Citations

Abstract Background Molecular underpinnings and clinical characteristics of ERBB2/HER2-mutated colorectal cancers (CRCs) remain poorly understood. We aimed to comprehensively characterize the genomic landscape and clinical features of ERBB2/HER2-mutated CRC and to compare them with those of ERBB2/HER2-amplified CRC. Patients and methods We analyzed cBioPortal data from 4348 CRC patients with available ERBB2/HER2 profiling. Clinicodemographic features, microsatellite instability (MSI), tumor mutational burden, and alterations in 94 cancer-associated genes were evaluated using chi-square/Fisher’s exact test, Kruskal–Wallis test, and hierarchical clustering. Results ERBB2/HER2 putative driver mutations were identified in 95 patients (2.2%), amplifications in 87 (2.0%), and wild-type status in 4166 (95.8%). In the overall cohort, ERBB2/HER2-mutated tumors demonstrated significant KRAS enrichment (50.5%) compared to wild-type (37.7%; P = .014) and amplified tumors (18.4%; P < .001), alongside MSI enrichment (37.2% vs 1.6%; P < .001), elevated tumor mutational burden, and right-sided predominance. ERBB2/HER2-mutated tumors also showed broad driver co-alterations largely reflecting their MSI background. In contrast, ERBB2/HER2-amplified tumors exhibited left-sided predominance, with microsatellite stable (MSS)-restricted analyses revealing selective mutual exclusivity with KRAS (Log2 OR = −1.58; q = 0.019) and TP53 co-occurrence (Log2 OR = 2.04; q = 0.019). Hierarchical clustering confirmed that mutated and amplified tumors consistently occupy separate clusters across anatomical sites. Conclusion ERBB2/HER2 mutations and amplifications represent molecularly and clinically distinct subgroups. ERBB2/HER2-mutated tumors are characterized by an MSI-enriched, hypermutated background with frequent concurrent KRAS alterations, whereas amplified tumors exhibit selective KRAS mutual exclusivity and TP53 co-occurrence. These exploratory findings support alteration-specific therapeutic strategies in CRC.

Abstract Background Identification of individuals at increased risk for synucleinopathies is becoming more feasible with advances in biomarkers. However, the ethical and practical aspects of communicating disease risk remain unresolved, particularly across diagnostic groups and cultural contexts. Objectives We aimed to evaluate attitudes toward disclosure of future synucleinopathy risk among individuals with isolated/idiopathic REM sleep behavior disorder (iRBD), as well as in individuals who developed Parkinson's disease (PD), or multiple system atrophy (MSA), in a large non‐Western registry. Methods This nationwide survey study included participants from 28 movement disorders and sleep centers across Türkiye. Questionnaires assessing attitudes toward risk disclosure, additional testing, and clinical trial participation were administered face‐to‐face. Responses were analyzed using contingency tables and regression models. Results are reported following the Consensus‐Based Checklist for Reporting of Survey Studies (CROSS) guideline. Results Among 1385 participants (1039 PD, 107 MSA, 239 iRBD), individuals with iRBD showed the highest support for risk disclosure (88.3%), exceeding PD (64.4%) and MSA (51.9%). Approval declined modestly (3–8%) when framed within the absence of disease‐modifying treatment. iRBD participants were more willing for additional testing but less willing to join clinical trials (31.8%) than PD (45.3%) or MSA (48%). MSA patients expressed the greatest concern about psychological impact. Male sex had more favorable views on disclosure and trial participation, while younger and better‐educated participants favored additional testing. Conclusions Attitudes toward risk disclosure differ markedly across the synucleinopathy spectrum and demographic characteristics. Culturally informed and diagnosis‐specific disclosure strategies will be essential for trial recruitment and patient‐centered care.

TPS3686 Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) represents a highly specific and sensitive approach (especially with serial monitoring) for identifying minimal/molecular residual disease (MRD) post-surgery in CC patients (pts), and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA–) are at a much lower risk of recurrence and may be spared the toxicities associated with AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose CC has been resected, ctDNA status may be used to risk-stratify for making decisions about AC. Methods: In this prospective phase II/III trial, up to 1,912 pts with resected stage IIB, IIC, and III CC will be enrolled. Based on the post-operative ctDNA status using personalized and tumor-informed assay (Signatera, bespoke assay), those who are ctDNA– (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP)+oxaliplatin (Ox) for 3-6 mos per established guidelines v serial ctDNA monitoring. Patients who are ctDNA+ post-operatively, or with serial monitoring (Cohort B), will be randomized to FP+Ox v more intensive AC with addition of irinotecan (I) for 6 mos. One cycle of chemotherapy is allowed while awaiting ctDNA testing results for cohort assignment. The primary endpoints for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) (phase III) in the immediate v delayed AC arms. The primary endpoint for Cohort B is DFS in the FP+Ox v FP+Ox+I arms for both phase II and phase III portions of the trial. Secondary endpoints include prevalence of detectable ctDNA post-operatively, time-to-event outcomes (overall survival and time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, as well as post-operative plus serial matched/normal blood samples, will be collected for exploratory correlative research. Active enrollment across the NCTN started in June 2022 with CCTG sites joining in August 2023. Accrual is 1,123/1,912 (as of 1/20/2026). *Drs. Dasari and Lieu contributed equally to the development of this trial. Clinical trial information: NCT05174169 .

e16486 Background: Allele-specific KRAS G12C inhibitors have revolutionized lung and colorectal cancer treatment, yet the biology of G12C in other gastrointestinal (GI) malignancies remains undefined. We aimed to elucidate the clinicopathologic and genomic landscape of KRAS G12C-mutated tumors compared to other G12 variants in a large non-colorectal GI cohort. Methods: We queried cBioPortal for pancreatic, esophagogastric, hepatobiliary, ampullary, and appendiceal adenocarcinomas. Following data quality control, the final cohort (n = 6,352) was stratified into KRAS wild-type (n = 3,293), G12C (n = 63), and other G12 variants (n = 2,996). Clinicopathologic features, tumor mutational burden (TMB), microsatellite instability status, and co-alteration in 96 key genes across 11 signaling pathways were compared. Statistical significance was assessed using Fisher’s exact or Chi-square tests for categorical variables and Kruskal-Wallis tests for continuous variables. The Benjamini-Hochberg method was applied to correct for multiple hypothesis testing. Results: KRAS G12C prevalence was 1.0% overall, with significant heterogeneity across cancer subtypes (p < 0.001). Appendiceal adenocarcinoma demonstrated the highest G12C prevalence at 5.71% (10/175), followed by ampullary (1.44%, 2/139), pancreatic (1.17%, 34/2906), hepatobiliary (0.88%, 12/1360), and esophagogastric cancers (0.28%, 5/1772). G12C patients were significantly older than wild-type patients (64.8±11.2 vs 62.5±12.9 years, mean±SD, p < 0.001) but younger than other G12 variant carriers (65.8±10.4 years). G12C tumors demonstrated intermediate genomic instability, with a TMB of 4.82±6.17 compared to 4.98±10.55 in wild-type tumors and 3.67±10.12 in other G12 variants (p < 0.001). Notably, G12C tumors were universally microsatellite stable (0% MSI-H vs 4.0% wild-type vs 0.9% other G12, p < 0.001). Genomic analysis revealed that AKT1 mutations were significantly enriched in the G12C cohort (6.3% vs 0.4%; q = 0.025) as compared to other G12 variants. A trend of increased mutation frequency in HRAS was observed specifically in pancreatic cancers in G12C tumors as compared to other variants (8.8% vs 0.7%; q = 0.083). In pancreatic adenocarcinoma, G12C tumors were enriched for chromatin modifiers, notably ARID1A (17.6% vs 7.7%, p = 0.045) and SETD2 / SETD26 (8.8% vs 1.1%, p = 0.006), though these did not reach FDR significance. Notably, the immunotherapy-resistance drivers STK11 and KEAP1 were absent (0%) in the whole G12C cohort. Conclusions: KRAS G12C represents a biologically distinct subgroup of exon 2 KRAS mutations compared to other KRAS G12 pathogenic variants. The absence of resistance markers and enrichment of actionable AKT1 and chromatin-modifier mutations suggest distinct therapeutic vulnerabilities in non-colorectal KRAS G12C-mutated GI cancers.

The 6th edition of the WHO Classification of Breast Tumours introduces both major and minor changes based on recent advances in our understanding of breast biology, developments in diagnostic modalities, identification of specific molecular targets and new treatment regimens necessitating modifications to pathology reporting and tumour biomarker categorisation. This review summarises the main changes that strive towards a classification of global relevance. In invasive carcinoma, predictive factors increasingly inform modern breast cancer treatment. The 6th edition provides an update on HER2 reporting categories following the DESTINY‐Breast 04 and 06 trials. Terminologies used to classify invasive tumours are clarified, with the term ‘variant’ now reserved for molecular/genetic alterations. Invasive lobular carcinoma (ILC) with extracellular mucin is recognised as a new diagnostic entity with prognostic implications. The diagnosis of mucinous carcinoma (MC) is reserved for mucin secreting carcinomas with grade 1 or 2 morphology and a favourable biomarker profile. The diagnosis of malignant phyllodes tumours requires only four of the original five adverse histological criteria. Classification of neuroendocrine tumours (NETs) is revised, recognising that the unified model, promoted in the 5th edition, is difficult to apply to the breast. New approaches to the classification of adenomyoepithelioma are discussed but the 5th edition system is broadly retained. A new section on ‘Small Diagnostic Samples’ outlines the merits of non‐operative biopsy diagnosis, the B coding system and the importance of multidisciplinary review. Changes to diagnostic practice and the emerging role of artificial intelligence, with advantages and challenges, are discussed in a new section on ‘Digital Pathology’.

Abstract Background and Aims Stroke and systemic embolism are recognized but poorly characterized complications of atrial fibrillation (AF) and left atrial flutter (AFL) catheter ablation. Their incidence, outcomes, and procedural associations remain insufficiently defined. Methods Retrospective global registry was initiated by the European Heart Rhythm Association Scientific Committee. A secure database captured data from ablation centres worldwide on general AF and left AFL ablation activity, as well as detailed information on patients with symptomatic embolic events between 2017 and 2024. Results Overall, 204 centres reported 335 743 ablation procedures and 550 embolic events (incidence 0.16%). Centre-level rate ranged from 0% to 3.1%. Most events were cerebral (94%), followed by peripheral (5%), and combined (1%). Coronary air embolism accounted for 62% of all peripheral events. Intraprocedural events occurred in 93 patients (17%), within 72 h in 357 (78%) and beyond 72 h in 100 (22%); 128 cases (23%) were diagnosed after hospital discharge. Nonparoxysmal AF (0.23% vs 0.15%; P &lt; .001), centre experience, and ablation energy source (radiofrequency, 0.16%; cryoballoon, 0.16%; pulsed field ablation, 0.25%; laserballoon, 0.88%; P &lt; .001) were associated with embolic risk. Median NIHSS score after stroke was 4 (interquartile range, 2–9). Three-month follow-up was available for 518 patients with embolism (95%): 181 (35%) had sequelae and 16 (3%) died. Conclusions Symptomatic embolic events are infrequent but associated with significant morbidity and mortality. Most events occur early, though a substantial proportion arise later. Higher event rates were observed with laser and possibly with pulsed field ablation. A greater centre experience was associated with a lower embolism incidence.

Background: Pancreatitis significantly alters the microbial composition of the oral and intestinal compartments, causing dysbiosis that may contribute to disease mechanisms and potentially serve as a basis for diagnosis or treatment. Objective: To determine whether the oral or gut microbial signature can classify chronic pancreatitis (CP). Methods: Stool samples (n=707) were collected from participants in the Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED). Samples were distributed among 200 healthy (HC), 310 CP, 49 acute pancreatitis (AP), and 148 recurrent acute pancreatitis (RAP). In addition, saliva samples were collected for a subset of participants (n=156). Whole genome sequencing was performed to assess microbiome composition. Machine learning algorithms were utilized to identify a signature with microbial features predictive of CP. Results: Gut alpha diversity was significantly decreased in AP, RAP, and CP compared with HC, with CP exhibiting the lowest diversity. In contrast, oral microbial diversity showed no significant variation across groups. Beta diversity analysis revealed distinct gut microbiome compositions between HC and pancreatitis subtypes, with CP showing the most pronounced differences. Random forest models using gut microbial species demonstrated robust predictive performance for CP using a minimum of 10 species (Area under the curve—AUC: 0.834; accuracy: 0.774). Despite similarities in gut microbiome composition across pancreatitis subtypes, a unique gut microbial signature for CP was identified highlighting the microbiome’s potential in CP diagnosis. Conclusion: Our study reveals a gut microbial signature predictive of CP using machine learning models in a large US multi-institutional cohort.

Abstract Clinical interventions and neuroimaging in the subcortex require anatomical definitions that exceed the resolution and anatomical detail of currently available deformable brain atlases. Here, we introduce a high-resolution human brain atlas comprising 95 manually segmented grey and white matter structures as well as 82 white matter tracts compiled from a multitude of resources including ex-vivo MRI, histology, fibre dissections, and neuroanatomy textbooks. The atlas is defined at an isotropic resolution of 100 μm and can be precisely deformed to individual subject brain anatomy. By providing precise definitions of both grey and white matter structures within and around the basal ganglia, thalamus, subthalamus, midbrain and cerebellum, the atlas provides a foundational resource for stereotactic surgery and subcortical brain imaging research, as well as for development of next-generation neuromodulation strategies.