Publications by authors named "Manila Antonelli"

82 Publications

Treatment and outcome of intracranial ependymoma after first relapse in AIEOP 2 nd protocol.

Neuro Oncol 2021 Oct 4. Epub 2021 Oct 4.

Neurology and Psichiatry Department of La Sapienza University, Rome, Italy.

Background: More than 40% of patients with intracranial ependymoma need a salvage treatment within 5 years after diagnosis, and no standard treatment is available as yet. We report the outcome after first relapse of 64 patients treated within the 2 nd AIEOP protocol.

Methods: We considered relapse sites and treatments ,i.e. various combinations of complete/incomplete surgery, if followed by standard or hypo-fractionated radiation(RT) ± chemotherapy(CT). Molecular analyses were available for 38/64 samples obtained at first diagnosis. Of the 64 cases, 55 were suitable for subsequent analyses.

Results: The median follow-up was 147 months after diagnosis, 84 after first relapse, 5-year EFS/OS were 26.2%/30.8% (median EFS/OS 13/32 months) after relapse. For patients with a local relapse(LR), the 5-year cumulative incidence of second LRs was 51.6%, with a 5-year event-specific probability of being LR-free of 40.0%. Tumor site/grade, need for shunting, age above/below 3 years, molecular subgroup at diagnosis, had no influence on outcomes. Due to variation in the RT dose/fractionation used and the subgroup sizes it was not possible to assess the impact of the different RT modalities. Multivariable analyses identified completion of surgery, absence of symptoms at relapse, and female sex as prognostically favorable. Tumors with a 1q gain carried a higher cumulative incidence of dissemination after first relapse.

Conclusions: Survival after recurrence was significantly influenced by symptoms and completeness of surgery. Only a homogeneous protocol with well posed, randomized questions could clarify the numerous issues, orient salvage treatment and ameliorate prognosis for this group of patients.
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http://dx.doi.org/10.1093/neuonc/noab230DOI Listing
October 2021

Comprehensive analysis of the ErbB receptor family in pediatric nervous system tumors and rhabdomyosarcoma.

Pediatr Blood Cancer 2022 Jan 21;69(1):e29316. Epub 2021 Sep 21.

Gustave Roussy Cancer Center, Department of Pediatric and Adolescent Oncology, INSERM U1015, Université Paris Saclay, Villejuif, France.

Background: There is a paucity of knowledge regarding pediatric biomarkers, including the relevance of ErbB pathway aberrations in pediatric tumors. We investigated the occurrence of ErbB receptor aberrations across different pediatric malignancies, to identify patterns of ErbB dysregulation and define biomarkers suitable for patient enrichment in clinical studies.

Procedure: Tissue samples from 297 patients with nervous system tumors and rhabdomyosarcoma were analyzed for immunohistochemical expression or gene amplification of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). Exploratory analyses of HER3/HER4 expression, and mRNA expression of ErbB receptors/ligands (NanoString) were performed. Assay validation followed general procedures, with additional validation to address Clinical Laboratory Improvement Amendments (CLIA) requirements.

Results: In most tumor types, samples with high ErbB receptor expression were found with heterogeneous distribution. We considered increased/aberrant ErbB pathway activation when greater than or equal to two EGFR/HER2 markers were simultaneously upregulated. ErbB pathway dysregulation was identified in ∼20%-30% of samples for most tumor types (medulloblastoma/primitive neuroectodermal tumors 31.1%, high-grade glioma 27.1%, neuroblastoma 22.7%, rhabdomyosarcoma 23.1%, ependymoma 18.8%), 4.2% of diffuse intrinsic pontine gliomas, and no recurrent or refractory low-grade astrocytomas. In medulloblastoma/primitive neuroectodermal tumors and neuroblastoma, this was attributed mainly to high EGFR polysomy/HER2 amplification, whereas EGFR gene amplification was observed in some high-grade glioma samples. EGFR/HER2 overexpression was most prevalent in ependymoma.

Conclusions: Overexpression and/or amplification of EGFR/HER2 were identified as potential enrichment biomarkers for clinical trials of ErbB-targeted drugs.
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http://dx.doi.org/10.1002/pbc.29316DOI Listing
January 2022

Angiocentric glioma-associated seizures: The possible role of EATT2, pyruvate carboxylase and glutamine synthetase.

Seizure 2021 Mar 16;86:152-154. Epub 2021 Feb 16.

Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Children's Hospital A. Meyer-University of Florence, Italy.

Purpose: Our purpose was to better understand the pathogenesis of seizures associated with angiocentric glioma. Angiocentric glioma is an indolent and rare low-grade glioma. Its typical clinical presentation is with epileptic seizures. The pathogenesis of tumor-associated seizures is poorly understood. Among the possible pathomechanisms, the increased neurotoxic concentrations of the glutamate has been proposed. Glutamate transporters, pyruvate carboxylase and glutamine synthetase are involved in maintaining the physiological concentration of glutamate in the inter synaptic spaces.

Methods: We evaluated the immunohistochemical expression of EAAT2 (the most important glutamate transporter), pyruvate carboxylase and glutamine synthetase in 17 angiocentric gliomas.

Results: EAAT2 was never expressed (0%) in the neoplastic cells in none of the cases studied. Pyruvate carboxylase was expressed in the cytoplasm of the neoplastic cells in 16/17 cases (94 %). Glutamine synthetase was expressed in the cytoplasm of the neoplastic cells in 15/17 cases (88 %).

Conclusion: The net result of this enzymatic expression, in particular considering the loss of EAAT2, could be an increased glutamate concentration in the synaptic clef, which might increase local network excitability initially involving intratumoral neurons. The observation that the angiocentric glioma-associated epilepsy might be at least in part related to EAAT2 deficiency opens up interesting therapeutic perspectives.
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http://dx.doi.org/10.1016/j.seizure.2021.02.014DOI Listing
March 2021

Correlation Between Immunohistochemistry and Sequencing in H3G34-Mutant Gliomas.

Am J Surg Pathol 2021 02;45(2):200-204

Department of Radiological, Oncological and Anatomo-pathological Sciences, University Sapienza.

Recurrent glycine-to-arginine/valine alterations at codon 34 (G34R/V) within H3F3A gene characterize a subset of hemispheric high-grade gliomas (HGG) affecting children and young adults. These tumors, defined as G34R/V-mutant gliomas, are histologically heterogenous, with microscopic features of either HGG or embryonal tumors (primitve neuroectodermal tumor-like features). To assess the value of immunohistochemistry (IHC) to detect G34R/V-mutated cases, we tested anti-histone G34V (clone 329E5) and anti-histone G34R (clone RM240) antibodies in a series of 28 formalin-fixed and paraffin-embedded samples. A total of 28 cases of hemispheric, IDH-wt HGG mainly affecting children and young adults were evaluated by IHC and by sequencing. The median age of patients at diagnosis was 17 years (0.1 to 26 y). By IHC, 10 of the 28 cases showed nuclear positivity for G34R and 3 of the 28 cases for G34V. Molecular analysis of G34R/V-mutation status was successful in 24 of the 28 cases. Mutation at glycine 34 of the H3F3A gene was identified in 9 of the 24 tumors (37%) by direct sequencing, revealing 7 of 9 positive case by sequencing and 2 of 9 false negative cases by IHC. Two of 15 negative case by sequencing demonstrated a false positivity by IHC. In total, in 4 (16.6%) of 24 cases, IHC and mutational results were discordant: 2 tumors were negative by IHC (false negative) but harbored G34R mutation by sequencing, and 2 cases were positive by IHC (false positive by IHC) but wild type by sequencing. Moreover, most mutated cases showed loss of ATRX expression and/or p53 expression. The positivity by IHC with specific antibody tested is not highly predictive for presence of G34R/V mutation, but confirmation by sequencing is mandatory; G34R/V mutations should be suspected in all hemispheric tumor IDH1/2 wild type, showing loss of OLIG2 and ATRX and/or p53 expression.
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http://dx.doi.org/10.1097/PAS.0000000000001571DOI Listing
February 2021

Diffuse midline glioma H3 K27M-mutant in adults: A report of six cases and literature review.

Clin Neuropathol 2021 Mar-Apr;40(2):108-117

Aim: Diffuse midline glioma (DMG) H3 K27M-mutant is a specific entity that, as the name indicates, tends to occur in midline structures including the thalamus, brainstem, and spinal cord. DMG predominates in children, is an aggressive tumor with poor prognosis, and is considered a WHO grade IV tumor regardless of histological features. The exact frequency of these mutations in adults diagnosed with glioma in the midline is unknown.

Materials And Methods: We report a series of 6 more adult cases, and we critically review the current literature on adults with DMG H3 K27M-mutant.

Results: There were 5 males and 1 female. The age ranged from 26 to 52 years (median 39 years). All cases showed astrocytic differentiation, with positive staining for H3 K27M protein, and loss of H3 K27me in the tumor cells confirming the diagnosis.

Conclusion: H3 K27M-mutant midline glioma can occur in adults, affecting midline structures. Increasing awareness of the reporting pathologists of this entity might help in a better determination of the frequency of mutant DMG in adults as well as better diagnosis and patient counseling of the outcome.
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http://dx.doi.org/10.5414/NP301331DOI Listing
February 2021

Second series by the Italian Association of Pediatric Hematology and Oncology of children and adolescents with intracranial ependymoma: an integrated molecular and clinical characterization with a long-term follow-up.

Neuro Oncol 2021 05;23(5):848-857

Departments of Neurology and Psychiatric, La Sapienza University, Rome, Italy.

Background: A prospective 2002-2014 study stratified 160 patients by resection extent and histological grade, reporting results in 2016. We re-analyzed the series after a median of 119 months, adding retrospectively patients' molecular features.

Methods: Follow-up of all patients was updated. DNA copy number analysis and gene-fusion detection could be completed for 94/160 patients, methylation classification for 68.

Results: Progression-free survival (PFS) and overall survival (OS) at 5/10 years were 66/58%, and 80/73%. Ten patients had late relapses (range 66-126 mo), surviving after relapse no longer than those relapsing earlier (0-5 y). On multivariable analysis a better PFS was associated with grade II tumor and complete surgery at diagnosis and/or at radiotherapy; female sex and complete resection showed a positive association with OS. Posterior fossa (PF) tumors scoring ≥0.80 on DNA methylation analysis were classified as PFA (n = 41) and PFB (n = 9). PFB patients had better PFS and OS. Eighteen/32 supratentorial tumors were classified as RELA, and 3 as other molecular entities (anaplastic PXA, LGG MYB, HGNET). RELA had no prognostic impact. Patients with 1q gain or cyclin-dependent kinase inhibitor 2A (CDKN2A) loss had worse outcomes, included significantly more patients >3 years old (P = 0.050) and cases of dissemination at relapse (P = 0.007).

Conclusions: Previously described prognostic factors were confirmed at 10-year follow-up. Late relapses occurred in 6.2% of patients. Specific molecular features may affect outcome: PFB patients had a very good prognosis; 1q gain and CDKN2A loss were associated with dissemination. To draw reliable conclusions, modern ependymoma trials need to combine diagnostics with molecular risk stratification and long-term follow-up.
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http://dx.doi.org/10.1093/neuonc/noaa257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099475PMC
May 2021

Alternative lengthening of telomeres in molecular subgroups of paediatric high-grade glioma.

Childs Nerv Syst 2021 03 31;37(3):809-818. Epub 2020 Oct 31.

Department of Radiological, Oncological and Anatomo-Pathological Sciences, Sapienza University of Rome, Rome, Italy.

Purpose: The maintenance of telomere length prevents cancer cell senescence and occurs via two mutually exclusive mechanisms: (a) reactivation of telomerase expression and (b) activation of alternative lengthening of telomeres (ALT). ALT is frequently related to alterations on ATRX, a chromatin-remodelling protein. Recent data have identified different molecular subgroups of paediatric high-grade glioma (pHGG) with mutations of H3F3A, TERTp and ATRX; however, differences in telomere length among these molecular subgroups were not thoroughly examined.

Methods: We investigated which genetic alterations trigger the ALT mechanism in 52 IDH-wildtype, 1p/19q-wildtype pHGG. Samples were analysed for telomere length using Tel-FISH. ATRX nuclear loss of expression was assessed by IHC, H3F3A and TERTp mutations by DNA sequencing, and TERTp methylation by MS-PCR.

Results: Mutant H3.3 was found in 21 cases (40.3%): 19.2% with K27M mutation and 21.1% with G34R mutation. All H3.3G34R-mutated cases showed the ALT phenotype (100%); on the opposite, only 40% of the H3.3K27M-mutated showed ALT activation. ATRX nuclear loss was seen in 16 cases (30.7%), associated sometimes with the G34R mutation, and never with the K27M mutation. ATRX nuclear loss was always related to telomere elongation. TERTp C250T mutations were rare (5.4%) and were not associated with high intensity Tel-FISH signals, as TERTp hyper-methylation detected in 21% of the cases. H3.3/ATRX/TERTp-wildtype pHGG revealed all basal levels of telomere length.

Conclusion: Our results show a strong association between H3.3 mutations and ALT, and highlight the different telomeric profiles in histone-defined subgroups: H3.3-G34R mutants always trigger ALT to maintain telomere length, irrespective of ATRX status, whereas only some H3.3-K27M tumours activate ALT. These findings suggest that acquiring the gly34 mutation on H3.3 might suffice to trigger the ALT mechanism.
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http://dx.doi.org/10.1007/s00381-020-04933-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875853PMC
March 2021

Dural-based atypical teratoid/rhabdoid tumor in an adult: DNA methylation profiling as a tool for the diagnosis.

CNS Oncol 2020 06 30;9(2):CNS54. Epub 2020 Jun 30.

Department of Radiological, Oncological & Anatomopathological Sciences, Sapienza University of Rome, Rome, Italy.

Atypical teratoid/rhabdoid tumor (ATRT) is a malignant CNS embryonal tumor that mostly occurs in childhood, adult cases are rare. We report a case of a 23-year-old male with an extra-axial dura-based lesion in the left frontal area, previously diagnosed as gliosarcoma. After 6 years, the patient had a recurrence and the previous slides were reviewed. Tumor was positive for vimentin and negative for INI1. The differential diagnosis for this extra-axial tumor with long survival was rhabdoid meningioma with INI1 loss or ATRT. DNA methylation profiling was performed to reach the final and the most definitive diagnosis; the result was ATRT. Our case suggests the usefulness of DNA methylation profiling for diagnosing challenging CNS tumors.
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http://dx.doi.org/10.2217/cns-2020-0006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341157PMC
June 2020

Reduced-dose craniospinal irradiation is feasible for standard-risk adult medulloblastoma patients.

J Neurooncol 2020 Jul 21;148(3):619-628. Epub 2020 Jun 21.

Department of Radiological, Oncological and Anatomo-Pathological Sciences, Sapienza University, Rome, Italy.

Introduction: Medulloblastoma is the most common malignant brain tumor in children, but accounts for only 1% of brain cancers in adults. For standard-risk pediatric medulloblastoma, current therapy includes craniospinal irradiation (CSI) at reduced doses (23.4 Gy) associated with chemotherapy. Whereas most same-stage adult patients are still given CSI at 36 Gy, with or without chemotherapy, we report here on our use of reduced-dose CSI associated with chemotherapy for older patients.

Methods: We gathered non-metastatic patients over 18 years old (median age 28 years, range 18-48) with minimal or no residual disease after surgery, no negative histological subtypes, treated between 1996-2018 at the Centre Léon Bérard (Lyon) and the INT (Milano). A series of 54 children with similar tumors treated in Milano was used for comparison.

Results: Forty-four adults were considered (median follow-up 101 months): 36 had 23.4 Gy of CSI, and 8 had 30.6 Gy, plus a boost to the posterior fossa/tumor bed; 43 had chemotherapy as all 54 children, who had a median 83-month follow-up. The PFS and OS were 82.2 ± 6.1% and 89 ± 5.2% at 5 years, and 78.5 ± 6.9% and 75.2 ± 7.8% at ten, not significantly different from those of the children. CSI doses higher than 23.4 Gy did not influence PFS. Female adult patients tended to have a better outcome than males.

Conclusion: The results obtained in our combined series are comparable with, or even better than those obtained after high CSI doses, underscoring the need to reconsider this treatment in adults.
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http://dx.doi.org/10.1007/s11060-020-03564-yDOI Listing
July 2020

Retrospective analysis on the consistency of MRI features with histological and molecular markers in diffuse intrinsic pontine glioma (DIPG).

Childs Nerv Syst 2020 04 17;36(4):697-704. Epub 2019 Dec 17.

Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Purpose: The diagnosis of diffuse intrinsic pontine glioma (DIPG) is based largely on a combination of clinical and radiological findings due to the difficulty of obtaining a biopsy. An accurate evaluation of magnetic resonance imaging (MRI) scans is consequently essential. Recent analyses on the genomic landscape of DIPG revealed recurrent mutations in the H3F3A and HIST1H3B histone genes. We reviewed cases with available tumor tissue from institutional DIPG series to ascertain the consistency between their histo-molecular findings and clinical-radiological features.

Methods: We conducted a radiological and pathological central review of 22 cases enrolled in institutional DIPG trials. We performed immunohistochemical analyses to detect H3F3A/HIST1H3B K27M mutations, histone trimethylation, and EZH2 expression. Mutational analysis was performed for ACVR1, H3F3A, and HIST1H3B genes.

Results: Patients' median age at diagnosis was 8 years, and their median overall survival was 11 months. Nineteen/22 cases (86%) showed evidence of K27M mutation on immunohistochemistry and/or mutation analysis. Histone trimethylation expression was low or lacking in these mutated cases. Sequence analysis revealed 13 cases with H3F3A and 1 case with HIST1H3B K27M mutation. There was no significant difference in EZH2 expression between the K27M mutant and wild-type DIPGs. Upon external, blinded MRI re-evaluation one lesion not consistent with DIPG showed no evidence of K27M mutation and retained histone trimethylation expression.

Conclusion: In conclusion, our study demonstrates a high frequency of histone K27M mutations in DIPG when MRI features are carefully assessed, thus confirming the consistency of imaging with biological markers in our institutional series of DIPG.
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http://dx.doi.org/10.1007/s00381-019-04463-yDOI Listing
April 2020

Transcriptional profiling of medulloblastoma with extensive nodularity (MBEN) reveals two clinically relevant tumor subsets with VSNL1 as potent prognostic marker.

Acta Neuropathol 2020 03 28;139(3):583-596. Epub 2019 Nov 28.

Clinical Cooperation Unit Neuropathology (B300), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.

Medulloblastoma with extensive nodularity (MBEN) is one of the few central nervous system (CNS) tumor entities occurring in infants which is traditionally associated with good to excellent prognosis. Some MBEN, however, have been reported with an unfavorable clinical course. We performed an integrated DNA/RNA-based molecular analysis of a multi-institutional MBEN cohort (n = 41) to identify molecular events which might be responsible for variability in patients' clinical outcomes. RNA sequencing analysis of this MBEN cohort disclosed two clear transcriptome clusters (TCL) of these CNS tumors: "TCL1 MBEN" and "TCL2 MBEN" which were associated with various gene expression signatures, mutational landscapes and, importantly, prognosis. Thus, the clinically unfavorable "TCL1 MBEN" subset revealed transcriptome signatures composed of cancer-associated signaling pathways and disclosed a high frequency of clinically relevant germline PTCH1/SUFU alterations. In contrast, gene expression profiles of tumors from the clinically favorable "TCL2 MBEN" subgroup were associated with activation of various neurometabolic and neurotransmission signaling pathways, and germline SHH-pathway gene mutations were extremely rare in this transcriptome cluster. "TCL2 MBEN" also revealed strong and ubiquitous expression of VSNL1 (visinin-like protein 1) both at the mRNA and protein level, which was correlated with a favorable clinical course. Thus, combining mutational and epigenetic profiling with transcriptome analysis including VSNL1 immunohistochemistry, MBEN patients could be stratified into clinical risk groups of potential value for subsequent treatment planning.
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http://dx.doi.org/10.1007/s00401-019-02102-zDOI Listing
March 2020

Clustered protocadherins methylation alterations in cancer.

Clin Epigenetics 2019 07 9;11(1):100. Epub 2019 Jul 9.

Department of Biomedical Sciences, Unit of Biology and Genetics, University of Cagliari, Cagliari, Italy.

Background: Clustered protocadherins (PCDHs) map in tandem at human chromosome 5q31 and comprise three multi-genes clusters: α-, β- and γ-PCDH. The expression of this cluster consists of a complex mechanism involving DNA hub formation through DNA-CCTC binding factor (CTCF) interaction. Methylation alterations can affect this interaction, leading to transcriptional dysregulation. In cancer, clustered PCDHs undergo a mechanism of long-range epigenetic silencing by hypermethylation.

Results: In this study, we detected frequent methylation alterations at CpG islands associated to these clustered PCDHs in all the solid tumours analysed (colorectal, gastric and biliary tract cancers, pilocytic astrocytoma), but not hematologic neoplasms such as chronic lymphocytic leukemia. Importantly, several altered CpG islands were associated with CTCF binding sites. Interestingly, our analysis revealed a hypomethylation event in pilocytic astrocytoma, suggesting that in neuronal tissue, where PCDHs are highly expressed, these genes become hypomethylated in this type of cancer. On the other hand, in tissues where PCDHs are lowly expressed, these CpG islands are targeted by DNA methylation. In fact, PCDH-associated CpG islands resulted hypermethylated in gastrointestinal tumours.

Conclusions: Our study highlighted a strong alteration of the clustered PCDHs methylation pattern in the analysed solid cancers and suggested these methylation aberrations in the CpG islands associated with PCDH genes as powerful diagnostic biomarkers.
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http://dx.doi.org/10.1186/s13148-019-0695-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617643PMC
July 2019

Telomere elongation via alternative lengthening of telomeres (ALT) and telomerase activation in primary metastatic medulloblastoma of childhood.

J Neurooncol 2019 May 4;142(3):435-444. Epub 2019 Mar 4.

Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy.

Purpose: Elongation of telomeres is necessary for tumor cell immortalization and senescence escape; neoplastic cells use to alternative pathways to elongate telomeres: telomerase reactivation or a telomerase-independent mechanism termed alternative lengthening of telomeres (ALT). Telomerase and ALT pathway has been explored in adult and pediatric gliomas and medulloblastomas (MDBs); however, these mechanisms were not previously investigated in MDBs metastatic at the onset. Therefore, we analyzed the activation of telomerase and ALT pathway in a homogenous cohort of 43 pediatric metastatic medulloblastomas, to investigate whether telomere elongation could play a role in the biology of metastatic MDB.

Methods: We evaluated telomeres length via telomere-specific fluorescence in situ hybridization (Telo-FISH); we assessed nuclear expression of ATRX by immunohistochemistry (IHC). H3F3A and TERT promoter mutations were analyzed by pyrosequencing, while UTSS methylation status was analyzed via methylation-specific-PCR (MS-PCR).

Results: H3F3A mutations were absent in all MDBs, 30% of samples showed ATRX nuclear loss, 18.2% of cases were characterized by TERT promoter mutations, while 60.9% harboured TERT promoter hyper-methylation in the UTSS region. Elongation of telomeres was found in 42.8% of cases. Metastatic MDBs control telomere elongation via telomerase activation (10.7%), induced by TERT promoter mutations in association with UTSS hyper-methylation, and ALT mechanism (32.1%), triggered by ATRX inactivation. Among non-metastatic MDBs, only 5.9% (1/17) showed ATRX nuclear loss with activation of ALT.

Conclusions: Our metastatic cases frequently activate ALT pathway, suggesting that it is a common process for senescence escape in primary metastatic medulloblastomas. Furthermore, the activation of mechanisms for telomere elongation is not restricted to certain molecular subgroups in this high-risk group of MDBs.
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http://dx.doi.org/10.1007/s11060-019-03127-wDOI Listing
May 2019

Intradural extramidullary dorsal melanocytoma in the adult: Case report and review of the literature.

J Clin Neurosci 2019 Apr 20;62:248-253. Epub 2018 Dec 20.

A.U.O. "Policlinico Umberto I", Neurosurgery Division, Sapienza University, Rome, Human Neurosciences Department, Via del Policlinico, 155, 00161 Roma, Italy.

Intradural Extramedullary Spinal Melanocytoma (IESM) is an extremely uncommon tumour arising from the spinal leptomeninges; both from a gross pathology and microscopic point of view it can mimick its malignant counterpart, the Melanoma. Such tumours are usually solitary, with a lower proliferating rate and without obvious SC invasion. Their common differential diagnoses include Spinal Schwannoma and Spinal Meningiomas since they share a significant amount of radiological similarities. It is a relatively benign condition which is, to date, with no more than 24 previously reported cases, yet widely unexplored and poorly understood. We report the detailed clinical history of a 60 years old individual suffering from IESM and, by means of a thorough Literature review, the most relevant features concerning the epidemiological issues, the clinical course, the radiological appearance, the surgical results and the typical gross and microscopic pathology of a cohort of previously reported cases of IESM are extensively discussed and systematically investigated through statistical analyses in order to add to the relevant Literature a dedicated work concerning this rare and enigmatic condition.
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http://dx.doi.org/10.1016/j.jocn.2018.12.004DOI Listing
April 2019

Pediatric intracranial ependymoma: correlating signs and symptoms at recurrence with outcome in the second prospective AIEOP protocol follow-up.

J Neurooncol 2018 Nov 14;140(2):457-465. Epub 2018 Aug 14.

Pediatric Oncology Unit (AT), Ospedale Vito Fazzi, Lecce, Italy.

Purpose: The aims of patients' radiological surveillance are to: ascertain relapse; apply second-line therapy; accrue patients in phase 1/2 protocols if second-line therapy is not standardized/curative; and assess/treat iatrogenic effects. To lessen the emotional and socioeconomic burdens for patients and families, we ideally need to establish whether scheduled radiological surveillance gives patients a better outcome than waiting for symptoms and signs to appear.

Methods: We analyzed a prospective series of 160 newly-diagnosed and treated pediatric/adolescent patients with intracranial ependymoma, comparing patients with recurrent disease identified on scheduled MRI (the RECPT group; 34 cases) with those showing signs/symptoms of recurrent disease (the SYMPPT group; 16 cases). The median follow-up was 67 months.

Results: No significant differences emerged between the two groups in terms of gender, age, tumor grade/site, shunting, residual disease, or type of relapse (local, distant, or concomitant). The time to relapse (median 19 months; range 5-104) and the MRI follow-up intervals did not differ between the SYMPPT and RECPT groups. The presence of signs/symptoms was an unfavorable factor for overall survival (OS) after recurrence (5-year OS: 8% vs. 37%, p = 0.001). On multivariable analysis, an adjusted model confirmed a significantly worse OS in the SYMPPT than in the RECPT patients.

Conclusions: Symptomatic relapses carried a significantly worse survival for ependymoma patients than recurrences detected by MRI alone. It would therefore be desirable to identify recurrences before symptoms develop. Radiological follow-up should be retained in ependymoma patient surveillance because there is a chance of salvage treatment for relapses found on MRI.
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http://dx.doi.org/10.1007/s11060-018-2974-6DOI Listing
November 2018

Nanoscale mechanics of brain abscess: An atomic force microscopy study.

Micron 2018 10 20;113:34-40. Epub 2018 Jun 20.

Physics Institute, Catholic University of Sacred Heart, Largo F. Vito, 1, Rome, 00168, Italy.

Mechanical stimuli are a fundamental player in the pathophysiology of the brain influencing its physiological development and contributing to the onset and progression of many diseases. In some pathological states, the involvement of mechanical and physical stimuli might be extremely subtle; in others, it is more evident and particularly relevant. Among the latter pathologies, one of the most serious life-threatening condition is the brain abscess (BA), a focal infection localized in the brain parenchyma, which causes large brain mechanical deformations, giving rise to a wide range of neurological impairments. In this paper, we present the first nano-mechanical characterization of surgically removed human brain abscess tissues by means of atomic force microscopy (AFM) in the spectroscopy mode. Consistently with previous histological findings, we modeled the brain abscess as a multilayered structure, composed of three main layers: the cerebritis layer, the collagen capsule, and the internal inflammatory border. We probed the viscoelastic behavior of each layer separately through the measure of the apparent Young's modulus (E), that gives information about the sample stiffness, and the AFM hysteresis (H), that estimates the contribution of viscous and dissipative forces. Our experimental findings provide a full mechanical characterization of the abscess, showing an average E of (94 ± 5) kPa and H of 0.37 ± 0.01 for the cerebritis layer, an average E = (1.04 ± 0.05) MPa and H = 0.10 ± 0.01 for the collagen capsule and an average E = (9.8 ± 0.4) kPa and H = 0.57 ± 0.01 for the internal border. The results here presented have the potential to contribute to the development of novel surgical instruments dedicated to the treatment of the pathology and to stimulate the implementation of novel constitutive mechanical models for the estimation of brain compression and damage during BA progression.
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http://dx.doi.org/10.1016/j.micron.2018.06.012DOI Listing
October 2018

Correction to: Results of nimotuzumab and vinorelbine, radiation and re-irradiation for diffuse pontine glioma in childhood.

J Neurooncol 2018 Jul;138(3):679-680

Radiotherapy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Via Venezian 1, 20133, Milano, Italy.

The therapeutic experience reported in the paper was conceived after the use of nimotuzumab and radiotherapy (BSCPED-05 international multicentric trial, EUDRACT 2005-003100-11) in 2009 when we decided to explore the activity of the same combination plus vinorelbine (see the paper for the rationale).
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http://dx.doi.org/10.1007/s11060-018-2893-6DOI Listing
July 2018

Clinical, Radiologic, Pathologic, and Molecular Characteristics of Long-Term Survivors of Diffuse Intrinsic Pontine Glioma (DIPG): A Collaborative Report From the International and European Society for Pediatric Oncology DIPG Registries.

J Clin Oncol 2018 07 10;36(19):1963-1972. Epub 2018 May 10.

Lindsey M. Hoffman and Nicholas K. Foreman, University of Colorado Denver; Lindsey M. Hoffman and Nicholas K. Foreman, Children's Hospital Colorado, Aurora, CO; Sophie E.M. Veldhuijzen van Zanten, Esther Hulleman, Gertjan J.L. Kaspers, Esther Sanchez, and Dannis G. van Vuurden, Vrije Universiteit University Medical Center, Amsterdam; William P. Vandertop, Academy of Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Niclas Colditz, Marion Hoffmann, Brigitte Bison, Monika Warmuth-Metz, and Christof M. Kramm, University Medical Center Goettingen, Goettingen; Torsten Pietsch and Gerrit H. Gielen, University of Bonn Medical Center, Bonn; David T.W. Jones, Dominik Sturm, Stefan M. Pfister, and Elke Pfaff, German Cancer Research Center, Hopp-Children's Cancer Center at the Nationale Centrum für Tumorerkrankungen Heidelberg, and German Consortium for Translational Cancer Research; Dominik Sturm, Stefan M. Pfister, and Elke Pfaff, Heidelberg University Hospital, Heidelberg, Germany; Joshua Baugh, Brooklyn Chaney, Adam Lane, Christine Fuller, Nancy Yanez Escorza, Renee Doughman, Rachid Drissi, James Leach, Blaise Jones, and Maryam Fouladi, Cincinnati Children's Hospital Medical Center, Cincinnati; Emmett Broxson, Wright State University and The Children's Medical Center, Dayton, OH; Lili Miles, Nemours Children's Hospital, Orlando, FL; Cynthia Hawkins, Ute Bartels, and Eric Bouffet, The Hospital for Sick Children, Toronto, Ontario; Anne Sophie Carret, Centre Hospitalier Universitaire Sainte-Justine; Nada Jabado, McGill University, Montreal, Quebec, Canada; Stewart Goldman, Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, IL; Sarah Leary, Seattle Children's Hospital, University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA; Roger Packer, Children's National Health System; Javad Nazarian, Children's National Medical Center, Washington, DC; Katherine E. Warren, National Cancer Institute, Bethesda, MD; Alberto Broniscer, St Jude Children's Research Hospital, Memphis, TN; Mark W. Kieran, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA; Jane Minturn, Children's Hospital of Philadelphia and The Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Melanie Comito, The Pennsylvania State University, Hershey, PA; Chie-Schin Shih, Indiana University, Indianapolis, IN; Soumen Khatua, The University of Texas MD Anderson Cancer Center; Murali Chintagumpala, Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, TX; Timothy Hassall, Lady Cilento Children's Hospital, Brisbane, Queensland; David S. Ziegler, Kids Cancer Centre, Sydney Children's Hospital, Randwick; David S. Ziegler, University of New South Wales, Sydney, New South Wales; Nicholas Gottardo and Hetal Dholaria, Princess Margaret Hospital for Children, Perth, Western Australia, Australia; Martin Benesch, Medical University of Graz, Graz, Austria; Nathalie Boddaert. Stephanie Puget, and Raphaël Calmon, Hôpital Necker Enfants Malades; Pascale Varlet, Hôpital Sainte-Anne, Université Paris V Descartes, Sorbonne Paris Cité, Paris; Géraldine Giraud, David Castel, and Jacques Grill, Gustave Roussy, Université Paris-Sud, Université Paris-Saclay, Villejuif, France; Géraldine Giraud, Uppsala University, Uppsala, Sweden; Chris Jones, The Institute of Cancer Research, Sutton; Darren Hargrave, Great Ormond Street Hospital, London; Guirish A. Solanki, Birmingham Women's and Children's Hospital, Birmingham; Simon Bailey, Great North Children's Hospital, Victoria Wing, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom; Piergiorgio Modena and Marzia Giagnacovo, Sant' Anna Como General Hospital, Como; Manila Antonelli, Sapienza University of Rome, Rome; Veronica Biassoni and Maura Massimino, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan, Italy; Nicolas U. Gerber and Michael A. Grotzer, University Children's Hospital of Zurich, Zurich; André O. von Bueren, University Hospital of Geneva and University of Geneva, Geneva, Switzerland; and Filip Jadrijevic Cvrlje and Gertjan J.L. Kaspers, Children's Hospital Zagreb, Zagreb, Croatia.

Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of < 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Materials and Methods Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia. Results Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival ≥ 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age < 3 or > 10 years (11% v 3% and 33% v 23%, respectively; P < .001) and with longer symptom duration ( P < .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002). Conclusion We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials.
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http://dx.doi.org/10.1200/JCO.2017.75.9308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075859PMC
July 2018

Pediatric extraspinal sacrococcygeal ependymoma (ESE): an Italian AIEOP experience of six cases and literature review.

Childs Nerv Syst 2018 07 3;34(7):1291-1298. Epub 2018 May 3.

Department of Radiology and Radiotherapy, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: Primary pediatric extraspinal sacrococcygeal ependymoma (ESE) is a very rare disease, poorly described in literature, whose diagnostic, therapeutic, and follow-up approach is still controversial.

Methods: We describe six cases of pediatric ESE treated at Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) centers in Italy since 1983, with a review of the literature.

Results: All six patients had primary sacrococcygeal disease (two presacral and four subcutaneous) with median age of 10 years. Three patients were males, and two of them are metastatic at diagnosis; 3/6 had myxopapillary ependymoma grade I and 3/6 had classic ependymoma grade II. Five patients underwent surgical resection with complete removal only in one case with coccygectomy. Adjuvant chemoradiotherapy was administered to one metastatic patient obtaining a complete remission. Two patients relapsed at 3 and 8 years from diagnosis: they were treated with salvage chemotherapy (high-dose sequential chemotherapy with myeloablative regimen in one case), surgery, and radiotherapy achieving complete remission (CR). All six patients are in complete continuous remission (CCR) at a median follow-up of 12.8 years.

Conclusions: Pediatric patients with this peculiar disease need to be referred to specialized pediatric cancer centers that can provide multidisciplinary treatment after a centralized pathology review. Our experience highlights the role of chemotherapy and radiotherapy in adjuvant and relapse setting. The final prognosis is relatively optimistic, but with a careful follow-up due to the high risk of recurrence.
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http://dx.doi.org/10.1007/s00381-018-3805-yDOI Listing
July 2018

Integrated DNA methylation analysis identifies topographical and tumoral biomarkers in pilocytic astrocytomas.

Oncotarget 2018 Mar 12;9(17):13807-13821. Epub 2018 Feb 12.

Unit of Biology and Genetics, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.

Pilocytic astrocytoma (PA) is the most common glioma in pediatric patients and occurs in different locations. Chromosomal alterations are mostly located at chromosome 7q34 comprising the oncogene with consequent activation of the mitogen-activated protein kinase pathway. Although genetic and epigenetic alterations characterizing PA from different localizations have been reported, the role of epigenetic alterations in PA development is still not clear. The aim of this study was to investigate whether distinctive methylation patterns may define biologically relevant groups of PAs. Integrated DNA methylation analysis was performed on 20 PAs and 4 normal brain samples by Illumina Infinium HumanMethylation27 BeadChips. We identified distinct methylation profiles characterizing PAs from different locations (infratentorial vs supratentorial) and tumors with onset before and after 3 years of age. These results suggest that PA may be related to the specific brain site where the tumor arises from region-specific cells of origin. We identified and validated the methylation alterations of some CpG islands. Furthermore, we evaluated the expression levels of selected differentially methylated genes and identified two biomarkers, one, , related to the tumor localization and the other, , as tumoral biomarker.
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http://dx.doi.org/10.18632/oncotarget.24480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862617PMC
March 2018

Role of Immunohistochemistry in the Identification of Supratentorial C11ORF95-RELA Fused Ependymoma in Routine Neuropathology.

Am J Surg Pathol 2019 01;43(1):56-63

Department of Radiological, Oncological and Anatomo-Pathological Sciences.

Ependymomas (EPs) are tumors of the brain and spinal cord constituting ∼10% of the childhood central nervous system neoplasms and about 30% in children aged <3 years. Their anatomic distribution varies according to the age, with those arising in the supratentorial (ST) compartment, spinal cord being more common in older children and adults, and those at the infratentorial location are more common and occurring more frequently in infants and children. Recently, molecular classification of EP subgroups has been proposed and a supratentorial ependymoma subgroup characterized by RELA-fusion genes (ST-EP-RELA) has been established. It would be useful to define a standardized, robust method for the diagnosis of these relevant fusion genes. We used real-time polymerase chain reaction, conventional real-time polymerase chain reaction, and Sanger sequencing to characterize RELA fusion status in formalin-fixed paraffin-embedded samples from 42 ST-EPs (12 adults and 30 pediatric). We tested p65/RELA and L1CAM protein immunohistochemistry for their ability to predict RELA-fusion status. We reviewed clinical data to assess significant associations in this anatomic subgroup. Of the 42 patients, we identified RELA-fusion genes in 17 cases. L1CAM immunostaining displayed 94% sensitivity, 76% specificity, 73% positive predictive value (PPV), 95% negative predictive value (NPV). The p65/RELA immunostaining displayed 100% sensitivity, 92% specificity, 89.5% PPV, 100% NPV. Concordant double immunostaining improves PPV to 92.5% and maintains 100% NPV. Immunohistochemistry using both p65/RELA and L1CAM antibodies is valuable for ST-EP-RELA diagnosis: the negativity with both antibodies consistently predicts the absence of RELA fusions, whereas verification of fusion transcripts by molecular analyses is warranted only in single-positive or double-positive staining cases.
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http://dx.doi.org/10.1097/PAS.0000000000000979DOI Listing
January 2019

Loss of miR-107, miR-181c and miR-29a-3p Promote Activation of Notch2 Signaling in Pediatric High-Grade Gliomas (pHGGs).

Int J Mol Sci 2017 Dec 17;18(12). Epub 2017 Dec 17.

Department of Experimental Medicine, Sapienza University, Viale Regina Elena, 291, 00161 Rome, Italy.

The mechanisms by which microRNAs control pediatric high-grade gliomas (pHGGs) have yet to be fully elucidated. Our studies of patient-derived pHGG tissues and of the pHGG cell line KNS42 revealed down-regulation in these tumors of three microRNAs, specifically miR-107, miR-181c, and miR-29a-3p. This down-regulation increases the proliferation of KNS42 cells by de-repressing expression of the Notch2 receptor (Notch2), a validated target of miR-107 and miR-181c and a putative target of miR-29a-3p. Inhibition (either pharmacologic or genetic) of Notch2 or re-expression of the implicated microRNAs (all three combined but also individually) significantly reduced KNS42 cell proliferation. These findings suggest that Notch2 pathway activation plays a critical role in pHGGs growth and reveal a direct epigenetic mechanism that controls Notch2 expression, which could potentially be targeted by novel forms of therapy for these childhood tumors characterized by high-morbidity and high-mortality.
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http://dx.doi.org/10.3390/ijms18122742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751342PMC
December 2017

Intracranial neuromuscular choristoma: Report of a case with literature review.

Neuropathology 2017 Aug 6;37(4):341-345. Epub 2017 Feb 6.

Department of Anatomic Pathology, Catholic University, Rome, Italy.

Neuromuscular choristoma (NMC), also called neuromuscular hamartoma or nerve rhabdomyoma, is a rare lesion of the spinal and cranial nerves composed of skeletal muscle intimately associated with nerve fibers. Its origin has not been precisely clarified and a malformative event, resulting from aberrant differentiation or a true neoplastic growth, have been proposed by authors. We hereby present a cerebellopontine angle NMC enlarging the eighth cranial nerve in a 3-year-old child, that histologically appeared composed of a large amount of striated muscle mixed with nerve fibers. We also provide a review of the intracranial NMC cases reported in the literature and an analysis of proposed hypotheses to explain the presence of muscle cells in nerve trunks.
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http://dx.doi.org/10.1111/neup.12368DOI Listing
August 2017

Nano-mechanical signature of brain tumours.

Nanoscale 2016 Dec;8(47):19629-19643

Istituto di Fisica, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, Italy.

Glioblastoma (GBM) and meningothelial meningioma (MM) are the most frequent malignant and benign brain lesions, respectively. Mechanical cues play a major role in the progression of both malignancies that is modulated by the occurrence of aberrant physical interactions between neoplastic cells and the extracellular matrix (ECM). Here we investigate the nano-mechanical properties of human GBM and MM tissues by atomic force microscopy. Our measures unveil the mechanical fingerprint of the main hallmark features of both lesions, such as necrosis in GBM and dural infiltration in MM. These findings have the potential to positively impact on the development of novel AFM-based diagnostic methods to assess the tumour grade. Most importantly, they provide a quantitative description of the tumour-induced mechanical modifications in the brain ECM, thus being of potential help in the search for novel ECM targets for brain tumours and especially for GBM that, despite years of intense research, has still very limited therapeutic options.
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http://dx.doi.org/10.1039/c6nr06840eDOI Listing
December 2016

Disseminated Cerebrospinal Embryonal Tumor in the Adult.

Case Rep Pathol 2016 13;2016:6785459. Epub 2016 Oct 13.

Department of Science and Medical Surgical Biotechnology, Sapienza University of Rome, Rome, Italy.

. According to the 2016 World Health Organization classification of Tumors of the Central Nervous System, the term Primitive Neuroectodermal Tumor has been replaced by the term Embryonal Tumor (ET). We present a case of disseminated cerebrospinal ET presenting in an adult patient. . A 49-year-old male presenting with low back pain, dysuria, and hypoesthesia of the lower extremities referred to our emergency department. Brain and whole spine contrast-enhanced MRI documented a diffusively disseminated heterogeneous neoplasm with intradural extra- and intramedullary involvement of the cervicothoracic tract and cauda equina. A primary biopsy of the lumbosacral localization was performed through L5 bilateral laminectomy. Histologic diagnosis was Embryonal Tumor Not Otherwise Specified. The patient underwent chemotherapy with postoperative adjuvant alternating Vincristine-Doxorubicin-Ifosfamide (VAI) and Ifosfamide-Etoposide (IE). . Spinal ETs are exceedingly rare especially when presenting in the adult patient. Neurosurgical and oncologic management is still unclear. When feasible, surgical removal should always be performed to obtain a histologic diagnosis. Postoperative adjuvant therapy might entail both chemo- and radiotherapy; however a consensus on this matter is still lacking.
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http://dx.doi.org/10.1155/2016/6785459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081462PMC
October 2016

SMARCB1/INI1 Involvement in Pediatric Chordoma: A Mutational and Immunohistochemical Analysis.

Am J Surg Pathol 2017 01;41(1):56-61

*Department of Radiological, Oncological and Anatomo-Pathological Sciences **Department of Neurological Sciences, Sapienza University §Institute of Pathology, Catholic University, Rome †Dipartimento Testa-Collo e Neuroscienze, Istituto Giannina Gaslini, Genoa ∥Department of Surgical Oncological and Gastroenterological Sciences, Urology University of Padova, Padova ¶IRCCS Neuromed, Pozzilli (IS) #Pediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy ‡Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany.

Chordomas arise in the skull base and spine and usually occur in adults and are rare in the pediatric population. Cases of chordoma in pediatric age are often poorly differentiated, showing cytologic atypia, increased cellularity, and mitosis, and their aggressive behavior is associated with a high incidence of metastatic spread and a short patient survival. Recent studies have described loss of SMARCB1/INI1 protein in poorly differentiated chordomas associated not with point mutations but with SMARCB1/INI1 gene deletions instead. In this study, we considered immunohistochemistry and SMARCB1/INI1 mutational status to examine SMARCB1 status in a series of pediatric chordomas (7 classic and 1 poorly differentiated). We performed immunohistochemical tests for INI1, brachyury, S100, and cytokeratins and conducted a genetic analysis on the SMARCB1 coding sequence (NM_003073) using the Sanger method and multiplex ligation-dependent probe amplification to detect abnormal copy numbers of the gene locus. All 8 cases were positive for brachyury, whereas there was no nuclear SMARCB1/INI1 expression in 4 of the 8 cases, including the poorly differentiated chordoma. Genetic analysis identified a missense mutation in 2 cases and a nonsense mutation associated with loss of SMARCB1/INI1 protein and features of poorly differentiated tumor in 1. These mutations were novel variants occurring in heterozygosity, and they were judged to be pathogenic by 3 different bioinformatic tools. In 7 of 8 cases we performed multiplex ligation-dependent probe amplification, and 3 cases showed deletions at the SMARCB1 locus. Our results confirm the pathogenic involvement of SMARCB1/INI1 in childhood chordoma. We also describe 3 novel pathogenic mutations.
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http://dx.doi.org/10.1097/PAS.0000000000000741DOI Listing
January 2017

NRAS(Q61K) mutated primary leptomeningeal melanoma in a child: case presentation and discussion on clinical and diagnostic implications.

BMC Cancer 2016 07 20;16:512. Epub 2016 Jul 20.

Department of Hematology, Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital IRCCS, Piazza Sant'Onofrio 4, 00165, Rome, Italy.

Background: Primary melanocytic neoplasms are rare in the pediatric age. Among them, the pattern of neoplastic meningitis represents a peculiar diagnostic challenge since neuroradiological features may be subtle and cerebrospinal fluid analysis may not be informative. Clinical misdiagnosis of neoplastic meningitis with tuberculous meningitis has been described in few pediatric cases, leading to a significant delay in appropriate management of patients. We describe the case of a child with primary leptomeningeal melanoma (LMM) that was initially misdiagnosed with tuberculous meningitis. We review the clinical and molecular aspects of LMM and discuss on clinical and diagnostic implications.

Case Presentation: A 27-month-old girl with a 1-week history of vomiting with mild intermittent strabismus underwent Magnetic Resonance Imaging, showing diffuse brainstem and spinal leptomeningeal enhancement. Cerebrospinal fluid analysis was unremarkable. Antitubercular treatment was started without any improvement. A spinal intradural biopsy was suggestive for primary leptomeningeal melanomatosis. Chemotherapy was started, but general clinical conditions progressively worsened and patient died 11 months after diagnosis. Molecular investigations were performed post-mortem on tumor tissue and revealed absence of BRAF(V600E), GNAQ(Q209) and GNA11(Q209) mutations but the presence of a NRAS(Q61K) mutation.

Conclusions: Our case adds some information to the limited experience of the literature, confirming the presence of the NRAS(Q61K) mutation in children with melanomatosis. To our knowledge, this is the first case of leptomeningeal melanocytic neoplasms (LMN) without associated skin lesions to harbor this mutation. Isolated LMN presentation might be insidious, mimicking tuberculous meningitis, and should be suspected if no definite diagnosis is possible or if antitubercular treatment does not result in dramatic clinical improvement. Leptomeningeal biopsy should be considered, not only to confirm diagnosis of LMN but also to study molecular profile. Further molecular profiling and preclinical models will be pivotal in testing combination of target therapy to treat this challenging disease.
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http://dx.doi.org/10.1186/s12885-016-2556-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4955223PMC
July 2016

Final results of the second prospective AIEOP protocol for pediatric intracranial ependymoma.

Neuro Oncol 2016 10 18;18(10):1451-60. Epub 2016 May 18.

Department of Pediatrics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy (M.M., L.B., V.B., E.S.); Department of Medical Statistics, Biometry, and Bioinformatics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy (R.M.); Pediatric Radiotherapy, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy (L.G., E.P., B.D.); Department of Radiology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy (G.C.); Department of Radiological, Oncological, and Anatomo-Pathological Sciences, Sapienza University, Rome, Italy (F.G., M.A.); Department of Neurology and Psychiatry, Sapienza University, Rome, Italy (F.R.B.); IRCCS Neuromed, Pozzilli, Italy (F.G.); Laboratory of Genetics, Pathology Unit, S. Anna General Hospital, Como, Italy (P.M.); Neurosurgery Department, IRCCS Istituto Neurologico Carlo Besta, Milan, Italy (P.F., L.V.); Pathology Unit, IRCCS Istituto Neurologico Carlo Besta, Milan, Italy (B.P.); Department of Pediatric Onco-Hematology, Regina Margherita Children's Hospital, Torino, Italy (D.B.); Department of Neurosurgery, Regina Margherita Children's Hospital, Torino, Italy (P.P.); Radiotherapy Unit, Regina Margherita Children's Hospital, Torino, Italy (A.M.); Istituto Giannina Gaslini, Genova, Italy (M.L.G., A.C.); Department of Neuro-oncology, Ospedale Pediatrico Meyer, Firenze, Italy (I.S.); Neurosurgery Unit, Ospedale Pediatrico Meyer, Firenze, Italy (L.G.); Pediatric Oncology Unit, Padova University, Padova, Italy (E.V.); Radiotherapy Department, IOV-IRCCS, Padova, Italy (G.S.); Department of Radiation Oncology, Careggy Hospital, Firenze, Italy (S.S.); Pathology Unit, Careggy Hospital, Firenze, Italy (A.B.); Department of Pediatric Radiotherapy, CRO, Aviano, Italy (M.M.); Department of Pediatric Oncology, Ospedale Santobono-Pausillipon, Napoli, Italy (L.Q.); Neurosurgery Unit, Ospedale Santobono-Pausillipon, Napoli, Italy (G.C.); Department of Radiation Oncology, IRCCS San Martino IST, National Cancer Research Institute, Ge

Background: This prospective study stratified patients by surgical resection (complete = NED vs incomplete = ED) and centrally reviewed histology (World Health Organization [WHO] grade II vs III).

Methods: WHO grade II/NED patients received focal radiotherapy (RT) up to 59.4 Gy with 1.8 Gy/day. Grade III/NED received 4 courses of VEC (vincristine, etoposide, cyclophosphamide) after RT. ED patients received 1-4 VEC courses, second-look surgery, and 59.4 Gy followed by an 8-Gy boost in 2 fractions on still measurable residue. NED children aged 1-3 years with grade II tumors could receive 6 VEC courses alone.

Results: From January 2002 to December 2014, one hundred sixty consecutive children entered the protocol (median age, 4.9 y; males, 100). Follow-up was a median of 67 months. An infratentorial origin was identified in 110 cases. After surgery, 110 patients were NED, and 84 had grade III disease. Multiple resections were performed in 46/160 children (28.8%). A boost was given to 24/40 ED patients achieving progression-free survival (PFS) and overall survival (OS) rates of 58.1% and 68.7%, respectively, in this poor prognosis subgroup. For the whole series, 5-year PFS and OS rates were 65.4% and 81.1%, with no toxic deaths. On multivariable analysis, NED status and grade II were favorable for OS, and for PFS grade II remained favorable.

Conclusions: In a multicenter collaboration, this trial accrued the highest number of patients published so far, and results are comparable to the best single-institution series. The RT boost, when feasible, seemed effective in improving prognosis. Even after multiple procedures, complete resection confirmed its prognostic strength, along with tumor grade. Biological parameters emerging in this series will be the object of future correlatives and reports.
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http://dx.doi.org/10.1093/neuonc/now108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035526PMC
October 2016
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