Publications by authors named "Andrea Carai"

67 Publications

Magnetic Resonance Imaging during Proton Therapy Irradiation Allows for the Early Response Assessment of Pediatric Chordoma.

Diagnostics (Basel) 2021 Jun 18;11(6). Epub 2021 Jun 18.

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

Chordoma in pediatric patients is very rare. Proton therapy has become a gold standard in the treatment of these neoplasms, as high dose escalation can be achieved regarding the target while maximizing the sparing of the healthy tissues near the tumor. The aim of the work was to assess the evolution of morphological sequences during treatment using T1/T2-weighted magnetic resonance imaging (MRI) for the early response assessment of a of the skull base in a pediatric patient who had undergone surgical excision. Our results demonstrated a significant quantitative reduction in the residual nodule component adhered to the medullary bulb junction, with an almost complete recovery of normal anatomy at the end of the irradiation treatment. This was mainly shown in the T2-weighted MRI. On the other hand, the component of the lesion was predominantly present and located around the tooth of the axis. The occipital condyles were morphologically and dimensionally stable for the entire irradiation period. In conclusion, the application of this type of monitoring methodology, which is unusual during the administration of a proton treatment for chordoma, highlighted the unexpected early response of the disease. At the same time, it allowed the continuous assessment of the reliability of the treatment plan.
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http://dx.doi.org/10.3390/diagnostics11061117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235054PMC
June 2021

Innovative and Promising Strategies to Enhance Effectiveness of Immunotherapy for CNS Tumors: Where Are We?

Front Immunol 2021 7;12:634031. Epub 2021 Jun 7.

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

Although there are several immunotherapy approaches for the treatment of Central Nervous System (CNS) tumors under evaluation, currently none of these approaches have received approval from the regulatory agencies. CNS tumors, especially glioblastomas, are tumors characterized by highly immunosuppressive tumor microenvironment, limiting the possibility of effectively eliciting an immune response. Moreover, the peculiar anatomic location of these tumors poses relevant challenges in terms of safety, since uncontrolled hyper inflammation could lead to cerebral edema and cranial hypertension. The most promising strategies of immunotherapy in neuro-oncology consist of the use of autologous T cells redirected against tumor cells through chimeric antigen receptor (CAR) constructs or genetically modified T-cell receptors. Trials based on native or genetically engineered oncolytic viruses and on vaccination with tumor-associated antigen peptides are also under evaluation. Despite some sporadic complete remissions achieved in clinical trials, the outcome of patients with CNS tumors treated with different immunotherapeutic approaches remains poor. Based on the lessons learned from these unsatisfactory experiences, novel immune-therapy approaches aimed at overcoming the profound immunosuppressive microenvironment of these diseases are bringing new hope to reach the cure for CNS tumors.
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http://dx.doi.org/10.3389/fimmu.2021.634031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216238PMC
June 2021

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228671PMC
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

Infra-Occipital Supra-Tentorial Approach for Resection of Low-Grade Tumor of the Left Lingual Gyrus: 2-Dimensional Operative Video.

Oper Neurosurg (Hagerstown) 2021 May 22. Epub 2021 May 22.

Neurosurgery Unit, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Surgical treatment of lesions involving the postero-medial occipito-temporal region is challenging because of high risk of morbidity due to damage or excessive retraction of critical neuro-vascular structures, especially within the dominant hemisphere.1-3  Here, we describe the case of a 17-yr-old patient who underwent resection of an epileptogenic low-grade tumor located within the left-dominant lingual gyrus. Seizures were characterized, as a first symptom, by right-sided simple visual hallucination that pointed to the left pericalcarine region, corresponding to the lesion location. No signs of primary involvement of anterior temporo-mesial structures (hippocampus/amygdala) were found. As the anatomo-electroclinical correlation was concordant, direct tumor removal was indicated through an infra-occipital supratentorial approach.  This route allowed direct access to the target through a safe extra-axial corridor, which limits intraparenchymal dissection until the tumor margin is identified and avoids critical vascular structures, such as the vein of Labbé.4,5 An external cerebrospinal fluid (CSF) drainage was used to facilitate brain relaxation, minimizing brain and venous retraction and, consequently, reducing the risk of postoperative neurological complications, especially for vision. Postoperative magnetic resonance imaging (MRI) demonstrated no surgical complications. Pathological examination revealed a ganglioglioma. At 9-mo follow-up, the neurological examination was normal, antiepileptic therapy was stopped, and the patient was seizure-free.  The video describes the main surgical steps, using both intraoperative videos and advanced 3-dimensional modeling of neuroimaging pictures.  Informed consent was obtained for surgery and video recording.
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http://dx.doi.org/10.1093/ons/opab172DOI Listing
May 2021

Tumor cell invasion into Matrigel: optimized protocol for RNA extraction.

Biotechniques 2021 Jun 10;70(6):327-335. Epub 2021 May 10.

Department of Onco-haematology, Gene & Cell Therapy, Bambino Gesù Children's Hospital-IRCCS, Rome, 00146, Italy.

3D models are increasingly used to study mechanisms driving tumor progression and mimicking processes such as invasion and migration. However, there is a need to establish more protocols based on 3D culture systems that allow for downstream molecular biology investigations. Here we present a method for optimal RNA extraction from highly aggressive primary glioma cells invading into Matrigel. The method has been established by comparing previously reported protocols, available commercial kits and optimizing specific steps for matrix dissociation, RNA separation and purification. The protocol allows RNA extraction from cells embedded into Matrigel, with optimal yield, purity and integrity suitable for subsequent sequencing analysis of both high and low molecular weight RNA.
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http://dx.doi.org/10.2144/btn-2021-0001DOI Listing
June 2021

Intraoperative Ultrasound-Assisted Extent of Resection Assessment in Pediatric Neurosurgical Oncology.

Front Oncol 2021 21;11:660805. Epub 2021 Apr 21.

Neurosurgery Unit, Department of Neurological and Psychiatric Sciences, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.

Central nervous system tumors represent the most frequent solid malignancy in the pediatric population. Maximal safe surgical resection is a mainstay of treatment, with significant prognostic impact for the majority of histotypes. Intraoperative ultrasound (ioUS) is a widely available tool in neurosurgery to assist in intracerebral disease resection. Despite technical caveats, preliminary experiences suggest a satisfactory predictive ability, when compared to magnetic resonance imaging (MRI) studies. Most of the available evidence on ioUS applications in brain tumors derive from adult series, a scenario that might not be representative of the pediatric population. We present our preliminary experience comparing ioUS-assisted resection assessment to early post-operative MRI findings in 154 consecutive brain tumor resections at our pediatric neurosurgical unit. A high concordance was observed between ioUS and post-operative MRI. Overall ioUS demonstrated a positive predictive value of 98%, a negative predictive value of 92% in assessing the presence of tumor residue compared to postoperative MRI. Overall, sensibility and specificity were 86% and 99%, respectively. On a multivariate analysis, the only variable significantly associated to unexpected tumor residue on postoperative MRI was histology. Tumor location, patient positioning during surgery, age and initial tumor volume were not significantly associated with ioUS predictive ability. Our data suggest a very good predictive value of ioUS in brain tumor resective procedures in children. Low-grade glioma, high-grade glioma and craniopharyngioma might represent a setting deserving specific endeavours in order to improve intraoperative extent of resection assessment ability.
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http://dx.doi.org/10.3389/fonc.2021.660805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097032PMC
April 2021

Oncolytic adenovirus and gene therapy with EphA2-BiTE for the treatment of pediatric high-grade gliomas.

J Immunother Cancer 2021 05;9(5)

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

Background: Pediatric high-grade gliomas (pHGGs) are among the most common and incurable malignant neoplasms of childhood. Despite aggressive, multimodal treatment, the outcome of children with high-grade gliomas has not significantly improved over the past decades, prompting the development of innovative approaches.

Methods: To develop an effective treatment, we aimed at improving the suboptimal antitumor efficacy of oncolytic adenoviruses (OAs) by testing the combination with a gene-therapy approach using a bispecific T-cell engager (BiTE) directed towards the erythropoietin-producing human hepatocellular carcinoma A2 receptor (EphA2), conveyed by a replication-incompetent adenoviral vector (EphA2 adenovirus (EAd)). The combinatorial approach was tested in vitro, in vivo and thoroughly characterized at a molecular level.

Results: After confirming the relevance of EphA2 as target in pHGGs, documenting a significant correlation with worse clinical outcome of the patients, we showed that the proposed strategy provides significant EphA2-BiTE amplification and enhanced tumor cell apoptosis, on coculture with T cells. Moreover, T-cell activation through an agonistic anti-CD28 antibody further increased the activation/proliferation profiles and functional response against infected tumor cells, inducing eradication of highly resistant, primary pHGG cells. The gene-expression analysis of tumor cells and T cells, after coculture, revealed the importance of both EphA2-BiTE and costimulation in the proposed system. These in vitro observations translated into significant tumor control in vivo, in both subcutaneous and a more challenging orthotopic model.

Conclusions: The combination of OA and EphA2-BiTE gene therapy strongly enhances the antitumor activity of OA, inducing the eradication of highly resistant tumor cells, thus supporting the clinical translation of the approach.
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http://dx.doi.org/10.1136/jitc-2020-001930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108682PMC
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

Infantile Brain Tumors: A Review of Literature and Future Perspectives.

Diagnostics (Basel) 2021 Apr 8;11(4). Epub 2021 Apr 8.

Pediatric Oncology Unit, Ospedale Vito Fazzi, Piazza Filippo Muratore, 1, 73100 Lecce, Italy.

Brain tumors in infants including those diagnosed in fetal age, newborns and under a year old represent less than 10% of pediatric nervous system tumors and present differently when compared with older children in terms of clinical traits, location and histology. The most frequent clinical finding is a macrocephaly but non-specific symptoms can also be associated. The prognosis is usually poor and depends on several factors. Surgery continues to be the main option in terms of therapeutic strategies whereas the role of chemotherapy is not yet well defined and radiotherapy is exceptionally undertaken. In view of this situation, a molecular characterization could assist in providing therapeutic options for these tumors. This review highlights the recent advances in the diagnosis and treatment of brain tumors in infants with a particular focus on the molecular landscape and future clinical applications.
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http://dx.doi.org/10.3390/diagnostics11040670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068230PMC
April 2021

Recent Advances in Understanding the Role of Autophagy in Paediatric Brain Tumours.

Diagnostics (Basel) 2021 Mar 9;11(3). Epub 2021 Mar 9.

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

Autophagy is a degradative process occurring in eukaryotic cells to maintain homeostasis and cell survival. After stressful conditions including nutrient deprivation, hypoxia or drugs administration, autophagy is induced to counteract pathways that could lead to cell death. In cancer, autophagy plays a paradoxical role, acting both as tumour suppressor-by cleaning cells from damaged organelles and inhibiting inflammation or, alternatively, by promoting genomic stability and tumour adaptive response-or as a pro-survival mechanism to protect cells from stresses such as chemotherapy. Neural-derived paediatric solid tumours represent a variety of childhood cancers with unique anatomical location, cellular origins, and clinical presentation. These tumours are a leading cause of morbidity and mortality among children and new molecular diagnostics and therapies are necessary for longer survival and reduced morbidity. Here, we review advances in our understanding of how autophagy modulation exhibits antitumor properties in experimental models of paediatric brain tumours, i.e., medulloblastoma (MB), ependymoma (EPN), paediatric low-grade and high-grade gliomas (LGGs, HGGs), atypical teratoid/rhabdoid tumours (ATRTs), and retinoblastoma (RB). We also discuss clinical perspectives to consider how targeting autophagy may be relevant in these specific paediatric tumours.
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http://dx.doi.org/10.3390/diagnostics11030481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000899PMC
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

Rhabdoid Tumor Predisposition Syndrome: From Clinical Suspicion to General Management.

Front Oncol 2021 22;11:586288. Epub 2021 Feb 22.

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

Rhabdoid tumors are rare aggressive malignancies in infants and young children with a poor prognosis. The most common anatomic localizations are the central nervous system, the kidneys, and other soft tissues. Rhabdoid tumors share germline and somatic mutations in or, more rarely, , members of the SWI/SNF chromatin-remodeling complex. Rhabdoid tumor predisposition syndrome (RTPS) is a condition characterized by a high risk of developing rhabdoid tumors, among other features. RTPS1 is characterized by pathogenic variants in the gene, while RTPS2 has variants in . Interestingly, germline variants of and have been identified also in patients with Coffin-Siris syndrome. Children with RTPS typically present with tumors before 1 year of age and in a high percentage of cases develop synchronous or multifocal tumors with aggressive clinical features. The diagnosis of RTPS should be considered in patients with rhabdoid tumors, especially if they have multiple primary tumors and/or in individuals with a family history. Because germline mutations result in an increased risk of carriers developing rhabdoid tumors, genetic counseling, and surveillance for all family members with this condition is recommended.
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http://dx.doi.org/10.3389/fonc.2021.586288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937887PMC
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

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

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

Asymptomatic intrapetrous carotid artery stenosis after a gunshot to the head.

Neurology 2020 12 14;95(23):1057-1058. Epub 2020 Oct 14.

From the Neurosurgery Unit (A.D.B., A. Carai, C.E.M.), Department of Neurological and Psychiatric Sciences (A.D.B., A. Carai, C.E.M.), and Neuroradiology Unit (G.S.C., A. Carboni), Imaging Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

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http://dx.doi.org/10.1212/WNL.0000000000011055DOI Listing
December 2020

Integration of Multiple Platforms for the Analysis of Multifluorescent Marking Technology Applied to Pediatric GBM and DIPG.

Int J Mol Sci 2020 Sep 15;21(18). Epub 2020 Sep 15.

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

The intratumor heterogeneity represents one of the most difficult challenges for the development of effective therapies to treat pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG). These brain tumors are composed of heterogeneous cell subpopulations that coexist and cooperate to build a functional network responsible for their aggressive phenotype. Understanding the cellular and molecular mechanisms sustaining such network will be crucial for the identification of new therapeutic strategies. To study more in-depth these mechanisms, we sought to apply the Multifluorescent Marking Technology. We generated multifluorescent pGBM and DIPG bulk cell lines randomly expressing six different fluorescent proteins and from which we derived stable optical barcoded single cell-derived clones. In this study, we focused on the application of the Multifluorescent Marking Technology in 2D and 3D in vitro/ex vivo culture systems. We discuss how we integrated different multimodal fluorescence analysis platforms, identifying their strengths and limitations, to establish the tools that will enable further studies on the intratumor heterogeneity and interclonal interactions in pGBM and DIPG.
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http://dx.doi.org/10.3390/ijms21186763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555235PMC
September 2020

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

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

Delayed referral of pediatric brain tumors during COVID-19 pandemic.

Neuro Oncol 2020 12;22(12):1884-1886

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

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http://dx.doi.org/10.1093/neuonc/noaa159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454759PMC
December 2020

Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes.

Cancer Discov 2020 07 1;10(7):942-963. Epub 2020 Apr 1.

Department of Neuropathology, University Hospital Hamburg-Eppendorf, and Research Institute Children's Cancer Center, Hamburg, Germany.

Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an "intrinsic" spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ( = 31), ( = 21), ( = 9), and ( = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. SIGNIFICANCE: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of , or gene fusions. Kinase fusion-positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype...
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http://dx.doi.org/10.1158/2159-8290.CD-19-1030DOI Listing
July 2020

Editorial: Pediatric Central Nervous System Tumors: State-of-the-Art and Debated Aspects.

Front Pediatr 2020 10;8:91. Epub 2020 Mar 10.

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

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http://dx.doi.org/10.3389/fped.2020.00091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076108PMC
March 2020
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