Copyright: © 2026 Booth et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Mechanisms by which the Stearoyl-CoA desaturase (SCD1) inhibitor aramchol kills tumor cells have recently been described, demonstrating that enhanced signaling through the AMPK played a key role in the processes regulating cell death. Metformin is an anti-hyperglycemic drug which utilizes AMPK signaling to reduce plasma glucose levels. The primary site of metastatic spread of uveal melanoma (UM) is the liver and aramchol concentrates in the liver compared to plasma and other tissues. Aramchol and metformin interacted to modestly enhance cell death in PDX UM cells, though this was less than that caused by the combination of aramchol and the multi-kinase inhibitor regorafenib. Metformin significantly enhanced killing by aramchol plus regorafenib. Metformin significantly enhanced autophagosome formation and autophagic flux caused by aramchol plus regorafenib. Knock down of Beclin1, ATG5 or LAMP2 reduced autophagosome and autolysosome formation, and tumor cell killing. Knock down of BID further enhanced the protective effect of Beclin1 knock down. Knock down of SCD1 enhanced the percentage of dead cells in vehicle control treated cells but did not alter the abilities of drugs to kill tumor cells. Our data demonstrates that UM cells are killed by treatment with aramchol plus regorafenib plus metformin via enhanced autophagic flux and that this combination may have the potential to control UM tumors that have metastasized to the liver.

Inflammatory breast cancer (IBC) is an aggressive form of cancer for which trimodality therapy (TMT) is standard, but TMT use may be decreasing. Survival outcomes between patients with IBC and non-IBC by tumor subtype are unclear, and survival trends over time have not been reported.

Gastric cancer (GC) remains a leading cause of cancer-related morbidity and mortality worldwide. Neural invasion (NI) is a common pathological behavior that worsens the prognosis in GC. However, the immune microenvironment of neural invasion-positive GC (NI+GC) and its potential therapeutic implications remain poorly defined. Here, we performed single-cell RNA sequencing (scRNA-seq) on tumor specimens from patients with NI+GC and neural invasion-negative GC (NI-GC) to comprehensively delineate the immune landscape. Our analysis revealed a significant enrichment of exhausted ANXA1+CD8+T cells within NI+GC tissues, which was validated by flow cytometry and multiplex immunohistochemistry assays. Clinically, patients with greater infiltration of ANXA1+CD8+ T cells had worse overall survival and disease progression. Mechanistically, ANXA1 bound to TRKA via N-terminal region, blocking NEDD4L-mediated ubiquitination and degradation of TRKA, thereby suppressing glycolytic metabolism and driving CD8⁺T cell exhaustion. Tumor-derived nerve growth factor (NGF) further amplified this exhaustion via TRKA engagement. Importantly, treatment with an ANXA1-derived peptide (A11) combined with TRKA inhibitors synergistically reversed T cell exhaustion and suppressed tumor growth in preclinical models. These findings unveil distinctive features of the immune microenvironment in NI+GC and elucidate the underlying molecular mechanisms of ANXA1/TRKA axis in facilitating immune evasion, which offer new insights for enhancing the sensitivity of immunotherapy to NI+GC patients.

Acquired resistance to tyrosine kinase inhibitors (TKIs) remains the primary obstacle to long-term disease control in targeted cancer therapy, yet whether resistance emerges gradually through clonal selection or abruptly via mutation acquisition remains unclear. We develop a four-dimensional ordinary differential equation model coupling drug-sensitive and drug-resistant tumor populations with dynamic vascular support and explicit TKI pharmacokinetics. Mathematical analysis establishes solution positivity and uniform boundedness, characterizes all equilibrium states, and determines local stability conditions via Jacobian eigenvalue analysis, revealing threshold relationships between drug efficacy and evolutionary outcomes. We perform systematic parameter estimation using differential evolution on longitudinal tumor mass data from a gastrointestinal stromal tumor patient treated with imatinib. Models assuming continuous effective drug pressure fail systematically, with best fit achieving only coefficient of determination R-squared equals 0.721, unable to reproduce the observed 24-fold tumor mass increase during relapse. In striking contrast, incorporating a sigmoid resistance modulation function-where cytotoxicity progressively vanishes due to mutant clonal expansion near day 683-yields near-perfect agreement with R-squared equals 0.999, accurately capturing all three clinical phases. The estimated transition rate implies a rapid 10â€"90 percent clonal takeover within approximately 2.5 days, providing quantitative evidence that explosive relapse reflects abrupt mutation acquisition rather than gradual selection.

Metabolic reprogramming is a hallmark of cancer. Tumor cells adapt to their environment by modulating glucose, lipid, and amino acid metabolism to supply raw materials for rapid growth and enhance treatment resistance. Among these, glucose metabolic reprogramming is particularly critical. In head and neck tumor cells, glycolysis-derived intermediate metabolites provide biosynthetic precursors and energy necessary for growth, sustaining proliferation and invasion. Additionally, these metabolites can remodel the tumor microenvironment, modulate signaling pathways, and alter tumor phenotypes, further promoting chemoresistance and radioresistance. Protein homeostasis (proteostasis) refers to the dynamic balance of cellular processes involving protein synthesis, folding, modification, transport, and degradation, which is essential for maintaining normal physiological functions. This review aims to explore how proteostasis-regulated degradation pathways-specifically the ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway-modulate glycolysis in head and neck tumors, thereby influencing tumor proliferation and invasion. These insights may provide a theoretical foundation for overcoming treatment resistance and improving prognosis, while also opening new avenues for future therapeutic research in head and neck oncology.

Studies on vaginal natural orifice transluminal endoscopic surgery (vNOTES), which provides enhanced endoscopic vision via the vaginal route, are limited. Therefore, this study aimed to evaluate the feasibility, safety, and perioperative outcomes of vNOTES hysterectomy in symptomatic patients with giant polymyomatous uteri and no prior vaginal delivery.

This study examines the symptom clusters present in patients with oral cancer and assesses the impact of age, sex, tumor site, and clinical stage as four covariates on their longitudinal trajectories.

Lung cancer is the third most common malignancy in Iceland and remains the leading cause of cancer-related mortality. Lung cancer may harbor driver mutations affecting the function of Epidermal growth factor receptor (EGFR), Anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1), B-raf proto-oncogene (BRAF), RET proto-oncogene (RET), MET proto-oncogene (MET), and NTRK, which can influence the selection of targeted therapies and treatment outcomes. In Iceland, EGFR testing was initiated in 2005, and in 2016, multigene targeted panel became standard for tumor testing. The objective was to determine the uptake of testing and frequency of targeted mutations in lung cancer nationwide, the utilization of targeted therapies, and duration of such treatments.

Angiosarcoma of the breast is a rare but aggressive disease that often requires wide-margin resection resulting in massive thoracic defects. In this report we present the unique case of a patient who underwent primary chest wall reconstruction with palliative intent using Kiss Latissimus Dorsi (LD) Flap after resection of a huge angiosarcoma of the right breast, followed 3 years later by a secondary shift to totally autologous aesthetic breast reconstruction which was achieved by combining the first flap with breast-sharing internal mammary artery perforator (IMAP) flap and simultaneous contralateral breast reduction. The defect after extended mastectomy, measuring 24 × 18 cm, was resurfaced with a Kiss LD flap designed with two skin paddles of 24 × 13 and 14 × 5 cm, respectively. Three years after the initial reconstruction, the patient was tumor-free and required breast symmetrization. Therefore, a left reduction mammaplasty with simultaneous breast sharing Internal Mammary Artery Perforator (IMAP) flap was performed, augmenting the hypoplastic right breast with the entire lower pole of the contralateral side, transferring an 18 × 9 cm flap based on the fifth IMAP. Vascular safety of the procedure was guaranteed by intra-operative indocyanine green angiography evaluation. Recovery was uneventful and the 6 months post-operative follow-up confirmed flap integration, volume symmetry and high aesthetic satisfaction. This report underlines the versatility of this innovative combination of flaps in complex reconstructive scenarios where complex microsurgical transfers are contraindicated.

External auditory canal squamous cell carcinoma (EACSCC) is rare, affecting 1.6 in a million individuals. We report a case of EACSCC in a 66-year-old woman carrying a heterozygous BRCA2 germline pathogenic variant (GPV) (c.8537_8538del), with prior history of breast cancer. Tumor copy-number analysis showed loss of heterozygosity at the BRCA2 locus. Genomic scar analysis supported homologous recombination repair deficiency (HRD), with mutational signatures showing the predominance of APOBEC activity and lower contributions of HRD-associated single base (SBS3, SBS8) and INDEL (ID6) signatures. A somatic TP53 pathogenic variant was also identified. These findings suggest a contributory role for BRCA2 in EACSCC development.

Palisading adenocarcinoma is a newly described salivary gland tumor known for its predilection for sublingual and submandibular glands. The mass tends to have a non-invasive growth, although signs of infiltrative growth can occur resulting in a neoformation more adherent to deep neck structures. The main histological feature is a biphasic cellular pattern composed of polygonal epithelioid cells with small nuclei arranged in trabeculae and pseudo-rosette like structures and a second population of scattered well-formed ductal structures with occasional mucocytes. The mass, located in the parotid gland, resembled a neuroendocrine neoplasia regarding its histological architecture and positivity for CD56, whereas the cytological examination resembled that of a pleomorphic adenoma. An accurate histological and immunohistochemical study was crucial to guide the differential diagnosis. Here we present the first case of palisading adenocarcinoma affecting the parotid gland to further enrich the literature and to shed additional light on this peculiar and recently investigated neoplastic entity.

Lung squamous cell carcinoma (LUSCC) lacks consistent morphological criteria for tumour grading. Tumour budding (TB), defined as isolated cells or clusters of fewer than 4 cells at the invasive front, is prognostic in several carcinomas but remains insufficiently validated in LUSCC.

To develop and validate a deep learning model trained on reticulin-stained whole slide images (MesoRet) to accurately identify transitional features and assist in the histologic subtyping of diffuse mesothelioma.

Perineuriomas are soft tissue neoplasms composed almost entirely of cells resembling perineurium and their occurrence in gastrointestinal tract is quite rare, with most of reported cases occurring in the colon. No more than 12 cases of gastric perineurioma have been reported to date, and the diagnosis in a routine endoscopy biopsy service can be challenging given the broad differentials of a bland-looking spindle cell proliferation in gastric mucosa. Here we present a case of a gastric perineurioma in a 39-year-old woman detected in routine endoscopy biopsy where a high degree of suspicion of the pathologist and targeted immunohistochemical investigations for perineurial markers EMA and GLUT1 allowed the correct diagnosis. Reviewing the literature, it appears that gastric perienuriomas most commonly occur in mid-age females and are often detected in routine endoscopies, with appearance of a benign-looking mid-sized sessile polyp. Special attention is needed to discriminate with GIST to avoid inappropriate further investigations and overtreatment. Moreover, we speculate that these lesions are likely underrecognized in busy routine gastrointestinal biopsy service, as most are probably dismissed as benign mesenchymal polyps/submucosal proliferations after exclusion of GIST or are misdiagnosed as inflammatory fibroid polyp in the case of CD34 positivity. However, the case presented demonstrates that, in light of the apparently typical occurrence in mid-aged females with endoscopic impression of benign polyp of the body, general pathologists of routine biopsy services should also have a high degree of suspicion and maybe add a perineural marker to their panel.

Primary mesenchymal tumors of the meninges include various types, with meningioma being the most prevalent. Non-meningothelial primary tumors of the meninges are uncommon and present diagnostic difficulties due to their potential morphological similarities with each other and with the anaplastic subtype of meningioma. Intracranial dedifferentiated chondrosarcoma is extremely rare and is defined by the presence of both a conventional chondrosarcoma component and a non-cartilaginous sarcoma component. Diagnosing this tumor can be particularly challenging in biopsy samples or when the chondrosarcoma component is not prominently represented. We report a rare case of dedifferentiated chondrosarcoma of the cavernous sinus in a specimen containing only the dedifferentiated component and exhibiting an IDH1 mutation, underscoring the importance of genetic characterization for the differential diagnosis of tumors in this anatomical region. Given the recent evidence supporting the efficacy of IDH inhibitors in chondrosarcomas, identifying mutations in these genes may also have significant therapeutic implications.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, characterized by distinct histopathological and molecular features and often associated with poor prognosis due to its high metastatic potential. While histology, BAP1 status, and chromosomal changes are established prognostic markers, integration of morphological, immunophenotypic, and molecular data is evolving.

Thymic carcinomas (TC) are rare and understudied tumors. Pitfalls exist with TC diagnosis, and biomarkers are needed to support the pathologist. Here, we tested a series of biomarkers to differentiate TC from type B3 thymoma.

The management of hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (MBC) relies on molecular testing to inform treatment decisions. PIK3CA mutations, present in ~40% of cases, represent a key predictive biomarker for PI3K-pathway-targeted therapies. Despite its clinical relevance, PIK3CA testing continues to face challenges related to laboratory organization, standardization, and access. We conducted a nationwide, cross-sectional survey to evaluate current practices and institutional readiness for PIK3CA testing in Italy, in the context of the anticipated expansion of PI3K-targeted therapies, including inavolisib. A total of 118 healthcare professionals from institutions across 15 regions participated, providing data on test availability, laboratory workflows, analytical methodologies, accreditation status, and implementation barriers. Descriptive statistics were used for analysis. Overall, 88.1% of institutions reported the ability to perform PIK3CA testing, with 57.6% offering on-site analysis. Testing was predominantly performed in pathology laboratories (76.5%), followed by molecular biology (16.2%) and genetics laboratories (7.4%). However, 46.6% of institutions lacked formal molecular accreditation, and ISO:15189 certification remained uncommon. Pre-analytical workflows relied mainly on formalin-fixed paraffin-embedded (FFPE) tissue samples (89.7%), with limited routine use of liquid biopsy. Next-generation sequencing (NGS) was the most frequently adopted analytical approach (45.6%), followed by combined NGS and PCR-based strategies (36.8%). Most institutions reported turnaround times of 7-15 days. In conclusion, this updated survey indicates progress in access to PIK3CA testing and consolidation of NGS-based methodologies in Italy. Nevertheless, persistent gaps in accreditation, heterogeneous workflows, and limited integration of liquid biopsy highlight ongoing challenges in standardization and diagnostic equity. Coordinated national strategies will be essential to ensure consistent, high-quality molecular diagnostics in HR+/HER2- MBC.

Novel therapies for HER2-(ultra)low breast cancer (BC) have changed the traditional binary classification of HER2 status into a multi-tiered system that captures the full spectrum of expression as determined by immunohistochemistry (IHC). Several pre-analytical and analytical variables can influence the accurate identification of HER2 expression within the lowest IHC range.

Alterations in the phosphoinositide 3-kinase (PI3K)/AKT/PTEN signaling pathway are a well-recognized mechanism of resistance in hormone receptor-positive, HER2-negative metastatic breast cancer (HR+/HER2- mBC). These alterations are present in approximately half of patients with HR+/HER2- mBC. The major alterations in the pathway are somatic mutations in the PIK3CA (40-45%) and AKT1 (5%) genes, and loss-of-function alterations in PTEN (5-10%). New targeted agents that act against these alterations have been developed. Therefore, it is important to determine the mutational status of genes in this pathway to potentially offer a therapeutic alternative for these patients. In this review, we discuss the clinical and biological significance of PI3K pathway alterations in HR+/HER2- mBC, focusing on tumors that progress following endocrine therapy and CDK4/6 inhibitor treatment. We then highlight how different diagnostic strategies, including sample type, testing methodology, and timing, can improve the identification of patients who are eligible for targeted therapies and promote the effective integration of molecular diagnostics into routine clinical care.