Claudio Lotesoriere

Background: Immunotherapy has changed the therapeutic approach to advanced gastric cancer (AGC) and has shown survival benefits compared with standard chemotherapy. However, in clinical practice, its use remains heterogeneous. Differences in diagnostic pathways, organisational aspects, and regional settings may lead to delays in treatment access. This study aimed to analyse these issues and to describe possible shared strategies to improve the use of immunotherapy in AGC in Italy. Materials and Methods: The analysis was performed in two steps. First, a focus group comprising 13 oncologists and pathologists from 5 national reference centres was organised to collect information on the use of immunotherapy biomarker tests and the main barriers encountered in daily practice. Based on the topics emerging from this discussion, a second step was conducted using a consensus questionnaire. The questionnaire was sent to a multidisciplinary group composed of 19 oncologists, pathologists, surgeons, pharmacists, and endoscopists. Results: Several common problems were reported during the focus group discussion. These included delays in biomarker testing, differences in pre-analytical procedures among centres, the absence of shared quality indicators, and difficulties in tracking tissue samples, especially when samples were sent from outside hospitals. In addition, limited interaction among different specialists was frequently mentioned. The results of the questionnaire indicated a high level of agreement on several proposed actions, such as the evaluation of regional differences, the use of organisational models already adopted in some Italian oncology networks, the introduction of new biomarkers together with dedicated training activities, and the use of digital tools to support the discussion of complex cases. All survey items reached the predefined consensus threshold. Conclusions: This study identified several organizational and diagnostic challenges affecting the implementation of immunotherapy in AGC. Participants highlighted a number of potential priorities for improvement, including optimization of diagnostic workflows, stronger multidisciplinary collaboration, and greater coordination across centres. These findings may inform future initiatives aimed at reducing variability in clinical practice and supporting equitable access to innovative treatments.

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.

PURPOSE: To investigate whether intermittent treatment after an induction phase of first-line schedule of fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus panitumumab (PAN) prevents or delays the onset of resistance and improves safety and compliance with treatment in patients with unresectable RAS / BRAF wild-type (wt) metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: IMPROVE (ClinicalTrials.gov identifier: NCT04425239 ) was an open-label, multicenter, randomized phase II noncomparative trial. Patients with unresectable RAS / BRAF wt mCRC were randomly assigned (1:1) to receive FOLFIRI plus PAN continuously until progression (arm A) or intermittently, with treatment-free intervals (arm B) until progression on treatment, toxicity, or death. The primary end point was progression-free survival on treatment (PFSot) at 12 months. Assuming a null hypothesis of median PFSot time ≤7 months and target PFSot ≥10 months, 65 patients per arm were needed to achieve 80% power and 10% type I error, according to the binomial test. RESULTS: Between May 2018 and June 2021, 69 patients were randomly assigned to arm A and 68 to arm B. The median number of treatment cycles was 13 in arm A and 16 in arm B. At a median follow-up of 43.2 months (IQR, 35.0-50.5), median PFSot was 11.2 and 17.5 months with 12-month PFSot rates of 45.7% and 58.5%, for arms A and B, respectively. The overall response rates were 68.1% and 61.2%, and median overall survival rates were 36.3 and 35.1 months in arms A and B, respectively. The overall rate of grade >2 skin PAN-related adverse events was 30.3% in arm A and 17.9% in arm B. CONCLUSION: Intermittent FOLFIRI plus PAN after the induction phase was feasible, and the primary end point was met with reduced toxicity while allowing patients more time off treatment.

Computational pathology enables the automatic tissue analysis of Whole Slide Images (WSIs), offering unmatched possibilities to capture quantitative tumor microenvironment (TME) characteristics that are essential for patients' prognosis and therapy response. The existing clinical and digital biomarkers do not encompass the morphometric features and spatial interactions between vascular networks and immunological compartment in the TME. To address this challenge, this work presents a high- throughput quantitative framework for automatic segmentation and assessment of aberrant phenotypes of blood vessels and immune cell clusters in hematoxylin & eosin-stained WSIs, to construct the Vascular-Immune Pathomic (VIPath) biomarker. For our study, we utilized three public datasets of Colon Adenocarcinoma (COAD) and Stomach Adenocarcinoma (STAD) from The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) projects: TCGA-COAD, TCGA-STAD, and CPTAC-COAD. Additionally, we collected two in-house gastric cancer cohorts of 80 and 51 patients : DBGC-M0 and DBGC-M1. The VIPath biomarker was incorporated in a Cox proportional hazards model trained on the TCGA-COAD. Then, it was validated for predicting Overall Survival (OS) in TCGA-STAD, DBGC-M0, and DBGC-M1, Disease Free Survival in CPTAC-COAD and second-line therapy Progression-free Survival (PFS-2) in DBGC-M1. VIPath encompasses features from both vascular and immunological compartments interacting in the TME. Results proved that VIPath was capable to significantly stratify risk groups for OS TCGA-STAD (p=0.018), OS DBGC-M0 (p=0.029), OS DBGC-M1 (p=0.014), and PFS-2 DBGC-M1 (p$< $0.005). Furthermore, when inserted in a Cox model, it led to an improvement of C-index and R² over all other considered prognostic factors, i.e., p-TNM, ECOG, MSI, HER2.

Angiogenesis inhibition treatments are limited and are often too late for advanced gastric cancer (GC) patients, in whom its efficacy is reduced. New molecular biomarkers are needed to optimize therapy regimens. In regard to this framework, circulating miRNAs, with high sensitivity and specificity, could be useful biomarkers of GC. The present longitudinal study was focused on analyzing the expression levels of a blood miRNA signature in a cohort of 40 patients receiving second-line therapy combining Ramucirumab and Paclitaxel, stratified based on their Progression-Free Survival (PFS). Using differential and bioinformatic analysis, miR-205-5p, miR-30e-3p, and miR-23b-3p were selected as possible predictive biomarkers, with the results showing that they were more highly expressed in patients exhibiting longer PFS and that they were involved in modulating angiogenesis. Furthermore, patients with longer PFS showed a progressive and significant decrease in the selected miRNA to minimal levels. The loss of the protective effect and the increased expression of the hypothetical targets, including angiopoietin-2, were then observed. The hypothesis was supported by the inverse correlation found for miR-205-5p and angiopoietin-2. Circulating levels of miR-205-5p were protective (HR = 0.37, p = 0.02) and patients with higher baseline miRNA levels had longer OS (12.47 vs. 9.00 months). Our findings suggest that these three miRNAs may be novel candidates as non-invasive predictive markers of therapy outcomes.

Autotaxin (ATX) is a member of the ectonucleotide pyrophosphate/phosphodiesterase (ENPP) family; it is encoded by the ENPP2 gene. ATX is a secreted glycoprotein and catalyzes the hydrolysis of lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA is responsible for the transduction of various signal pathways through the interaction with at least six G protein-coupled receptors, LPA Receptors 1 to 6 (LPAR1–6). The ATX–LPA axis is involved in various physiological and pathological processes, such as angiogenesis, embryonic development, inflammation, fibrosis, and obesity. However, significant research also reported its connection to carcinogenesis, immune escape, metastasis, tumor microenvironment, cancer stem cells, and therapeutic resistance. Moreover, several studies suggested ATX and LPA as relevant biomarkers and/or therapeutic targets. In this review of the literature, we aimed to deepen knowledge about the role of the ATX–LPA axis as a promoter of cancer development, progression and invasion, and therapeutic resistance. Finally, we explored its potential application as a prognostic/predictive biomarker and therapeutic target for tumor treatment.

Introduction: About 90% of cholangiocarcinomas are adenocarcinomas with glandular or tubular structures lined by epithelial cells, with no bile production and with a variable degree of differentiation, arising in the background of desmoplastic stroma. The remaining 10% is represented by rarer histological variants of which there is little knowledge regarding the biological behavior, molecular characterization, and sensitivity to the various possible therapies, including molecular-based treatments. Such rare tumors are described only in case reports or small retrospective series because of their exclusion from clinical trials. This national initiative, here presented, aims to address the following knowledge gap: a) how much does histological diversity translate into clinical manifestation variety? b) are those chemotherapy regimens, recommended for conventional biliary tract cancers, potentially active in rare variants? Therefore, epidemiological, pathological, and clinical characterization of series of rare biliary histotypes/variants, for which therapeutic and follow-up data are available, will be collected. Methods: An Italian task force on rare tumors of the biliary tract (IRaBiCa) has been created, whose initiative is a multicenter retrospective study involving 34 Italian cancer centers. Clinical data from approximately 100 patients will be collected and analyzed. Continuous variables will be presented as median ± standard deviation, while categorical variables will be expressed in terms of frequency. Kaplan-Maier analyses will be used to compare disease free, progression free and overall survival, according to the different histotypes. Conclusions: We expect to gather novel data on rare histotypes of biliary tract cancer that will be useful to support their molecular and immunological characterization.