible, graded masking mechanism that suppresses effector realization without erasing latent capacity, thereby explaining the coexistence of preserved chromatin accessibility, rapid functional rebound, and heterogeneous responses to checkpoint blockade. Incorporating nonlinear self-maintenance of epigenetic programs together with checkpoint-dependent erosion of latent capacity reveals a bistable regime and a history-dependent point of no return, beyond which exhaustion becomes irreversible. Critically, the model demonstrates that PD-1 checkpoint blockade unmasks pre-existing effector potential but cannot recreate lost capacity, because therapeutic reversibility is governed by the prior dynamical stability of a latent epigenetic state rather than by instantaneous transcriptional output. This framework establishes a mathematical foundation for mechanistically predictive AI in PD-1 blockade therapy by identifying latent, history-dependent variables that can be inferred from epigenetic and transcriptional data to predict therapeutic responsiveness and irreversibility.

Treatment guidelines for Clostridioides difficile infection (CDI) have been published by infectious disease and gastroenterology professional societies; however, adherence in clinical practice remains poorly characterized, particularly for recurrent disease. We conducted a retrospective chart review of 100 patients with CDI (350 episodes: 115 initial, 235 recurrent) referred to a tertiary complicated CDI clinic between 2018 and 2023. Guideline adherence was assessed by comparing treatment with IDSA/SHEA and ACG recommendations, and referring diagnoses were compared with final specialist diagnoses. Guideline adherence was significantly higher in initial compared to recurrent episodes (70.4% vs. 41.3%, p < 0.0001). Among guideline non-adherent recurrent episodes, 51.3% used standard antibiotic regimens inappropriate for the recurrence tier. Specialist review reclassified 12.0% of episodes, with colonization increasing from 2.6% to 8.9%. Misdiagnosed colonization cases had a 6.2-fold higher treatment failure rate than confirmed CDI (39.3% vs. 6.3%, p < 0.0001). Guideline non-adherence showed a non-significant trend toward treatment failure (10.0% vs. 6.7%, p = 0.31). Guideline adherence for recurrent CDI is inadequate in pre-referral settings, and diagnostic misclassification is common. Early specialist involvement may improve both diagnostic accuracy and treatment appropriateness for patients with recurrent CDI.

OBJECTIVE Dural arteriovenous fistulas (dAVFs) are rare cerebrovascular anomalies. Tentorial dAVFs (TDAVFs) have more aggressive features, making them prone to symptomatic presentations and hemorrhage. TDAVFs are heterogenous and require tailored surgical approaches. Presented is a multicenter analysis of TDAVF surgical outcomes. METHODS The Consortium for Dural Arteriovenous Fistula Outcomes Research (CONDOR) consortium compiled data on dAVFs from 16 international centers from 1990 to 2021 retrospectively. Microsurgical treatment success was defined as angiographically confirmed complete obliteration of the fistula or discontinuation of cortical venous drainage (CVD) in high-grade TDAVFs. TDAVF subtypes and tailored surgical approaches were reviewed. RESULTS Of 1360 patients in CONDOR, 161 had TDAVFs and 27% (44/161) of these patients underwent surgical management, with the majority (52% [23/44]) receiving surgery as a salvage treatment following failed embolization. The mean age (SD) of this cohort was 56 (15) years, and 68% (30/44) were male. In total, 91% (40/44) of surgically treated patients presented with aggressive symptoms: 64% (28/44) presented with hemorrhage and 27% (12/44) with nonhemorrhagic neurological deficit (NHND). The median (IQR) duration from symptom onset to diagnosis was 1 (1–4) day. The median time (IQR) between diagnosis and surgery was 15 (3–80) days. Surgical approaches varied across the cohort, with the retrosigmoid being the most common (44% [18/41]), followed by the midline suboccipital (24% [10/41]) and occipital (15% [6/41]) approaches. Perioperative complications occurred in 11% (5/44) of cases, as well as permanent neurological deficits in 2% (1/44). Surgical success was achieved in 90% of patients (38/42). During the mean 3-year follow-up, 2 patients experienced a recurrence of their fistula including representation of CVD (2/38 [5%]) and 1 patient had a new NHND (1/43 [2%]). Shorter symptom duration was significantly associated with success (15.6 vs 181.5 days, p = 0.001). Primary versus salvage microsurgery showed no difference in outcomes. Both patients with recurrent fistula were effectively treated with Gamma Knife radiosurgery. CONCLUSIONS Resection is safe and durable for the treatment of TDAVF not otherwise amenable to embolization. It can achieve a high degree of success with a low rate of perioperative complications and permanent neurological deficits, benefits far exceeding the risks associated with TDAVF natural history or management with less effective modalities.

OBJECTIVE Neuromuscular choristoma (NMC) is a rare developmental lesion that may give rise to desmoid-type fibromatosis (DTF) within the same nerve territory (NMC-DTF). While MRI features of NMC are well established, the natural history of progression to NMC-DTF has not been systematically described. This study aimed to define radiological groups from NMC to NMC-DTF using serial MRI and a literature review. METHODS Following IRB approval, the authors retrospectively analyzed 28 patients with NMC from their institutional database. Diagnosis was based on pathology or classic clinicoradiological features. Sequential MR images were reviewed to evaluate nerve enlargement, enhancement patterns, low T1/T2 foci, and NMC-DTF formation. Cases were classified into 3 radiological groups: 1) classic NMC with typical MRI features (group I), 2) NMC plus, with atypical features (foci of low T1/T2 signal intensity and/or at least moderate postcontrast enhancement; group II), and 3) NMC-DTF with a mass outside of the epineurium (group III). Data were correlated with pathology results and prior reports from the literature. RESULTS Of the 28 patients, 24 underwent serial MRI. Eleven patients presented with group I features, 4 with group II, and 9 with group III. Among group I patients with follow-up imaging, 4 (36.4%) progressed to group III over a mean of 6.2 years and 1 (9.1%) to group II. All 4 group II patients (100%) developed NMC-DTF within a mean of 3.0 years. All group III patients demonstrated NMC-DTF extending beyond the epineurium. No prior cases in the literature documented radiological progression from NMC to NMC-DTF on serial MR images. CONCLUSIONS The authors propose a framework for NMC progression based on radiological features, identifying group II as being high risk and a potential transitional phase for the formation of DTF. Structured surveillance with serial MRI is essential to prevent iatrogenic triggers and improve management strategies in patients with NMC.

OBJECTIVE Essential tremor (ET) is common and disabling in older adults. Many patients aged ≥ 80 years are ineligible for deep brain stimulation due to medical comorbidities. Data on noninvasive alternatives, such as MR-guided high-intensity focused ultrasound (MRgHIFU), remain limited in this population. The aim of this study was to evaluate the safety and efficacy of unilateral MRgHIFU thalamotomy targeting the ventral intermediate nucleus (VIM) for the treatment of ET in patients ≥ 80 years of age. METHODS This retrospective multicenter cohort study included consecutive patients aged ≥ 80 years with medically refractory ET treated with unilateral MRgHIFU VIM thalamotomy between 2016 and 2023 at five academic neurosurgical centers. All patients met skull density ratio criteria and underwent standardized targeting. Clinical assessments were conducted at baseline, immediately posttreatment, and at the 3-month follow-up. The primary outcome was change in tremor severity assessed by using the Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS). Secondary outcomes included the Clinical Rating Scale for Tremor (CRST) score, Dynamic Gait Index score, patient-reported tremor relief, and adverse events. RESULTS One hundred twenty-nine patients (76 male, mean age 84 years) were included. At 3 months, the mean TETRAS score improved by 9.2 points (p < 0.001). CRST scores also showed significant improvement. The mean patient-reported tremor relief was 81%. Adverse events were mild and transient, with a 1.6% rate of nonsurgical adverse events. Subgroup analysis comparing patients 80–84 years versus those ≥ 85 years of age showed no significant differences in treatment response. Gait outcomes improved modestly but were not significant in the age ≥ 85 years group. CONCLUSIONS Unilateral MRgHIFU thalamotomy is a safe and effective noninvasive treatment for ET in patients ≥ 80 years of age. It results in significant improvements in tremor and disability, with a low complication rate. These findings support its consideration for older patients who are ineligible for invasive procedures and highlight the importance of age-specific metrics in neuromodulation outcomes research.

Summary Longitudinal plasma cell-free DNA profiling from the phase 3 Alliance A031201 trial revealed divergent resistance trajectories in metastatic castration-resistant prostate cancer. Rapid progressors harbored non–androgen receptor (AR) alterations suggesting intrinsic resistance, whereas delayed progressors showed progressive AR amplifications, structural rearrangements, and extrachromosomal DNA–associated evolution. These findings support biomarker-guided strategies targeting AR-dependent and AR-independent disease states. See related article by Valentín López et al., p. 2413

Abstract Purpose: Immune checkpoint blockade (ICB) induces frequent and durable responses in metastatic deficient DNA mismatch repair (dMMR) colorectal cancer, yet substantial molecular heterogeneity and resistance remain. We sought to identify candidate tumor- and immune-related biomarkers associated with clinical outcomes following anti–PD-1 therapy. Experimental Design: Consecutive patients with metastatic dMMR colorectal cancer (N = 39) treated with anti–PD-1 therapy underwent tumor profiling using a validated immune-enhanced exome and transcriptome platform. Microsatellite instability (MSI) burden was quantified as the percentage of unstable microsatellite loci using MSIsensor-pro. Associations with objective response were evaluated, and progression-free survival (PFS) and overall survival (OS) were analyzed using Cox proportional hazards models. Results: Higher MSI burden was associated with improved objective response (P = 0.018) and survival. The dichotomized MSI level (Q2–4 vs. Q1) was associated with longer PFS [hazard ratio (HR), 0.18; 95% confidence interval (CI), 0.06–0.56; P = 0.003] and OS (HR, 0.20; 95% CI, 0.07–0.58; P = 0.003), with similar results when modeled continuously. MSI burden correlated with neoantigen clonality but not burden (R = 0.53, P = 0.01). Responders exhibited significantly greater T-cell receptor repertoire diversity; both T- and B-cell receptor diversities were associated with survival. Although human leukocyte antigen (HLA) A, HLA-B, and HLA-C expression was not prognostic, the HLA-B*07:02 allele was associated with the best overall response. In contrast, overexpression of immune exhaustion–related genes and cytotoxic T-cell and natural killer cell exhaustion phenotypes were associated with ICB resistance and poorer prognosis. Conclusions: Integrated exome/transcriptome profiling with MSI quantification identified MSI burden and adaptive immune repertoire diversity as potential correlates of response and survival following ICB. These findings suggest a mechanistic link among genomic instability, antigen recognition diversity, and immunotherapy benefit.