Publications by authors named "Evelina Miele"

91 Publications

Embryonal tumors in the WHO CNS5 classification: A Review.

Indian J Pathol Microbiol 2022 May;65(Supplement):S73-S82

Department of Radiological, Oncological and Anatomo-pathological Sciences, University Sapienza of Rome, Rome; IRCCS Neuromed, Pozzilli (IS), Italy.

Embryonal tumors are a heterogenous group of neoplasms mostly defined by recurrent genetic driver events. They have been, previously, broadly classified as either medulloblastoma or supratentorial primitive neuroectodermal tumors (PNETs). However, the application of DNA methylation/gene expression profiling in large series of neoplasms histologically defined as PNET, revealed tumors, which showed genetic events associated with glial tumors. These findings led to the definitive removal of the term "PNET" in the 2016 World Health Organization (WHO) classification of CNS tumors. Moreover, further studies on a large scale of methylation profiling have allowed the identification of new molecular-defined entities and have largely influenced the 5 edition of the WHO classification of CNS tumors (WHO CNS5) for both medulloblastomas and other CNS embryonal tumors. The importance of molecular characteristics in CNS embryonal tumors is well represented by the identification of different molecular groups and subgroups in medulloblastoma. So, in the CNS5, the emerged group 3 and group 4 belong to the classification, and the four molecular and morphologic types are now combined into a unique section. Among other embryonal tumors, two new recognized entities are introduced in CNS5: CNS neuroblastoma, FOXR2-activated, and CNS tumor with BCOR internal tandem duplication (ITD). Embryonal tumor with multilayered rosettes (ETMR), already present in the previous classification now has a revised nomenclature as a result of the new DICER1 alteration, additional to the formerly known C19MC. Regarding atypical teratoid/rhabdoid tumor (AT/RT), three molecular subgroups are recognized in CNS5. The combination of histopathological and molecular features reflects the complexity of all these tumors and gives critical information in terms of prognosis and therapy. This encourages the use of a layered diagnostic report with the integrated diagnosis at the top, succeeded by layers including the histological, molecular, and other essential details.
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http://dx.doi.org/10.4103/ijpm.ijpm_1049_21DOI Listing
May 2022

Paediatric astroblastoma-like neuroepithelial tumour of the spinal cord with a MAMLD1-BEND2 rearrangement.

Neuropathol Appl Neurobiol 2022 Mar 17:e12814. Epub 2022 Mar 17.

Pathology Unit, Department of Laboratories, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Astroblastomas are neuroepithelial tumours defined by the presence of MN1 rearrangement and are typically located in the cerebral hemispheres. Rare cases of astroblastoma-like tumours carrying an EWSR1-BEND2 fusion have been recently described in the brain stem and spinal cord. We report a paediatric case of neuroepithelial astroblastoma-like tumour occurring in the spine and carrying a novel MAMLD1-BEND2 fusion. We believe that our case aligns with the rare astroblastoma-like tumours with EWSR1-BEND2 fusion, in terms of non-hemispheric location, pathology, methylation profile and activation of BEND2 transcription. Whether they may represent a distinct entity or a variant of MN1-altered astroblastoma is not clear.
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http://dx.doi.org/10.1111/nan.12814DOI Listing
March 2022

Molecular Landscape in Infant High-Grade Gliomas: A Single Center Experience.

Diagnostics (Basel) 2022 Feb 1;12(2). Epub 2022 Feb 1.

Department of Onco-Hematology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, Scientific Institute for Reasearch, Hospitalization and Healthcare (IRCCS), 00165 Rome, Italy.

High-grade gliomas (HGG) represent about 15% of all pediatric brain tumors, with a dismal prognosis and survival rates ranging from 15 to 35%. Approximately 10-12% of pediatric HGGs (pHGG) occur in children younger than five years of age at diagnosis, specifically infants (iHGG), with an unexpected overall survival rate (OS) in 60-70% of cases. In the literature, iHGGs include a large variety of heterogeneous lesions with different molecular profiles that likely explain their different outcomes. We report our single-institution experience of iHGG including 11 children under five years of age with newly diagnosed HGG between 2011 and 2021. All patients received surgery and adjuvant chemotherapy; only two patients received radiotherapy because their age at diagnosis was more than four years-old. Molecular investigations, including next generation sequencing (NGS) and DNA methylation, detected three NTRK-fusions, one ROS1-fusions, one MN1-rearrangement, and two PATZ1-fusions. According to the molecular results, when chemotherapy failed to control the disease, two patients benefited from target therapy with a NTRK-Inhibitor larotrectinib, achieving a complete remission and a very good partial response, respectively, and no severe side-effects. In conclusion, molecular investigations play a fundamental role in the diagnostic work-up and also in the therapeutic decision. Their routine use in clinical practice could help to replace highly toxic chemotherapy regimens with a target therapy that has moderate adverse effects, even in long-term follow-up.
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http://dx.doi.org/10.3390/diagnostics12020372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8871476PMC
February 2022

Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for -Related Syndrome.

Int J Mol Sci 2022 Feb 5;23(3). Epub 2022 Feb 5.

Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada.

Wiedemann-Steiner syndrome (WDSTS) is a Mendelian syndromic intellectual disability (ID) condition associated with hypertrichosis cubiti, short stature, and characteristic facies caused by pathogenic variants in the gene. Clinical features can be inconclusive in mild and unusual WDSTS presentations with variable ID (mild to severe), facies (typical or not) and other associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Interpretation and classification of rare variants can be challenging. A genome-wide DNA methylation episignature for -related syndrome could allow functional classification of variants and provide insights into the pathophysiology of WDSTS. Therefore, we assessed genome-wide DNA methylation profiles in a cohort of 60 patients with clinical diagnosis for WDSTS or Kabuki and identified a unique highly sensitive and specific DNA methylation episignature as a molecular biomarker of WDSTS. WDSTS episignature enabled classification of variants of uncertain significance in the gene as well as confirmation of diagnosis in patients with clinical presentation of WDSTS without known genetic variants. The changes in the methylation profile resulting from mutations involve global reduction in methylation in various genes, including homeobox gene promoters. These findings provide novel insights into the molecular etiology of WDSTS and explain the broad phenotypic spectrum of the disease.
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http://dx.doi.org/10.3390/ijms23031815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8836705PMC
February 2022

Long-term response to crizotinib in a 17-year-old boy with treatment-naïve ALK-positive non-small-cell lung cancer.

Cancer Rep (Hoboken) 2022 03 28;5(3):e1483. Epub 2022 Jan 28.

Department of Hematology/Oncology, Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.

Background: Lung cancer is the leading cause of cancer-related death. NSCLC accounts for 80-90% of cases. In young patients, adenocarcinoma is the most frequent histotype and 3-7% expresses the rearrangement of ALK oncogene, sensitive to TKIs. Crizotinib is the first ALK inhibitor approved by the FDA.

Case: We present a case of a 17-year-old male with metastatic treatment-naïve ALK-positive adenocarcinoma. He was treated with crizotinib and obtained a prolonged response with PFS of 33 months.

Conclusion: Crizotinib can be extremely effective in adolescents with treatment-naïve ALK-positive NSCLC but fail to prevent a central nervous system relapse. Resistance mechanisms need to be investigated.
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http://dx.doi.org/10.1002/cnr2.1483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8955048PMC
March 2022

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

Neuropathology 2022 Jan 18. Epub 2022 Jan 18.

IRCCS Neuromed, Pozzilli, Italy.

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 β-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.
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http://dx.doi.org/10.1111/neup.12799DOI Listing
January 2022

Cerebellar liponeurocytoma in an elderly patient: DNA methylation profiling as a helpful diagnostic tool.

Clin Neuropathol 2022 Jan-Feb;41(1):12-17

Aim: Cerebellar liponeurocytoma is a rare primary cerebellar neoplasm that mostly occurs in adults, however, it is rare in the elderly.

Materials And Methods: We report, in a 79-year-old female, a recurrent vermian cerebellar mass that was previously diagnosed as primary cerebellar tumor with neuroendocrine differentiation. The recurrent lesion showed anaplastic features and lipidization.

Results: DNA methylation profiling was performed for the recurrent tumor, which showed a high score match for cerebellar liponeurocytoma.

Conclusion: This report confirms the usefulness of DNA methylation profiling for the diagnosis of challenging CNS tumors.
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http://dx.doi.org/10.5414/NP301415DOI Listing
January 2022

PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum.

Acta Neuropathol 2021 11 21;142(5):841-857. Epub 2021 Aug 21.

Paediatric and Adolescent Medicine, Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.

Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens.
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http://dx.doi.org/10.1007/s00401-021-02354-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500868PMC
November 2021

Childhood-onset dystonia-causing KMT2B variants result in a distinctive genomic hypermethylation profile.

Clin Epigenetics 2021 08 11;13(1):157. Epub 2021 Aug 11.

Department of Pathology and Laboratory Medicine, Western University, London, ON, N6A 3K7, Canada.

Background: Dystonia is a clinically and genetically heterogeneous movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements and/or postures. Heterozygous variants in lysine methyltransferase 2B (KMT2B), encoding a histone H3 methyltransferase, have been associated with a childhood-onset, progressive and complex form of dystonia (dystonia 28, DYT28). Since 2016, more than one hundred rare KMT2B variants have been reported, including frameshift, nonsense, splice site, missense and other in-frame changes, many having an uncertain clinical impact.

Results: We characterize the genome-wide peripheral blood DNA methylation profiles of a cohort of 18 patients with pathogenic and unclassified KMT2B variants. We resolve the "episignature" associated with KMT2B haploinsufficiency, proving that this approach is robust in diagnosing clinically unsolved cases, properly classifying them with respect to other partially overlapping dystonic phenotypes, other rare neurodevelopmental disorders and healthy controls. Notably, defective KMT2B function in DYT28 causes a non-random DNA hypermethylation across the genome, selectively involving promoters and other regulatory regions positively controlling gene expression.

Conclusions: We demonstrate a distinctive DNA hypermethylation pattern associated with DYT28, provide an epigenetic signature for this disorder enabling accurate diagnosis and reclassification of ambiguous genetic findings and suggest potential therapeutic approaches.
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http://dx.doi.org/10.1186/s13148-021-01145-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359374PMC
August 2021

Epigenetic modulators for brain cancer stem cells: Implications for anticancer treatment.

World J Stem Cells 2021 Jul;13(7):670-684

Department of Pediatric Hematology/Oncology and Cellular and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome 00165, Italy.

Primary malignant brain tumors are a major cause of morbidity and mortality in both adults and children, with a dismal prognosis despite multimodal therapeutic approaches. In the last years, a specific subpopulation of cells within the tumor bulk, named cancer stem cells (CSCs) or tumor-initiating cells, have been identified in brain tumors as responsible for cancer growth and disease progression. Stemness features of tumor cells strongly affect treatment response, leading to the escape from conventional therapeutic approaches and subsequently causing tumor relapse. Recent research efforts have focused at identifying new therapeutic strategies capable of specifically targeting CSCs in cancers by taking into consideration their complex nature. Aberrant epigenetic machinery plays a key role in the genesis and progression of brain tumors as well as inducing CSC reprogramming and preserving CSC characteristics. Thus, reverting the cancer epigenome can be considered a promising therapeutic strategy. Three main epigenetic mechanisms have been described: DNA methylation, histone modifications, and non-coding RNA, particularly microRNAs. Each of these mechanisms has been proven to be targetable by chemical compounds, known as epigenetic-based drugs or epidrugs, that specifically target epigenetic marks. We review here recent advances in the study of epigenetic modulators promoting and sustaining brain tumor stem-like cells. We focus on their potential role in cancer therapy.
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http://dx.doi.org/10.4252/wjsc.v13.i7.670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316861PMC
July 2021

DICER1-associated malignancies mimicking germ cell neoplasms: Report of two cases and review of the literature.

Pathol Res Pract 2021 Sep 16;225:153553. Epub 2021 Jul 16.

Pathology Unit, Department of Laboratories, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy 00165. Electronic address:

DICER1 syndrome is characterized by a unique combination of features and a growing list of associated rare tumors. Traditionally, gonadal or extra-gonadal teratomas have not been considered part of this spectrum, with only rare DICER1-related teratoid neoplasms recently reported. Besides, their methylation profiles remain elusive. We report two DICER1-associated malignancies involving the lumbar spine of a 22-year-old man (case 1) and the pelvic cavity of a 14-year-old girl (case 2). Both tumors exhibited teratoma-like features with a high-grade malignant somatic component, including rhabdomyosarcomatous elements for case 1 and a malignant neuroectodermal neoplasm with features of an embryonal tumor with multilayered rosettes (ETMR) for case 2. Both tumors showed strong SALL4 expression and H3K27me3 loss by immunohistochemistry. Next-generation sequencing studies confirmed biallelic DICER1 mutations with additional pathogenic missense mutations in KRAS (case 1) and CTNNB1 (case 2). The methylation profile of case 1 clustered with DICER1-associated sarcomas, whereas case 2 classified as an ETMR (albeit low raw and calibrated score). In conclusion, we report two DICER1-related malignancies with teratoma-like features, further expanding their morphologic spectrum and highlighting the multipotentiality of their presumed cell of origin. Notably, we describe the first ETMR identified outside the CNS with a documented DICER1 biallelic inactivation. Our findings also highlight the potential role of other molecular alterations such as KRAS and CTNNB1 mutations in defining the phenotype of embryonal and primitive DICER1-associated neoplasms, a notion that deserves further studies.
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http://dx.doi.org/10.1016/j.prp.2021.153553DOI Listing
September 2021

Targeting cancer stem cells in medulloblastoma by inhibiting AMBRA1 dual function in autophagy and STAT3 signalling.

Acta Neuropathol 2021 09 24;142(3):537-564. Epub 2021 Jul 24.

Department of Paediatric Haematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Medulloblastoma (MB) is a childhood malignant brain tumour comprising four main subgroups characterized by different genetic alterations and rate of mortality. Among MB subgroups, patients with enhanced levels of the c-MYC oncogene (MB) have the poorest prognosis. Here we identify a previously unrecognized role of the pro-autophagy factor AMBRA1 in regulating MB. We demonstrate that AMBRA1 expression depends on c-MYC levels and correlates with Group 3 patient poor prognosis; also, knockdown of AMBRA1 reduces MB stem potential, growth and migration of MB stem cells. At a molecular level, AMBRA1 mediates these effects by suppressing SOCS3, an inhibitor of STAT3 activation. Importantly, pharmacological inhibition of autophagy profoundly affects both stem and invasion potential of MB stem cells, and a combined anti-autophagy and anti-STAT3 approach impacts the MB outcome. Taken together, our data support the c-MYC/AMBRA1/STAT3 axis as a strong oncogenic signalling pathway with significance for both patient stratification strategies and targeted treatments of MB.
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http://dx.doi.org/10.1007/s00401-021-02347-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357694PMC
September 2021

Mesenchymal PLAG1 Tumor With PCMTD1-PLAG1 Fusion in an Infant: A New Type of "Plagoma".

Am J Dermatopathol 2022 01;44(1):54-57

Department of Pathology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA.

Abstract: In the past decade, there have been major advances in knowledge related to mesenchymal tumors, and new genetic alterations are being delineated. We report a mesenchymal spindle cell neoplasm harboring a novel gene fusion in an infant. Histopathologically, the neoplasm shared some features with sclerosing perineurioma, but immunohistochemically, EMA was negative, whereas GLUT1, NK1-C3, and BCOR were positive. Next-generation sequencing revealed a PCMTD1-pleomorphic adenoma gene 1 (PLAG1) fusion. PLAG1 contributes to the expression of a variety of genes implicated in regulating cell proliferation, and PCMTD1 has been related to the development of certain carcinomas. Recently, other soft tissue tumors in young children associated with PLAG1 fusion variants have been reported. Perhaps, mesenchymal neoplasms presenting PLAG1 fusions with different genes would confirm a specific group (PLAG mesenchymal tumours or "plagomas") in the near future.
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http://dx.doi.org/10.1097/DAD.0000000000001978DOI Listing
January 2022

Cytotoxic effects and tolerability of gemcitabine and axitinib in a xenograft model for c-myc amplified medulloblastoma.

Sci Rep 2021 07 7;11(1):14062. Epub 2021 Jul 7.

Children's Hospital, Pediatric Hematology, Oncology and Stem Cell Transplantation, Würzburg University Hospital, 31, Josef-Schneider-Str. 2, 97080, Würzburg, Germany.

Medulloblastoma is the most common high-grade brain tumor in childhood. Medulloblastomas with c-myc amplification, classified as group 3, are the most aggressive among the four disease subtypes resulting in a 5-year overall survival of just above 50%. Despite current intensive therapy regimens, patients suffering from group 3 medulloblastoma urgently require new therapeutic options. Using a recently established c-myc amplified human medulloblastoma cell line, we performed an in-vitro-drug screen with single and combinatorial drugs that are either already clinically approved or agents in the advanced stage of clinical development. Candidate drugs were identified in vitro and then evaluated in vivo. Tumor growth was closely monitored by BLI. Vessel development was assessed by 3D light-sheet-fluorescence-microscopy. We identified the combination of gemcitabine and axitinib to be highly cytotoxic, requiring only low picomolar concentrations when used in combination. In the orthotopic model, gemcitabine and axitinib showed efficacy in terms of tumor control and survival. In both models, gemcitabine and axitinib were better tolerated than the standard regimen comprising of cisplatin and etoposide phosphate. 3D light-sheet-fluorescence-microscopy of intact tumors revealed thinning and rarefication of tumor vessels, providing one explanation for reduced tumor growth. Thus, the combination of the two drugs gemcitabine and axitinib has favorable effects on preventing tumor progression in an orthotopic group 3 medulloblastoma xenograft model while exhibiting a favorable toxicity profile. The combination merits further exploration as a new approach to treat high-risk group 3 medulloblastoma.
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http://dx.doi.org/10.1038/s41598-021-93586-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263612PMC
July 2021

Rosette-Forming Glioneuronal Tumor of the Fourth Ventricle: A Case of Relapse Treated with Proton Beam Therapy.

Diagnostics (Basel) 2021 May 19;11(5). Epub 2021 May 19.

Proton Therapy Center, Hospital of Trento, Azienda Provinciale per I Servizi Sanitari (APSS), 38123 Trento, Italy.

Rosette-forming glioneuronal tumors (RGNTs) are rare, grade I, central nervous system (CNS) tumors typically localized to the fourth ventricle. We describe a 9-year-old girl with dizziness and occipital headache. A magnetic resonance imaging (MRI) revealed a large hypodense posterior fossa mass lesion in relation to the vermis, with cystic component. Surgical resection of the tumor was performed. A RGNT diagnosis was made at the histopathological examination. During follow-up, the patient experienced a first relapse, which was again surgically removed. Eight months after, MRI documented a second recurrence at the local level. She was a candidate for the proton beam therapy (PBT) program. Three years after the end of PBT, the patient had no evidence of disease recurrence. This report underlines that, although RGNTs are commonly associated with an indolent course, they may have the potential for aggressive behavior, suggesting the need for treatment in addition to surgery. Controversy exists in the literature regarding effective management of RGNTs. Chemotherapy and radiation are used as adjuvant therapy, but their efficacy management has not been adequately described in the literature. This is the first case report published in which PBT was proposed for adjuvant therapy in place of chemotherapy in RGNT relapse.
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http://dx.doi.org/10.3390/diagnostics11050903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159123PMC
May 2021

Establishment and Characterization of a Cell Line (S-RMS1) Derived from an Infantile Spindle Cell Rhabdomyosarcoma with Fusion Transcript.

Int J Mol Sci 2021 May 22;22(11). Epub 2021 May 22.

Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy.

: Spindle cell rhabdomyosarcoma (S-RMS) is a rare tumor that was previously considered as an uncommon variant of embryonal RMS (ERMS) and recently reclassified as a distinct RMS subtype with NCOA2, NCOA1, and VGLL2 fusion genes. In this study, we established a cell line (S-RMS1) derived from a four-month-old boy with infantile spindle cell RMS harboring gene fusion. : Morphological and molecular characteristics of S-RMS1 were analyzed and compared with two RMS cell lines, RH30 and RD18. Whole genome sequencing of S-RMS1 and clinical exome sequencing of genomic DNA were performed. : S-RMS1 showed cells small in size, with a fibroblast-like morphology and positivity for MyoD-1, myogenin, desmin, and smooth muscle actin. The population doubling time was 3.7 days. Whole genome sequencing demonstrated that S-RMS1 retained the same genetic profile of the tumor at diagnosis. A Western blot analysis showed downregulation of AKT-p and YAP-p while RT-qPCR showed upregulation of endoglin and GATA6 as well as downregulation of TGFßR1 and Mef2C transcripts. : This is the first report of the establishment of a cell line from an infantile spindle cell RMS with SRF-NCOA2 gene fusion. S-RMS1 should represent a useful tool for the molecular characterization of this rare and almost unknown tumor.
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http://dx.doi.org/10.3390/ijms22115484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196948PMC
May 2021

Assessment of Resistance Mechanisms and Clinical Implications in Patients with KRAS Mutated-Metastatic Breast Cancer and Resistance to CDK4/6 Inhibitors.

Cancers (Basel) 2021 Apr 16;13(8). Epub 2021 Apr 16.

U.O.C. Territorial Oncology of Aprilia, Sapienza University of Rome, 04011 Aprilia, Italy.

Despite therapeutic improvements, resistance to palbociclib is a growing clinical challenge which is poorly understood. This study was conducted in order to understand the molecular mechanisms of resistance to palbociclib, and to identify biomarkers to predict who will take advantage from cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). A total of about a thousand blood samples were collected from 106 patients with hormone receptor positive (HR+) human epidermal growth factor receptor 2 (HER2) negative metastatic breast cancer who received palbociclib in combination with fulvestrant as the first-line metastatic therapy enrolled in this study. The genotyping of their plasma cell-free DNA was studied, including serial plasma samples. Collectively, our findings identify the appearance of KRAS mutations leading to palbociclib resistance acquisition within 6 months, and provide critical information for the prediction of therapeutic responses in metastatic breast cancer. By monitoring KRAS status through liquid biopsy, we could predict who will take advantage from the combination of palbociclib and fulvestrant, offering highly-individualized treatment plans, thus ensuring the best patient quality of life.
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http://dx.doi.org/10.3390/cancers13081928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073052PMC
April 2021

Molecular Characterization of Medulloblastoma in a Patient with Neurofibromatosis Type 1: Case Report and Literature Review.

Diagnostics (Basel) 2021 Apr 2;11(4). Epub 2021 Apr 2.

Department of Onco-Hematology and Cell and Gene Therapy, Bambino Gesù Children's Hospital (IRCCS), 00165 Rome, Italy.

Brain tumors are the most common solid neoplasms of childhood. They are frequently reported in children with Neurofibromatosis type 1 (NF1). The most frequent central nervous system malignancies described in NF1 are optic pathway gliomas and brainstem gliomas. Medulloblastoma (MB) in NF1 patients is extremely rare, and to our knowledge, only 10 cases without molecular characterization are described in the literature to date. We report the case of a 14-year-old girl with NF1 that came to our attention for an incidental finding of a lesion arising from cerebellar vermis. The mass was completely resected, revealing a localized classic medulloblastoma (MB), subgroup 4. She was treated as a standard-risk MB with a dose-adapted personalized protocol. The treatment proved to be effective, with minor toxicity. Brain and spine MRI one year after diagnosis confirmed the complete remission of the disease. To our knowledge, this is the only case of MB reported in a patient with NF1 with molecular characterization by the methylation profile. The association between NF1 and MB, although uncommon, may not be an accidental occurrence.
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http://dx.doi.org/10.3390/diagnostics11040647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067061PMC
April 2021

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

Cancers (Basel) 2021 Feb 9;13(4). Epub 2021 Feb 9.

Department of Pediatric Onco-Hematology and Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy.

MNTI is a rare tumor of indeterminate histogenesis and molecular signature. We performed methylation and copy number variation (CNV) profiles in patients with MNTI ( = 7) and PAT ( = 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.
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http://dx.doi.org/10.3390/cancers13040706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916108PMC
February 2021

Medulloblastoma Associated with Down Syndrome: From a Rare Event Leading to a Pathogenic Hypothesis.

Diagnostics (Basel) 2021 Feb 7;11(2). Epub 2021 Feb 7.

Department of Onco-Hematology and Cell and Gene Therapy, Bambino Gesù Children's Hospital IRCCS, Piazza Sant'Onofrio 4, 00146 Rome, Italy.

Down syndrome (DS) is the most common chromosome abnormality with a unique cancer predisposition syndrome pattern: a higher risk to develop acute leukemia and a lower incidence of solid tumors. In particular, brain tumors are rarely reported in the DS population, and biological behavior and natural history are not well described and identified. We report a case of a 10-year-old child with DS who presented with a medulloblastoma (MB). Histological examination revealed a classic MB with focal anaplasia and the molecular profile showed the presence of a variant associated with the wingless (WNT) molecular subgroup with a good prognosis in contrast to our case report that has shown an early metastatic relapse. The nearly seven-fold decreased risk of MB in children with DS suggests the presence of protective biological mechanisms. The cerebellum hypoplasia and the reduced volume of cerebellar granule neuron progenitor cells seem to be a possible favorable condition to prevent MB development via inhibition of neuroectodermal differentiation. Moreover, the NOTCH/WNT dysregulation in DS, which is probably associated with an increased risk of leukemia, suggests a pivotal role of this pathway alteration in the pathogenesis of MB; therefore, this condition should be further investigated in future studies by molecular characterizations.
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http://dx.doi.org/10.3390/diagnostics11020254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915142PMC
February 2021

Medulloblastoma and familial adenomatous polyposis: Good prognosis and good quality of life in the long-term?

Pediatr Blood Cancer 2021 04 18;68(4):e28912. Epub 2021 Jan 18.

Hereditary Digestive Tract Tumors Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.

Introduction: Mutations of the APC (adenomatous polyposis coli) gene correlate mainly with familial adenomatous polyposis (FAP), but can occasionally be pathogenic for medulloblastoma (MBL) wingless-related integration site (WNT) subtype, the course of which has only recently been described.

Methods: We retrieved all patients with documented germline APC mutations and a diagnosis of MBL to examine their outcome, late effects of treatment, and further oncological events.

Results: Between 2007 and 2016, we treated six patients, all with a pathogenic APC variant mutation and all with MBL, classic histotype. None had metastatic disease. All patients were in complete remission a median 65 months after treatment with craniospinal irradiation at 23.4 Gy, plus a boost on the posterior fossa/tumor bed up to 54 Gy, followed by cisplatin/carboplatin, lomustine, and vincristine for a maximum of eight courses. Five of six diagnostic revised MRI were suggestive of the WNT molecular subgroup typical aspects. Methylation profile score (in two cases) and copy number variation analysis (chromosome 6 deletion in two cases) performed on four of six retrieved samples confirmed WNT molecular subgroup. Four out of six patients had a positive family history of FAP, while gastrointestinal symptoms prompted its identification in the other two cases. Four patients developed other tumors (desmoid, MELTUMP, melanoma, pancreatoblastoma, thyroid Tir3) from 5 to 7 years after MBL.

Discussion: Our data confirm a good prognosis for patients with MBL associated with FAP. Patients' secondary tumors may or may not be related to their syndrome or treatment, but warrant adequate attention when planning shared guidelines for these patients.
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http://dx.doi.org/10.1002/pbc.28912DOI Listing
April 2021

Expanding the spectrum of EWSR1-PATZ1 rearranged CNS tumors: An infantile case with leptomeningeal dissemination.

Brain Pathol 2021 05 15;31(3):e12934. Epub 2021 Feb 15.

Pathology Unit, Department of Laboratories, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

We report on a case of EWSR1-PATZ1 rearranged brain tumor occurring in a 17 month-old child, originally interpreted as an infantile glioblastoma. Our case shows important analogies with the 2 previously reported cases, including the intraventricular location, the histologic appearance (pushing borders, oligodendrocyte-like morphology, rich vascular network) and the glioneural immunophenotype, supporting the role of these features as relevant clues to the diagnosis. On the other hand, our case displays unique characteristics, i.e. the onset in an infant, the presence of a focal high-grade component and the leptomeningeal dissemination, pointing to the importance of considering this entity in the differential diagnosis of an infantile glial/glioneural tumor.
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http://dx.doi.org/10.1111/bpa.12934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8412111PMC
May 2021

Upfront treatment with mTOR inhibitor everolimus in pediatric low-grade gliomas: A single-center experience.

Int J Cancer 2020 Dec 15. Epub 2020 Dec 15.

Department of Paediatric Haematology/Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Pediatric low-grade gliomas (pLGGs) are the most frequent brain tumor in children. Adjuvant treatment, consisting in chemotherapy and radiotherapy, is often necessary if a complete surgical resection cannot be obtained. Traditional treatment approaches result in a significant long-term morbidity, with a detrimental impact on quality of life. Dysregulation of the mitogen-activated protein kinase (MAPK) pathway is the molecular hallmark of pLGGs and hyperactivation of the downstream mammalian target of rapamycin (mTOR) pathway is frequently observed. We report clinical and radiological results of front-line treatment with everolimus in 10 consecutive patients diagnosed with m-TOR positive pLGGs at the Bambino Gesù Children's Hospital in Rome, Italy. Median duration of treatment was 19 months (range from 13-60). Brain magnetic resonance imaging showed stable disease in 7 patients, partial response in 1 and disease progression in 2. Therapy-related adverse events were always reversible after dose reduction or temporary treatment interruption. To the best of our knowledge, this is the first report of everolimus treatment for chemo- and radiotherapy-naïve children with pLGG. Our results provide preliminary support, despite low sample size, for the use of everolimus as target therapy in pLGG showing lack of progression with a manageable toxicity profile.
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http://dx.doi.org/10.1002/ijc.33438DOI Listing
December 2020

Cancer Predisposition Syndromes Associated With Pediatric High-Grade Gliomas.

Front Pediatr 2020 12;8:561487. Epub 2020 Nov 12.

Neurosurgery Unit, Department of Neurological and Psychiatric Sciences, Istituto di Ricovero e Cura a Carattere Scientifico Bambino Gesù Children's Hospital, Rome, Italy.

Pediatric High-Grade Gliomas (pHGG) are among the deadliest childhood brain tumors and can be associated with an underlying cancer predisposing syndrome. The thorough understanding of these syndromes can aid the clinician in their prompt recognition, leading to an informed genetic counseling for families and to a wider understanding of a specific genetic landscape of the tumor for target therapies. In this review, we summarize the main pHGG-associated cancer predisposing conditions, providing a guide for suspecting these syndromes and referring for genetic counseling.
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http://dx.doi.org/10.3389/fped.2020.561487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690624PMC
November 2020

Cancer Predisposition Syndromes and Medulloblastoma in the Molecular Era.

Front Oncol 2020 29;10:566822. Epub 2020 Oct 29.

Department of Hematology/Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Medulloblastoma is the most common malignant brain tumor in children. In addition to sporadic cases, medulloblastoma may occur in association with cancer predisposition syndromes. This review aims to provide a complete description of inherited cancer syndromes associated with medulloblastoma. We examine their epidemiological, clinical, genetic, and diagnostic features and therapeutic approaches, including their correlation with medulloblastoma. Furthermore, according to the most recent molecular advances, we describe the association between the various molecular subgroups of medulloblastoma and each cancer predisposition syndrome. Knowledge of the aforementioned conditions can guide pediatric oncologists in performing adequate cancer surveillance. This will allow clinicians to promptly diagnose and treat medulloblastoma in syndromic children, forming a team with all specialists necessary for the correct management of the other various manifestations/symptoms related to the inherited cancer syndromes.
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http://dx.doi.org/10.3389/fonc.2020.566822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658916PMC
October 2020

Clinical, Genetic, and Prognostic Features of Adrenocortical Tumors in Children: A 10-Year Single-Center Experience.

Front Oncol 2020 15;10:554388. Epub 2020 Oct 15.

Department of Paediatric Haematology/Oncology Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Pediatric adrenocortical tumors (ACTs) are very rare endocrine neoplasms in childhood. In this study, we performed a retrospective analysis of children with ACT treated at our institution by examining clinical and genetic disease features, treatment strategies, and outcomes. We retrospectively analyzed a cohort of 13 children treated at the Bambino Gesù Children's Hospital from November 2010 to March 2020. The median age at diagnosis was 17 months (range = 0-82 months). The female: male ratio was 3.3/1. Mixed symptomatology (>1 hormone abnormality) was the most common presentation (46.1%). In three cases, the tumor was detected during prenatal or perinatal echographic screening. All patients presented with localized disease at diagnosis and underwent total adrenalectomy. Six patients were identified as having malignancies according to the Wieneke scoring system, five benign, and two undetermined. Seven patients underwent mitotane adjuvant therapy for 12 months. There was metastatic disease in three patients, with no correlation with age or Wieneke score. The most common sites of metastases were the liver and lungs. Metastatic patients were treated with surgery ( = 2), mitotane ( = 1), chemotherapy ( = 2) associated with anti-EGFR ( = 1), or immunotherapy with anti-PD1 (pembrolizumab) ( = 1); two patients achieved complete disease remission. Overall 2- and 5-year survival rates were 100%, with a median follow-up of 5 years (range = 2-9.5 years). Two- and 5-year disease free survival was 76.9 and 84.6%, respectively (95% confidence interval = -66.78-114.76 months). All patients are alive, 12 without disease, and one with stable disease. Genetic analyses showed TP53 germline mutations in six of eight patients analyzed (five inherited, one ). One patient had Beckwith-Wiedemann syndrome, with mosaic paternal uniparental disomy of chromosome 11, in both neoplastic and healthy adrenal tissue. We report the cases of 13 patients treated for ACT, including 12 aged <4 years at diagnosis, with a relative short time from symptoms onset. Our cohort experienced an excellent prognosis. TP53 mutation was found in 75% of tested patients (6/8) confirming the need to perform genetic tests and familial counseling in this disease.
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http://dx.doi.org/10.3389/fonc.2020.554388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593337PMC
October 2020

The spectrum of rare central nervous system (CNS) tumors with EWSR1-non-ETS fusions: experience from three pediatric institutions with review of the literature.

Brain Pathol 2021 01 6;31(1):70-83. Epub 2020 Nov 6.

General Pathology and Cytopathology Unit, Department of Medicine-DIMED, University of Padova, Padova, Italy.

The group of CNS mesenchymal (non-meningothelial) and primary glial/neuronal tumors in association with EWSR1-non-ETS rearrangements comprises a growing spectrum of entities, mostly reported in isolation with incomplete molecular profiling. Archival files from three pediatric institutions were queried for unusual cases of pediatric (≤21 years) CNS EWSR1-rearranged tumors confirmed by at least one molecular technique. Extra-axial tumors and cases with a diagnosis of Ewing sarcoma (EWSR1-ETS family fusions) were excluded. Additional studies, including anchored multiplex-PCR with next-generation sequencing and DNA methylation profiling, were performed as needed to determine fusion partner status and brain tumor methylation class, respectively. Five cases (median 17 years) were identified (M:F of 3:2). Location was parenchymal (n = 3) and undetermined (n = 2) with topographic distributions including posterior fossa (n = 1), frontal (n = 1), temporal (n = 1), parietal (n = 1) and occipital (n = 1) lobes. Final designation with fusion findings included desmoplastic small round cell tumor (EWSR1-WT1; n = 1) and tumors of uncertain histogenesis (EWSR1-CREM, n = 1; EWSR1-CREB1, n = 1; EWSR1-PLAGL1, n = 1; and EWSR1-PATZ1, n = 1). Tumors showed a wide spectrum of morphology and biologic behavior. For EWSR1-CREM, EWSR1-PLAGL1 and EWSR1-PATZ1 tumors, no significant methylation scores were reached in the known brain tumor classes. Available outcome (4/5) was reported as favorable (n = 2) and unfavorable (n = 2) with a median follow-up of 30 months. In conclusion, we describe five primary EWSR1-non-ETS fused CNS tumors exhibiting morphologic and biologic heterogeneity and we highlight the clinical importance of determining specific fusion partners to improve diagnostic accuracy, treatment and monitoring. Larger prospective clinicopathological and molecular studies are needed to determine the prognostic implications of histotypes, anatomical location, fusion partners, breakpoints and methylation profiles in patients with these rare tumors.
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http://dx.doi.org/10.1111/bpa.12900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018079PMC
January 2021

Downregulation of miR-326 and its host gene β-arrestin1 induces pro-survival activity of E2F1 and promotes medulloblastoma growth.

Mol Oncol 2021 02 31;15(2):523-542. Epub 2020 Dec 31.

Department of Experimental Medicine, Sapienza University, Rome, Italy.

Persistent mortality rates of medulloblastoma (MB) and severe side effects of the current therapies require the definition of the molecular mechanisms that contribute to tumor progression. Using cultured MB cancer stem cells and xenograft tumors generated in mice, we show that low expression of miR-326 and its host gene β-arrestin1 (ARRB1) promotes tumor growth enhancing the E2F1 pro-survival function. Our models revealed that miR-326 and ARRB1 are controlled by a bivalent domain, since the H3K27me3 repressive mark is found at their regulatory region together with the activation-associated H3K4me3 mark. High levels of EZH2, a feature of MB, are responsible for the presence of H3K27me3. Ectopic expression of miR-326 and ARRB1 provides hints into how their low levels regulate E2F1 activity. MiR-326 targets E2F1 mRNA, thereby reducing its protein levels; ARRB1, triggering E2F1 acetylation, reverses its function into pro-apoptotic activity. Similar to miR-326 and ARRB1 overexpression, we also show that EZH2 inhibition restores miR-326/ARRB1 expression, limiting E2F1 pro-proliferative activity. Our results reveal a new regulatory molecular axis critical for MB progression.
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http://dx.doi.org/10.1002/1878-0261.12800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858128PMC
February 2021

Infantile/Congenital High-Grade Gliomas: Molecular Features and Therapeutic Perspectives.

Diagnostics (Basel) 2020 Aug 28;10(9). Epub 2020 Aug 28.

Department of Onco-Hematology and Cell and Gene Therapy, Bambino Gesù Children's Hospital (IRCCS), Piazza Sant'Onofrio 4, 00146 Rome, Italy.

Brain tumors in infants account for less than 10% of all pediatric nervous system tumors. They include tumors diagnosed in fetal age, neonatal age and in the first years of life. Among these, high-grade gliomas (HGGs) are a specific entity with a paradoxical clinical course that sets them apart from their pediatric and adult counterparts. Currently, surgery represents the main therapeutic strategy in the management of these tumors. Chemotherapy does not have a well-defined role whilst radiotherapy is rarely performed, considering its late effects. Information about molecular characterization is still limited, but it could represent a new fundamental tool in the therapeutic perspective of these tumors. Chimeric proteins derived from the fusion of several genes with neurotrophic tyrosine receptor kinase mutations have been described in high-grade gliomas in infants as well as in neonatal age and the recent discovery of targeted drugs may change the long-term prognosis of these tumors, along with other target-driven therapies. The aim of this mini review is to highlight the recent advances in the diagnosis and treatment of high-grade gliomas in infants with a particular focus on the molecular landscape of these neoplasms and future clinical applications.
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http://dx.doi.org/10.3390/diagnostics10090648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555400PMC
August 2020
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