Performance and clinical utility of two targeted multigene panels for GIST molecular characterization Margherita Nannini, Annalisa Astolfi, Thais Maloberti, Maria Concetta Nigro, Livia Gozzellino, Alice Costa, Maria Giulia Pirini, Antonio De Leo, Marco Grillini, Annalisa Altimari, Massimo Del Gaudio, Bruno Vincenzi, Elena Fumagalli, Antonella Brunello, Giovanni Grignani, Sandra Aliberti, Angela Dalia Ricci, Fabio Gelsomino, Elisabetta Setola, Giovanni Tallini, Dario de Biase, Maria Abbondanza Pantaleo 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
Reproducible safety and efficacy of durvalumab with or without tremelimumab for hepatocellular carcinoma in clinical practice: Results of the DT-real study Ciro Celsa, Tiziana Pressiani, Naoshi Nishida, Shadi Mohamad Chamseddine, Ashwini Arvind, Michael Li, Marta Fortuny, Najib Ben Khaled, Massimo Iavarone, Hidenori Toyoda, Ilario Giovanni Rapposelli, Andrea Casadei-Gardini, Caterina Vivaldi, Susanna Ulahannan, Haripriya Andanamala, Bernhard Scheiner, Matthias Pinter, Elena Orlandi, Claudia A.M. Fulgenzi, Giulia F. Manfredi, Pasquale Lombardi, Antonio D’Alessio, Bernardo Stefanini, Rosanna Villani, Francesca Romana Ponziani, Leonardo Stella, Ornella Carminati, Angela Dalia Ricci, Melina Gonzalez, Alba Sparacino, Gabriele Di Maria, Marco Vaccaro, Giuseppe Cabibbo, Calogero Cammà, Maria Reig, Robin K. Kelley, Amit G. Singal, Ahmed O. Kaseb, Masatoshi Kudo, Lorenza Rimassa, David James Pinato Jhep Reports, 2026 Background & Aims: Durvalumab plus tremelimumab (STRIDE) has emerged as a first-line systemic treatment option for unresectable hepatocellular carcinoma (HCC). This international multicentre study aimed to evaluate the efficacy and tolerability of STRIDE or durvalumab monotherapy in routine clinical practice, comparing outcomes between patients within and outside key eligibility criteria for the HIMALAYA trial. Methods: From a database of 1,423 patients with advanced/unresectable HCC treated with immunotherapy across 35 centres, we analysed 233 patients receiving STRIDE or durvalumab monotherapy. Patients were categorized as HIMALAYA-IN or HIMALAYA-OUT based on key trial eligibility criteria (no prior systemic therapy, ECOG-PS 0-1, Child-Pugh class A, no Vp4 thrombosis). Baseline characteristics were assessed for overall survival (OS) and hepatic decompensation using a multivariable Cox model and competing-risk analysis, respectively. Objective response rates and treatment-related adverse events were recorded. Results: = 0.03). Macrovascular invasion and hepatic decompensation were independent negative prognostic factors in the whole cohort. Hepatic decompensation occurred in 10.5% of patients within 12 months from treatment start. Objective response rate was 23.7% and 17.8% of HIMALAYA-IN and -OUT patients, respectively. Patients achieving disease control (whole cohort: 59.4%) demonstrated 24-month OS of 58.2% in HIMALAYA-IN and 44.8% in HIMALAYA-OUT groups. Grade 3-4 treatment-related adverse events occurred in 16.3% of patients. Conclusions: STRIDE shows reproducible effectiveness and an acceptable safety profile in real-world practice. Achieving disease control and maintaining liver function emerged as key determinants of long-term survival benefit. Impact and implications: The DT-real study validates the efficacy and safety of STRIDE (durvalumab plus tremelimumab) in routine clinical practice, with HIMALAYA trial-eligible patients achieving 23-month median survival, and showing a safety profile comparable to that observed in the pivotal trial. Nearly half of real-world patients received treatment despite not meeting original trial criteria, reflecting urgent clinical need in this population with limited therapeutic options. As for other immunotherapy-based combinations, hepatic decompensation is a critical determinant of survival. Patients achieving disease control demonstrated substantially improved 24-month overall survival rates compared to those with progressive disease, confirming the findings of the exploratory analyses of the HIMALAYA trial.
Liquid biopsy for biliary tract cancer: available evidence and future research directions Enes Erul, Angela Dalia Ricci, Mario Della Mura, Gerardo Cazzato, Raffaella Massafra, Pınar Kubilay Tolunay, Yüksel Ürün, Alessandro Rizzo Expert Review of Molecular Diagnostics, 2026 INTRODUCTION: Biliary tract cancers (BTCs) are molecularly heterogeneous, and early genomic profiling is becoming increasingly important for treatment decisions. Because tissue sampling is often limited or inadequate, there is a clear need for minimally invasive biomarkers that can support treatment selection and longitudinal disease assessment. AREAS COVERED: This narrative review summarizes current and emerging liquid-biopsy (LB) applications in BTC, with a primary focus on plasma circulating tumor DNA (ctDNA). The evidence base was assembled through targeted searches of PubMed/MEDLINE and Embase up to 1 February 2026, supported by selective ClinicalTrials.gov searches for ongoing biomarker-driven studies. We discuss ctDNA-based molecular profiling for actionable alterations, its prognostic role including minimal residual disease assessment, and its use in serial monitoring of treatment response and acquired resistance. We also consider how LB may support clinical-trial enrichment and biomarker-guided endpoints, and briefly review complementary approaches using bile and other analytes, while highlighting current evidence gaps. EXPERT OPINION: In BTC, ctDNA is best viewed as a complement to tissue-based profiling, especially when tissue is inadequate or when rapid genotyping is needed. Its broader clinical impact will depend on assay standardization, clearer interpretation frameworks for low-shedding disease, and prospective studies showing that ctDNA-guided decisions improve patient outcomes.
Nivolumab plus ipilimumab for hepatocellular carcinoma: a game-changer? Lorenza Di Marco, Federica Valerio, Yuri Maculan, Bianca Medici, Andrea Spallanzani, Massimo Dominici, Angela Dalia Ricci, Alessandro Rizzo, Massimiliano Salati Expert Opinion on Biological Therapy, 2026 INTRODUCTION: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, largely arising in the setting of chronic liver disease and cirrhosis. Given the immunosuppressive hepatic tumor microenvironment, optimizing immunotherapeutic strategies is critical to improve patient outcomes. AREAS COVERED: This review examines the biological rationale and clinical evidence supporting dual immune checkpoint inhibition with nivolumab plus ipilimumab in advanced HCC. We discuss mechanisms of immune tolerance in cirrhosis and tumor progression, including regulatory T cells, myeloid-derived suppressor cells, hypoxia, metabolic reprogramming, and T-cell exhaustion. Key clinical data from early-phase studies, such as CheckMate 040 and the phase III CheckMate 9DW, are analyzed, focusing on overall survival, response rates, and durability of response compared with tyrosine kinase inhibitors. A structured literature search of PubMed, Embase, and major oncology congress proceedings was conducted to identify relevant preclinical and clinical studies. EXPERT OPINION: Dual checkpoint blockade represents an effective first-line option for selected patients with advanced HCC, offering meaningful survival benefit at the cost of increased immune-related toxicity. Future progress depends on improved patient selection, biomarker development, and rational combination strategies.
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, Andrea Palloni, Chiara Ricci, Ingrid Garajova, Elena Orlandi, Ina Valeria Zurlo, Angelica Petrillo, Anna Diana, Angela Dalia Ricci, Alessandro Rizzo, Martina Manni, Ornella Garrone, Massimo Dominici, Michele Ghidini 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.
Treatment options for advanced small bowel adenocarcinoma: a systematic review M. Ghidini, A. Parisi, I.V. Zurlo, M.M. Laterza, L. Gervaso, A.D. Ricci, A. Biasi, A. Nicastro, O. Garrone, G. Tomasello, A. Petrillo, F. Petrelli ESMO Gastrointestinal Oncology, 2025 Small bowel adenocarcinoma (SBA) is a rare and increasingly recognised malignancy, accounting for only 3.4% of all gastrointestinal cancers.It often presents with non-specific or late-stage symptoms, resulting in delayed diagnosis and poor prognosis.For advanced disease, treatment recommendations rely primarily on small phase II trials and retrospective series with no established standard therapy.Moreover, although SBA commonly harbours KRAS mutations (43%), CDKN2A (p16) loss, and HER2/ERBB2 mutations (12%), no targeted biological agents have demonstrated clinical efficacy against this disease.Our systematic review was conducted to comprehensively evaluate the available evidence on systemic therapies for patients with advanced or metastatic SBA, with particular focus on treatment efficacy, safety profiles, and the potential influence of molecular biomarkers.
Pharmacometric and Digital Twin modeling for adaptive scheduling of combination therapy in advanced gastric cancer Michela Prunella, Nicola Altini, Rosalba D’Alessandro, Annalisa Schirizzi, Angela Dalia Ricci, Claudio Lotesoriere, Paolo Scarabaggio, Raffaele Carli, Mariagrazia Dotoli, Gianluigi Giannelli, Vitoantonio Bevilacqua Computer Methods and Programs in Biomedicine, 2025 BACKGROUND AND OBJECTIVE: Combining targeted therapeutics can significantly help address the dynamic changes in cancer biology abnormalities and thus improve the duration of response and outcome. However, the efficacy of such approaches is highly dependent on the combination, interactions, and timing between the administered drugs. Current clinical trials can test only a low number of schedules with fixed designs. Pharmacometric tools can assist in exploring and selecting the most effective drug dosages and schedules by modeling traits of patients with different clinical and biological characteristics. METHODS: This study proposes a pharmacokinetic-pharmacodynamic model describing the networked system of tumor development and angiogenesis under the control of antiangiogenic and cytotoxic, i.e., Ramucirumab and Paclitaxel second-line combination therapy. A two-step scalable algorithm is proposed to calibrate model parameters and match virtual to real population therapy outcomes, followed by fine-tuning directly on the Progression-free Survival (PFS)-2 Kaplan-Meier curve. Two cohorts of advanced gastric cancer patients were considered: a calibration cohort from South Korea, and an external verification cohort from IRCCS "S. De Bellis", an Italian research hospital. These real-world patients had heterogeneous clinical starting conditions. We perform prospective evaluations of new combination regimens that adhere to pharmacological constraints that are paramount for clinical translation, in which the administration time of the cytotoxic agent is triggered by the normalization window opening, monitored by a tumor microenvironment digital biomarker. RESULTS: The calibration procedure led to the discovery of a new mathematical biomarker describing the influence of intrinsic tumor growth and angiogenesis on treatment outcomes. The predictive value was assessed through the log-rank test between two PFS-2 groups, which exhibited different (p-value <0.0001) therapy response trends. Our results showcase a new regimen that, by using 33% less cytotoxic drug, achieves indistinguishable PFS-2. Additionally, we present another regimen that extends PFS-2 from 49.2% to 60.9% after 121 days of therapy (p-value <0.0001), by using the same dosing as the standard protocol. CONCLUSIONS: This study proposes an in-silico quantitative platform for virtual expansion of real-world patient cohorts. Furthermore, the estimation of the efficacy of adaptive dose schedules of a combined therapy can complement and inform clinical trial design.
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, Antonio Di Sabatino, Emanuela Miceli, Sara Massironi, Nicola Zucchini, Renato Cannizzaro, Stefano Realdon, Giuseppe Losurdo, Antonia Valeria Borraccino, Elisa Marabotto, Edoardo Giovanni Giannini, Andrea Pasta, Francesco Calabrese, Luca Mastracci, Roberta Elisa Rossi, Valentina Sciola, Antonella Contaldo, Antonio Pisani, Angela Dalia Ricci, Maria Savino, Gianluigi Giannelli, Mario Milco D’Elios, Chiara Della Bella, Damiano Martino, Fabiana Zingone, Fabio Farinati 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, Federica Rizzi, Angela Dalia Ricci, Giampiero De Leonardis, Claudio Lotesoriere, Gianluigi Giannelli, Rosalba D’Alessandro, Maria Principia Scavo 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.
VEGFA Status as a Predictive Marker of Therapy Outcome in Metastatic Gastric Cancer Patients Following Ramucirumab-Based Treatment Annalisa Schirizzi, Aram Arshadi, Doron Tolomeo, Laura Schirosi, Anna Maria Valentini, Giampiero De Leonardis, Maria Grazia Refolo, Rossella Donghia, Clelia Tiziana Storlazzi, Alfredo Zito, Angela Dalia Ricci, Simona Vallarelli, Carmela Ostuni, Maria Bencivenga, Giovanni De Manzoni, Caterina Messa, Raffaele Armentano, Gianluigi Giannelli, Claudio Lotesoriere, Rosalba D’Alessandro Biomedicines, 2023
Second-Line Chemotherapy in Elderly Patients with Advanced Biliary Tract Cancer: A Multicenter Real-World Study Alessandro Rizzo, Massimiliano Salati, Giorgio Frega, Valeria Merz, Francesco Caputo, Alessandro Di Federico, Andrea Palloni, Riccardo Carloni, Angela Dalia Ricci, Gennaro Gadaleta-Caldarola, Carlo Messina, Andrea Spallanzani, Fabio Gelsomino, Stefania Benatti, Gabriele Luppi, Davide Melisi, Massimo Dominici, Giovanni Brandi Medicina Lithuania, 2022
Hacking pancreatic cancer: Present and future of personalized medicine Alessandro Di Federico, Valentina Tateo, Claudia Parisi, Francesca Formica, Riccardo Carloni, Giorgio Frega, Alessandro Rizzo, Dalia Ricci, Mariacristina Di Marco, Andrea Palloni, Giovanni Brandi Pharmaceuticals, 2021
