Search Results (621)

Background: Leukemic non-nodal variant mantle cell lymphoma (nnMCL) is an uncommon subtype of mantle cell lymphoma that lacks lymphadenopathy and generally follows an indolent clinical course. Adverse genetic alterations such as TP53 inactivation and del(13q) may have prognostic significance. Clinical findings such as splenomegaly may serve as a clue to the diagnosis and should prompt further evaluation. Case Presentation: We describe a 91-year-old woman who presented with a one-month history of anemia (hemoglobin 12.3 g/dL), mild thrombocytopenia (platelets 136 × 10⁹/L), isolated splenomegaly and no palpable lymphadenopathy. Despite a normal total white blood cell count, intermittent relative lymphocytosis with atypical lymphocytes (4%) and smudge cells was detected on the complete blood count. Peripheral blood flow cytometry demonstrated a monoclonal kappa-restricted B-cell population negative for CD5 and CD10, comprising approximately 20% of lymphocytes. Conventional karyotyping and fluorescent in situ hybridization (FISH) analysis identified del(13q), del(17p)/TP53, and IGH-CCND1 rearrangement in 8–19.5% of peripheral blood leukocytes. A month after the initial assessment, the patient presented following a fall. CT imaging of the abdomen revealed marked splenomegaly, a large subcapsular/perisplenic hematoma, and moderate-to-large hemoperitoneum. Emergent laparotomy showed an enlarged spleen (1490 g, 23 × 16 × 7.5 cm) with laceration. Histologic evaluation showed atypical lymphoid cells positive for CD20 and cyclin D1, with strong p53 expression, negative for CD5 and SOX11, and a low Ki-67 index. Similar involvement was identified in the small bowel and appendix. Targeted sequencing of splenic tissue, performed as part of a retrospective molecular characterization, identified a pathogenic TP53 variant (p.His179Gln). Conclusions: This case provides a rare opportunity to evaluate splenic and small intestinal involvement by nnMCL at both the gross and histologic levels. It highlights the importance of integrating clinical findings with flow cytometry, imaging, cytogenetic, and molecular data in establishing the diagnosis. Even when peripheral blood findings suggest a low disease burden, imaging may better define the extent of disease and support appropriate clinical assessment, particularly in elderly patients at risk for complications related to splenomegaly. Full article

Background: Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality despite major advances in diagnostics and therapies. The prognosis remains poor, mostly due to late-stage presentation and molecular heterogeneity. Epidermal growth factor receptor (EGFR) mutations are common drivers of NSCLC. The development of EGFR tyrosine kinase inhibitors (TKIs) has significantly improved outcomes in patients with EGFR mutations. Variant allele frequency (VAF) is a quantitative genomic measure representing the proportion of sequencing reads harboring a given mutation. In NSCLC tissue, the EGFR mutation VAF reflects tumor clonality and intratumoral heterogeneity, and accumulating evidence suggests an association between EGFR VAF and response to EGFR-targeted TKIs. Methods: To address the limited synthesis of data on the relevance of EGFR mutation VAF in NSCLC, we conducted a narrative review of the literature using PubMed/MEDLINE and Embase databases and current clinical guidelines, synthesizing available evidence on EGFR VAF, including its biological, molecular, and therapeutic implications in EGFR-mutated disease. The review was structured in accordance with the SANRA (Scale for the Assessment of Narrative Review Articles) checklist. Results: EGFR VAF and on-treatment VAF dynamics are consistently associated with treatment response, progression-free survival, and overall survival in osimertinib-treated NSCLC. Baseline VAF enables risk stratification, early clearance kinetics predict durable benefit, and longitudinal VAF monitoring facilitates early detection of resistance. Importantly, the prognostic implications of VAF differ fundamentally between tissue-based and plasma-based measurements: high tissue VAF reflects clonal homogeneity and predicts favorable TKI response, whereas high plasma VAF indicates elevated tumor burden and is associated with inferior outcomes. In the second-line setting, the T790M/activating mutation ratio serves as a surrogate for resistance clonality and independently predicts osimertinib efficacy. Conclusions: EGFR VAF represents a promising dynamic molecular biomarker for treatment monitoring and precision decision-making in EGFR-mutated NSCLC. Full article

Background: Accurate and early detection of hematological disorders from microscopic peripheral blood smear images remains a technically challenging task due to inherent imaging limitations, including noise contamination, low contrast, staining variability, and significant cellular overlap. Conventional deep learning-based object detection frameworks often exhibit limited robustness under such conditions and demonstrate reduced sensitivity to small-scale morphological structures, particularly platelets and abnormal cell variants. Methods: To address these challenges, this study proposes a hybrid detection framework that integrates a fuzzy logic-driven image preprocessing module with the YOLOv11 object detection architecture. The proposed preprocessing pipeline employs adaptive fuzzy membership functions to normalize pixel intensity distributions, suppress high-frequency noise, and enhance edge-defined cellular boundaries. This transformation produces a structurally optimized feature representation, improving downstream feature extraction and localization performance. The proposed framework was evaluated on a curated dataset of 3000 annotated microscopic blood smear images spanning five hematological classes. Results: Experimental results show that the fuzzy logic module improves mAP@0.5 by +3.4% and mAP@0.5:0.95 by +3.6%, confirming its effectiveness in enhancing both classification and localization accuracy. Conclusions: These findings demonstrate the robustness and practical applicability of the proposed hybrid approach under challenging imaging conditions. Full article

Background: Gaucher disease (GD) arises from pathogenic variants in the GBA1 gene and is known for its wide range of clinical presentations—a variability that genotype alone cannot adequately account for. Objective: This study aimed to explore transcriptomic factors that might help explain why two genetically identical twins with type 1 GD developed noticeably different clinical outcomes. Methods: We isolated peripheral blood mononuclear cells from both twins and two age-matched controls, then differentiated them into macrophages in vitro before conducting RNA sequencing. Gene expression differences were analyzed using established bioinformatics pipelines, and a subset of genes were subsequently assessed by quantitative real-time PCR (qRT-PCR) to confirm the sequencing findings. Results: Both twins shared a GD-associated transcriptional signature broadly reflecting immune activation and lysosomal stress. Interestingly, the twin who experienced systemic complications had a relative enrichment of interferon-responsive transcripts, while the less severely affected twin showed more pronounced suppression of small nucleolar RNA clusters. That said, neither difference held up after correcting for multiple comparisons, so these patterns are best viewed as exploratory trends rather than definitive findings. The qRT-PCR results lend partial support to this picture: stress- and immune-related genes (DDIT4, RPH3A, SAMSN1) trended toward higher expression in patients versus controls, and interferon-stimulated genes (ISG15, RSAD2, IFI44L) were more elevated in M2 than in M1. Conclusions: Taken together, these findings suggest that factors beyond genetics—whether epigenetic, environmental, or otherwise—may play a meaningful role in shaping how GD manifests differently even between individuals with identical DNA. Although the data are preliminary, they point to transcriptomic profiling, paired with targeted validation, as a useful starting point for building hypotheses about why this disease looks so different from one patient to the next, even when the underlying mutation is the same. Full article

Background/Objectives: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm characterized by the clonal proliferation of Langerhans-like dendritic cells and constitutive activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK-ERK) signaling pathway. Nearly 80% of ERK pathway activation can be attributed to B-Raf proto-oncogene, serine/threonine kinase (BRAF V600E), and mitogen-activated protein kinase kinase 1 (MAP2K1) variants, with BRAF V600E specifically detected in approximately 50% of pediatric LCH cases and associated with a higher risk of severe disease and treatment failure. The use of the HistioTrak clinical assay to detect the presence of BRAF V600E mutations in peripheral blood mononuclear cells (PBMCs) has emerged as a useful diagnostic tool and biomarker. Methods: This study is a single-center retrospective study that explores the favorable outcomes of treatment with trametinib on a small number of patients with LCH. We retrospectively analyzed the records of 11 children with LCH treated with trametinib at diagnosis as front-line therapy (n = 6), due to progressive disease (n = 3) or intolerance (n = 1) to chemotherapy, or at relapse (n = 1). Results: HistioTrak identified the presence of BRAF V600E PBMCs in five patients. In this small single-center retrospective cohort, trametinib was associated with favorable short-term outcomes in all patients, and serial HistioTrak testing appeared feasible in selected patients. Conclusions: Prospective studies are needed before routine diagnostic or monitoring use can be recommended. Full article

Pure mediastinal yolk sac tumor is an uncommon and aggressive malignant germ cell neoplasm that presents considerable diagnostic difficulties owing to its pronounced clinical and morphological variability. Mediastinal yolk sac tumors, in contrast to their gonadal equivalents, typically occur at later stages, are typically associated with mixed germ cell components, and have a diverse array of histologic patterns that may resemble both germ cell and somatic malignancies. Accurate identification of these types of cancer is essential since diagnostic misclassification may significantly impact treatment and prognosis. This review provides a comprehensive overview of the morphologic spectrum of mediastinal yolk sac tumor, with emphasis on both classic and variant histologic patterns, including reticular, solid, glandular, papillary, hepatoid, and other less common growth forms. The immunohistochemical correlations of these patterns and their role in resolving diagnostic dilemmas are discussed, along with key differential diagnoses encountered in small mediastinal biopsy specimens. Particular attention is given to the limitations of limited tissue sampling, the impact of post-chemotherapy morphologic changes, and the potential for misinterpretation in this challenging anatomic site. By integrating morphologic features with clinical, radiologic, and laboratory findings, this review aims to enhance diagnostic accuracy and improve recognition of mediastinal yolk sac tumor across its diverse presentations. Full article

The 2025 approval of the selective NaV1.8 blocker suzetrigine for acute pain marked a pivotal advance in analgesic drug development. Yet the subsequent failure of Vertex’s next-generation NaV1.8 inhibitor VX993 to demonstrate clinical analgesia underscores enduring challenges in translating mechanistic promise into patient benefit. This review examines why promising targets and compounds, spanning NaV and TRP channels, often falter and outlines a path toward more reliable target selection and validation. I first summarize the pain pathway, from nociceptor transduction through spinal processing to cortical perception, emphasizing how inflammation and peripheral sensitization reshape excitability. Historically serendipitous, pain drug discovery now prioritizes molecular precision. Most approved chronic pain therapies act in the CNS and are limited by modest efficacy and adverse effects. Nociceptor-enriched targets (NaV1.7/1.8/1.9; TRP channels) remain attractive, yet redundancy among NaV subtypes and the necessity of blocking targets at the correct anatomical sites complicate translation. Human genetics and multi-omics provide a powerful, unbiased engine for target discovery. Rare high-impact variants offer strong causal hypotheses, while common polygenic contributions illuminate broader susceptibility. Large biobanks increasingly reveal a mismatch between legacy pain targets and genetically supported candidates across neuronal and non-neuronal cells. Human DRG transcriptomics highlight NaV channel redundancy. Human in vitro electrophysiology and PK/PD analyses show suzetrigine achieves ~90–95% NaV1.8 engagement, yet neurons can still fire unless additional channels are blocked. Species differences and drug distribution (including BBB/PNS penetration and P-gp efflux) critically influence efficacy; centrally accessible blockade (e.g., for NaV1.7 or TRPA1) may be necessary to achieve robust analgesia, challenging peripherally restricted strategies. Osteoarthritis illustrates how obesity-driven metabolic inflammation, synovial immune activation, subchondral bone remodeling, and specific nociceptor subtypes converge to drive mechanical pain. Multi-omic integration across diseased human tissues can pinpoint causal processes and cell types, enabling more selective and safer target choices. I propose a practical framework for target validation that integrates: (i) rigorous human genetic support; (ii) cell-type and site-of-action mapping; (iii) human-relevant electrophysiology and PK/PD with verified target engagement; (iv) species-appropriate models; (v) consideration of modality (small molecule, biologic, RNA, targeted protein degradation). Advancing genetically and anatomically aligned targets, tested at the right sites and exposures, offers the best path to genuinely effective, better-tolerated pain therapeutics. Full article

Background: Staphylococcus aureus bacteremia (SAB) is a common and life-threatening bloodstream infection often caused by methicillin-resistant SA (MRSA) isolates. Up to 35% of SAB patients fail to clear infection with gold-standard anti-MRSA antibiotics, even if the isolate meets susceptibility breakpoints in conventional assays in vitro. Such outcomes are termed persistent and may involve small colony variant (SCV) adaptation of SA in vivo. Methods: In this study, we assessed virulence phenotypes and mechanisms in persistent (PB) vs. resolving (RB) MRSA isolates from SAB. Results: Overall, PB isolates caused less hemolysis or biofilm formation than RB isolates, but proteolysis was equivalent. Attenuation of these virulence phenotypes increased longitudinally during the course of SAB. Although PB vs. RB isolates had similar human endothelial cell invasion rates, PB isolates more frequently formed SCVs intracellularly and inversely correlated with pH. Study PB and RB isolates exhibited distinct susceptibilities to prototypic human host defense peptides (HDPs), which were influenced by antibiotics and pH. Furthermore, mechanistic signatures of HDPs differed between PB and RB isolates. Conclusions: Together, these results reveal that MRSA isolates from PB vs. RB outcomes of SAB have differential virulence profiles that suggest coordinated immune subversion in PB. Understanding MRSA adaptations that promote persistence in SAB may enable innovative agents and strategies to address these challenging infections. Full article

Programmed death-ligand 1 (PD-L1) expression is routinely used to guide immune checkpoint inhibitor (ICI) therapy in advanced non-small cell lung cancer (NSCLC), yet clinical benefit remains heterogeneous even among PD-L1–high tumors. Liquid biopsy based on cell-free DNA (cfDNA) enables minimally invasive, real-time monitoring of tumor evolution. We report four cases of metastatic lung adenocarcinoma treated with atezolizumab, integrating longitudinal whole-exome sequencing (WES) of cfDNA with radiological assessment. Four patients with PD-L1–positive (≥60%) metastatic NSCLC received atezolizumab monotherapy. Serial cfDNA samples (1–3 per patient) were analyzed by high-depth WES. Distinct molecular trajectories paralleled divergent clinical outcomes. One patient achieved a complete molecular response, characterized by progressive clearance of KRAS, ATM, and NF1 mutant clones, which was concordant with radiological remission. A second patient showed an initial molecular response, followed by clonal rebound of TP53, NF1, and NOTCH2 mutant populations and the emergence of PTEN and KIF1A variants, suggesting clinical progression. Two patients exhibited primary resistance despite high PD-L1 expression, with persistent or expanding clones and early subclonal diversification; in one case, new EGFR and BRAF alterations emerged under treatment pressure. Notably, switching to platinum-based chemotherapy in a non-responder induced a measurable molecular response, highlighting discordance between PD-L1 status and immunotherapy efficacy. Longitudinal cfDNA WES captured dynamic clonal remodeling under immunotherapy and anticipated radiological outcomes. These findings underscore the clinical necessity of integrating dynamic molecular monitoring by liquid biopsy to overcome the limitations of static PD-L1 assessment, refine therapeutic stratification, and identify early resistance mechanisms in advanced NSCLC. Full article

Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a rare lung malignancy characterized by an aggressive clinical course and an unfavorable prognosis. Next-generation sequencing (NGS) has revealed that LCNECs exhibit molecular features resembling either small-cell lung carcinoma (SCLC-like LCNEC) or non-small cell lung carcinoma (NSCLC-like LCNEC). This study aimed to characterize the incidence of actionable gene variants in a retrospective cohort of LCNEC patients using a targeted NGS approach. Microscopic diagnosis was established according to the 2021 World Health Organization (WHO) classification using a standard immunohistochemical (IHC) panel. In total, 216 LCNEC tumor samples were analyzed for molecular variants in 17 genes using the RNA-based Archer FusionPlex Lung NGS assay (Integrated DNA Technologies, USA) and the MiSeq platform (Illumina, USA)—an algorithm utilized for routine NSCLC diagnosis. Overall, 46 variants were identified in 46/216 (21.3%) tumor samples, with 28/216 (13%) LCNECs harboring at least one actionable molecular variant potentially targetable by registered or investigational agents. KRAS variants (5%; including G12C at 2%) and PIK3CA variants (5%) were the most prevalent, followed by RET single-nucleotide variants (3%), uncommon EGFR variants (1%), and BRAF class II and III variants (<1%). Notably, no classical EGFR exon 18–21 mutations nor ALK, FGFR1/2/3, or ROS1 alterations (mutations or fusions) were detected, despite the technical capability of the assay to identify such variants. A novel in-frame gene fusion (TMEM79::NTRK1) was identified in a single tumor sample (0.5%). Our results confirm that LCNECs harbor potentially targetable alterations in KRAS, PIK3CA, RET, BRAF, and NTRK1, albeit at lower frequencies than those typically observed in NSCLC. Full article

Background: Cardiac amyloidosis (CA) is an increasingly recognized cause of heart failure with preserved ejection fraction, resulting from myocardial deposition of misfolded amyloid fibrils derived predominantly from transthyretin (ATTR wild-type [ATTRwt] or variant [ATTRv]) or immunoglobulin light chains (AL). Despite advances in noninvasive imaging and disease-modifying therapies, delayed diagnosis remains common, and clinically actionable molecular biomarkers for early detection, phenotypic discrimination, and therapeutic monitoring are limited. MicroRNAs (miRNAs), small noncoding regulators of post-transcriptional gene expression, have emerged as key modulators of cardiovascular remodeling and systemic amyloid biology. Methods: We performed a comprehensive review of experimental, translational, and clinical studies to evaluate the role of miRNAs in transthyretin and light-chain cardiac amyloidosis, incorporating data from myocardial tissue analyses, circulating miRNA profiling, and mechanistic studies in cellular and animal models. Results: Dysregulated miRNA networks contribute to amyloid-induced cardiac injury by modulating mitochondrial energetics, oxidative stress, inflammation, fibrosis, proteostasis, and neurocardiac signaling. Specific miRNAs, including members of the miR-21, miR-29, and miR-30 families, as well as miR-150-5p and miR-339, have been associated with amyloid burden, adverse myocardial remodeling, plasma cell biology, and disease severity. Distinct circulating and tissue miRNA signatures differentiate transthyretin from light-chain cardiac amyloidosis and correlate with functional status, heart failure biomarkers, and clinical outcomes. Conclusions: MiRNAs represent promising diagnostic and prognostic biomarkers in cardiac amyloidosis and offer mechanistic insights into disease pathogenesis. Integration of miRNA profiling with multimodality imaging and emerging RNA-based therapeutics may enable earlier diagnosis and support precision management of amyloid-related heart failure. Full article

Background: Tumor neoantigens are key targets for personalized vaccines and T-cell therapies, yet most pipelines focus on neoantigens derived from SNV/small indel and often yield a limited number of high-quality candidates. SVs are prevalent in tumors and can generate novel chimeric sequences and neopeptides, making them a promising additional source of neoantigens. However, SV-derived neoantigen prediction remains challenging due to breakpoint uncertainty, isoform-dependent coding inference, and limited integration of multi-dimensional evidence and reproducibility. Methods: We developed SVNeoPP (Structural Variant Neoantigen Prediction and Prioritization), an end-to-end workflow for SV-derived neoantigen analysis. SVNeoPP takes WGS and RNA-seq as inputs, performs SV calling and annotation, and reconstructs altered transcripts and coding sequences in a traceable, isoform-aware manner to generate candidate peptides. Candidates are prescreened by integrating antigen-processing features with HLA binding prediction, and then hierarchically filtered and prioritized based on transcript expression, LC–MS/MS proteomics evidence, immunogenicity predictions, and sequence similarity to experimentally validated neoantigen databases. SVNeoPP is implemented in Snakemake to enable modular extension, checkpoint-based restarts, and end-to-end reproducibility. Results: Using a hepatocellular carcinoma (HCC) multi-omics dataset as a proof of concept, we demonstrated the performance of SVNeoPP and obtained a high-priority shortlist of candidate peptides. Compared with other methods, SVNeoPP substantially expanded the candidate search space for SV-derived neoantigens and showed more favorable distributions of antigen-processing and HLA binding features. Conclusions: SVNeoPP provides a reusable, traceable, and interpretable multi-dimensional evidence-driven framework for SV-derived neoantigens. As a complementary module to SNV/small-indel pipelines, it broadens the neoantigen candidate repertoire and generates ranked candidates with interpretable evidence to facilitate downstream prioritization and decision-making. Full article

A miniaturized variant of the artificial luciferase (ALuc), named picALuc, has been generated through the deletion of N- and C-terminal residues in ALuc. Although picALuc is small and active, questions remain regarding its the structural organization and inter-residue interactions in the protein. Here, combining computational analysis and mutational studies, we show that the E50A mutation in picALuc results in an increased bioluminescence activity of the protein. Specifically, we generated a structural model of picALuc using the available structure of the Gaussia luciferase (GLuc) that revealed a ‘hole’ in the structure due to the deletion of N-terminal α-helices. Gaussian-accelerated molecular dynamics (GaMD) simulation revealed a rapid ‘compaction’ of the picALuc structure during the initial phase of the simulation and a number of residues such as E10, E50, and D94 showed salt bridge interactions. Mutation of the residues E10, E50, and D94 individually to an A revealed increased bioluminescence activity of the E50A mutant, while E10A and D94A mutants showed activities similar to the WT protein in living cells. In vitro assays revealed an increase in the V_max of the E50A mutant, while K_half and thermal stability of the mutant remained unchanged. Further, dynamic cross-correlation and principal component analyses of the GaMD simulation trajectories of the WT and the E50A mutant picALuc revealed altered collective dynamics in the protein. Finally, we developed a protein fragment complementation assay using picALuc that allows for the monitoring protein–protein interactions (PPIs) in live cells. We envisage that the brighter picALuc reported here will find broad applicability in developing bioluminescence-based assays. Full article

Background: Lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC), the major subtypes of non-small cell lung cancer (NSCLC), exhibit distinct molecular landscapes that demand precision in prognosis and therapy. While deep learning models can achieve high predictive accuracy, their black-box nature limits clinical translation. Methods: We introduce AttentioFuse, an interpretable deep learning framework employing a Reactome-guided mid-fusion strategy for multi-omics integration. AttentioFuse builds on three pillars: (i) dual-phase learning with omics-specific encoders to preserve modality-unique patterns, (ii) hierarchical attention mechanisms (cross-omics, feature-level, and fusion-layer) to quantify layer contributions dynamically, and (iii) integrated explainability combining DeepSHAP and global attention weights for gene-to-pathway interpretation. Two depth variants are instantiated under identical priors: a three-layer configuration (3F) for main discrimination and a five-layer configuration (AttentioFuse-5X) for deeper hierarchical interpretation; the 5X variant is trained end-to-end and yields comparable accuracy while enhancing pathway-level resolution. Results: Evaluated on The Cancer Genome Atlas (TCGA) LUAD/LUSC cohorts, AttentioFuse matches state-of-the-art performance in TNM staging while uncovering actionable biological insights, including pan-NSCLC AKT/mTOR metabolic control, histology-divergent Notch signaling roles, and additional pathways related to developmental reactivation, microbiota-associated metastasis, and extracellular matrix remodeling. Conclusions: By design, AttentioFuse-5X bridges predictive performance with hierarchical, pathway-resolved explanations, advancing oncology by transforming black-box predictions into biologically grounded decision support. Full article

Cervical small-cell neuroendocrine carcinoma (SCNEC) is a rare cervical cancer with high metastatic potential and is frequently associated with high-risk human papillomavirus (HPV) infection. Because of its low incidence, SCNEC remains understudied and treatment options are limited, posing major therapeutic challenges. This study aimed to characterize SCNEC at the molecular and functional levels to support more informed therapeutic strategies. Organoids and spheroids were generated from a cervical SCNEC biopsy, and a matched organoid-derived xenograft was established in immunodeficient mice. Model fidelity was evaluated by histopathology and immunohistochemistry. HPV status was assessed by p16 immunostaining and HPV18 PCR, and viral–host integration sites were inferred using whole-exome sequencing (WES) junction reads. WES was also used to compare shared somatic variants and copy-number alterations across the patient tumor, organoid, and xenograft. Drug responses were assessed in organoids and spheroids following exposure to a panel of chemotherapeutic agents and a targeted inhibitor. Organoids exhibited robust growth, morphologic maturation, and efficient recovery after cryopreservation. The organoids and matched xenografts faithfully recapitulated SCNEC, with preserved neuroendocrine differentiation (CD56, synaptophysin, and NSE positivity), a high Ki-67 proliferative index (>80%), and strong p16 expression. HPV18 status was conserved across the primary tumor, organoids, and xenografts, with an integration site at chr8 (8q24.21) associated with increased MYC expression. WES revealed strong cross-model concordance, including 26 shared somatic variants with a canonical PIK3CA hotspot mutation (p.E542K) and conserved oncogenic copy-number gains of PIK3CA, TERT, and MYC, as well as copy number loss of TP53. Functional assays showed dose-dependent loss of viability following exposure to conventional cytotoxic agents or an mTOR pathway inhibitor. This study presents the first integrated molecular and functional analyses of patient tumors and matched organoid and xenograft models in cervical SCNEC. These models offer robust resources for mechanistic studies and may enable precision therapeutic strategies for this rare malignancy. Full article