Citations

Abstract Endocytosis regulates receptor trafficking and signaling, yet its role in colorectal cancer (CRC) remains unclear. We analyzed transcriptomic data from 15,025 CRC tumors to evaluate gene expression in clathrin-mediated endocytosis (CME) and the endosomal sorting complexes required for transport (ESCRT) pathway. Pathway-level signatures were compared across consensus molecular subtypes (CMS) and examined in relation to oncogenic signaling programs, while individual endocytosis-related genes were evaluated for associations with clinical outcomes in an independent randomized trial cohort. Expression of CME and ESCRT pathways varied by CMS, with the highest expression in CMS4 and the lowest in CMS3. Endocytosis signatures correlated with multiple oncogenic signaling pathways, including MAPK, TGF-β, WNT, PI3K, NOTCH, and angiogenesis, suggesting broad links between endocytic activity and tumor biology. In the randomized phase III CALGB/SWOG 80405 trial, low expression of AP2M1 —a core adaptor in the CME complex—was significantly associated with longer overall survival and progression-free survival in patients treated with anti-EGFR agents, but not in those receiving anti-VEGF agents. These findings suggest that endocytic trafficking may be associated with oncogenic signaling and differential therapeutic benefit in patients with metastatic CRC. The endocytosis pathway reflects biologically relevant heterogeneity in CRC and may help guide therapeutic stratification.

Abstract Background Rare pediatric and young adult brain tumors pose major diagnostic and therapeutic challenges due to limited evidence and scattered expertise. The International Rare Brain Tumor Board was established to enable multidisciplinary case review, shared learning, and collaborative decision support. Methods Launched in February 2025, the Rare Brain Tumor Board is a monthly collaborative initiative led by Children’s National Hospital and the National Institutes of Health (NIH). Close partnership with the European Pediatric Rare CNS Tumor Board enhances transatlantic exchange and alignment of diagnostic and treatment recommendations. De-identified cases are presented with clinical history, neuroimaging, histopathology, and molecular profiling, including DNA methylation classification, available for the majority of cases. Sessions are structured to support integrated diagnosis and evidence-informed management recommendations through multidisciplinary discussion (neuropathology, neuroradiology, neurosurgery, radiation oncology, and pediatric as well as adult neuro-oncology). Findings Since its inception, 12 sessions have been held averaging 138 participants per session, reviewing a total of 32 cases (mean 3 cases/session; range 1–4) from 7 different countries and 3 different continents. Entities reviewed include DICER1-intracranial sarcoma (n = 5), astroblastoma (n = 4), FOXR2-activated neuroblastoma (n = 4), CNS tumors with BCOR internal tandem duplication (n = 3) and, BCOR-fused tumors (n = 3), CIC-rearranged-sarcoma (n = 3), intracranial mesenchymal tumor FET::CREB fusion positive (n = 3), MN1::PATZ1 fusion tumors (n = 2), undifferentiated sarcoma (n = 2), PLAG1-fusion tumor (n = 1), medullomyoblastoma (n = 1), and EZHIP-altered diffuse midline glioma (DMG) (n = 1). Multidisciplinary review has supported diagnostic clarification, strengthened familiarity with ultra-rare entities, and informed real-world treatment discussions in settings where prospective data are limited. Discussions have also increased awareness of rare brain tumor registries and opportunities for systematic case capture. Conclusion An international multidisciplinary rare brain tumor board is a feasible, scalable model to advance integrated diagnosis and collaborative management of ultra-rare pediatric and young adult brain tumors, while building a shared knowledge base across institutions.

SUMMARY Neurodegenerative diseases are often accompanied by systemic comorbidities, including changes in bone health, but the molecular relationship between neurodegeneration, skeletal decline, and cellular senescence remains poorly understood. In this study, we investigated sex-specific changes in circulating bone- and senescence-related proteins across the spectrum of Alzheimer’s disease(AD), Lewbody dementia(LB) and Parkinson’s disease(PD). Plasma proteomic profiling was performed on samples from 408 participants deeply phenotyped for neurodegenerative diseases, followed by differential protein and pathway analyses. This study reveals sex-dependent alterations in bone and senescence-related circulating proteins in AD-related, PD and LB-related neurodegenerative diseases, providing insights into the complex relationship between neurodegeneration and bone health. Several candidate proteins were also associated with established plasma neurodegeneration biomarkers, particularly pTau181. Pathway analyses revealed shared mitochondrial and metabolic dysfunction across neurodegenerative diseases, with disease-specific features including vesicle trafficking disruption in AD and inflammatory-senescence pathways in LB, plus sex-divergent patterns in inflammatory signaling and bone-related pathways.

An exhalation delivery system for fluticasone (EDS-FLU) is designed to deposit drug into sinonasal regions above the inferior turbinate, particularly sinus drainage pathways not reached by standard nasal steroid sprays. We evaluated the efficacy and safety of EDS-FLU for chronic rhinosinusitis (CRS). We reviewed four independent randomized controlled trials derived from three published articles identified through searches of PubMed, Embase, SCOPUS, Google Scholar, Web of Science, and the Cochrane Library up to April 2024. Outcomes included 22-item Sinonasal Outcome Test (SNOT-22) scores, nasal symptom scores, nasal polyp scores, patient global impression of change (PGIC), responder and surgical indication rates, and adverse events. Compared with EDS-placebo, EDS-FLU produced greater reductions in nasal polyp scores and SNOT-22 scores over 6 months. At 3 months, nasal congestion, facial pain, rhinorrhea, and olfactory dysfunction improved more with EDS-FLU, and PGIC responder and complete response rates were higher at 3 and 6 months. EDS-FLU reduced surgical indication and increased overall responder rates at 3 months but not at 6 months. Epistaxis and nasal septal erosion or ulceration occurred more frequently with EDS-FLU, whereas rates of headache, nasal congestion, nasopharyngitis, and upper respiratory infection were similar between groups. EDS-FLU provides clinically meaningful improvements in subjective and objective outcomes in CRS but is associated with an increased risk of local nasal adverse events, warranting individualized risk-benefit assessment.

Abstract Aims Pulsed field ablation for atrial fibrillation offers shorter procedural times and improved safety compared with thermal ablation, but the optimal anaesthesia strategy remains uncertain. Most centres in the USA use general anaesthesia with endotracheal intubation, whereas monitored anaesthesia care without endotracheal intubation may be a safe and efficient alternative. Objectives To compare procedural efficiency and safety between monitored anaesthesia care and general anaesthesia for pulsed field ablation. Methods and results Consecutive adults who underwent pulsed field ablation for atrial fibrillation between 2024 and 2025 at Marshfield Clinic Health System were included. The anaesthesia approach was determined by operator preference. Procedural times, medication use, complications, and patient tolerance were recorded prospectively. Among 200 patients, 100 received monitored anaesthesia care without endotracheal intubation, and 100 received general anaesthesia. The mean age was 67 years, 42% were female, and the mean body mass index was 33 kilograms per square metre. Monitored anaesthesia care shortened case duration (77 vs. 95 min; P < 0.001) and laboratory time (118 vs. 153 min; P = 0.002) and required fewer adjunct medications (P < 0.001). Twenty-five procedures (25%) were challenging due to cough or motion but were all completed safely. Complications occurred in one monitored anaesthesia care case and six general anaesthesia cases (P = 0.054). Pulmonary vein isolation was achieved in all patients. Conclusion Monitored anaesthesia care without endotracheal intubation was safe, efficient, and resource-sparing compared with general anaesthesia for pulsed field atrial fibrillation ablation.

Abstract Purpose: B7-H3 (CD276) represents a promising therapeutic target tested in high-risk localized and treatment-refractory metastatic prostate cancer. To guide therapeutic development and treatment strategies, we examined prostate tumors and evaluated expression, molecular features, and overall survival (OS), accounting for tissue site, hormone sensitivity status, and race. Experimental Design: A total of 8,157 prostate cancer samples with paired DNA/RNA were analyzed based on annotations by tissue site, self-reported race, and disease state: hormone-sensitive prostate cancer (HSPC), castration-resistant prostate cancer (CRPC), or neuroendocrine prostate cancer (NEPC). Expression quartiles were B7-H3–high (>75th percentile) or B7-H3–low (<25th percentile). The OS was evaluated using Kaplan–Meier and Cox proportional hazards models. Results: B7-H3 expression was broadly maintained but varied by tumor site, hormone sensitivity status, and race. High expression aligned with AR-associated transcription factors (HOXB13 and FOXA1), AR-associated pathogenic dysregulations (AR-V7, SPOP, FOXA1, and TMPRSS2:ERG fusions), and actionable surface antigens (TROP2 and NECTIN-4). Weak correlations were found for lineage-plastic program regulators (EZH2, SOX2, and ASCL1) and NEPC-associated surface antigens (DLL3 and CEACAM5). High B7-H3 expression in primary tumors and HSPCs portended adverse OS [hazard ratio (HR), 1.342 and 1.30; confidence interval (CI), 1.19–1.512 and 1.15–1.46; q < 0.0001] although it was favorable in metastatic tumors (HR, 0.823; CI, 0.719–0.942; q = 0.0048). No significant differences in OS were observed among CRPCs and NEPCs, although OS varied by race, with the poorest survival in Asian/Pacific Islander patients with metastatic prostate cancer (HR, 3.72; CI, 1.49–9.29; q = 0.012). Conclusions: Maintained B7-H3 expression in various prostate cancer settings supports its viability as a target. The associations with AR-related molecular factors, surface antigens, and investigative targets for cell therapy or antibody–drug conjugates suggest potential dual-targeting strategies. See related article by Sharma et al., p. 3365

Suppression of insulin-like growth factor-1 (IGF-1) signaling extends mammalian life span and protects against a range of age-related diseases. Unexpectedly, we found that reduced IGF-1 signaling fails to extend the life span of mitochondrial mutator mice. Most of the longevity pathways that are normally initiated by IGF-1 suppression were either blocked or blunted in the mutator mice. These observations suggest that the prolongevity effects of IGF-1 suppression critically depend on the integrity of the mitochondrial genome, revealing an unexpected hierarchy in the pathways that control mammalian aging. Together, these findings deepen our understanding of the interactions between the hallmarks of aging and underscore the need for interventions that preserve the integrity of the mitochondrial genome.

Abstract Annual breast cancer screening is a critical piece of women’s health. While mammography remains the gold standard, increased breast density leads to decreased sensitivity, underscoring the need for more sensitive and accessible screening methods. Liquid-based biopsies for early breast cancer detection are emerging but currently remain out of reach for clinical use. Recent data on nucleotide assessment from plasma in breast cancer have been mixed with 87% sensitivity for late-stage disease (stage 3-4) but only 20% sensitivity for early-stage disease (stage 0-2). Proteomics is an exciting area for early cancer screening where improvements in sample preparation and equipment have enabled major advances in early cancer detection. This is particularly true for a deep proteome assay as proteins can be identified which are 8-9 orders of magnitude less abundant than the most common plasma proteins. This study evaluates the presence of breast cancer using label-free shotgun mass spectrometry-based proteomics on less than 1 ml of plasma from 1,259 women classified as either healthy or newly diagnosed treatment naïve breast cancer patients with a focus on early-stage disease. We trained using a cohort of 845 women, comprising of 466 healthy and 379 with breast cancer and validated on 397 women (195 healthy and 202 breast cancer) using a protein-based machine learning classifier to distinguish these groups. All plasma samples were processed in a blinded manner coupled with semi-quantitative, label-free mass spectrometry (MS)-based analysis. The median number of proteins detected per patient across breast cancer and healthy individuals was 7,064 and 7,054, respectively. The validation performance achieved 92.3% specificity for healthy controls and an overall sensitivity of 92.6% with an AUC of 0.975 (95% CI: 0.961-0.987) for breast cancer patients. Sensitivity broken down by clinical stage (0-IV), molecular subtypes (HR+/HER2+, HR-/HER2+, HR+/HER2-, and HR-/HER2-) and pathological subtypes (LCIS, DCIS, ILC, and IDC) were ≥85% and indistinguishable across all stages and subtypes. Gene set enrichment analyses (GSEA) identified pathways including epithelial-to-mesenchymal transition (EMT) and PI3K-AKT signaling as enriched in the breast cancer samples, highlighting that our test can identify cancer-related proteins in early-stage patients. Overall, we have developed a highly sensitive blood-based assay that utilizes deep proteomic profiling to identify distinctive cancer specific signatures in women who are undergoing screening for breast cancer. This work enables us to develop a protein-based classifier from plasma for early detection of breast cancer and enhances screening strategies for women with dense breasts who are at average or high-risk based on family history, specific genetic mutations such as BRCA1/2, race, or other factors. Citation Format: Alec Horrmann, Yash Travadi, Jacob Carey, Kevin Mallery, Ella Boytim, Grant Schaap, Carissa Rungkittikhun, Kaylee Kamalanathan, Nathaniel R. Bristow, Catalina Galeano-Garces, Adam Groth, Alexa R. Hesch, Pooja Advani, Justin Hwang, Badrinath R. Konety, Justin M. Drake. Deep plasma proteomics for early-stage breast cancer detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4073.

Abstract Introduction: The HER2-targeted doublet, tucatinib and trastuzumab, recently received FDA approval for previously treated HER2-positive metastatic colorectal cancer (mCRC). While the intensity of HER2 IHC staining and ERBB2 amplification have been proposed as potential markers of response, our understanding of the role of the tumor microenvironment remains limited. Methods: The phase II MOUNTAINEER Trial (NCT03043313) enrolled patients for tucatinib plus trastuzumab based on HER2 positivity (IHC or NGS amplification). Patients from cohort A with available HER2 IHC and H&E slides were included in this analysis. Previously validated AI-based models (Lunit SCOPE uIHC and SCOPE IO) were used to quantify the percentage of HER2 3+ stained tumor cells (AI-H3+) and the densities of tumor infiltrating lymphocytes (TILs) in the cancer epithelium (iTIL) and stroma (sTIL). Results: The analyzed cohort (N=30) had an objective response rate (ORR) of 43.4% and median progression-free survival (PFS) of 8.0 months. AI-H3+ percentage showed a strong, dose-dependent association with an ORR of 57.1%, 66.6%, and 80.0% for tumors with AI-H3+ ≥10% (n=14), ≥25% (n=12), and ≥50% (n=10), respectively. This benefit extended to PFS, with the ≥50% cohort reporting a PFS HR of 0.17 (P=0.002) compared to tumors with AI-H3+ <50%. Tumors with below median iTIL or sTIL had significantly shorter PFS. Notably, tumors with sTIL density in the bottom quantile had an ORR of 0% and PFS HR of 4.40 (P=0.002) despite including cases with high AI-H3+. TIL densities and AI-H3+ percentage were not correlated. Conclusion: These findings confirm AI-quantified HER2 intensity as a marker of response and suggests the importance of TILs, which may have a role through immunogenic cell death. Stratification by HER2 and TIL may be an approach to consider as this regimen progresses into the first-line setting. Citation Format: Mitsuho Imai, John H. Strickler, Woochan Hwang, Kara Bonneau, Andrew B. Nixon, Jongchan Park, Chang Ho Ahn, Tanios Bekaii-Saab, Takayuki Yoshino. HER2 expression and tumor-infiltrating lymphocytes predict response to tucatinib plus trastuzumab in HER2-positive metastatic colorectal cancer (MOUNTAINEER): Exploratory analysis of a multicenter, Phase II trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7735.

Background: Sinonasal malignancies (SNM) are rare cancers associated with poor prognosis and impaired quality of life (QOL). The 22-question Sino-Nasal Outcome Test (SNOT-22) has been used to assess QOL in patients with SNM. Objective: To determine the minimal clinically important difference (MCID) for the SNOT-22 in patients with SNM. Methods: About 264 patients with SNM were drawn from a prospective, longitudinal, multi-institutional study. SNOT-22 scores were collected at pre-treatment baseline and follow-up through 5 years post-treatment. Cronbach’s alpha was used to assess the internal consistency of the SNOT-22. Distribution-based approaches were used to estimate the MCID. Multivariable regression identified factors associated with SNOT-22 improvement exceeding the determined MCID. Results: Cronbach’s alpha was >.85. The estimated MCIDs were: 1.44 (Cohen’s effect size), 1.32 (standard error of the mean), 10.45 (1/2 of baseline standard deviation), and 3.67 (minimum detectable change). The mean MCID across methods was 4.22. Multivariable regression demonstrated higher odds of clinically meaningful improvement from baseline in patients with early-stage disease (odds ratio (OR) 3.510, P = .035), no neck irradiation (OR 11.050, P = .014), and neoadjuvant therapy (OR 16.667, P = .047). Conclusions: The SNOT-22 MCID was estimated as 4.22 in a large multi-center cohort of patients with SNM, suggesting that relatively small QOL changes are clinically relevant. When applying the MCID to the current cohort, advanced stage, treatment of neck disease, and not requiring neoadjuvant therapy were predictive of worse QOL.