Background Alterations in the PI3K/AKT/mTOR signaling pathway represent a mechanism of resistance to endocrine therapy in advanced HR+/HER2- breast cancer. The identification of activating mutations in PIK3CA has gained therapeutic relevance, guiding the use of PIK3CA-targeted inhibitors such as alpelisib and inavolisib. Methods A multidisciplinary panel of Italian experts conducted a structured consensus process to develop shared recommendations for molecular testing of PIK3CA in advanced HR+/HER2- breast cancer, addressing preanalytical, analytical, and clinical-therapeutic areas of concern. Results A total of 23 out of 29 statements reached complete agreement (100%). The resulting recommendations encompass sample selection, analytical methodologies, sensitivity thresholds, result reporting, and clinical interpretation and integration. Additional guidance is provided for the management of non-canonical gene variants and for other genes involved in the PI3K/AKT/mTOR pathway. Conclusions This consensus document provides operational and interpretative guidelines aimed at standardizing PIK3CAtesting and assessing related genes in clinical practice. These recommendations promote a harmonized approach to patient care, in line with the latest scientific evidence.
Background/Objectives: The neutrophil-to-lymphocyte ratio (NLR) is a simple biomarker reflecting systemic inflammatory status and has been investigated in head and neck cancer (HNC) as a potential prognostic indicator. Its role in relation to radiotherapy-related toxicity remains uncertain. The aim of this study was to provide a descriptive evaluation of NLR values in relation to oral mucositis severity and swallowing-related quality of life in patients undergoing radiotherapy-based treatment. Methods: We retrospectively evaluated 32 patients with locally advanced HNC treated with radiotherapy, with or without concomitant chemotherapy, in the definitive or adjuvant setting (March 2025-January 2026). NLR was calculated at baseline (T0), at a predefined mid-treatment timepoint (T3), and during week 6 of treatment (T6). Mucositis severity was assessed using CTCAE and the Oral Mucositis Assessment Scale (OMAS), while swallowing-related quality of life was measured using the MD Anderson Dysphagia Inventory (MDADI). Relationships between NLR values and toxicity endpoints were descriptively assessed using Spearman correlation analysis. Results: No statistically significant correlations were observed between NLR values and OM severity or swallowing-related outcomes at any evaluated timepoint. At T3, non-significant correlations were observed between NLR and CTCAE mucositis grade and between NLR and MDADI global score. No statistically significant correlations were observed between NLR values and OMAS at any evaluated timepoint. Conclusions: In this retrospective cohort, no association between NLR and radiotherapy-related mucositis severity or swallowing-related quality of life was demonstrated. These findings are descriptive and limited by the small sample size, the retrospective design, and the absence of control for potential confounding factors. No inferential or causal conclusions can be drawn. Further prospective studies with larger and more homogeneous cohorts are required to better characterize NLR behavior in this clinical setting.
Lorlatinib is a third-generation tyrosine kinase inhibitor approved for first- and second-line treatment of ALK-positive advanced non-small cell lung cancer. The CROWN study demonstrated that first-line lorlatinib significantly improves progression-free survival and intracranial control compared to crizotinib, with sustained benefits observed over a follow-up period of up to 5 years. As lorlatinib is associated with a distinct adverse event (AE) profile, we aim to analyze lorlatinib's safety profile, focusing on AEs incidence, severity, timing and management. A comprehensive safety management framework is also outlined to address lorlatinib-associated toxicity, drawing on evidence from the literature and the clinical expertise of an Italian expert panel. The most frequent AEs associated with lorlatinib are hypercholesterolemia and hypertriglyceridemia, which emerge early after treatment initiation. The 5-year analysis of the CROWN study revealed minimal changes in most AE rates over time. Pharmacological and non-pharmacological approaches effectively resolved most AEs; lorlatinib dose reduction did not affect its efficacy. The proposed safety management framework emphasizes patient preparation and regular monitoring to predict AE occurrence, indicating AE-specific interventions, mitigation strategies and multidisciplinary collaboration to optimize outcomes. Lorlatinib's toxicity appears generally predictable and manageable; the safety framework offers pragmatic guidance to clinicians for appropriate management in clinical practice.
Background Encorafenib + cetuximab (EC) and mFOLFOX6 or irinotecan, leucovorin, and fluorouracil (FOLFIRI) is approved in several countries for BRAF V600E-mutant metastatic colorectal cancer (mCRC) based on results from the BREAKWATER trial. Patients and methods In BREAKWATER Cohort 3, eligible patients with previously untreated BRAF V600E-mutant mCRC were randomly assigned 1:1 to receive EC+FOLFIRI or FOLFIRI with or without bevacizumab (control). The primary endpoint was objective response rate (ORR) by blinded independent central review (BICR), and the key secondary endpoint was progression-free survival (PFS) by BICR. Other secondary endpoints included overall survival (OS) and safety. Results A total of 147 patients were randomly allocated in Cohort 3 (EC+FOLFIRI, n = 73; control, n = 74) with similar baseline demographics and disease characteristics across arms. EC+FOLFIRI demonstrated clinically meaningful and statistically significant improvement in ORR by BICR {64.4% versus 39.2%, odds ratio = 2.756 [95% confidence interval (CI) 1.420-5.348], one-sided P-value = 0.0011}, meeting the primary endpoint (1 March 2025, data cutoff). At the 6 January 2026 data cutoff, the key secondary endpoint was met, with EC+FOLFIRI demonstrating a clinically meaningful and statistically significant PFS [hazard ratio = 0.44 (95% CI 0.27-0.70), one-sided P-value = 0.0002, 15.2 versus 8.3 months]. Prolonged OS was also observed with EC+FOLFIRI (hazard ratio = 0.56 [95% CI 0.34-0.94], not estimable versus 20.3 months). Serious adverse event rates were 49.3% versus 44.1% for the EC+FOLFIRI versus control arms, respectively. The safety profile was consistent with that known for each agent. Conclusions EC+FOLFIRI demonstrated clinically meaningful and statistically significant improvements in ORR and PFS, with prolonged OS versus control in BRAF V600E-mutant mCRC. The safety profile was generally manageable, with no new safety signals. These data support EC+FOLFIRI as an additional new standard of care for patients with BRAF V600E-mutant mCRC, enabling treatment personalisation.
Myelofibrosis (MF) splenomegaly reflects not only extramedullary hematopoiesis (EMH) but a compartmental organization of the splenic microenvironment into spatially distinct niches. Using Spatial whole transcriptome profiling on FFPE spleen tissue from three MF patients, we interrogated three anatomically defined compartments: Intravascular (IV), Perivascular (PV) and Red Pulp (RP). Differential expression was estimated through pairwise compartment contrasts with Benjamini-Hochberg false discovery rate correction (FDR < 0.05, |log2FC|≥1), and compartment “core signatures” were defined by directional concordance across the two contrasts relevant to each compartment. IV regions of interest (ROIs) showed an endothelial/adhesion and vascular stress program (e.g., PECAM1, VCAM1; antioxidant enzymes). PV ROIs were characterized by fibro-remodeling and immune-structured signals (COL1A1/COL3A1, LOXL1, MMP2/TIMP1; HLA‑DRA/CD74) including CXCL12, consistent with a PV niche coupling extracellular matrix remodeling to hematopoietic retention cues. RP ROIs captured an EMH-associated erythroid/heme program (ALAS2, FECH, BLVRB) with stress and inflammatory alarmins (S100A8/S100A9). Together, these findings support a compartmental “division of labor” in MF spleen, vascular interface activation, PV remodeling/chemokine niches, and RP EMH/redox stress, providing a spatial framework to interpret splenomegaly as structured niche dependencies and to prioritize candidate microenvironmental dependencies for follow‑up validation.
