FSTL5 expression is a marker of Group C metastatic medulloblastomas

INTRODUCTION: Medulloblastoma (MB) is the most commonmalignant brain tumor in children. Four different molecular subgroups are recognized, which differ in gene expression, genomic aberrations, histology, demographics and survival:WNT and SHH groups, having specific mutations in the homonymous pathway, and groups C and D having several genetic alternations not specific to a single pathway. The gene for follistatin-like protein 5, FSTL5, is overexpressed in nonSHH/nonWNT MBs poorly characterized. Highexpression of FSTL5 is significantly associated with reduced event-free and overall survival in non-WNT/non-SHHMBs. The major aim of this project is to study the FSTL5 expression level in pediatric MBs with metastasis at the onset. METHOD: We investigated the protein expression of biomarkers involved in metastatic pathways by IHC and FSTL5 expression level by RT-PCR in 26 metastatic MBs samples and correlated these data with the outcomes by Kaplan-Meier statistic analysis. RESULTS: 83% of Group C MBs showed high level of FSTL5 while none of these presented down-expression. Low-expression level of FSTL5 was find in 60% of SHH MBs and none showed over-expression. Kaplan-Meier test revealed that, in our cohort, highexpression ofFSTL5didnot correlatewithworse outcomewhile lowexpression of FSTL5 was associated with good prognosis and the co-presence of FSTL5 with other biomarkers correlated with poorer prognosis. CONCLUSION: FSTL5 is a marker of Group C in medulloblastomas with metastasis at the onset and the results highlighted decreased FSTL5 expression as a marker of good prognosis. Group C MBs have characteristic molecular features that confirm the poorest outcome also inMBs with metastasis at the onset

Expanding the spectrum of "mesenchymal" tumors of the central nervous system

: In this review, we summarize the clinical, histopathological, and molecular features of central nervous system (CNS) tumors with BCOR internal tandem duplication, intracranial mesenchymal tumor with FET/CREB fusion, CNS CIC-rearranged sarcomas and primary intracranial sarcoma DICER1-mutant, now included in the 2021 WHO classification of CNS tumors. Possible relationships between tumors occurring in the CNS and their systemic counterparts are discussed

Sporadic High-Grade Malignant Peripheral Nerve Sheath Tumor of the Hypoglossal Nerve

n/

Atypical teratoid/rhabdoid tumor in adults: a systematic review of the literature with meta‑analysis and additional reports of 4 cases

Introduction Atypical teratoid/rhabdoid tumor (AT/RT) is a highly aggressive embryonal CNS neoplasm, characterized by inactivation of SMARCB1 (INI1) or rarely of SMARCA4 (BRG1). While it is predominantly a childhood tumor, AT/RT is rare in adults. Methods We provide a comprehensive systematic review of literature with meta-analysis; 92 adult cases were found from 74 articles. We additionally present 4 cases of adult AT/RTs (age ranging from 19 to 29 years), located to cerebellum in 2 cases, to ponto-cerebellar angle in 1 case and to spinal cord in the remaining case. Results Microscopic features of our 4 cases showed a highly cellular tumor with rhabdoid morphology and high mitotic activity. All tumor cells lacked nuclear SMARCB1/INI1 protein expression. In case no. 3 we also performed methylation profiling which clustered the tumor with pediatric AT/RT-MYC subgroup. Prognosis remains poor in both pediatric and adult population with a median overall survival of 11 months. Our review demonstrated median overall survival of 15 months among the adult populations. However, consistent with a recent review, adult AT/RT seems to have highly variable prognosis and some patients reach long term survival with 22.9% of 5-year survival without evidence of disease and mean follow up time of 35.9 months (SD = 36.5). 27.1% of dissemination was also reported among the adult population. Conclusions Adult AT/RTs predominantly arise in female patients and in supratentorial location. Midline structures, including the sellar region, are the most affected sites, especially among females aged > 40 years. Male gender is more prevalent between the age of 18 and 40 years and more frequently associated with non-midline tumors. Factors significantly associated with better prognosis are patient’s age (< 40 years), combined radio-chemotherapy adjuvant approach and Ki-67 score < 40%

Paediatric-type diffuse high-grade gliomas in the 5th CNS WHO Classification

As a relevant element of novelty, the fifth CNS WHO Classification highlights the distinctive pathobiology underlying gliomas arising primarily in children by recognizing for the first time the families of paediatric-type diffuse gliomas, both high-grade and low-grade. This review will focus on the family of paediatric-type diffuse high-grade gliomas, which includes four tumour types: 1) Diffuse midline glioma H3 K27-altered; 2) Diffuse hemispheric glioma H3 G34-mutant; 3) Diffuse paediatric-type high-grade glioma H3-wildtype and IDH-wildtype; and 4) Infant-type hemispheric glioma. The essential and desirable diagnostic criteria as well as the entities entering in the differential will be discussed for each tumour type. A special focus will be given on the issues encountered in the daily practice, especially regarding the diagnosis of the diffuse paediatric-type high-grade glioma H3-wildtype and IDH-wildtype. The advantages and the limits of the multiple molecular tests which may be utilised to define the entities of this tumour family will be evaluated in each diagnostic context

Role of 1p/19q Codeletion in Diffuse Low-grade Glioma Tumour Prognosis

Background/Aim: In the latest 2021 WHO classification of central nervous system tumours (CNS), gliomas that present isocitrate dehydrogenase (IDH) mutations are defined as diffuse low-grade gliomas (DLGGs). IDH mutations are commonly observed in this tumour type. The Extent of Resection (EOR) positively influence survival; however, it is still debated whether the predictive value of EOR is independent of the 1p/19q co-deletion. We carried out a retrospective analysis on patients operated on for DLGG at the Sant’Andrea University Hospital Sapienza University of Rome, correlating the outcome with the presence of 1p/19q co-deletion and EOR. Patients and Methods: The study examined 66 patients with DLGG who had undergone surgery for tumour resection between 2008 and 2018. Patients with DLGG were divided into two groups; diffuse astrocytoma (DA) in which 1p/19q codeletion is absent and oligodendroglioma (OG) in which 1p/19q codeletion is present. According to EOR, both groups were divided into two subgroups: subtotal resection (STR) and gross total resection (GTR). Three end-point variables were considered: overall survival (OS), progression-free survival (PFS) and time to malignant transformation (TMT). Results: In the DA group, the GTR subgroup had an average OS of 81.6 months, an average PFS of 45.9 months and an average TMT of 63.6 months. After surgery, these patients had an average Karnofsky Performance Score (KPS) of 83.4. The STR subgroup had an average OS of 60.4 months, PFS was 38.7 months, and TMT was 46.4 months, post-operative KPS was 83.4. In contrast, in the OG group, the GTR averagely had 101.7 months of OS, 64.9 months of PFS, 80.3 months of TMT and an average post-operative KPS of 84.2, and the STR subgroup had an average of OS of 73.3 months, PFS of 48.2 months, TMT of 57.3 and an average postoperative KPS of 96.2. Conclusion: In patients affected by DLGGs, 1p/19q codeletion is significantly associated with prolonged survival and longer time-to-malignant transformation (TMT) compared to the absence of 1p/19q codeletion. Also, the extent of surgical resection (EOR) in DLGG patients has been confirmed as one of the main prognostic factors. However, its predictive value is substantially influenced by the presence of the 1p/19q codeletion

Secreting Germ Cell Tumors of the Central Nervous System: A Long-Term Follow-up Experience

Simple Summary Nongerminomatous germ cell tumors of the central nervous system are rare tumours. Differently from germinomas, they have a severe prognosis above all when presenting with high alfafetoprotein levels. We report the results of a combined chemo- and radiotherapy approach in 28 patients affected by this disease with craniospinal irradiation and a boost tailored on the response to pre-radiant chemotherapy. Metastatic patients and high-risk disease are discussed as well. The 5 years overall survival and event-free survival were both 81% while at 10 years they were 81% and 76% respectively. Our series, even if small, concerns nongerminomatous germ cell tumors only (whereas in some papers they are mixed with pure germinomas), furthermore our patients had a very long follow-up (over 11 years) with encouraging survival data for localized and metastatic disease. Improving survival while trying to contain/avoid the long-term sequelae of chemotherapy and radiotherapy are the main goals of future studies. Introduction: Due to the rarity of nongerminomatous germ cell tumors (NGGCT) with non-standard treatment as yet, we report retrospectively our 30 year experience with chemotherapy followed by craniospinal irradiation (CSI), plus a boost of whole ventricular irradiation (WVI)/tumor bed (TB), tailored to pre-radiation chemotherapy response. Methods: Between 1988 and 2016, 28 patients received four cycles of PEB (cisplatin/etoposide/bleomycin), then CSI, and two further PEB cycles. Between 1988 and1994, CSI was 25.5 Gy for patients in complete remission (CR), 30 Gy if in partial remission (PR) or metastatic, with a boost to TB up to 45-54 Gy. In the period of 1995-2010, the boost included WVI and any extra-ventricular tumor sites up to 45 Gy. After 2010, CSI was reduced to 25.5 Gy for all non-metastatic patients, and a boost was given only to TB up to 40.5/45.5 Gy, depending on patients' CR/PR status. After 2003, patients with alfafetoprotein (alpha FP) > 1000 ng/mL received intensified treatment, also including autologous stem cell transplantation. Results: Among 28 patients (23 males; median age 12 years, 6 metastatic), 25 responded to PEB, and three progressed (PD) after one to four cycles; 26 received radiotherapy obtaining 13 CR, 7 PR and 5 stable disease (SD), 1 PD; 6 (21%) died (5 for disease, 1 for pneumonia while in CR). Five-year overall survival (OS) and progression-free survival (PFS) were both 81%; 10 year OS and PFS 81% and 76%, respectively (median follow-up 11 years). Conclusions: Survival for children with NGGCT, independently from disease extent, was encouraging. Further studies should elucidate which patients could benefit from reduced volume and dose irradiation

A microRNA prognostic signature in patients with diffuse intrinsic pontine gliomas through non-Invasive liquid biopsy

SIMPLE SUMMARY: Diffuse intrinsic pontine glioma (DIPG) is a neuro-radiologically defined tumor of the brainstem, primarily affecting children, with most diagnoses occurring between 5 and 7 years of age. Surgical removal in DIPGs is not feasible. Subsequent tumor progression is almost universal and no biomarker for predicting the course of the disease has entered into clinical practice so far. Under these premises, it is essential to develop reliable biomarkers that are able to improve outcomes and stratify patients using non-invasive methods to determine tumor profiles. We designed a study assessing circulating miRNA expression by a high-throughput platform and divided patients into training and validation phases in order to disclose a potential signature with clinical impact. Our results for the first time have proved the usefulness of blood-circulating nucleic acids as powerful, easy-to-assay molecular markers of disease status in DIPG. ABSTRACT: Diffuse midline gliomas (DMGs) originate in the thalamus, brainstem, cerebellum and spine. This entity includes tumors that infiltrate the pons, called diffuse intrinsic pontine gliomas (DIPGs), with a rapid onset and devastating neurological symptoms. Since surgical removal in DIPGs is not feasible, the purpose of this study was to profile circulating miRNA expression in DIPG patients in an effort to identify a non-invasive prognostic signature with clinical impact. Using a high-throughput platform, miRNA expression was profiled in serum samples collected at the time of MRI diagnosis and prior to radiation and/or systemic therapy from 47 patients enrolled in clinical studies, combining nimotuzumab and vinorelbine with concomitant radiation. With progression-free survival as the primary endpoint, a semi-supervised learning approach was used to identify a signature that was also tested taking overall survival as the clinical endpoint. A signature comprising 13 circulating miRNAs was identified in the training set (n = 23) as being able to stratify patients by risk of disease progression (log-rank p = 0.00014; HR = 7.99, 95% CI 2.38–26.87). When challenged in a separate validation set (n = 24), it confirmed its ability to predict progression (log-rank p = 0.00026; HR = 5.51, 95% CI 2.03–14.9). The value of our signature was also confirmed when overall survival was considered (log-rank p = 0.0021, HR = 4.12, 95% CI 1.57–10.8). We have identified and validated a prognostic marker based on the expression of 13 circulating miRNAs that can shed light on a patient’s risk of progression. This is the first demonstration of the usefulness of nucleic acids circulating in the blood as powerful, easy-to-assay molecular markers of disease status in DIPG. This study provides Class II evidence that a signature based on 13 circulating miRNAs is associated with the risk of disease progression

Low Expression of miR-466f-3p Sustains Epithelial to Mesenchymal Transition in Sonic Hedgehog Medulloblastoma Stem Cells Through Vegfa-Nrp2 Signaling Pathway

High-throughput analysis has improved the knowledge of medulloblastoma (MB), the leading cause of cancer related death in children, allowing a better comprehension of the key molecular pathways in MB pathogenesis. However, despite these advances, 30% of patients still die from the disease and survivors face severe long-term side effects. Cancer stem cells (CSCs) represent a subset of cells that not only drive tumorigenesis, but are also one of the main determinants of chemoresistance. Epithelial mesenchymal transition (EMT) is a hallmark of cancer and up to now few data is available in MB. To give insight into the role of the EMT process in maintaining the mesenchymal phenotype of CSCs, we analyzed the expression of EMT related transcripts and microRNAs in these cells. We firstly isolated CSCs from Sonic Hedgehog (SHH) MB derived from Ptch1 heterozygous mice and compared their expression level of EMT-related transcripts and microRNAs with cerebellar NSCs. We identified two molecules linked to SHH and EMT, Vegfa and its receptor Nrp2, over-expressed in SHH MB CSCs. Inhibition of Vegfa showed impairment of cell proliferation and self-renewal ability of CSCs concurrent with an increase of the expression of the EMT gene, E-cadherin, and a decrease of the EMT marker, Vimentin. Moreover, among deregulated microRNAs, we identified miR-466f-3p, a validated inhibitor of both Vegfa and Nrp2. These results allowed us to describe a new EMT molecular network, involving the down-regulation of miR-466f-3p together with the concordant up-regulation of Vegfa and Nrp2, that sustains the mesenchymal phenotype of SHH MB CSCs

Melanotic Neuroectodermal Tumor of Infancy (MNTI) and Pineal Anlage Tumor (PAT) Harbor A Medulloblastoma Signature by DNA Methylation Profiling

MNTI is a rare tumor of indeterminate histogenesis and molecular signature. We performed methylation and copy number variation (CNV) profiles in patients with MNTI (n = 7) and PAT (n = 1) compared to the methylation brain tumor classifier v11b4 (BT-C) and the medulloblastoma (MB) classifier group 3/4 v1.0 (MB3/4-C). The patients’ mean age was 8 months (range: 4–48). The BT-C classified five MNTIs and one PAT (relapse) as class family MB-G3/G4, subclass group 3 (score: >0.9). The remaining two MNTIs and PAT (primary) were classified as class family plexus tumor, subclass pediatric (scores: >0.45). The MB3/4-C classified all MNTIs as high-risk MB-G3, Subtype II (score: >0.45). The primary PAT was classified as subtype III (score: 0.99) and its relapse as subtype II/III. MNTI and PAT clustered close to MB-G3. CNV analysis showed multiple rearrangements in one PAT and two MNTIs. The median follow-up was 54 months (four MNTIs in remission, one PAT died). In conclusion, we demonstrated that MNTI shares a homogenous methylation profile with MB-G3, and possibly with PAT. The role of a multipotent progenitor cell (i.e., early cranial neural crest cell) in their histogenesis and the influence of the anatomical site, tumor microenvironment, and other cytogenetic events in their divergent biologic behavior deserve further investigation