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SMARCB1 inactivation is a well-established trigger event in atypical teratoid/rhabdoid tumor. Recently, a role for SMARCB1 inactivation has emerged as a mechanism of clonal evolution in other tumor types, including rare brain tumors. We describe an unusual malignant intra-axial SMARCB1-deficient spindle cell desmoplastic neoplasm, occurring in a 6-year-old child with meningioangiomatosis and a long history of seizures. Striking features of the tumor were a storiform pattern and strong CD34 expression. Undifferentiated round cell areas with isolated rhabdoid cells showing high mitotic index and focal necrosis with INI1 expression loss were present. The meningioangiomatosis component showed few chromosomal imbalances, including chromosomal 22 monosomy (where SMARCB1 maps) and gain at 6q14.3. In addition to these abnormalities, the spindle cell desmoplastic neoplasm and its dedifferentiated SMARCB1-deficient component shared several other aberrations, including homozygous deletion at 9p21.3, losses at 1p, 3p, 3q, 10p, and 13q, gains and losses at 5p and 11p. In line with INI1 loss, the dedifferentiated component showed remarkably decreased levels of SMARCB1 transcript. The residual SMARCB1 allele was wildtype. Our findings suggest progression from the meningioangiomatosis to the malignant desmoplastic neoplasm through the occurrence of complex chromosomal abnormalities, and point to functional silencing of SMARCB1 in the dedifferentiation component.

A case of a nasal myiasis in a 3-yr-old Italian girl who was referred to Bambino Gesù Hospital in Rome, Italy, is reported. Larvae discharged with the nasal mucus were microscopically identified as Megaselia spp.; DNA barcoding analysis showed that they belonged to the ‘scuttle fly’ species Megaselia rufipes (Meigen). Based on the patient’s history, she became infected when she played outside. This is the first report of myiasis in humans due to M. rufipes (Diptera: Phoridae).

Several molecular biomarkers have been suggested as predictors of outcome for pediatric ependymomas but deserve further validation in independent case series. We analyzed intracranial ependymomas belonging to a series of 60 patients prospectively treated according to the protocol sponsored by the Italian Association of Pediatric Hematology-Oncology. We used a tissue microarray to analyze nucleolin (NCL), cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein 53 (TP53), and epidermal growth factor receptor (EGFR) by immunohistochemistry and by 1q gain by fluorescent in situ hybridization. The mRNA expression levels of EGFR, human telomerase reverse-transcriptase (HTERT), and Prominin 1 (PROM 1)/CD133 were evaluated by quantitative real-time PCR from cases with fresh-frozen tumor material available. Univariate and multivariate analyses of updated clinical data confirmed the prognostic significance of surgery (P < .01) and tumor grading (P < .05) for both relapse-free survival (RFS) and overall survival (OS). Among biomolecular markers, HTERT mRNA expression emerged with the strongest association with OS at multivariate analysis (hazard ratio [HR] = 9.9; P = .011); the 5-year OS was 84% versus 48% in the subgroups with HTERT median value

Epigenetic profiling has shown that a proportion of cases diagnosed as CNS PNET in the past can be assigned to other tumour entities with similar morphological appearance. In an international effort to re-analyze CNS-PNET aiming for disease-specific re-evaluation of survival data and the development of diagnostic guidelines providing the basis for improved therapeutic approaches, 256 tumours diagnosed and treated as CNS-PNET in the last two decades in 17 countries were reviewed by a panel of neuropathologists according to today’s standards of clinical neuropathological diagnostics including immunohistochemical and molecular pathological assays. The majority of cases were also independently analyzed by methylation array hybridization and classified by random forest algorithm. In this unique cohort, we identified 20 different tumor entities including frequent high grade gliomas. 41% of cases were confirmed as CNS-PNET (now termed CNS-embryonal tumors (CNS-ET) according to the revised WHO-classification) representing two main entities: ETMR displayed typical histopathological features, LIN28A expression and/or C19MC alteration. The other represented a group of tumors with variable degrees of differentiation along neuroblastic/ganglionic lines, corresponding to the WHO diagnoses CNS-(Ganglio)-neuroblastoma or CNS-ET, NOS. The vast majority of these tumors could be assigned to the FOXR2 CNS-NB group by methylation array-based classification. Crossvalidation of neuropathological and epigenetic classification proved that methylation classification represents a useful complimentary tool in the differential diagnosis of CNS-ET. Re-evaluation of prototypic tumors and cases with discrepant diagnoses enabled us to develop an optimized diagnostic algorithm to securely delineate this tumor type from other entities with largely divergent clinical and biological behaviour.

Medulloblastoma (MB) is the most common malignant brain tumor. It is classified into four subgroups characterized by distinct mutations, deregulation of specific signaling pathways and different clinical outcomes. A series of pathways and epigenetic mechanisms are deregulated across multiple subtypes, thus representing a window of opportunity for the identification of common targets. A common feature is the presence of stem-like cells (SLCs), a fraction of the tumor bulk which retains the ability to sustain tumor growth and may represent the progenitor giving rise to MB. Recent studies have highlighted the crucial role of microRNAs tumor signaling pathway deregulation. We have previously identified microRNAs deregulated MB and showed that miR-326 is strongly downregulated and represses Hedgehog/Gli signaling. Human and murine MB SLCs were derived and cultured as oncospheres. We investigated the expression levels of miR-326 and its host gene β-arrestin1 in MB specimens and in SLC, the role of the two molecules in MB and the regulation of miR-326/ β-arrestin1 transcriptional unit in SLC. A pharmacological approach was utilized to modulate the expression of miR-326/ β-arrestin1 in MB both in vitro and in vivo. We found that miR-326 cooperates with its host gene β-arrestin1 as tumor suppressor, and is lost in both MB and SLC. Such unit suppresses Hedgehog signaling at multiple levels: β-arrestin1 modulates Gli1-K518 acetylation while miR-326 controls Gli2 and Smo, activatory molecules of the pathway. The analysis of the potential mechanisms involved in the downregulation of this transcriptional unit showed that β-arrestin1/miR-326 are silenced through epigenetic mechanisms at histone levels. Indeed, epigenetic drugs are able to reactivate the miR-326/β- arrestin1 expression and suppress MB and SLC growth in vitro and in vivo. Our study reveals a new microRNA/host gene network in MB and proposes miR-326/β-arrestin1 as tumor suppressors for medulloblastoma patients, susceptible to be re-expressed by epigenetic treatments.