INTRODUCTION:Genetic mutations have been reported in patients with acromegaly, potentially influencing clinical phenotype, tumor invasiveness, and prognosis. The genetic and molecular landscape of patients with acromegaly has been partially explored. Therefore, this study aimed to investigate germline genetic variants in patients with acromegaly through clinical exome sequencing (CES) analysis and to explore a possible correlation with the molecular and histological characteristics of somatotropinomas and the clinical features of acromegaly. METHODS:A retrospective observational study was conducted to investigate the genetic profile of 46 patients with sporadic acromegaly through CES analysis, in comparison with 39 controls. RESULTS:CES analysis identified 5759 unique variants in patients with acromegaly, without revealing predominant variants. However, a missense variant of uncertain significance (VUS) in the KCNJ12 gene (c.1289 A>G, p.Glu430Gly, rs5021699) was more frequent in patients with invasive tumors (P = 0.017) and in those with a higher Ki-67% (P = 0.033). DISCUSSION:This study performed an extensive exploration of germline variants using CES analysis in patients with sporadic acromegaly. No predominant variants were identified in this cohort of somatotropinomas, but a VUS in the KCNJ12 gene was significantly associated with tumor invasiveness and a higher proliferative index, suggesting increased proliferation of tumor cells in patients carrying this genetic alteration. CONCLUSION:These findings may contribute to understanding the genetic landscape of acromegaly, and the gene identified may be of interest for further research on gene regulation of invasiveness and proliferation in somatotropinomas.

Familial Isolated Pituitary Adenoma (FIPA) is a rare autosomal dominant condition associated with germline mutations in the Aryl Hydrocarbon Receptor-Interacting Protein (AIP) gene in 20

Abstract Objectives To assess the diagnostic potential of magnetic resonance imaging (MRI) radiomics and machine learning models using T2-weighted and contrast-enhanced (CE)-T1-weighted images, individually and combined, to predict the invasiveness of pituitary neuroendocrine tumors (PitNETs). Materials and methods Patients with macro-PitNETs were retrospectively enrolled from 2019 to 2022. Radiomic features were extracted from manually segmented lesions on preoperative T2-weighted and CE-T1-weighted images and, after a feature selection step, used to assess invasiveness, defined following Trouillas’ classification. Five machine learning models (logistic regression, random forest, gradient boosting, AdaBoost, XGBoost) were trained using CE-T1-weighted, T2-weighted, and CE-T1-weighted plus T2-weighted features. Performance was evaluated on a test set using the area under the receiver operating characteristic curve (AUC). Results Two hundred patients were included in the study: 95 PitNETs were noninvasive (74 grade 1a; 21 grade 1b) and 105 invasive (70 grade 2a; 35 grade 2b). A total of 102 radiomic features were extracted per sequence. The best-performing model was the XGBoost, using five combined CE-T1-weighted and T2-weighted features, with an AUC of 0.85 (95% confidence interval: 0.75‒0.95). Lower AUC values were obtained for logistic regression using CE-T1-weighted images (0.80) and AdaBoost using T2-weighted images (0.78). Conclusion The XGBoost model, incorporating tumor shape, texture, and first-order features extracted from both CE-T1-weighted and T2-weighted MRI, showed high performance in predicting PitNETs invasiveness. This radiomic model might help identify tumors with a higher risk of disease persistence, recurrence, or progression. Relevance statement The radiomic model based on contrast-enhanced T1-weighted and T2-weighted MRI demonstrated high discriminative ability in predicting invasiveness of pituitary neuroendocrine tumors and could aid in identifying tumors that may be at higher risk for recurrence or progression, ultimately improving patient outcomes through personalized treatment strategies. Key Points Pituitary neuroendocrine tumors (PitNETs) represent a significant challenge in clinical practice. Accurate preoperative prediction of PitNET invasiveness is crucial for surgery and prognosis. Contrast-enhanced T1-weighted and T2-weighted MRI-based radiomic model effectively predicts PitNET invasiveness. The developed radiomic model could help optimize individualized treatment decisions before surgery. Graphical Abstract

BackgroundAcromegaly associated with Morris syndrome has never been reported in the literature. Case PresentationWe present the case of a 49-year-old woman with Morris syndrome, diagnosed in 1992, who has undergone gonadectomy and hormone replacement therapy for about 15 years. The patient was referred to our centre for the clinical suspicion of acromegaly in June 2022, for the enlargement of the acral extremities and the development of prognathism in the last 10 years. The patient underwent mandibular reduction surgery and removal of a tubular adenoma of the colon in 2010. In June 2021, the patient performed random GH, IGF-I, and prolactin (PRL) dosages that confirmed the diagnosis of acromegaly. A contrasted pituitary MRI showed the presence of an 8 mm intrasellar pituitary adenoma. Therefore, a transsphenoidal resection of the pituitary tumor was conducted in September 2021. The histological examination proved the diagnosis of somatotropinoma. At the last follow-up at our center in June 2024, the patient presented in a fair general clinical condition, with recovery of related acromegaly symptoms, normalized IGF-I levels, and a negative pituitary MRI for signs of somatotropinoma recurrence. ConclusionOur clinical case describes for the first time the association between Morris syndrome and acromegaly. Due to the singularity of this case, we decided to conduct more in-depth genetic analyses through a clinical exome study and CGH Array evaluation, which, however, did not lead to the discovery of a genetic association between the two conditions.Although this condition is rare, further genetic studies are needed to demonstrate a genetic association between these two conditions.

BRAF mutations are oncogenic drivers present in about 7% of human cancers, with the V600E substitution being the most frequent. In the nervous system, BRAFV600E has been identified in both low- and high-grade gliomas (LGG and HGG) and in tumors of the peripheral nervous system. To investigate the mechanisms underlying BRafV600E-driven tumorigenesis, we generated a mouse model in which the BRafV600E mutation and Pten deletion can be induced through the Sox2-CreERT2 system. This inducible deleter is active in adult neural stem/progenitor cells (aNSPCs) and Schwann cell precursors (SCPs). In this model, BRafV600E-mutated/Pten-deleted telencephalic aNSPCs give rise to diffuse LGG with oligodendroglioma-like features resembling the human diffuse LGG, MAPK pathway-altered subtype. In contrast, mutated SCPs develop schwannomas, cutaneous neurofibromas, and malignant peripheral nerve sheath tumors (MPNSTs). Sox2 deletion in BRafV600E/Ptendel mice markedly reduces tumor formation, indicating that aNSPCs act as tumor cells of origin. In vitro analyses show increased proliferation of BRafV600E/Ptendel aNSPCs and preferential differentiation toward oligodendroglia-like tumor cells. BRaf-mutant aNSPCs display increased Sox2 protein, but not mRNA levels, suggesting post-transcriptional regulation. Sox2 phosphorylation at T118 is promoted by BRafV600E, potentially stabilizing the protein during aNSPC transformation, although the involvement of downstream kinases cannot be excluded.

Medulloblastoma is the most common malignant brain tumor in children, but it presents distinct challenges when occurring in adolescents and young adults (AYAs, aged 15-39 years). Recent molecular profiling has identified four principal medulloblastoma subgroups-WNT-activated, SHH-activated, Group 3, and Group 4-each demonstrating unique biological characteristics and clinical outcomes. AYA patients exhibit age-specific molecular patterns and therapeutic responses substantially different from those of younger children. This review synthesizes current evidence regarding epidemiology, diagnostic challenges, molecular characterization, risk stratification, treatment modalities, and outcomes specific to AYA medulloblastoma patients, highlighting the critical need for age-adapted therapeutic strategies and dedicated clinical research in this underserved population.

Acromegaly is a rare disease, due in most of the cases to a growth hormone (GH)-secreting pituitary adenoma (PA), namely neuroendocrine tumour (PitNET). The treatment of patients with acromegaly is multimodal and multi-step, including surgery, medical therapies, and radiotherapy. In the last 30 years, the therapeutic armamentarium for the treatment of acromegaly has progressively increased, and the therapeutic algorithm has been significantly modified through the identification of clinical, biochemical, and molecular biomarkers of treatment outcome. The personalization of acromegaly treatment has shifted the paradigm from a 'trial-and-error' to a 'target-to-treat' treatment approach to achieve early disease control and to reduce the risk of disease-related comorbidities that may lead to an increased mortality. Nevertheless, despite the numerous improvements in the treatment of patients with acromegaly, disease control is not achieved in all patients, according to the results of randomized clinical trials, interventional studies, and prospective and retrospective observational studies. In parallel, the normalization of GH and IGF-I levels may not be sufficient to control acromegaly related symptoms and prevent disease-related comorbidities. In this review, we will report on the most recent aims of treatment and cure in patients with acromegaly, on the efficacy and predictors of response to conventional treatments (such as first- and second-generation somatostatin receptor ligands and growth hormone receptor antagonist). A specific section will focus on the rarer aggressive disease pictures and on the treatment with systemic therapies (such as temozolomide and capecitabine) and on target therapies (such as neo-angiogenesis and immune checkpoint inhibitors).

Craniopharyngiomas (CPs) are rare benign epithelial tumors, whose management remains one of the most challenging feats in skull base surgery. Over recent decades, the evolution from transcranial microsurgical approaches (TCA) to extended endoscopic endonasal approaches (EEEA) has reshaped their management. This systematic review and meta-analysis aimed to elucidate the evolution of surgical treatment and define the functional outcomes of adult CP patients. A systematic review of the literature was carried out according to PRISMA 2020 guidelines, including papers from PubMed, Scopus, and Ovid databases. Meta-analyses of proportions were conducted using random-effects models (REML estimator), with heterogeneity assessed via the I² statistic. Meta-regression analyses explored the influence of publication year and geographic origin. Thirty-one retrospective studies encompassing 1,855 adult patients met the inclusion criteria. The mean age clustered between the fourth and fifth decades, with balanced sex distribution and follow-up durations ranging from 12 to 126 months. Preoperatively, anterior hypopituitarism occurred in 61.5

Background:Following the encouraging results of the REGOMA Phase 2 trial, regorafenib is increasingly used for the treatment of recurrent glioblastoma, IDH-wildtype. Identifying predictive factors for response to regorafenib is of paramount importance. DNA methylation profiling is considered the gold standard for diagnosing and classifying central nervous system tumors. We explored the predictive value of methylation profiling in recurrent glioblastoma patients treated with regorafenib. Methods:Thirty-three recurrent glioblastoma patients were enrolled in the study. DNA methylation profile was performed on paraffin-embedded tumor obtained at first surgery. Results:Median progression-free survival (PFS) and overall survival (OS) following regorafenib treatment were 3 and 7.5 months, respectively, aligning with findings from the REGOMA trial. Methylation classes RTK2 and mesenchymal were associated with an improved survival after regorafenib. Copy number variation analysis showed that imbalances in the p53-MDM2 and cyclin-Rb pathways negatively predict survival after regorafenib treatment. Multivariable analysis demonstrated that CCND2 gene gain/amplification and chromosome 13 deletion, encompassing the RB1 gene, were associated with reduced PFS, while MDM2 gain/amplification was linked to diminished OS after regorafenib. We developed methylation-based scores for predicting PFS and OS outcomes. Notably, the PFS score exhibited a 100% negative predictive value, enabling precise patients selection. Differentially methylated region analysis suggested that resistance to regorafenib may involve disruptions in WNT signaling, cadherin-mediated adhesion, and presenilin pathways. Conclusions:These findings highlight the potential of DNA methylation profiling in guiding therapeutic strategies and warrant further validation in clinical settings.

Regardless of remission status, residual pain (RP) might persist in rheumatoid arthritis (RA). The aim of this study was to characterize RP, its perception, and patient-dependent features and to evaluate its possible association with residual synovitis in patients with RA in remission. Ninety-seven patients with RA, including 68 in sustained clinical and ultrasound remission (Rem/RA) and 29 in high/moderate DAS28-CRP disease activity (H-Mo/RA) were enrolled in the study. Thirty patients with fibromyalgia were enrolled as a control group(FIBRO). At study entry, demographic, clinical, ultrasound characteristics, and pain dimension assessment (VAS-pain, FACIT, CSI, GHQ, and RAID) were collected for each patient. RA patients underwent synovial tissue biopsy to evaluate the degree of synovitis using the Krenn synovitis score (KSS). Forty-eight percent of Rem/RA still declared unacceptable pain (VAS-Pain > 20) compared to 80

Transthyretin amyloidosis (ATTR amyloidosis) is a rare systemic disorder characterized by the extracellular deposition of amyloid fibrils, which can affect multiple tissues. Lumbar spinal stenosis (LSS), a condition involving narrowing of the lumbar spinal canal, has been frequently associated with amyloid deposition in the ligamentum flavum (LF). This study aimed to evaluate the prevalence of ATTR deposits in LF samples obtained from patients undergoing LSS surgery at two Italian centers. A total of 37 patients were included, with LF thickness measured via pre-operative MRI scans. Amyloid deposits were detected in 27% of patients, all confirmed as ATTR by immunohistochemistry. DNA analysis revealed no pathogenic mutations in the TTR gene, suggesting that the detected amyloid fibrils originated from the wild-type protein. LF thickness values were consistent with those reported in literature, supporting LF thickening as a potential marker of amyloid deposition. These findings contribute to the understanding of ATTR involvement in LSS and highlight the need for further research to explore the pathophysiological mechanisms and clinical significance of amyloid deposits in the LF.

Ependymoma (EPN) is the third most common malignant tumor of the central nervous system in children. The spatial and temporal heterogeneity of cancer cell populations can impact the ability of EPN to overcome microenvironmental constraints. Data set analysis revealed that CD147 expression is increased in glioma, and its expression correlates with detrimental survival and higher mutational burden. We performed spatial phenotyping of tumor microenvironment in childhood posterior fossa type A EPN (PFA-EPN) central nervous system World Health Organization grade 2 (G2; n = 5) and grade 3 (G3; n = 7). Tumors were comprehensively assessed using multiplex immunofluorescence panels to detect immune, microglial, endothelial, and tumor cells. We observed significant differences in immune cell populations according to grading: a high number of T cells and cytotoxic T cell infiltration were features of G2 when compared with G3 cancers. The distance between CD4+ and CD8+ cells was lower in G3 tumors, highlighting an increase in cell interactions between T-cell populations in more aggressive tumors. Two tumor-associated macrophage subsets with distinct functional phenotypes (CD68+MCP1+ and CD68+CD44+), associated with tumor progression, were previously identified by single-cell RNA sequencing analyses in spinal EPN. We demonstrated that the CD68+CD44+ population was higher in G3 compared with G2 PFA. CD147+ microglia cells were closer to CD8+ cells and CD147+ tumor-proliferating cells in G3 than G2 counterparts. In G3 tumors, CD4+ cells were more distant from CD147+ microglial cells and from CD8+ lymphocytes and were closer to CD147+ tumor-proliferating cells. We provided evidence that CD147+ microglial cells could be playing a key role in PFA-EPN progression, promoting CD8+ T cells' exclusion. These findings highlight grading-related differences in PFA-EPN tumor microenvironment.

Recent single-cell multi-omic and spatial analyses of synovial biopsies have transformed our understanding of myeloid cell-driven mechanisms underlying human joint pathology and tissue homeostasis in Rheumatoid arthritis (RA). However, the developmental trajectories of synovial tissue macrophage (STM) subsets in humans remain poorly understood, due in part to the lack of models that faithfully replicate synovial tissue niches. This hinders the exploration of the therapeutic potential of targeting specific synovial myeloid cell clusters. Using multi-omics analyses of synovial tissue from an allogeneic bone marrow transplant recipient, we show that joint-specific tissue-resident STM subsets, including both health- and disease-associated clusters, can derive from peripheral blood monocytes. Analysis of embryonic synovial joints revealed that macrophage localization and maturation in the joints are preceded by local stromal niche specialisation, indicating that synovial fibroblasts (FLS) provide tissue-specific instructive cues to STM precursors. To elucidate human STM developmental trajectories, we established a SNP-based fate-tracking human synovial organoid system by embedding distinct blood-derived myeloid precursors, together with FLS clusters from RA synovial biopsies and endothelial cells, into 3D structures. These organoids reproduced key synovial tissue features, including lining and sublining architecture and stromal-myeloid cell cluster composition. Importantly, they supported differentiation of all resident STM subsets: homeostatic lining TREM2pos macrophages, their pathogenic TREM2lowSPP1pos counterparts that characterize the RA hyperplastic lining, and both homeostatic and RA-associated perivascular LYVE1pos STM clusters, all traced to monocytic precursors. In summary, we show that development of STM subsets is driven by fibroblast-conditioned spatial niches. We have established a novel, tractable ex vivo platform to dissect the niche-specific cues driving homeostatic versus pathogenic phenotypic clusters.

Pituitary adenomas (PAs) are generally benign neoplasms, though in rare cases may exhibit aggressive behavior. In 2024, the PANOMEN-3 workshop released a new clinical-pathological classification. The objective of this study was to examine the potential of the PANOMEN-3 classification to predict prognosis of PAs and guide treatment in our single center cohort of patients with PAs. A longitudinal, retrospective, observational study was performed on patients with a PA diagnosis. The PANOMEN 3 classification was applied to each patient 6 months after surgery. Resultant grades were correlated with surgical outcome, disease recurrence or progression. 289 patients were included. According to the PANOMEN-3 classification, 9 patients (3.1

OBJECTIVE:Synovial inflammation plays a crucial role in osteoarthritis (OA) by producing key cytokines that mediate synovium-cartilage interaction and drive damage progression. In this study, we aimed to evaluate relationships between histological features of synovitis, radiographic damage and patients' clinical characteristics. METHODS:This observational cross-sectional study included consecutive patients with knee OA from 2016 to 2022. Enrolled patients were aged between 40 and 90 years, had chronic knee pain lasting at least 3 months and showed ultrasound evidence of synovitis. All patients underwent a general rheumatological evaluation, including the collection of clinical and laboratory data and ultrasound (US)-guided minimally invasive synovial tissue biopsy. The severity of synovitis was assessed by histology using the Krenn Synovitis Score (KSS). RESULTS:A total of 161 patients were considered for the analysis. The multivariate analysis showed that both US effusion and Kellgren-Lawrence (KL) grade were positively associated with histological synovitis. In contrast, age, sex, body mass index, levels of inflammatory markers, pain intensity and cardiovascular risk factors were not associated with histological synovitis. A strong positive correlation was found between KL grades and the KSS. A moderate positive correlation emerged between KL grades and the proportion of patients with lymphocytes and plasma cells in synovial tissue. CONCLUSIONS:More severe histological synovitis in patients with non-end-stage knee OA is associated with worse radiographic structural damage. In the advanced stages of structural damage, the likelihood of detecting a lymphoplasmacytic inflammatory infiltrate in the synovial membrane increases. US-detected effusion serves as a marker of histological synovitis.

Introduction Cytokine and chemokines have been recognized to be involved in the progression and prognosis of pituitary adenoma/neuroendocrine tumors (PAs/PitNETs), also known as pituitary adenomas. We aim to investigate the expression of cytokine and chemokine in PAs/PitNETs, and their association with PAs/PitNETs clinical and biological behavior. Patients and methods A prospective and monocenter study was performed on 16 patients diagnosed for PAs/PitNETs. Cytokine and chemokine were detected on freshly collected PAs/PitNETs samples. Tumor infiltering immune cells were investigated on formally fixed and paraffin-embedded PAs/PitNETs samples. Clinical, biochemical, molecular and morphological data were collected from patients’ medical records. Result Out of 72 patients with PAs/PitNETs that underwent surgical removal at the Neurosurgery Division of our Institution between January and June 2023, sixteen patients were enrolled in the study. Out of 42 cytokines and chemokines that we investigated, we found that the expressions of the growth-regulated oncogene (GRO)/CXCL1, thymus- and activation-regulated chemokine (TARC)/CCL17 and epidermal growth factor (EGF) were higher in invasive tumors than in not-invasive ones (respectively p = 0.01, p = 0.002 and p = 0.002). The EGF expression was higher in tumors with a MIB1 > 3% than in those with MIB1 < 3% ( p = 0.014). A positive correlation was detected between the expressions of EGF and CXCL1 ( p = 0.003, r: 0.7), EGF and GRO-a ( p = 0.01, r:0.61), and the number of tumors infiltering CD68 + macrophages and the expression of CCL2 ( p = 0.008, r = 0.695). Conclusion Our preliminary results support that in PAs/PitNETs, the cytokines and chemokines generate an immune network, that may contribute to regulating the cell proliferation and pattern of growth.

DNA methylation-based classification is now central to contemporary neuro-oncology, as highlighted by the World Health Organization (WHO) classification of central nervous system (CNS) tumors. We present the Heidelberg CNS Tumor Methylation Classifier version 12.8 (v12.8), trained on 7,495 methylation profiles, which expands recognized entities from 91 classes in version 11 (v11) to 184 subclasses. This expansion is a result of newly identified tumor types discovered through our large online repository and global collaborations, underscoring CNS tumor heterogeneity. The random forest-based classifier achieves 95% subclass-level accuracy, with its well-calibrated probabilistic scores providing a reliable measure of confidence for each classification. Its hierarchical output structure enables interpretation across subclass, class, family, and superfamily levels, thereby supporting clinical decisions at multiple granularities. Comparative analyses demonstrate that v12.8 surpasses previous versions and conventional WHO-based approaches. These advances highlight the improved precision and practical utility of the updated classifier in personalized neuro-oncology.