Marco Gessi

Purpose 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% of the cases. This study aims to characterize a novel AIP variant in a Sardinian family through genetic, clinical and immunohistochemical analyses and evaluate its pathogenicity. Methods The proband, a 17-year-old girl with an invasive prolactin (PRL)-secreting Pituitary Neuroedocrine Tumor (Pit-NET), also known as a pituitary adenoma, underwent germline AIP testing, extended to family members. All variant carriers underwent clinical and radiologic evaluation. Immunohistochemistry for AIP expression was performed on Pituitary adenoma/PitNet tissue from an affected relative. Variant pathogenicity was classified according to guidelines. Results A novel heterozygous AIP germline variant, c.479del (p.Pro160LeufsTer11 ), was identified in the proband and six relatives. Cabergoline treatment led to PRL levels normalization and tumor shrinkage in the proband. An affected cousin had an aggressive GH-secreting Pituitary adenoma/PitNet requiring multiple treatments. All other carriers had no clinical findings, and their imaging was unremarkable. The variant causes a premature stop codon leading to a truncated protein, lacking the three C-terminal tetratricopeptide repeat domains, essential for AIP protein-protein interactions and tumor suppressor function. Immunohistochemistry showed reduced AIP expression. The variant is classified as pathogenic. Conclusion This report expands the variants spectrum of AIP-related FIPA, confirming intra-familial phenotypic variability, from asymptomatic carriers to aggressive Pituitary adenoma/PitNet. Early genetic screening and surveillance are essential for timely diagnosis and personalized management.

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.

In this case report, we described the pitfalls in the differential diagnosis of a pituitary stalk lesion in a patient affected by Klinefelter Syndrome (KS) that was initially suspected of infundibulo-neuro-hypophysitis (INH). According to the atypical radiological picture for INH, the not-conclusive pathology findings, and the partial response to glucocorticoid treatment, a [18F] fluorocholine ([18F] FCH) positron emission computed tomography (PET-CT) scan was performed and identified a pituitary stalk proliferative lesion that was suggestive for neoplasia. This clinical case emphasizes the prospective and potential diagnostic role of the [18F] FCH PET-CT in pituitary stalk lesions and in the diagnosis of pituitary germinoma. Our article also includes a brief review of the literature, focusing on the differential diagnosis of lesions involving the pituitary stalk, the oncological risk associated with KS, and the role of nuclear imaging in the evaluation of such cases.

Background/Objectives: Astroblastoma is a rare glial neoplasm more frequent in young female patients, with unclear clinical behaviors and outcomes. The diagnostic molecular alteration is a rearrangement of the Meningioma 1 (MN1) gene. MicroRNAs (miRNAs) are important gene expression regulators with strong implications in biological processes. Here, we investigated microRNA expression, regulation, and biological processes correlated to target genes of deregulated miRNAs in MN1-altered astroblastoma. Methods: A cohort of 14 tumor samples, histologically classified as astroblastoma, was retrospectively collected and analyzed through their DNA methylation profiles. MiRNA expression profiles were then detected on MN1-altered astroblastomas (n = 8) and normal brain controls (n = 2) by Nanostring technology and validated by RT-qPCR; then, the expression of deregulated miRNAs was correlated with clinical-pathological characteristics. Subsequently, the methylation status of promoters of deregulated miRNAs was investigated through a methylation profiling microarray. Finally, bioinformatics analysis was conducted to explore the biological processes (BPs) and target genes of differentially expressed miRNAs. Results: Eight MN-altered astroblastoma were identified. Thirty-nine miRNAs were deregulated in tumor samples compared to normal brain tissue. Downregulated microRNAs exhibited an association with an increased risk of recurrence. The promoter methylation status was investigated in 32/39 miRNAs: 14/32 were epigenetically deregulated. None of them were genetically regulated. Conclusions: MN1-altered astroblastomas have an miRNA expression signature that identifies specific BPs and pathways. Our findings suggested that the involved pathways could be associated with clinical and pathological characteristics of MN1-altered astroblastomas. Also, the biology of this rare tumor could have potential implications on prognostic markers and therapy.

Background and Objectives: The temporoparietal fascia flap (TPFF) has recently emerged as an option for skull base reconstruction in endoscopic transnasal surgery when vascularized nasal flaps are not available. This study provides a systematic literature review of its use in skull base surgery and describes a novel cohort of patients. Methods: PRISMA guidelines were used for the review. Patients undergoing skull base reconstruction with TPFF in our center from May 2022 to April 2024 were retrospectively included. Data were collected on pre- and post-operative clinical and radiological features, histology, surgical procedures, and complications. Results: Sixteen articles were selected, comprising 42 patients who underwent TPFF reconstruction for treatment of complex skull base pathologies. In total, 5 of 358 patients (0.9%) who underwent tumor resection via endoscopic transanal surgery in the study period in our institution required TPFF. All had been previously treated with surgery and radiation therapy for different pathologies (three chordomas, one giant pituitary neuroendocrine tumor (PitNET), and one sarcoma). Post-operative complications included CSF leak, which resolved after flap revision, and an internal carotid artery pseudoaneurysm requiring endovascular embolization. Conclusions: TPFF is an effective option for skull base reconstruction in complex cases and should be part of the armamentarium of the skull base surgeon.

Background: This study explores the potential for hidden variations within seemingly uniform regions of growth hormone-secreting pituitary neuroendocrine tumors (GH-PitNETs). We employed archived tissue samples using Laser Capture Microdissection Sequencing (LCM-RNAseq) to probe the molecular landscape of these tumors at a deeper level. Methods: A customized protocol was developed to extract, process, and sequence small amounts of RNA from formalin-fixed, paraffin-embedded (FFPE) tissues derived from five patients with GH-secreting PitNETs and long-term follow-up (≥10 years). This approach ensured precise isolation of starting material of enough quality for subsequent sequencing. Results: The LCM-RNAseq analysis revealed a surprising level of diversity within seemingly homogeneous tumor regions. Interestingly, the 30 most highly expressed genes included the well-known long noncoding RNA (lncRNA) MALAT1. We further validated the levels of MALAT1 and of other tumor-associated lncRNAs using digital droplet PCR. Conclusions: This study demonstrates the potential of LCM-RNAseq to unlock hidden molecular diversity within archived pituitary tumor samples. By focusing on specific cell populations, we identified lncRNAs expressed at different levels within the tumors, potentially offering new insights into the complex biology of GH-secreting PitNETs. This evidence prompts further research into the role of lncRNAs in pituitary neuroendocrine tumor aggressiveness and personalized treatment strategies.

Background: Primary spinal cord diffuse gliomas (SpDG) are rare tumors that may harbor, like diffuse intrinsic pontine gliomas (DIPG), H3^K27M mutations. According to the WHO (2021), SpDGs are included in diffuse midline H3K27-altered gliomas, which occur more frequently in adults and show unusual clinical presentation, neuroradiological features, and clinical behavior, which differ from H3 G34-mutant diffuse hemispheric glioma. Currently, homogeneous adult-only case series of SpDG, with complete data and adequate follow-up, are still lacking. Methods: We conducted a qualitative systematic review, focusing exclusively on adult and young adult patients, encompassing all studies reporting cases of primitive, non-metastatic SpDG with H3^K27 mutation. We analyzed the type of treatment administered, survival, follow-up duration, and outcomes. Results: We identified 30 eligible articles published between 1990 and 2023, which collectively reported on 62 adult and young adult patients with primitive SpDG. Postoperative outcomes were assessed based on the duration of follow-up, with outcomes categorized as either survival or mortality. Patients who underwent surgery were followed up for a mean duration of 17.37 months, while those who underwent biopsy had a mean follow-up period of 14.65 months. Among patients who were still alive, the mean follow-up duration was 18.77 months. The radiological presentation of SpDG varies widely, indicating its lack of uniformity. Conclusion: Therefore, we presented a descriptive scenario where SpDG was initially suspected to be a meningioma, but was later revealed to be a malignant SpDG with H3^K27M mutation.

The primary treatment for glioblastoma (GBM) is removing the tumor mass as defined by MRI. However, MRI has limited diagnostic and predictive value. Tumor-associated macrophages (TAM) are abundant in GBM tumor microenvironment (TME) and are found in peripheral blood (PB). FKBP51 expression, with its canonical and spliced isoforms, is constitutive in immune cells and aberrant in GBM. Spliced FKBP51s supports M2 polarization. To find an immunologic signature that combined with MRI could advance in diagnosis, we immunophenotyped the macrophages of TME and PB from 37 patients with GBM using FKBP51s and classical M1-M2 markers. We also determined the tumor levels of FKBP51s, PD-L1, and HLA-DR. Tumors expressing FKBP51s showed an increase in various M2 phenotypes and regulatory T cells in PB, indicating immunosuppression. Tumors expressing FKBP51s also activated STAT3 and were associated with reduced survival. Correlative studies with MRI and tumor/macrophages cocultures allowed to interpret TAMs. Tumor volume correlated with M1 infiltration of TME. Cocultures with spheroids produced M1 polarization, suggesting that M1 macrophages may infiltrate alongside cancer stem cells. Cocultures of adherent cells developed the M2 phenotype CD163/FKBP51s expressing pSTAT6, a transcription factor enabling migration and invasion. In patients with recurrences, increased counts of CD163/FKBP51s monocyte/macrophages in PB correlated with callosal infiltration and were accompanied by a concomitant decrease in TME-infiltrating M1 macrophages. PB PD-L1/FKBP51s connoted necrotic tumors. In conclusion, FKBP51s identifies a GBM subtype that significantly impairs the immune system. Moreover, FKBP51s marks PB macrophages associated with MRI features of glioma malignancy that can aid in patient monitoring.Significance:Our research suggests that by combining imaging with analysis of monocyte/macrophage subsets in patients with GBM, we can enhance our understanding of the disease and assist in its treatment. We discovered a similarity in the macrophage composition between the TME and PB, and through association with imaging, we could interpret macrophages. In addition, we identified a predictive biomarker that drew more attention to immune suppression of patients with GBM.