Application of the NSE score (Neurology-Stability-Epidural compression assessment) to establish the need for surgery in spinal metastases of elderly patients: a multicenter investigation.

PURPOSE: This retropective multicentric study aims to investigate the clinical applicability of the NSE score in the elderly, to verify the role of this tool as an easy help for decision making also for this class of patients. METHODS: All elderly patients (> 65 years) suffering from spinal metastases undergoing surgical or non-surgical treatment at the authors' Institutions between 2015 and 2022 were recruited. An agreement group (AG) and non-agreement group (NAG) were identified accordingly to the agreement between the NSE score indication and the performed treatment. Neurological status and axial pain were evaluated for both groups at follow-up (3 and 6 months). The same analysis was conducted specifically grouping patients older than 75 years. RESULTS: A strong association with improvement or preservation of clinical status (p < 0.001) at follow-up was obtained in AG. The association was not statistically significant in NAG at the 3-month follow-up (p 1.00 and 0.07 respectively) and at 6 months (p 0.293 and 0.09 respectively). The group of patients over 75 years old showed similar results in terms of statistical association between the agreement group and better outcomes. CONCLUSION: Far from the need or the aim to build dogmatic algorithms, the goal of preserving a proper performance status plays a key role in a modern oncological management: functional outcomes of the multicentric study group showed that the NSE score represents a reliable tool to establish the need for surgery also for elderly patients.

Brain Metastases from Breast Cancer Histologically Exhibit Solid Growth Pattern with at Least Focal Comedonecrosis: A Histopathologic Study on a Monocentric Series of 30 Cases.

Since there are no morphological clues capable of making a pathologist suspect a possible mammary origin of a metastatic lesion without adequate clinical information, the histologic diagnosis of brain metastasis from BC is still based on the immunohistochemical expression of mammary gland markers such as GATA-3, ERs, PgRs and HER-2. The present retrospective study aimed to select purely morphological features capable of suggesting the mammary origin of a metastatic carcinoma in the brain. The following histological features were collected from a series of 30 cases of brain metastases from breast cancer: (i) a solid growth pattern; (ii) the presence of comedonecrosis; and (iii) glandular differentiation. Our results showed that most cases histologically exhibited a solid growth pattern with at least focal comedonecrosis, producing an overall morphology closely reminiscent of mammary high-grade ductal carcinoma in situ. Although the above-mentioned morphological parameters are not strictly specific to a mammary origin, they may have an important diagnostic utility for leading pathologists to suspect a possible breast primary tumor and to include GATA-3, ERs, PgRs and HER-2 in the immunohistochemical panel.

Short Efficacy Evaluation of External Ventricular Drains Versus Ventriculosubgaleal Shunt in the Management of Neonatal Posthemorrhagic Hydrocephalus: A Retrospective Single-Center Cohort Study.

BACKGROUND: Different temporizing neurosurgical procedures are available for the management of posthemorrhagic hydrocephalus in preterm newborns. OBJECTIVE: To evaluate the short efficacy of the external ventricular drains (EVDs) and the ventriculosubgaleal (VSG) shunt. METHODS: This is a Strengthening the Reporting of Observational Studies in Epidemiology-conformed retrospective cohort study. The inclusion criteria were (1) gestational age <37 weeks, (2) birth weight <1500 g, (3) posthemorrhagic hydrocephalus because of intraventricular hemorrhage grade II/III, and (4) EVD or VSG shunt procedure before ventriculoperitoneal (VP)-definite shunt. Twenty-four newborns were collected from 2006 to 2022. The end points considered were infectious events, proteinorrachia, reintervention rate, and time to conversion to definite VP shunt. RESULTS: Overall, 12/24 newborns underwent EVD, and the remnant had a VSG shunt. The results showed a statistically significant difference ( P = .02) concerning cerebrospinal fluid infections between the EVD group (50%) and VSG shunt 1 (8.33%). The reintervention rate of EVD was significantly higher (66.67%) compared with that of the VSG shunt group (8.33%). A statistically significant difference was stated between the 2 groups (t[13] = -8.250; P < .001) (mean difference ± standard error; 10.5 ± 1.273) in the mean number of days elapsed from the achievement of the ideal weight (2000 g) to the definitive VP drainage. CONCLUSION: The increased infectious risk and the higher reintervention rate in EVD were confirmed in this study. In addition, a significant delay in the time to -conversion from EVD to VP shunt was demonstrated. Despite these optimal results, the VSG shunt remains a low practiced intervention, probably because of the limited operator experience.

Surgical management of Glioma Grade 4: technical update from the neuro-oncology section of the Italian Society of Neurosurgery (SINch®): a systematic review.

PURPOSE: The extent of resection (EOR) is an independent prognostic factor for overall survival (OS) in adult patients with Glioma Grade 4 (GG4). The aim of the neuro-oncology section of the Italian Society of Neurosurgery (SINch®) was to provide a general overview of the current trends and technical tools to reach this goal. METHODS: A systematic review was performed. The results were divided and ordered, by an expert team of surgeons, to assess the Class of Evidence (CE) and Strength of Recommendation (SR) of perioperative drugs management, imaging, surgery, intraoperative imaging, estimation of EOR, surgery at tumor progression and surgery in elderly patients. RESULTS: A total of 352 studies were identified, including 299 retrospective studies and 53 reviews/meta-analysis. The use of Dexamethasone and the avoidance of prophylaxis with anti-seizure medications reached a CE I and SR A. A preoperative imaging standard protocol was defined with CE II and SR B and usefulness of an early postoperative MRI, with CE II and SR B. The EOR was defined the strongest independent risk factor for both OS and tumor recurrence with CE II and SR B. For intraoperative imaging only the use of 5-ALA reached a CE II and SR B. The estimation of EOR was established to be fundamental in planning postoperative adjuvant treatments with CE II and SR B and the stereotactic image-guided brain biopsy to be the procedure of choice when an extensive surgical resection is not feasible (CE II and SR B). CONCLUSIONS: A growing number of evidences evidence support the role of maximal safe resection as primary OS predictor in GG4 patients. The ongoing development of intraoperative techniques for a precise real-time identification of peritumoral functional pathways enables surgeons to maximize EOR minimizing the post-operative morbidity.

Histologic Definition of Enhancing Core and FLAIR Hyperintensity Region of Glioblastoma, IDH-Wild Type: A Clinico-Pathologic Study on a Single-Institution Series.

The extent of resection beyond the enhancing core (EC) in glioblastoma IDH-wild type (GBM, IDHwt) is one of the most debated topics in neuro-oncology. Indeed, it has been demonstrated that local disease recurrence often arises in peritumoral areas and that radiologically-defined FLAIR hyperintensity areas of GBM IDHwt are often visible beyond the conventional EC. Therefore, the need to extend the surgical resection also to the FLAIR hyperintensity areas is a matter of debate. Since little is known about the histological composition of FLAIR hyperintensity regions, in this study we aimed to provide a comprehensive description of the histological features of EC and FLAIR hyperintensity regions sampled intraoperatively using neuronavigation and 5-aminolevulinic acid (5-ALA) fluorescence, in 33 patients with GBM, IDHwt. Assessing a total 109 histological samples, we found that FLAIR areas consisted in: (i) fragments of white matter focally to diffusely infiltrated by tumor cells in 76% of cases; (ii) a mixture of white matter with reactive astrogliosis and grey matter with perineuronal satellitosis in 15% and (iii) tumor tissue in 9%. A deeper knowledge of the histology of FLAIR hyperintensity areas in GBM, IDH-wt may serve to better guide neurosurgeons on the choice of the most appropriate surgical approach in patients with this neoplasm.

Lactate modulates microglia polarization via IGFBP6 expression and remodels tumor microenvironment in glioblastoma.

Lactic acidosis has been reported in solid tumor microenvironment (TME) including glioblastoma (GBM). In TME, several signaling molecules, growth factors and metabolites have been identified to induce resistance to chemotherapy and to sustain immune escape. In the early phases of the disease, microglia infiltrates TME, contributing to tumorigenesis rather than counteracting its growth. Insulin-like Growth Factor Binding Protein 6 (IGFBP6) is expressed during tumor development, and it is involved in migration, immune-escape and inflammation, thus providing an attractive target for GBM therapy. Here, we aimed at investigating the crosstalk between lactate metabolism and IGFBP6 in TME and GBM progression. Our results show that microglia exposed to lactate or IGFBP6 significantly increased the Monocarboxylate transporter 1 (MCT1) expression together with genes involved in mitochondrial metabolism. We, also, observed an increase in the M2 markers and a reduction of inducible nitric oxide synthase (iNOS) levels, suggesting a role of lactate/IGFBP6 metabolism in immune-escape activation. GBM cells exposed to lactate also showed increased levels of IGFBP6 and vice-versa. Such a phenomenon was coupled with a IGFBP6-mediated sonic hedgehog (SHH) ignaling increase. We, finally, tested our hypothesis in a GBM zebrafish animal model, where we observed an increase in microglia cells and igfbp6 gene expression after lactate exposure. Our results were confirmed by the analysis of human transcriptomes datasets and immunohistochemical assay from human GBM biopsies, suggesting the existence of a lactate/IGFBP6 crosstalk in microglial cells, so that IGFBP6 expression is regulated by lactate production in GBM cells and in turn modulates microglia polarization.

circSMARCA5 Is an Upstream Regulator of the Expression of miR-126-3p, miR-515-5p, and Their mRNA Targets, Insulin-like Growth Factor Binding Protein 2 (IGFBP2) and NRAS Proto-Oncogene, GTPase (NRAS) in Glioblastoma.

The involvement of non-coding RNAs (ncRNAs) in glioblastoma multiforme (GBM) pathogenesis and progression has been ascertained but their cross-talk within GBM cells remains elusive. We previously demonstrated the role of circSMARCA5 as a tumor suppressor (TS) in GBM. In this paper, we explore the involvement of circSMARCA5 in the control of microRNA (miRNA) expression in GBM. By using TaqMan® low-density arrays, the expression of 748 miRNAs was assayed in U87MG overexpressing circSMARCA5. Differentially expressed (DE) miRNAs were validated through single TaqMan® assays in: (i) U87MG overexpressing circSMARCA5; (ii) four additional GBM cell lines (A172; CAS-1; SNB-19; U251MG); (iii) thirty-eight GBM biopsies; (iv) twenty biopsies of unaffected brain parenchyma (UC). Validated targets of DE miRNAs were selected from the databases TarBase and miRTarbase, and the literature; their expression was inferred from the GBM TCGA dataset. Expression was assayed in U87MG overexpressing circSMARCA5, GBM cell lines, and biopsies through real-time PCR. TS miRNAs 126-3p and 515-5p were upregulated following circSMARCA5 overexpression in U87MG and their expression was positively correlated with that of circSMARCA5 (r-values = 0.49 and 0.50, p-values = 9 × 10-5 and 7 × 10-5, respectively) in GBM biopsies. Among targets, IGFBP2 (target of miR-126-3p) and NRAS (target of miR-515-5p) mRNAs were positively correlated (r-value = 0.46, p-value = 0.00027), while their expression was negatively correlated with that of circSMARCA5 (r-values = -0.58 and -0.30, p-values = 0 and 0.019, respectively), miR-126-3p (r-value = -0.36, p-value = 0.0066), and miR-515-5p (r-value = -0.34, p-value = 0.010), respectively. Our data identified a new GBM subnetwork controlled by circSMARCA5, which regulates downstream miRNAs 126-3p and 515-5p, and their mRNA targets IGFBP2 and NRAS.

Immunoexpression of p62/SQSTM1/Sequestosome-1 in human primary and recurrent IDH1/2 wild-type glioblastoma: A pilot study.

p62/SQSTM1/Sequestosome-1 is an autophagic protein that serves a crucial role in cellular metabolism, proliferation and malignant growth. Notably, autophagy may influence the development and resistance to therapy of numerous types of human cancer. In the present pilot study, the immunohistochemical pattern of p62 was analyzed in a cohort of patients with isocitrate dehydrogenase (IDH)1/2 wild-type glioblastoma (GBM), in primary and recurrent samples, in order to verify the concordance or discordance between the primary and recurrent tumors. In addition, the association between p62, and patient outcome and O6-methylguanine-DNA methyltransferase (MGMT) status was assessed. The results revealed p62 immunoexpression in the nucleus and cytoplasm of neoplastic elements in 45% of primary and 55% of recurrent cases of GBM. A discordant p62 immunoreactivity was detected in 35% of cases, with a variation either with positive or negative conversion of p62 status. Statistically, p62 expression and MGMT status exhibited a significant prognostic value by univariate analysis, whereas only MGMT promoter methylation status emerged as an independent prognostic factor by multivariate analysis. Finally, the most favorable prognosis was documented when the same GBM case was positively concordant for both p62 expression and MGMT methylated status. Since little data are available regarding the association between p62 expression and MGMT in GBM, further investigations may be required to determine if new targeted therapies may be addressed against autophagy-related proteins, such as p62.

Lactate Induces the Expressions of MCT1 and HCAR1 to Promote Tumor Growth and Progression in Glioblastoma.

The tumor microenvironment (TME) plays a pivotal role in establishing malignancy, and it is associated with high glycolytic metabolism and lactate release through monocarboxylate transporters (MCTs). Several lines of evidence suggest that lactate also serves as a signaling molecule through its receptor hydroxycarboxylic acid receptor 1 (HCAR1/GPR81), thus functioning as a paracrine and autocrine signaling molecule. The aim of the present study was to investigate the role of lactate in glioblastoma (GBM) progression and metabolic reprogramming in an in vitro and in vivo model. The cell proliferation, migration, and clonogenicity were tested in vitro in three different human GBM cell lines. The expressions of MCT1, MCT4, and HCAR1 were evaluated both in vitro and in a zebrafish GBM model. The results were further validated in patient-derived GBM biopsies. Our results showed that lactate significantly increased the cell proliferation, migration, and colony formation capacity of GBM cells, both in vitro and in vivo. We also showed that lactate increased the expressions of MCT1 and HCAR1. Moreover, lactate modulated the epithelial-mesenchymal transition protein markers E-cadherin and ß-catenin. Interestingly, lactate induced mitochondrial mass and the OXPHOS gene, suggesting improved mitochondrial fitness. Similar effects were observed after treatment with 3,5-dihydroxybenzoic acid, a known agonist of HCAR1. Consistently, the GBM zebrafish model exhibited an altered metabolism and increased expressions of MCT1 and HCAR1, leading to high levels of extracellular lactate and, thus, supporting tumor cell proliferation. Our data from human GBM biopsies also showed that, in high proliferative GBM biopsies, Ki67-positive cells expressed significantly higher levels of MCT1 compared to low proliferative GBM cells. In conclusion, our data suggest that lactate and its transporter and receptor play a major role in GBM proliferation and migration, thus representing a potential target for new therapeutic strategies to counteract tumor progression and recurrence.

Relapsing High-Grade Glioma from Peritumoral Zone: Critical Review of Radiotherapy Treatment Options.

Glioblastoma (GBM) is the most common and aggressive brain tumor in adults, with a median survival of about 15 months. After the prior treatment, GBM tends to relapse within the high dose radiation field, defined as the peritumoral brain zone (PTZ), needing a second treatment. In the present review, the primary role of ionizing radiation in recurrent GBM is discussed, and the current literature knowledge about the different radiation modalities, doses and fractionation options at our disposal is summarized. Therefore, the focus is on the necessity of tailoring the treatment approach to every single patient and using radiomics and PET/MRI imaging to have a relatively good outcome and avoid severe toxicity. The use of charged particle therapy and radiosensitizers to overcome GBM radioresistance is considered, even if further studies are necessary to evaluate the effectiveness in the setting of reirradiation.

Regional Development of Glioblastoma: The Anatomical Conundrum of Cancer Biology and Its Surgical Implication.

Glioblastoma (GBM) are among the most common malignant central nervous system (CNS) cancers, they are relatively rare. This evidence suggests that the CNS microenvironment is naturally equipped to control proliferative cells, although, rarely, failure of this system can lead to cancer development. Moreover, the adult CNS is innately non-permissive to glioma cell invasion. Thus, glioma etiology remains largely unknown. In this review, we analyze the anatomical and biological basis of gliomagenesis considering neural stem cells, the spatiotemporal diversity of astrocytes, microglia, neurons and glutamate transporters, extracellular matrix and the peritumoral environment. The precise understanding of subpopulations constituting GBM, particularly astrocytes, is not limited to glioma stem cells (GSC) and could help in the understanding of tumor pathophysiology. The anatomical fingerprint is essential for non-invasive assessment of patients' prognosis and correct surgical/radiotherapy planning.

A Custom DNA-Based NGS Panel for the Molecular Characterization of Patients With Diffuse Gliomas: Diagnostic and Therapeutic Applications.

The management of patients with Central Nervous System (CNS) malignancies relies on the appropriate classification of these tumors. Recently, the World Health Organization (WHO) has published new criteria underlining the importance of an accurate molecular characterization of CNS malignancies, in order to integrate the information generated by histology. Next generation sequencing (NGS) allows single step sequencing of multiple genes, generating a comprehensive and specific mutational profile of the tumor tissue. We developed a custom NGS-based multi-gene panel (Glio-DNA panel) for the identification of the correct glioma oncotype and the detection of its essential molecular aberrations. Specifically, the Glio-DNA panel targets specific genetic and chromosomal alterations involving ATRX chromatin remodeler (ATRX), cyclin dependent kinase inhibitor 2A (CDKN2A), isocitrate dehydrogenase (NADP+) 1 (IDH1) and the telomerase reverse transcriptase (TERT) promoter while also recognizing the co-deletion of 1p/19q, loss of chromosome 10 and gain of chromosome 7. Furthermore, the Glio-DNA panel also evaluates the methylation level of the O-6-methylguanine-DNA methyltransferase (MGMT) gene promoter that predicts temozolomide efficacy. As knowledge of the mutational landscape of each glioma is mandatory to define a personalized therapeutic strategy, the Glio-DNA panel also identifies alterations involving "druggable" or "actionable" genes. To test the specificity of our panel, we used two reference mutated DNAs verifying that NGS allele frequency measurement was highly accurate and sensitive. Subsequently, we performed a comparative analysis between conventional techniques - such as immunohistochemistry or fluorescence in situ hybridization - and NGS on 60 diffuse glioma samples that had been previously characterized. The comparison between conventional testing and NGS showed high concordance, suggesting that the Glio-DNA panel may replace multiple time-consuming tests. Finally, the identification of alterations involving different actionable genes matches glioma patients with potential targeted therapies available through clinical trials. In conclusion, our analysis demonstrates NGS efficacy in simultaneously detecting different genetic alterations useful for the diagnosis, prognosis and treatment of adult patients with diffuse glioma.

Glioblastoma, IDH-Wild Type With FGFR3-TACC3 Fusion: When Morphology May Reliably Predict the Molecular Profile of a Tumor. A Case Report and Literature Review.

It has been reported that in-frame FGFR3-TACC3 fusions confer to glioblastomas, IDH-wild type (GBMs, IDHwt) some unusual morphologic features, including monomorphous rounded cells with ovoid nuclei, nuclear palisading, endocrinoid network of "chicken-wire" vessels, microcalcifications and desmoplastic stroma, whose observation may predict the molecular profile of the tumor. We herein present a case of recurrent GBMs, IDHwt, exhibiting some of the above-mentioned morphological features and a molecularly-proven FGFR3-TACC3 fusion. A 56-year-old man presented to our hospital for a recurrent GBM, IDHwt, surgically treated at another center. Histologically, the tumor, in addition to the conventional GBM morphology, exhibited the following peculiar morphologic features: (1) monomorphous neoplastic cells with rounded nuclei and scant pale cytoplasm; (2) thin capillary-like vessels with "chicken-wire" pattern; (3) nuclear palisading; (4) formation of vague perivascular pseudorosettes; (5) spindled tumor cells embedded in a loose, myxoid background. Based on this unusual morphology, molecular analyses were performed and an FGFR3 exon17-TACC3 exon 10 fusion was found. The present case contributes to widening the morphologic spectrum of FGFR3-TACC3-fused GBM, IDHwt and emphasizes that pathologists, in the presence of a GBM, IDHwt with unconventional morphology, should promptly search for this fusion gene.

A mesenchymal chondrosarcoma with aberrant nuclear expression of STAT6: a potential diagnostic pitfall.

STAT6 is usually considered to be a very sensitive and specific immunomarker for diagnosis of solitary fibrous tumor (SFT), being a surrogate of the NAB2-STAT6 fusion gene identified in most cases of this tumor. STAT6 expression has also been reported in rare cases of other soft tissue tumors, such as low-grade fibromyxoid sarcoma, myxoid/round cell liposarcoma, dedifferentiated liposarcoma and deep fibrous histiocytoma. The aim of this study was to report, for the first time, a case of mesenchymal chondrosarcoma showing diffuse aberrant immunohistochemical expression of STAT6. Molecular biology, showing the HEY1-NCOA2 fusion gene, was crucial to rule out SFT.

Histological and immunohistochemical findings in a fatal case of thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination.

This case report describes a fatal case of a young woman with superior sagittal, transverse and sigmoid sinus thrombosis after administration of the ChAdOx1 nCov-19 vaccination. Eleven days post-vaccination she was found unconscious and transferred to the Emergency Department. Blood parameters showed low platelets, and a CT scan showed an extensive left intracranial hemorrhage and the presence of an occlusive thrombus of the superior sagittal sinus. She under-went a craniectomy, but after the intervention, she remained in a comatose state. After a few days, her clinical conditions worsened, and she died. A complete autopsy was performed which showed a thrombosis of the cerebral venous district, of the upper and lower limbs. A blood sample was also performed to carry out a gene study about the predisposition to thrombosis. The organ samples were studied through light microscope both in hematoxylin-eosin and immunohistochemical examination, and showed a strong inflammatory response in all samples and at the site of thrombosis. Our study aims to provide a proper autopsy technique to study the entire cerebral venous system through a multidisciplinary approach (anatomical dissection and neurosurgery) in post-vaccine venous thrombosis.

Cerebellar liponeurocytoma: clinical, histopathological and molecular features of a series of three cases, including one recurrent tumor.

Cerebellar liponeurocytoma (CL) is an unusual tumor, histologically composed of a mixture of small to medium-sized, rounded neurocytic cells and a variable lipomatous component. Although CL was originally considered as a subtype of medulloblastoma, subsequent molecular studies demonstrated that this tumor was a distinct entity, exhibiting the tumor protein p53 gene (TP53) missense mutations in 20% of cases, chromosome 17 deletion, and the absence of mutations in the adenomatous polyposis coli gene (APC), the protein patched homolog gene (PTCH), the kinase insert domain receptor gene (KDR), and the ß-catenin gene (CTNNB). Apart from these molecular features, little is known about the pathogenesis and the genetic landscape of CL to date. In order to characterize the mutational landscape of CL and identify alterations that are driving tumorigenesis, we report a series of three cases, including one recurrent tumor, analysed by next-generation sequencing (NGS), which identified a total of 22 variants, of which four were missense mutations, nine were synonymous variants, and nine were located on intronic regions. In particular, DNA sequencing identified missense mutations in APC, KDR, and TP53 that could be implicated in promoting tumor progression and angiogenesis of CL. Furthermore, the NGS analysis revealed that recurrent CL did not have additional genetic changes compared with the primary tumor. Moreover, the high frequencies of detected mutations suggested that the identified alterations are germline variants. Indeed, an additional NGS on the genomic DNA obtained from one of the three patients confirmed the presence of the variants in the germline DNA. In conclusion, the obtained data support the hypothesis that CL is a distinct pathological entity that does not show specific somatic alterations driving tumorigenesis.

Feasibility on the Use of Radiomics Features of 11[C]-MET PET/CT in Central Nervous System Tumours: Preliminary Results on Potential Grading Discrimination Using a Machine Learning Model.

BACKGROUND/AIM: Nowadays, Machine Learning (ML) algorithms have demonstrated remarkable progress in image-recognition tasks and could be useful for the new concept of precision medicine in order to help physicians in the choice of therapeutic strategies for brain tumours. Previous data suggest that, in the central nervous system (CNS) tumours, amino acid PET may more accurately demarcate the active disease than paramagnetic enhanced MRI, which is currently the standard method of evaluation in brain tumours and helps in the assessment of disease grading, as a fundamental basis for proper clinical patient management. The aim of this study is to evaluate the feasibility of ML on 11[C]-MET PET/CT scan images and to propose a radiomics workflow using a machine-learning method to create a predictive model capable of discriminating between low-grade and high-grade CNS tumours. MATERIALS AND METHODS: In this retrospective study, fifty-six patients affected by a primary brain tumour who underwent 11[C]-MET PET/CT were selected from January 2016 to December 2019. Pathological examination was available in all patients to confirm the diagnosis and grading of disease. PET/CT acquisition was performed after 10 min from the administration of 11C-Methionine (401-610 MBq) for a time acquisition of 15 min. 11[C]-MET PET/CT images were acquired using two scanners (24 patients on a Siemens scan and 32 patients on a GE scan). Then, LIFEx software was used to delineate brain tumours using two different semi-automatic and user-independent segmentation approaches and to extract 44 radiomics features for each segmentation. A novel mixed descriptive-inferential sequential approach was used to identify a subset of relevant features that correlate with the grading of disease confirmed by pathological examination and clinical outcome. Finally, a machine learning model based on discriminant analysis was used in the evaluation of grading prediction (low grade CNS vs. high-grade CNS) of 11[C]-MET PET/CT. RESULTS: The proposed machine learning model based on (i) two semi-automatic and user-independent segmentation processes, (ii) an innovative feature selection and reduction process, and (iii) the discriminant analysis, showed good performance in the prediction of tumour grade when the volumetric segmentation was used for feature extraction. In this case, the proposed model obtained an accuracy of ~85% (AUC ~79%) in the subgroup of patients who underwent Siemens tomography scans, of 80.51% (AUC 65.73%) in patients who underwent GE tomography scans, and of 70.31% (AUC 64.13%) in the whole patients' dataset (Siemens and GE scans). CONCLUSIONS: This preliminary study on the use of an ML model demonstrated to be feasible and able to select radiomics features of 11[C]-MET PET with potential value in prediction of grading of disease. Further studies are needed to improve radiomics algorithms to personalize predictive and prognostic models and potentially support the medical decision process.

A "polymorphous low-grade neuroepithelial tumor of the young (PLNTY)" diagnosed in an adult. Report of a case and review of the literature.

BACKGROUND: Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a rare neuropathological entity, recently introduced in neuro-oncology. These tumors, histologically similar to oligodendrogliomas, cause epilepsy, occurring in children and young adults. Only few cases of PLNTY have been described in literature and all reported cases invariably focused on the onset of these tumors in children and young adults. CASE DESCRIPTION: We report the case of a 50-year-old woman suffering from epilepsy since the 1st year of her life. Computed tomography scan and magnetic resonance imaging of the brain documented the presence of a calcified mass involving left temporal lobe. The tumor was surgically excised and the histological examination showed a hypocellular and massively calcified neoplasm with morphological and immunohistochemical features consistent with the diagnosis of "PLNTY." CONCLUSION: A review of the literature revealed that there are 31 cases of PLNTY reported in literature, most of which are children or young adults. The present case represents the second PLNTY diagnosed in a middle-aged adult to the best of our knowledge, suggesting that PLNTY should always be included in the differential diagnosis of low-grade brain tumors, also in adult patients.

Serum Extracellular Vesicle-Derived circHIPK3 and circSMARCA5 Are Two Novel Diagnostic Biomarkers for Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is the most frequent and deadly human brain cancer. Early diagnosis through non-invasive biomarkers may render GBM more easily treatable, improving the prognosis of this currently incurable disease. We suggest the use of serum extracellular vesicle (sEV)-derived circular RNAs (circRNAs) as highly stable minimally invasive diagnostic biomarkers for GBM diagnosis. EVs were isolated by size exclusion chromatography from sera of 23 GBM and 5 grade 3 glioma (GIII) patients, and 10 unaffected controls (UC). The expression of two candidate circRNAs (circSMARCA5 and circHIPK3) was assayed by droplet digital PCR. CircSMARCA5 and circHIPK3 were significantly less abundant in sEVs from GBM patients with respect to UC (fold-change (FC) of -2.15 and -1.92, respectively) and GIII (FC of -1.75 and -1.4, respectively). Receiver operating characteristic curve (ROC) analysis, based on the expression of sEV-derived circSMARCA5 and circHIPK3, allowed us to distinguish GBM from UC (area under the curve (AUC) 0.823 (0.667-0.979) and 0.855 (0.704 to 1.000), with a 95% confidence interval (CI), respectively). Multivariable ROC analysis, performed by combining the expression of sEV-derived circSMARCA5 and circHIPK3 with preoperative neutrophil to lymphocyte (NLR), platelet to lymphocyte (PLR) and lymphocyte to monocyte (LMR) ratios, three known diagnostic and prognostic GBM markers, allowed an improvement in the GBM diagnostic accuracy (AUC 0.901 (0.7912 to 1.000), 95% CI). Our data suggest sEV-derived circSMARCA5 and circHIPK3 as good diagnostic biomarkers for GBM, especially when associated with preoperative NLR, PLR and LMR.