BACKGROUND AND OBJECTIVES:Molecularly defined oligodendrogliomas are rare tumors whose prognosis has improved over time because of more effective treatments. However, several aspects of management are still controversial, and studies with long-term follow-up are needed. The main aim of this study was to analyze and compare the natural history and management of patients with OG2 and OG3 and define which factors have the strongest effect on outcome. METHODS:We reviewed an institutional retrospective cohort (1996-2024) of patients with molecularly defined OG2 and OG3 according to World Health Organization 2021. We retrieved information on baseline clinical features, MRI characteristics (i.e., presence and pattern of contrast enhancement), extent of resection, initial treatment modalities after surgery, and management at progression. The relationships of these factors with progression-free survival (PFS) and overall survival (OS) were studied with univariate and multivariate analyses. RESULTS:Among 240 patients with IDH-mutant 1p/19q-codeleted oligodendrogliomas, grade 2 tumors were 149 (62.1%) and grade 3 were 91 (37.9%) with a median age of 42 and 44 years, respectively. Male/female ratio was 73/76 (49%/51%). Among patients with OG3, 70/91 (77%) exhibited a diffuse grade 3 histology (OG3d), whereas 21/91 (23%) had focal grade 3 areas only (OG3f). Overall, patients with OG2 and OG3 had similar median PFS (57.6 months, CI 53.2-61.9, vs 59.8 months, CI 41.9-77.6, p = 0.25), and prolonged median OS (274 months vs not reached). However, patients with OG3 exhibited a shorter time to radiotherapy at progression and their survival probability declined more rapidly within the first decade after surgery. The extent of resection was the only factor that significantly affected both PFS and OS in a multivariate analysis (for PFS, hazard ratio [HR] 0.90, 0.62-0.99, p = 0.026; for OS, HR 0.29, 0.13-0.79, p = 0.016), whereas tumor grade did not. Temozolomide alone as initial treatment of high-risk OG2 and OG3 with large residual tumor after surgery was not detrimental for survival. The same was true for observation in a small group of young patients with nonenhancing OG3 who have undergone complete resection and with only focal areas of malignancy (OG3f). DISCUSSION:This large retrospective cohort of IDH-mutant 1p/19q-codeleted oligodendrogliomas receiving standard treatments could serve as a benchmark for comparison with new IDH inhibitors in future clinical studies.

Background and ObjectivesMolecularly defined oligodendrogliomas are rare tumors whose prognosis has improved over time because of more effective treatments. However, several aspects of management are still controversial, and studies with long-term follow-up are needed. The main aim of this study was to analyze and compare the natural history and management of patients with OG2 and OG3 and define which factors have the strongest effect on outcome.MethodsWe reviewed an institutional retrospective cohort (1996-2024) of patients with molecularly defined OG2 and OG3 according to World Health Organization 2021. We retrieved information on baseline clinical features, MRI characteristics (i.e., presence and pattern of contrast enhancement), extent of resection, initial treatment modalities after surgery, and management at progression. The relationships of these factors with progression-free survival (PFS) and overall survival (OS) were studied with univariate and multivariate analyses.ResultsAmong 240 patients with IDH-mutant 1p/19q-codeleted oligodendrogliomas, grade 2 tumors were 149 (62.1%) and grade 3 were 91 (37.9%) with a median age of 42 and 44 years, respectively. Male/female ratio was 73/76 (49%/51%). Among patients with OG3, 70/91 (77%) exhibited a diffuse grade 3 histology (OG3d), whereas 21/91 (23%) had focal grade 3 areas only (OG3f). Overall, patients with OG2 and OG3 had similar median PFS (57.6 months, CI 53.2-61.9, vs 59.8 months, CI 41.9-77.6, p = 0.25), and prolonged median OS (274 months vs not reached). However, patients with OG3 exhibited a shorter time to radiotherapy at progression and their survival probability declined more rapidly within the first decade after surgery. The extent of resection was the only factor that significantly affected both PFS and OS in a multivariate analysis (for PFS, hazard ratio [HR] 0.90, 0.62-0.99, p = 0.026; for OS, HR 0.29, 0.13-0.79, p = 0.016), whereas tumor grade did not. Temozolomide alone as initial treatment of high-risk OG2 and OG3 with large residual tumor after surgery was not detrimental for survival. The same was true for observation in a small group of young patients with nonenhancing OG3 who have undergone complete resection and with only focal areas of malignancy (OG3f).DiscussionThis large retrospective cohort of IDH-mutant 1p/19q-codeleted oligodendrogliomas receiving standard treatments could serve as a benchmark for comparison with new IDH inhibitors in future clinical studies.

High-grade vaginal intraepithelial neoplasia (HG VaIN) is a rare preinvasive lesion characterized by a high risk of recurrence. Management strategies encompass both surgical excision, ablative procedures, and topical treatments. Brachytherapy provides a less invasive option, particularly for recurrent HG VaIN cases where other therapies have been unsuccessful or are not feasible. The present study assessed effectiveness and safety of brachytherapy in treating HG VaIN, with a focus on long-term outcomes, including local disease control, progression to invasive carcinoma, and treatment-associated adverse effects. A single-center retrospective analysis was performed on 31 patients with histologically proven HG VaIN who underwent brachytherapy at St. Anna University Hospital in Turin, Italy, from 1997 to 2024. High-dose-rate vaginal brachytherapy (HDR-VBT) was delivered, with dosage and fractionation schedules customized based on the characteristics of the lesions and individual patient factors. The median age of the patients was 65 years, with 87.1

Late metastatic relapses still represent a major clinical challenge in breast cancer, particularly in hormone receptor-positive (HR+) disease, with dormant disseminated tumor cells (DTCs) playing a critical role in driving late metastatic relapses. In fact, these cells can persist in a quiescent, non-proliferative state in metabolically hostile microenvironments such as the bone marrow, where they can resist conventional therapies, driving metastatic relapses even years after primary tumor removal. Recent advances highlight the crucial role of lipid metabolism in protecting dormant DTCs from ferroptosis—a form of regulated cell death characterized by iron-dependent lipid peroxidation. Dormant DTCs can avoid lipid peroxidation by incorporating monounsaturated fatty acids (MUFAs) into membrane phospholipids through ACSL3 and SCD1 activity, while accumulating lipid droplets (LDs) that sequester oxidizable polyunsaturated fatty acids (PUFAs), thus limiting the substrates available for ferroptosis. In parallel, antioxidant systems such as the GPX4–glutathione axis further prevent lethal lipid-derived reactive oxidative species (ROS) accumulation. This review highlights the central role of lipid metabolism, redox regulation and ferroptosis resistance in dormant DTCs; it also explores emerging therapeutic opportunities to overcome dormancy-associated resistance and reduce late relapse risk in breast cancer.

Generative models (GANs or Diffusion Models) have achieved state-of-the-art performance in image synthesis in various domains, including the medical field. Many works have shown that it is possible to fully train deep models (e.g. classifiers) solely based on synthesized data and that augmenting real data with synthesized samples can lead to superior discriminative power. However, large datasets are needed to train realistic generative models. On the other hand, this can be an issue in certain domains, such as medical imaging, where datasets are typically smaller and more costly to annotate. Small sample size poses a fundamental problem in the applicability of generative models for data augmentation, as a generative model will not necessarily approximate the real data distribution better than a simple classifier in a low-data regime. To tackle this issue, we introduce prior information in the generative process to compensate for the lack of data, unlocking generative augmentation in low-data settings. In this work, we focus on computational pathology, specifically on the sensitive topic of the classification of colorectal polyp dysplasia. To guide the generative process, we take advantage of medical knowledge on tissue morphology taken from the World Health Organization (WHO) guidelines for the classification of dysplasia. By incorporating our proposed generative pipeline into a contrastive learning framework, we achieve state-of-the-art results in the detection of high-grade dysplasia on the UnitoPatho dataset.

The transmembrane transport of molecules and ions is fundamental to cellular homeostasis and coordination of physiological processes. During tumorigenesis, these processes undergo significant alterations in response to oncogenic transformations and microenvironmental pressures. However, a comprehensive systems-level characterization of transportome alterations across cancer types has been lacking. Here, we integrate structural, functional, and mechanistic annotations of all known human ion channels and transporters (ICTs) into a curated database, organizing them into biologically coherent gene sets based on shared physiological and biophysical properties such as permeant species, gating mechanism, and transport directionality. By leveraging Gene Set Enrichment Analysis across transcriptomic profiles from 19 tumor types, we reveal a recurrent downregulation of multiple ICT families-particularly ion channels-accompanied by selective upregulation of specific pump classes. Paired Clinical Proteomic Tumor Analysis Consortium transcriptomic-proteomic datasets further support this signature, showing that transportome tumor-normal transcript changes are largely preserved at the protein level, with high directional concordance. We interpret this pattern as a molecular signature of cancer-associated dedifferentiation and sensory signal decoupling, pointing toward a broader and underappreciated strategy by which tumors reconfigure their transmembrane communication interfaces to favor autonomy, immune evasion, and metabolic adaptation. Our findings uncover a widely conserved transportome reprogramming and provide a quantitative framework for future integrative studies of ICT function and their roles in cancer systems biology.NEW & NOTEWORTHY We provide a novel computational framework for transportome analysis. By applying it to transcriptomics and proteomics large public datasets, we found a striking and previously unrecognized pattern whereby ion channel families are consistently downregulated, whereas most transporter families are either preserved or upregulated. This functional asymmetry suggests a widespread suppression of channel-mediated signaling processes as a general strategy by which tumors reconfigure their transmembrane communication interfaces to favor dedifferentiation, autonomy, immune evasion, and metabolic adaptation.

Precision oncology relies on precision diagnostics, and histopathological diagnosis, along with biomarker evaluation, currently represents the cornerstone for personalized treatment. In gastrointestinal neoplasms, diagnostic assessment and molecular profiling are often performed on biopsy tissue, which may be quantitatively/qualitatively limited. Therefore, appropriate sample management is essential to avoid unnecessary waste and to obtain all the information necessary for treatment planning. Several factors may significantly impact biomarker testing: (i) pre-analytical issues; (ii) heterogeneity in biomarker expression; (iii) lack of standardization in biomarker testing and evaluation. Moreover, in the metastatic setting, inadequate/incomplete clinical information can lead to inappropriate sample handling, with negative implications. The application of appropriate guidelines in testing and reporting biomarker status according to clinical context is, therefore, strongly encouraged. In this position paper, the Italian Group of Gastrointestinal Pathologists (GIPAD), a section of the Italian Society of Pathological Anatomy and Cytology (SIAPeC-IAP), aims to summarize all the clinical and pathological requirements for adequate assessment of prognostic and predictive biomarkers in the gastrointestinal oncology patient, from biopsy acquisition to diagnostic reporting.

AIMS:Homozygous deletion (HD) of CDKN2A/B represents an adverse prognostic biomarker in meningiomas and a diagnostic criterion for CNS WHO grade 3 assignment. However, fluorescence in situ hybridisation (FISH) thresholds and the role of immunohistochemistry (IHC) surrogates remain uncertain. This study evaluated multiple CDKN2A/B FISH cutoffs and assessed the diagnostic and prognostic performance of MTAP and p16 IHC. METHODS AND RESULTS:Ninety-two meningiomas (CNS WHO grades 1-3) were analysed by FISH evaluating ≥ 10%, ≥ 20% and ≥ 30% CDKN2A/B HD thresholds. CDKN2A/B HD was identified in 18.5%, 6.5% and 4.3% of cases using the respective cutoffs and was significantly associated with shorter disease-specific survival across all thresholds (HD ≥ 10% p = 0.001; HD ≥ 20% p = 0.0001; HD ≥ 30% p = 0.043). Patients with HD ≥ 20% and ≥ 30% experienced universal disease-specific mortality within a median survival time of approximately 2 years. MTAP and p16 IHC were performed in matched areas. MTAP IHC showed high specificity (90%-92%) but limited sensitivity (30%-50%), while p16 IHC displayed variable sensitivity (41%-75%) and lower specificity (63%). Combined MTAP/p16 negativity improved sensitivity (up to 100%) but reduced specificity (57%). Neither MTAP nor p16 loss correlated significantly with survival. Spatially heterogeneous IHC patterns corresponded to regional variability in CDKN2A/B deletion by FISH. CONCLUSIONS:CDKN2A/B HD detected by FISH, particularly using thresholds equal or greater than 20%, is strongly associated with poor outcome in meningiomas. MTAP and p16 IHC, alone or combined, lack sufficient accuracy as independent surrogates but may guide tissue selection for molecular testing in heterogeneous tumours.

BackgroundPrognostic models are crucial for prostate cancer (PCa) treatment decision making at the time of diagnosis, particularly for distinguishing active surveillance (AS) candidates from those requiring curative treatment. While several models exist, their ability to predict metastatic disease—the primary driver of PCa mortality—remains underexplored.MethodsWe analysed the Turin Prostate Cancer Prognostication cohort, which includes 891 unselected PCa patients diagnosed between 2008 and 2013 in Turin, Italy. Three widely used prognostic models—D’Amico, CAPRA, and MSKCC—were updated and compared based on optimism-corrected discrimination and overall prediction error for metastatic PCa (mPCa) within five years of diagnosis, accounting for competing risks. Overall survival was also assessed. Additionally, we investigated whether replacing standard AS eligibility criteria with nomogram-based risk thresholds could better identify patients at low risk of metastasis, maximizing AS uptake while minimising metastatic risk.ResultsThe MSKCC nomogram (optimism-corrected AUCt: 0.81; scaled Brier score: 0.15) outperforming the CAPRA score (AUCt: 0.77; Brier score: 0.11) and the D’Amico classification (AUCt 0.64; Brier score: 0.03) in predicting mPCa. The same ranking was observed for overall mortality prediction. When 95th percentile of MSKCC’s predicted probabilities among patients selected for six different AS protocols was used as a threshold, the proportion of potentially eligible patients increased from 7.8% when UCSF criterion was used to 57.0% without substantially increasing metastatic risk (observed 5-year risk: 1.7%).ConclusionsThe MSKCC nomogram outperformed other models in predicting mPCa and overall mortality. Implementing risk-based AS eligibility thresholds derived from MSKCC could enhance patient selection while facilitating shared decision-making between patients and clinicians.

Glioblastoma (GBM) arises from stem-like cells (GSCs) that exhibit intrinsic therapeutic resistance and can be positively selected by treatment, rendering recurrent GBM intractable. Mechanistic dissection of therapeutic resistance evolution has been limited by scarce matched primary/recurrent tractable models. To address this gap, we developed "resistant GSC families", a within-patient matched platform that models therapy-driven selection by ex vivo deriving, from the same primary whole GBM, temozolomide (TMZ)- and ionizing radiation (IR)-selected GSCs, alongside a treatment-naive control (CTRL-GSC). This design enables pressure-specific dissection of resistance evolution, separating chemotherapy- and radiotherapy-associated genetic alterations and adaptations that are often confounded in primary-versus-recurrent comparisons. Using this framework, we link TMZ-driven relapse-like states to either mismatch repair (MMR)-dependent stable resistance or O6-methylguanine-DNA methyltransferase (MGMT)-independent drug tolerance, and identify adaptive DNA damage response and cell-cycle changes as a route to increased radioresistance. Across pressures, treatment-emergent GSCs accumulate chromosomal alterations and exhibit adaptive phenotypic remodeling, including increased receptor tyrosine kinase activity. Resistant GSC families represent a model enabling mechanistic studies and hypothesis-driven testing of strategies aimed at preventing or treating GBM recurrence.

TIMP1 mediates brain metastasis in a CD8+ T cell-dependent manner. Supplementary Figure 5 shows additional data corresponding to Figure 4.

Malignant colorectal polyps (MCPs) are early-stage colorectal cancers (CRC) generally diagnosed following endoscopic removal of otherwise bland lesions. Due to nodal metastatic potential and risk of residual disease, diagnosis and risk stratification of MCPs are critical for determining appropriate clinical management, which can range from clinical/endoscopic/imaging follow-up to radical surgery with locoregional lymphadenectomy. Although a dedicated multidisciplinary team should discuss this decision, the MCP histopathologic assessment is crucial and raises several issues. Following productive discussions that occurred in dedicated meetings and educational activities, the Italian Group of Gastrointestinal Pathologists have developed these recommendations for the histopathologic assessment and multidisciplinary management of MCPs, addressing diagnostic challenges and proposing standardized criteria. This document is based on a comprehensive review of the literature and opinions from pathologists with dedicated gastrointestinal experience. Key topics include pre-analytical specimen handling, histopathologic criteria for MCP diagnosis, and assessment of histopathologic features associated with MCP high-risk behavior. The role and integration of features inferred from advanced CRCs, such as mismatch repair protein status testing, are also addressed and discussed. The proposed recommendations aim to improve MCP risk stratification by structuring and standardizing the histopathologic approach. The adoption of a multidisciplinary team discussion remains crucial for MCP patient management.

Overall survival according to TIMP1 in the CSF. Overall survival of brain metastasis patients with different primary tumors according to their levels of TIMP1 in the cerebrospinal fluid (CSF). The table contains information corresponding to Supplementary Figure 9B.

TIMP1 is a downstream target of STAT3 in brain metastasis-associated astrocytes. Supplementary Figure 3 shows additional data corresponding to Figure 3.

TIMP1 levels from ELISA applied to CSF from patient samples. Levels of TIMP1 in the blood or in the cerebrospinal fluid (CSF) of non-cancer patients and brain metastasis patients from different primary tumors. Immune Cluster is shown for patients in Figure 7N. The table contains information corresponding to Figure 7L, 7N and Supplementary Figure 9A,C-D.

TIMP1 through CD63 alters relevant properties of CD8+ T cells. Supplementary Figure 6 shows additional data corresponding to Figure 6.

DEG cluster 3 brain metastasis-associated astrocytes. Differentially expressed genes (DEGs) found in cluster number 3 of brain metastasis associated-astrocytes. Significantly deregulated genes are highlighted. Red indicates upregulation and green indicates downregulation respect to tumor free condition. The table contains information corresponding to Figure 1D.

Phosphoproteomic analysis of CD8+ T cells incubated with astrospheres conditioned medium. Results from phosphopeptides quantification of the LC-MS/MS analysis of CD8+ lymphocytes incubated with pSTAT3- (D1) and wt (D2) or cKOGFAP-Timp1 (D2KO) pSTAT3+ astrospheres conditioned medium. The table contains information corresponding to Figure 6K and Supplementary Figure 7A.