Performance and clinical utility of two targeted multigene panels for GIST molecular characterization Margherita Nannini, Annalisa Astolfi, Thais Maloberti, Maria Concetta Nigro, Livia Gozzellino, et al. Scientific Reports, 2026 Molecular analysis is mandatory in the diagnostic work-up of gastrointestinal stromal tumors (GISTs). Indeed, it is essential for clinical decisions, from patients’ selection for systemic treatment to identifying unrecognized syndromic conditions. Since GISTs are recognized as a heterogeneous family of different clinical entities, molecular analysis should also require a feasible, rapid, and reliable diagnostic workflow. Herein, we present our experience on the performance and clinical utility of two lab-developed multigene-NGS panels specifically built for GIST analysis. Among 163 analyzed GISTs, 72.4% carried KIT mutations while 11.0% were PDGFRA -mutant. Among putative KIT / PDGFRA WT cases that arrived at our attention from an external analysis, nine of 10 were found carrying either KIT or PDGFRA pathogenic mutations by our panel. On 26 KIT/PDGFRA/BRAF WT patients at the first level, the second level panel identified NF1 or SDHA mutations in 16 cases, while 10 patients did not display any mutation, except for two of them found as carriers of SDHC epimutation. This optimized NGS diagnostic approach helps to characterize the molecular profiles of GIST and drastically reduces the number of truly non-KIT and non-PDGFRA-addicted GIST cases.
Unlocking New Possibilities: Dual Immune Blockade in Brain Metastases from Rare Tumors Angela Dalia Ricci, Alessandro Rizzo Clinical Cancer Research, 2026 Summary The results of a recent trial undoubtedly contribute a vital element to the overarching management of rare tumors and offer new treatment hopes for patients with brain metastases, thereby paving the way for future research in immunotherapy. See related article by Ahluwalia et al., p. 1928
Preliminary report on advanced biliary cancer patients receiving multimodality treatment in the immunotherapy era: a real-world multicentre experience Massimiliano Salati, Eleonora Borghi, Riccardo Cuoghi Costantini, Alessandro Parisi, Alessia Lancianese, et al. Therapeutic Advances in Medical Oncology, 2026 Background: Advanced biliary cancer (ABC) is still regarded as an incurable condition. However, the improved depth and duration of response enabled by chemo-immunotherapy may foster intensified strategies, including surgical procedures, radiotherapy and intra-arterial techniques. Objectives: The prevalence, clinical features and treatment outcomes of ABC receiving multimodality treatment in the immunotherapy era are unknown. Design: Newly diagnosed ABC treated with chemo-immunotherapy and loco-regional procedures from February 2022 to December 2024 were retrospectively identified at 10 tertiary referral cancer centres in Italy. Methods: Categorical variables were compared using the chi-squared test, and the inverse probability of treatment weighting analysis was performed to reduce selection biases. Results: Of 241 ABC receiving first-line treatment, 12 (4.9%) fulfilled the inclusion criteria. The median age was 69 (range 36–80), and 9 patients (75%) had intrahepatic cholangiocarcinoma (iCCA). Ten (83.3%) presented with de novo unresectable ABC: 3 (25%) had locally advanced, and 7 (50.3%) had metastatic disease. The median number of metastatic sites was one, with lymph nodes being the most commonly involved location (41.6%, n = 5). Patients treated with intensified therapy were more likely to have low tumour burden ( p = 0.03) and iCCA ( p = 0.06). Overall, four patients underwent surgery, three transarterial radioembolization, three stereotactic body radiotherapy and two liver transplants. As of data cut-off, 11 patients were alive (91.6%), and five patients were disease-free (41.6%). After adjusting for age, gender, Eastern Cooperative Group Performance Status (ECOG PS), primary site, disease status and number of metastases, the overall survival for the multimodality strategy versus systemic treatment alone was not reached versus 14.1 months ( p < 0.001). Conclusion: This study, the first on multimodality treatment of ABC in the immunotherapy era, suggests that a highly selected subset of patients may achieve long-term disease control with an intensified approach. Oligometastatic patients and those affected by iCCA appear as the best candidates. Future studies are needed to confirm these preliminary findings.
Clinical and Endoscopic-Histological Features of Multifocal and Corpus-Restricted Atrophic Gastritis Patients With Non-Cardia Gastric Cancer or Dysplasia: A Multicenter, Cross-Sectional Study Edith Lahner, Bruno Annibale, Emanuele Dilaghi, Cristina Millado Luciano, Marco Vincenzo Lenti, et al. Clinical and Translational Gastroenterology, 2025 Background: Helicobacter pylori(Hp)-related atrophic gastritis(AG) affects corpus and antral mucosa, resulting in multifocal AG(MF-AG), autoimmunity-driven AG is corpus-restricted(CR-AG). AG carries increased gastric dysplasia(GD) and cancer(GC) risk, well established in MF-AG, but debated in CR-AG. This study aimed to assess clinical, endoscopic-histological characteristics of GD-GC in MF-AG and CR-AG patients. Methods: Multicenter-cross-sectional study across 11 Italian gastroenterology centres on data of non-cardia GD-GC in MF-AG or CR-AG adult patients based on clinical, endoscopic, and histological charts. Results: 84 patients were included with MF-AG and CR-AG in 45(53.6%) and 39(46.4%), respectively. Low-grade(LG)-GD, high-grade(HG)-GD, and GC were diagnosed in 31(36.9%), 6(7.1%), and 47(56.0%). GD-GC similarly occurred in MF-AG and CR-AG patients: HG-GD in 4(8.9%) vs 2(5.1%), LG-GD in 17(37.8%) vs 14(35.9%), GC in 24(53.5%) vs 23(59.0%)(p>0.05). Compared to MF-AG, in CR-AG patients GD-GC were more commonly polypoid (51.6% vs 27.3%, p=0.048) and more frequently in the corpus (55.3% vs 28.6%,p=0.02), but occurred also in the antrum (34.2%) and incisura (10.5%). Surgery was more frequent in CR-AG than in MF-AG (48.6% vs 23.1%,p=0.02). Corpus atrophy severity and intestinal metaplasia were not different (p>0.05), histological Hp positivity was low in both (2.3% vs 2.9%,p=0.87), but in Hp-negatives active inflammation was present in the antrum in 26.7% and 7.7%(p=0.02), in the corpus in 31.1% and 21.5%(p=0.27). Conclusions: Non-cardia GC and GD may occur in both MF-AG and CR-AG, displaying differences in topography and endoscopic presentation but similarities in non-lesional mucosa, differentiation and staging. Surveillance should be considered in corpus AG, regardless of extension and supposed etiology.
Unravelling Paclitaxel Resistance in Gastric Cancer: The Role of Small Extracellular Vesicles in Epithelial Mesenchymal Transition and Extracellular Matrix Remodelling Giorgia Panzetta, Annalisa Schirizzi, Francesco Balestra, Maria De Luca, Nicoletta Depalo, et al. Cancers, 2025 Background: Gastric cancer (GC) is a highly aggressive disease often complicated by resistance to chemotherapy agents like paclitaxel (PTX), which targets microtubules to induce apoptosis. Resistance arises through complex molecular mechanisms, including the overexpression of pro-angiogenic factors (VEGFA, ANG-2), activation of survival pathways (PDGFRβ, PPARγ), and epithelial-mesenchymal transition (EMT) driven by proteins such as VIM, E-CAD, N-CAD, and FLOT-1. The extracellular matrix (ECM), regulated by COL1A1 and influenced by PPARγ, acts as a physical barrier to drug penetration. Small extracellular vesicles (sEVs) have emerged as critical mediators of intercellular communication and may influence these resistance pathways. Methods: This study investigated the role of sEVs isolated from metastatic GC patients treated with Ramucirumab and PTX. Patients were stratified by progression-free survival (PFS) into rapidly progressing (RP) and controlled disease (CD) groups. sEVs from these patients were applied to HCEC-1CT and HEPA-RG cell lines. Cell viability assays, gene and protein expression analyses, and bioinformatic studies were conducted to assess the impact of sEVs on resistance-related markers. Results: Results showed that sEVs from CD patients reduced the expression of markers associated with drug resistance, while sEVs from RP patients increased these markers, promoting angiogenesis, EMT, and ECM remodeling. These changes correlated with enhanced cell survival and resistance phenotypes. Bioinformatic analyses confirmed that sEVs modulate inflammation, ECM dynamics, and EMT pathways. Conclusions: In conclusion, sEVs from metastatic GC patients significantly influence chemoresistance and tumor progression. Targeting sEV-mediated signaling may offer novel therapeutic strategies to overcome resistance and improve treatment outcomes in gastric cancer.
