Publications by authors named "Antonella Cacchione"

36 Publications

Synchronous Presentation of Rare Brain Tumors in Von Hippel-Lindau Syndrome.

Diagnostics (Basel) 2021 May 31;11(6). Epub 2021 May 31.

Neuroradiology Unit, Department of Imaging, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy.

Von Hippel-Lindau (VHL) disease is a heritable cancer syndrome in which benign and malignant tumors and/or cysts develop throughout the central nervous system (CNS) and visceral organs. The disease results from mutations in the VHL tumor suppressor gene located on chromosome 3 (3p25-26). A majority of individuals (60-80%) with VHL disease will develop CNS hemangioblastomas (HMG). Endolymphatic sac tumor (ELST) is an uncommon, locally aggressive tumor located in the medial and posterior petrosal bone region. Its diagnosis is based on clinical, radiological, and pathological correlation, and it can occur in the setting of VHL in up to 10-15% of individuals. We describe a 17-year-old male who presented with a chief complaint of hearing loss. Brain and spine Magnetic Resonance Imaging documented the presence of an expansive lesion in the left cerebellar hemisphere, compatible with HMG in association with a second cerebellopontine lesion compatible with ELST. The peculiarity of the reported case is due to the simultaneous presence of two typical characteristics of VHL, which led to performing comprehensive genetic testing, thus allowing for the diagnosis of VHL. Furthermore, ELST is rare before the fourth decade of life. Early detection of these tumors plays a key role in the optimal management of this condition.
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http://dx.doi.org/10.3390/diagnostics11061005DOI Listing
May 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

ALK-rearranged histiocytosis: Report of two cases with involvement of the central nervous system.

Neuropathol Appl Neurobiol 2021 May 28. Epub 2021 May 28.

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

Aims: Histiocytoses are a heterogeneous group of localized or disseminated diseases. Clinical presentation and patients' outcome vary greatly, ranging from mild to life-threatening disorders. Rare cases of systemic or localized histiocytosis harboring ALK rearrangement have been reported.

Methods: Two cases of CNS histiocytosis were thoroughly investigated by implementing multiple molecular tests, i.e. FISH, RT-qPCR, NGS analysis.

Results: In a 10-month old girl (patient #1), MRI showed two left hemispheric lesions and a right fronto-mesial lesion histologically consisting of a moderately cellular infiltrative proliferation, composed by CD68(PGM1)+/CD163+ spindle cells. ALK 5'/3'-imbalance and a KIF5B(exon 24)-ALK(exon 20) fusion were documented by RT-qPCR and NGS analysis, respectively. A subsequent CT scan showed multiple hepatic and pulmonary lesions. The patient was started on chemotherapy (vinblastine) associated to an ALK-inhibitor (Alectinib) with remarkable response. In a 11-year-old girl (patient #2), MRI showed a right frontal 1.5 cm lesion. Neuropathological examination revealed a histiocytic proliferation composed by medium sized CD68(PGM1)+/HLA-DR+ cells, showing moderate ALK1 positivity. ALK rearrangement and a KIF5B(exon 24)-ALK(exon 20) fusion were demonstrated also in this case. Subsequent CT, 18F-FDG-PET and MRI scans showed the presence of a single right femoral lesion, proved to be a fibrous cortical defect.

Conclusions: In ALK-histiocytoses, CNS involvement may occur as part of a systemic disease or, rarely, as its only primary disease localization, which could remain otherwise asymptomatic. The diagnosis often relies on neuropathological examination of brain biopsy, which may pose a diagnostic challenge due to the variable histopathological features. An integrated histological and molecular approach in such cases is recommended.
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http://dx.doi.org/10.1111/nan.12739DOI Listing
May 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

The Multidimensional Assessment for Pediatric Patients in Radiotherapy (M.A.P.-RT) Tool for Customized Treatment Preparation: RADAR Project.

Front Oncol 2021 29;11:621690. Epub 2021 Mar 29.

UOC di Radioterapia Oncologica, Dipartimento Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.

Pediatric patients may experience considerable distress during radiotherapy. Combining psychological interventions with standard therapies can reduce the need for sedation. The RADAR Project aims to use a systematic method of recording data that can reveal patients' difficulties and fragility during treatment. In this context, the aim of our study was to investigate the ability of a multidimensional assessment tool (M.A.P.-RT schedule) to predict the need for sedation during radiotherapy. The schedule, which is administered during the first evaluation, was created to collect information on patients and their families in a standardized way. The study enrolled pediatric patients (aged 0-18 years or 18-21 with cognitive impairment). Data were collected by means of the M.A.P.-RT module; this explores various thematic areas, and is completed by the radiation oncologist, psychologist and nurse during their first evaluation. Features were selected by means of the Boruta method (random forest classifier), and the totals of the significant partial scores on each subsection of the module were inserted into a logistic model in order to test for their correlation with the use of anesthesia and with the frequency of psychological support. The results of logistic regression (LR) were used to identify the best predictors. The AUC was used to identify the best threshold for the scores in the evaluation. A total of 99 patients were considered for this analysis. The feature that best predicted both the need for anesthesia and the frequency of psychological support was the total score (TS), the AUC of the ROC being 0.9875 for anesthesia and 0.8866 for psychological support. During the first evaluation, the M.A.P.-RT form can predict the need for anesthesia in pediatric patients, and is a potential tool for personalizing therapeutic and management procedures.
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http://dx.doi.org/10.3389/fonc.2021.621690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039366PMC
March 2021

Expansion of the clinical and molecular spectrum of an XPD-related disorder linked to biallelic mutations in ERCC2 gene.

Clin Genet 2021 Jun 5;99(6):842-848. Epub 2021 Apr 5.

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

Bi-allelic inactivation of XPD protein, a nucleotide excision repair (NER) signaling pathway component encoded by ERCC2 gene, has been associated with several defective DNA repair phenotypes, including xeroderma pigmentosum, photosensitive trichothiodystrophy, and cerebro-oculo-facio-skeletal syndrome. We report a pediatric patient harboring two compound heterozygous variants in ERCC2 gene, c.361-1G>A and c.2125A>C (p.Thr709Pro), affected by severe postnatal growth deficiency, microcephaly, facial dysmorphisms and pilocytic astrocytoma of the brainstem. Some of these features point to a DNA repair syndrome, and altogether delineate a phenotype differentiating from disorders known to be associated with ERCC2 mutations. The DNA repair efficiency following UV irradiation in the proband's skin fibroblasts was defective indicating that the new set of ERCC2 alleles impacts on NER efficiency. Sequencing analysis on tumor DNA did not reveal any somatic deleterious point variant in cancer-related genes, while SNP-array analysis disclosed a 2 Mb microduplication involving the 7q34 region, spanning from KIAA1549 to BRAF, and resulting in the KIAA1549:BRAF fusion protein, a marker of pilocytic astrocytoma. In conclusion, this report expands the clinical and mutational spectrum of ERCC2-related disorders.
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http://dx.doi.org/10.1111/cge.13957DOI Listing
June 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

DICER1 Syndrome and Cancer Predisposition: From a Rare Pediatric Tumor to Lifetime Risk.

Front Oncol 2020 21;10:614541. Epub 2021 Jan 21.

Department of Onco - Hematology and Cell and Gene Therapy, Bambino Gesù Pediatric Hospital (IRCCS), Roma, Italy.

DICER1 syndrome is a rare genetic condition predisposing to hereditary cancer and caused by variants in the gene. The risk to present a neoplasm before the age of 10 years is 5.3 and 31.5% before the age of 60. variants have been associated with a syndrome involving familial pleuropulmonary blastoma (PPB), a rare malignant tumor of the lung, which occurs primarily in children under the age of 6 years and represents the most common life-threatening manifestation of DICER1 syndrome. Type I, II, III, and Ir (type I regressed) PPB are reported with a 5-year overall survival ranging from 53 to 100% (for type Ir). gene should be screened in all patients with PPB and considered in other tumors mainly in thyroid neoplasms (multinodular goiter, thyroid cancer, adenomas), ovarian tumors (Sertoli-Leydig cell tumor, sarcoma, and gynandroblastoma), and cystic nephroma. A prompt identification of this syndrome is necessary to plan a correct follow-up and screening during lifetime.
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http://dx.doi.org/10.3389/fonc.2020.614541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859642PMC
January 2021

Congenital Craniofacial Plexiform Neurofibroma in Neurofibromatosis Type 1.

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

Oncological Neuroradiology Unit, Department of Imaging, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy.

We present a case demonstrating the performance of different radiographical imaging modalities in the diagnostic work-up of a patient with neurofibromatosis type 1 (NF1) and plexiform neurofibroma (PN). The newborn boy showed an expansive-infiltrative cervical and facial mass presented with macrocrania, craniofacial disfigurement, exophthalmos and glaucoma. A computer tomography (CT) and a magnetic resonance imaging (MRI) were performed. The CT was fundamental to evaluate the bone dysmorphisms and the MRI was crucial to estimate the mass extension. The biopsy of the lesion confirmed the suspicion of PN, thus allowing the diagnosis of NF1. PN is a variant of neurofibromas, a peripheral nerves sheath tumor typically associated with NF1. Even through currently available improved detection techniques, NF1 diagnosis at birth remains a challenge due to a lack of pathognomonic signs; therefore congenital PN are recognized in 20% of cases. This case highlights the importance of using different radiological methods both for the correct diagnosis and the follow-up of the patient with PN. Thanks to MRI evaluation, it was possible to identify earlier the progressive increasing size of the PN and the possible life threatening evolution in order to perform a tracheostomy to avoid airways compression.
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http://dx.doi.org/10.3390/diagnostics11020218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913090PMC
February 2021

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

Brain Pathol 2021 May 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
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

Early Onset Epilepsy Caused by Low-Grade Epilepsy-Associated Tumors and Focal Meningeal Involvement.

Brain Sci 2020 Oct 18;10(10). Epub 2020 Oct 18.

Rare and Complex Epilepsies, Department of Neurological Science, Bambino Gesù Children's Hospital, IRCCS, Member of European Reference Network EpiCARE, 00165 Rome, Italy.

: Low-grade epilepsy-associated neuroepithelial tumors (LEATs) are a frequent etiology in pediatric patients with epilepsy undergoing surgery. : To identify differences in clinical and post-surgical follow-up between patients with focal meningeal involvement (MI) and those without MI within our cohort of pediatric patients with LEATs. : We retrospectively reviewed all pediatric patients (<18 y) who underwent epilepsy surgery between 2011 and 2017 at our hospital. Cohort inclusion required histological diagnosis of LEATs and post-surgical follow-up of ≥2 y. We subsequently stratified patients according to presence of neuroradiological MI. : We identified 37 patients: five with MI and 32 without. Half of patients (19) were drug sensitive at surgery; similar between groups. The group with MI differed mainly for age of epilepsy-onset (0.6 vs. 7.0 y) but not for epilepsy duration (0.9 vs. 1.5 y). Post-surgery radiological follow-up (median 4.0 y; IQR 2.8-5.0 y) did not indicate disease progression. Seizure outcome was excellent in both groups, with 34 patients overall being both drug- and seizure-free. : Our study identified a new subgroup of LEATs with focal MI and excellent post-surgical outcome. Moreover, this highlights the effectiveness of early surgery in pediatric LEATs.
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http://dx.doi.org/10.3390/brainsci10100752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603244PMC
October 2020

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

Low-Grade Gliomas in Patients with Noonan Syndrome: Case-Based Review of the Literature.

Diagnostics (Basel) 2020 Aug 12;10(8). Epub 2020 Aug 12.

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

Noonan syndrome (NS) is a congenital autosomic dominant condition characterized by a variable spectrum from a clinical and genetical point of view. Germline mutations in more than ten genes involved in RAS-MAPK signal pathway have been demonstrated to cause the disease. An higher risk for leukemia and solid malignancies, including brain tumors, is related to NS. A review of the published literature concerning low grade gliomas (LGGs) in NS is presented. We described also a 13-year-old girl with NS associated with a recurrent mutation in , who developed three different types of brain tumors, i.e., an optic pathway glioma, a glioneuronal neoplasm of the left temporal lobe and a cerebellar pilocytic astrocytoma. Molecular characterization of the glioneuronal tumor allowed to detect high levels of phosphorylated MTOR (pMTOR); therefore, a therapeutic approach based on an mTOR inhibitor (everolimus) was elected. The treatment was well tolerated and proved to be effective, leading to a stabilization of the tumor, which was surgical removed. The positive outcome of the present case suggests considering this approach for patients with RASopathies and brain tumors with hyperactivated MTOR signaling.
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http://dx.doi.org/10.3390/diagnostics10080582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460327PMC
August 2020

Imaging post-177Lu-peptide receptor radionuclide therapy in a child with advanced progressive somatostatin-receptor-positive medulloblastoma.

Eur J Nucl Med Mol Imaging 2021 03 7;48(3):937-939. Epub 2020 Aug 7.

Nuclear Medicine Unit/Imaging Department, IRCCS Bambino Gesù Children's Hospital, Piazza Sant'Onofrio 4, 00165, Rome, Italy.

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http://dx.doi.org/10.1007/s00259-020-04966-wDOI Listing
March 2021

Role of DNA Methylation Profile in Diagnosing Astroblastoma: A Case Report and Literature Review.

Front Genet 2019 30;10:391. Epub 2019 Apr 30.

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

Astroblastoma is a rare tumor of the central nervous system (CNS) with uncertain clinical behavior. Recently, DNA methylation profiling has been shown to provide a highly robust and reproducible approach for the classification of all CNS tumors across different age groups. By using DNA methylation profiling, a subset of CNS high-grade tumors with astroblastoma-like morphology characterized by the meningioma 1 gene () rearrangements, has been identified; they were termed "CNS high-grade neuroepithelial tumors with alteration" (CNS-HGNET-MN1). Here, we describe a case of CNS-HGNET-MN1 diagnosed by DNA methylation profiling, using Illumina Infinium HumanMethylationEPIC BeadChip (EPIC), that offers the opportunity to conduct a brief literature review. The patient presented with an episode of partial seizures involving the right hemisoma. A gross total resection was performed. No other treatment was proposed in light of the histological and molecular findings. After 21 months, the patient is disease-free in good clinical conditions. Also in view of this case, we recommend DNA-methylation profiling as an important tool for diagnosis and more effective patient stratification and management.
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http://dx.doi.org/10.3389/fgene.2019.00391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6502896PMC
April 2019

Vemurafenib Treatment of Pleomorphic Xanthoastrocytoma in a Child With Down Syndrome.

Front Oncol 2019 12;9:277. Epub 2019 Apr 12.

Neuro-oncology Unit, Department of Hematology, Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital (IRCCS), Rome, Italy.

Brain tumors are the most common solid neoplasms of childhood, but they are very rarely reported in children with Down Syndrome (DS), who develop more commonly different types of malignancies. In particular, we hereby report the case of an 8-years-old child with DS that presented to our attention for neurological and endocrinological issues. Brain imaging revealed the presence of a mass that was partially resected revealing a histological diagnosis of Pleomorphic Xanthoastrocytoma (PXA), a rare WHO grade II tumor extending from the diencephalic region into the surrounding brain tissue. These tumors can harbor the mutation p.V600E, targetable by the specific inhibitor Vemurafenib. After confirming the presence of the mutation in the tumor, the patient was treated with Vemurafenib. The treatment proved to be effective, leading to a partial response and a stabilization of the disease. Usually, in patients with DS a reduction of the dose of chemotherapeutic drugs is necessary. Vemurafenib was instead well-tolerated as the only observed adverse effect was grade I skin toxicity. This is, to our knowledge, the first case of a PXA reported in a child with DS and the first DS patient treated with Vemurafenib.
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http://dx.doi.org/10.3389/fonc.2019.00277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474392PMC
April 2019

Direct Involvement of Cranial Nerve V at Diagnosis in Patients With Diffuse Intrinsic Pontine Glioma: A Potential Magnetic Resonance Predictor of Short-Term Survival.

Front Oncol 2019 4;9:204. Epub 2019 Apr 4.

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

Diffuse intrinsic pontine glioma (DIPG) has a dismal prognosis. Magnetic resonance imaging (MRI) remains the gold standard for non-invasive DIPG diagnosis. MRI features have been tested as surrogate biomarkers. We investigated the direct involvement of cranial nerve V (CN V) in DIPG at diagnosis and its utility as predictor of poor overall survival. We examined MRI scans of 35 consecutive patients with radiological diagnosis of DIPG. Direct involvement of CN V was assessed on the diagnostic scans. Differences in overall survival (OS) and time to progression (TTP) were analyzed for involvement of CN V, sex, age, tumor size, ring enhancement, and treatment regimen. Correlations between involvement of CN V and disease dissemination, magnet strength and slice thickness were analyzed. Statistical analyses included Kaplan-Meier curves, log-rank test and Spearman's Rho. After excluding six long-term survivors, 29 patients were examined (15 M, 14 F). Four patients presented direct involvement of CN V. Histological data were available in 12 patients. Median OS was 11 months (range 3-23 months). Significant differences in OS were found for direct involvement of CN V (median OS: 7 months, 95% CI 1.1-12.9 months for involvement of CN V vs. 13 months, 95% CI 10.2-15.7 for lack of involvement of CN V, respectively, < 0.049). Significant differences in TTP were found for the two treatment regimens (median TTP: 4 months, 95% CI 2.6-5.3 vs. 7 months, 95% CI 5.9-8.1, respectively, < 0.027). No significant correlation was found between involvement of CN V and magnet strength or slice thickness ( = -0.201; = NS). A trend toward positive correlation was found between direct involvement of CN V at diagnosis and dissemination of disease at follow-up ( = 0.347; < 0.065). In our cohort, direct involvement of CN V correlated with poor prognosis. Based on our data, we suggest that in DIPG direct involvement of CN V should be routinely evaluated on diagnostic scans.
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http://dx.doi.org/10.3389/fonc.2019.00204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458256PMC
April 2019

Burkitt lymphoma in a patient with Kabuki syndrome carrying a novel KMT2D mutation.

Am J Med Genet A 2019 01 20;179(1):113-117. Epub 2018 Dec 20.

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

Kabuki syndrome (KS) is an extremely rare genetic disorder, mainly caused by germline mutations at specific epigenetic modifier genes, including KMT2D. Because the tumor suppressor gene KMT2D is also frequently altered in many cancer types, it has been suggested that KS may predispose to the development of cancer. However, KS being a rare disorder, few data are available on the incidence of cancer in KS patients. Here, we report the case of a 5-year-old boy affected by KS who developed Burkitt lymphoma (BL). Genetic analysis revealed the presence of a novel heterozygous mutation in the splice site of the intron 4 of KMT2D gene in both peripheral blood-extracted DNA and tumour cells. In addition, the tumour sample of the patient was positive for the classical somatic chromosomal translocation t(8;14) involving the c-MYC gene frequently identified in BL. We propose that the mutated KMT2D gene contributes to the development of both KS and BL observed in our patient and we suggest that strict surveillance must be performed in KS patients.
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http://dx.doi.org/10.1002/ajmg.a.60674DOI Listing
January 2019

V600E Inhibitor (Vemurafenib) for V600E Mutated Low Grade Gliomas.

Front Oncol 2018 14;8:526. Epub 2018 Nov 14.

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

Low-grade gliomas (LGG) are the most common central nervous system tumors in children. Prognosis depends on complete surgical resection. For patients not amenable of gross total resection (GTR) new approaches are needed. The mutation V600E is critical for the pathogenesis of pediatric gliomas and specific inhibitors of the mutated protein, such as Vemurafenib, are available. We investigated the safety and efficacy of Vemurafenib as single agent in pediatric patients with V600E LGG. From November 2013 to May 2018, 7 patients have been treated in our Institution; treatment was well-tolerated, the main concern being dermatological toxicity. The best responses to treatment were: 1 complete response, 3 partial responses, 1 stable disease, only one patient progressed; in one patient, the follow-up is too short to establish the clinical response. Two patients discontinued treatment, and, in both cases, immediate progression of the disease was observed. In one case the treatment was discontinued due to toxicity, in the other one the previously assessed V600E mutation was not confirmed by further investigation. Two patients, after obtaining a response, progressed during treatment, suggesting the occurrence of resistance mechanisms. Clinical response, with improvement of the neurologic function, was observed in all patients a few weeks after the therapy was started. Despite the limitations inherent to a small and heterogeneous cohort, this experience, suggests that Vemurafenib represents a treatment option in pediatric patients affected by LGG and carrying mutation V600E.
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http://dx.doi.org/10.3389/fonc.2018.00526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6246660PMC
November 2018

MRI features as a helpful tool to predict the molecular subgroups of medulloblastoma: state of the art.

Ther Adv Neurol Disord 2018 18;11:1756286418775375. Epub 2018 Jun 18.

Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, Rome, Italy.

Medulloblastoma is the most common malignant pediatric brain tumor. Medulloblastoma should not be viewed as a single disease, but as a heterogeneous mixture of various subgroups with distinct characteristics. Based on genomic profiles, four distinct molecular subgroups are identified: Wingless (WNT), Sonic Hedgehog (SHH), Group 3 and Group 4. Each of these subgroups are associated with specific genetic aberrations, typical age of onset as well as survival prognosis. Magnetic resonance imaging (MRI) is performed for all patients with brain tumors, and has a key role in the diagnosis, surgical guidance and follow up of patients with medulloblastoma. Several studies indicate MRI as a promising tool for early detection of medulloblastoma subgroups. The early identification of the subgroup can influence the extent of surgical resection, radiotherapy and chemotherapy targeted treatments. In this article, we review the state of the art in MRI-facilitated medulloblastoma subgrouping, with a summary of the main MRI features in medulloblastoma and a brief discussion on molecular characterization of medulloblastoma subgroups. The main focus of the article is MRI features that correlate with medulloblastoma subtypes, as well as features suggestive of molecular subgroups. Finally, we briefly discuss the latest trends in MRI studies and latest developments in molecular characterization.
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http://dx.doi.org/10.1177/1756286418775375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6024494PMC
June 2018

Growth hormone excess in children with neurofibromatosis type-1 and optic glioma.

Am J Med Genet A 2017 Sep 20;173(9):2353-2358. Epub 2017 Jun 20.

Rare Diseases and Medical Genetics Unit, Bambino Gesù Children Hospital, IRCCS, Rome, Italy.

In children with neurofibromatosis type 1 (NF1) and optic pathways glioma (OPG), growth hormone (GH) excess has been rarely reported and mainly associated to central precocious puberty. The aim of our study is to evaluate the prevalence of GH excess, the association with central precocious puberty, the relation with tumor site and the evolution over time in a large cohort of children with NF1 and OPG. Sixty-four NF1 children with OPG were evaluated. Patients with stature and/or height velocity >2 SD for age were studied for GH secretion. Seven out of 64 children (10.9%) with NF1 and optic pathways glioma showed GH excess, isolated in 5 cases and associated to central precocious puberty in 2. All the children with GH excess had a tumor involving the chiasma. Children with GH excess underwent medical treatment with lanreotide and a minimum clinical/biochemical follow up of 2 years is reported. The present study demonstrates that GH excess should be considered as a relative frequent endocrine manifestation in NF1 patients, similarly to central precocious puberty. Therefore, these patients should undergo frequent accurate auxologic evaluations. On the other hand, an increase in height velocity in children with NF1, even despite normal ophthalmological exams, can suggest the presence of OPG and therefore represents an indication to perform brain MRI.
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http://dx.doi.org/10.1002/ajmg.a.38308DOI Listing
September 2017

Robot-Assisted Stereotactic Biopsy of Diffuse Intrinsic Pontine Glioma: A Single-Center Experience.

World Neurosurg 2017 May 27;101:584-588. Epub 2017 Feb 27.

Neurosurgery Unit, Department of Neuroscience and Neurorehabilitation, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Background: Diffuse intrinsic pontine glioma (DIPG) is a childhood tumor with a dismal prognosis. Emerging molecular signatures have paved the way for stereotactic biopsy in selected centers. We present our experience in DIPG stereotactic needle biopsy using the Robotic Stereotactic-Assisted system (ROSA) in a series of consecutive pediatric patients.

Methods: All stereotactic biopsy procedures for DIPG performed during the last year at our institution were considered. All procedures were carried out using the ROSA surgical assistant through a precoronary approach. All children underwent a postoperative computed tomography scan to document possible surgical complications and confirm the site of biopsy. Postoperative clinical changes were recorded to test morbidity of the procedure.

Results: In the last year, we performed 7 pontine needle biopsies. Specimens were diagnostic and useful for molecular analysis in all cases. No surgical complications were observed. One child showed a transient neurologic worsening related to the biopsy that resolved within 2 weeks. The combination of the precoronary approach and use of the stereotactic ROSA system allowed single-session surgeries in all cases.

Conclusions: Pontine biopsy for DIPG is a safe procedure in selected centers. The advantages of the single-session procedure we described might be of particular interest in the pediatric setting.
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http://dx.doi.org/10.1016/j.wneu.2017.02.088DOI Listing
May 2017

Magnetic resonance imaging patterns of treatment-related toxicity in the pediatric brain: an update and review of the literature.

Pediatr Radiol 2017 May 9;47(6):633-648. Epub 2016 Dec 9.

Neuroradiology Unit, Department of Imaging, Bambino Gesù Children's Hospital, IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy.

Treatment-related neurotoxicity is a potentially life-threatening clinical condition that can represent a diagnostic challenge. Differentiating diagnoses between therapy-associated brain injury and recurrent disease can be difficult, and the immediate recognition of neurotoxicity is crucial to providing correct therapeutic management, ensuring damage reversibility. For these purposes, the knowledge of clinical timing and specific treatment protocols is extremely important for interpreting MRI patterns. Neuroradiologic findings are heterogeneous and sometimes overlapping, representing the compounding effect of the different treatments. Moreover, MRI patterns can be acute, subacute or delayed and involve different brain regions, depending on (1) the mechanism of action of the specific medication and (2) which brain regions are selectively vulnerable to specific toxic effects. This review illustrates the most common radiologic appearance of radiotherapy, chemotherapy and medication-associated brain injury in children, with special focus on the application of advanced MRI techniques (diffusion, perfusion and proton spectroscopy) in the diagnosis of the underlying processes leading to brain toxicity.
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http://dx.doi.org/10.1007/s00247-016-3750-4DOI Listing
May 2017

Anomalous vascularization in a Wnt medulloblastoma: a case report.

BMC Neurol 2016 Jul 15;16:103. Epub 2016 Jul 15.

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

Background: Medulloblastoma is the most common malignant brain tumor in children. To date only few cases of medulloblastoma with hemorrhages have been reported in the literature. Although some studies speculate on the pathogenesis of this anomalous increased vascularization in medulloblastoma, the specific mechanism is still far from clearly understood. A correlation between molecular medulloblastoma subgroups and hemorrhagic features has not been reported, although recent preliminary studies described that WNT-subtype tumors display increased vascularization and hemorrhaging.

Case Presentation: Herein, we describe a child with a Wnt-medulloblastoma presenting as cerebellar-vermian hemorrhagic lesion. Brain magnetic resonance imaging (MRI) showed the presence of a midline posterior fossa mass with a cystic hemorrhagic component. The differential diagnosis based on imaging included cavernous hemangioma, arteriovenous malformation and traumatic lesion. At surgery, the tumor appeared richly vascularized as documented by the preoperative angiography.

Conclusions: The case we present showed that Wnt medulloblastoma may be associated with anomalous vascularization. Further studies are needed to elucidate if there is a link between the hypervascularization and the Wnt/β-catenin signaling activation and if this abnormal vasculature might influence drug penetration contributing to good prognosis of this medulloblastoma subgroup.
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http://dx.doi.org/10.1186/s12883-016-0632-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4946170PMC
July 2016

IDO1 involvement in mTOR pathway: a molecular mechanism of resistance to mTOR targeting in medulloblastoma.

Oncotarget 2016 Aug;7(33):52900-52911

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

Medulloblastoma (MB) is the most common malignant brain tumor in children. Despite therapeutic advancements, high-risk groups still present significant mortality. A deeper knowledge of the signaling pathways contributing to MB formation and aggressiveness would help develop new successful therapies. The target of rapamycin, mTOR signaling, is known to be involved in MB and is already targetable in the clinical setting. Furthermore, mTOR is a master metabolic regulator able to control cell growth versus autophagy decisions in conditions of amino-acid deprivation that can be due to IDO1 enzymatic activity. IDO1 has been also implicated in the regulation of inflammation, as well as of T cell-mediated immune responses, in a variety of pathological conditions, including brain tumors. In particular, IDO1 induces expansion of regulatory T-cells (Treg), preventing immune response against tumor cells. Analysis of 27 MB tissue specimens for the expression of both mTOR and IDO1 showed their widespread expression in all samples. Testing their cooperation in vitro, a significant involvement of IDO1 in mTOR immunogenic pathway was found, able to counteract the aim of rapamycin treatment. In MB cell lines, inhibition of mTOR strongly induced IDO1 expression and activity, corroborating its ability to recruit Treg cells in the tumor microenvironment. The mTOR/IDO1 cross talk was found to be strictly specific of MB cells. We demonstrated that mTOR pathway cross talks with IDO1 pathway to promote MB immune escape, possibly contributing to failure of mTOR- targeted therapy.
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http://dx.doi.org/10.18632/oncotarget.9284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288157PMC
August 2016

Pediatric spinal glioblastoma of the conus medullaris: a case report of long survival.

Chin J Cancer 2016 May 9;35:44. Epub 2016 May 9.

Neurosurgery Unit, Department of Neuroscience and Neurorehabilitation, Bambino Gesù Children's Hospital, Piazza Sant'Onofrio 4, 00165, Rome, Italy.

High-grade gliomas of the spinal cord represent a rare entity in children. Their biology, behavior, and controversial treatment options have been discussed in a few pediatric cases. These tumors are associated with severe disability and poor prognosis. We report a case of a 4-year-old child diagnosed with an isolated glioblastoma multiforme of the conus medullaris. The patient underwent subtotal surgical excision, followed by adjuvant radiotherapy and oral chemotherapy. He is alive with mild neurologic deficits at 52 months after diagnosis. We describe the peculiar characteristics of this rare condition in pediatric oncology. We also provide an overview of current multidisciplinary therapeutic approaches and prognostic factors for this disease.
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http://dx.doi.org/10.1186/s40880-016-0107-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862181PMC
May 2016