190 results on '"Buccoliero AM"'
Search Results
2. Pediatric rhabdoid meningioma: a morphological, immunohistochemical, ultrastructural and molecular case study
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Buccoliero, Am, Castiglione, F, Rossi Degl'Innocenti, Duccio, Franchi, Alessandro, Sanzo, M, Cetica, V, Giunti, Laura, Sardi, I, Mussa, F, Genitori, L, and Taddei, G. L.
- Published
- 2011
3. Subependymal giant cell astrocytoma (SEGA): Is it an astrocytoma? Morphological, immunohistochemical and ultrastructural study
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Buccoliero, Am, Franchi, Alessandro, Castiglione, F, Gheri, Cf, Mussa, F, Genitori, L, and Taddei, G. L.
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- 2009
4. Gestational diabetes insipidus: a morphological study of the placenta
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Castiglione, F, Buccoliero, Am, Garbini, F, Gheri, Cf, Moncini, D, Poggi, G, Saladino, V, Rossi Degl'Innocenti, D, Gheri, Rg, and Taddei, Gl
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gestational diabetes insipidus - Published
- 2009
5. Infratentorial tumor in a middle-aged woman.
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Buccoliero AM, Bacci S, Mennonna P, and Taddei GL
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- 2004
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6. Plasma cell granuloma--an enigmatic lesion.
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Buccoliero AM, Caldarella A, Santucci M, Ammannati F, Mennonna P, Taddei A, and Taddei GL
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We present an unusual case of intracranial plasma cell granuloma in a 70-year-old man with a 6-month history of progressive visual disturbance. The lesion extensively involved the cranial base, extended into the frontal region, and reached the floor of the third ventricle in the suprasellar area. Microscopic examination of multiple diagnostic transsphenoidal biopsies showed an inflammatory proliferation with a predominance of cells that were immunohistochemically determined to be polyclonal plasma cells. Ultrastructural analysis confirmed the presence of numerous mature plasma cells in a mixed inflammatory proliferation. In situ hybridization for Epstein-Barr viral RNA revealed no evidence of viral expression. The patient was treated with steroid therapy and radiotherapy, without any appreciable reduction of the lesion's size. He is alive with persistent severe visual disturbance 14 months after the diagnosis. We discuss the etiopathogenetic, diagnostic, and therapeutic issues related to this entity, and review the literature. [ABSTRACT FROM AUTHOR]
- Published
- 2003
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7. Clinicopathologic Features of Primary Immunodeficiency Monogenic Disease-related Very Early Onset Inflammatory Bowel Disease: Focus on Gastrointestinal Histologic Features in IFIH1 Mutations.
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Santoro L, Grillo F, D'Armiento M, Buccoliero AM, Rocco M, Ferro J, Vanoli A, Cafferata B, Macciomei MC, Mescoli C, Cananzi M, Alaggio R, Fassan M, Mastracci L, Francalanci P, and Parente P
- Abstract
Very early onset inflammatory bowel disease (VEO-IBD) is a clinical term referring to IBD-like symptomatology arising in children younger than 6 years. VEO-IBD may be due to polygenic etiology in "pure" IBD (Crohn disease-CD and ulcerative colitis-UC), or it may be caused by primary immunodeficiency underlined by monogenic disease. Primary immunodeficiency monogenic diseases have a Mendelian inheritance and affect the immune system with multiorgan morbidity and possible effects on the gastrointestinal system. Primary Immunodeficiency monogenic diseases differ from "pure" IBD as the latter primarily affect the gastrointestinal tract with mitigated extraintestinal symptomatology. Since their first description, primary immunodeficiency monogenic diseases, although rare, have been the subject of increasing interest due to their dramatic phenotype, difficulty in reaching a timely diagnosis, and specific therapeutic approach. In this paper, we present a brief review of primary immunodeficiency monogenic diseases, focusing on to their clinicopathologic features as well as delving, in greater detail, into monogenic diseases caused by IFIH1 mutations. The clinicopathologic features of 4 patients with IFIH1, a gene involved in interferon pathway deficiency, will be described using a histologic pattern of damage approach confirming the need to avoid the histologic diagnosis of VEO-IBD in children younger than 6 years., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2024
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8. Case report: complete long-lasting response to multimodal third line treatment with neurosurgical resection, carmustine wafer implantation and dabrafenib plus trametinib in a BRAFV600E mutated high-grade glioma.
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Castelli B, Tellini M, Guidi M, Di Nicola M, Giunti L, Buccoliero AM, Censullo ML, Iacono A, Desideri I, Genitori L, Sardi I, and Fonte C
- Abstract
Dabrafenib plus trametinib is a promising new therapy for patients affected by BRAFV600E -mutant glioma, with high overall response and manageable toxicity. We described a complete and long-lasting response in a case of recurrent anaplastic pleomorphic xanthoastrocytoma CNS WHO-grade 3 BRAFV600E mutated. Due to very poor prognosis, there are a few described cases of high-grade glioma (HGG) patients treated with the combined target therapy as third-line treatment. The emergence of optimized sequencing strategies and targeted agents, including multimodal and systemic therapy with dabrafenib plus trametinib, will continue to broaden personalized therapy in HGG improving patient outcomes., Competing Interests: CF took part in the Advisory Board financed by Novartis on September 5th 2022 and she took part as principal investigator in CDRB436G2201 NCT02684058 study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Castelli, Tellini, Guidi, Di Nicola, Giunti, Buccoliero, Censullo, Iacono, Desideri, Genitori, Sardi and Fonte.)
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- 2024
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9. Corrigendum: Pediatric CNS tumors and 2021 WHO classification: what do oncologists need from pathologists?
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d'Amati A, Bargiacchi L, Rossi S, Carai A, Bertero L, Barresi V, Errico ME, Buccoliero AM, Asioli S, Marucci G, Del Baldo G, Mastronuzzi A, Miele E, D'Antonio F, Schiavello E, Biassoni V, Massimino M, Gessi M, Antonelli M, and Gianno F
- Abstract
[This corrects the article DOI: 10.3389/fnmol.2024.1268038.]., (Copyright © 2024 d'Amati, Bargiacchi, Rossi, Carai, Bertero, Barresi, Errico, Buccoliero, Asioli, Marucci, Del Baldo, Mastronuzzi, Miele, D'Antonio, Schiavello, Biassoni, Massimino, Gessi, Antonelli and Gianno.)
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- 2024
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10. Pediatric CNS tumors and 2021 WHO classification: what do oncologists need from pathologists?
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d'Amati A, Bargiacchi L, Rossi S, Carai A, Bertero L, Barresi V, Errico ME, Buccoliero AM, Asioli S, Marucci G, Del Baldo G, Mastronuzzi A, Miele E, D'Antonio F, Schiavello E, Biassoni V, Massimino M, Gessi M, Antonelli M, and Gianno F
- Abstract
The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, established new approaches to both CNS tumor nomenclature and grading, emphasizing the importance of integrated diagnoses and layered reports. This edition increased the role of molecular diagnostics in CNS tumor classification while still relying on other established approaches such as histology and immunohistochemistry. Moreover, it introduced new tumor types and subtypes based on novel diagnostic technologies such as DNA methylome profiling. Over the past decade, molecular techniques identified numerous key genetic alterations in CSN tumors, with important implications regarding the understanding of pathogenesis but also for prognosis and the development and application of effective molecularly targeted therapies. This review summarizes the major changes in the 2021 fifth edition classification of pediatric CNS tumors, highlighting for each entity the molecular alterations and other information that are relevant for diagnostic, prognostic, or therapeutic purposes and that patients' and oncologists' need from a pathology report., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 d’Amati, Bargiacchi, Rossi, Carai, Bertero, Barresi, Errico, Buccoliero, Asioli, Marucci, Del Baldo, Mastronuzzi, Miele, D’Antonio, Gessi, Antonelli and Gianno.)
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- 2024
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11. Outcome of Epilepsy Surgery in MRI-Negative Patients Without Histopathologic Abnormalities in the Resected Tissue.
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Sanders MW, Van der Wolf I, Jansen FE, Aronica E, Helmstaedter C, Racz A, Surges R, Grote A, Becker AJ, Rheims S, Catenoix H, Duncan JS, De Tisi J, Jacques TS, Cross JH, Kalviainen R, Rauramaa T, Chassoux F, Devaux BC, Di Gennaro G, Esposito V, Bodi I, Honavar M, Bien CG, Cloppenborg T, Coras R, Hamer HM, Marusic P, Kalina A, Pieper T, Kudernatsch M, Hartlieb TS, Von Oertzen TJ, Aichholzer M, Dorfmuller G, Chipaux M, Noachtar S, Kaufmann E, Schulze-Bonhage A, Scheiwe CF, Özkara C, Grunwald T, Koenig K, Guerrini R, Barba C, Buccoliero AM, Giordano F, Rosenow F, Menzler K, Garbelli R, Deleo F, Krsek P, Straka B, Arzimanoglou AA, Toulouse J, Van Paesschen W, Theys T, Pimentel J, Loução De Amorim IM, Specchio N, De Palma L, Feucht M, Scholl T, Roessler K, Toledano Delgado R, Gil-Nagel A, Raicevic S, Ristic AJ, Schijns O, Beckervordersandforth J, San Antonio-Arce V, Rumia J, Blumcke I, and Braun KP
- Subjects
- Humans, Cohort Studies, Electroencephalography, Magnetic Resonance Imaging, Retrospective Studies, Seizures, Treatment Outcome, Epilepsies, Partial diagnostic imaging, Epilepsies, Partial surgery, Epilepsy diagnostic imaging, Epilepsy surgery, Epilepsy, Temporal Lobe surgery
- Abstract
Background and Objective: Patients with presumed nonlesional focal epilepsy-based on either MRI or histopathologic findings-have a lower success rate of epilepsy surgery compared with lesional patients. In this study, we aimed to characterize a large group of patients with focal epilepsy who underwent epilepsy surgery despite a normal MRI and had no lesion on histopathology. Determinants of their postoperative seizure outcomes were further studied., Methods: We designed an observational multicenter cohort study of MRI-negative and histopathology-negative patients who were derived from the European Epilepsy Brain Bank and underwent epilepsy surgery between 2000 and 2012 in 34 epilepsy surgery centers within Europe. We collected data on clinical characteristics, presurgical assessment, including genetic testing, surgery characteristics, postoperative outcome, and treatment regimen., Results: Of the 217 included patients, 40% were seizure-free (Engel I) 2 years after surgery and one-third of patients remained seizure-free after 5 years. Temporal lobe surgery (adjusted odds ratio [AOR]: 2.62; 95% CI 1.19-5.76), shorter epilepsy duration (AOR for duration: 0.94; 95% CI 0.89-0.99), and completely normal histopathologic findings-versus nonspecific reactive gliosis-(AOR: 4.69; 95% CI 1.79-11.27) were significantly associated with favorable seizure outcome at 2 years after surgery. Of patients who underwent invasive monitoring, only 35% reached seizure freedom at 2 years. Patients with parietal lobe resections had lowest seizure freedom rates (12.5%). Among temporal lobe surgery patients, there was a trend toward favorable outcome if hippocampectomy was part of the resection strategy (OR: 2.94; 95% CI 0.98-8.80). Genetic testing was only sporadically performed., Discussion: This study shows that seizure freedom can be reached in 40% of nonlesional patients with both normal MRI and histopathology findings. In particular, nonlesional temporal lobe epilepsy should be regarded as a relatively favorable group, with almost half of patients achieving seizure freedom at 2 years after surgery-even more if the hippocampus is resected-compared with only 1 in 5 nonlesional patients who underwent extratemporal surgery. Patients with an electroclinically identified focus, who are nonlesional, will be a promising group for advanced molecular-genetic analysis of brain tissue specimens to identify new brain somatic epilepsy genes or epilepsy-associated molecular pathways.
- Published
- 2024
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12. Corrigendum: Bevacizumab-Irinotecan combination therapy in recurrent low-grade glioma, previously treated with chemo-radiotherapy: a case report.
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Castelli B, Fonte C, Guidi M, Tellini M, Di Nicola M, Iacono A, Buccoliero AM, Greto D, Genitori L, and Sardi I
- Abstract
[This corrects the article DOI: 10.3389/fonc.2023.1244628.]., (Copyright © 2024 Castelli, Fonte, Guidi, Tellini, Di Nicola, Iacono, Buccoliero, Greto, Genitori and Sardi.)
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- 2024
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13. Application of a pattern-based approach to histological diagnosis in very early onset IBD (VEO-IBD) in a multicentric cohort of children with emphasis on monogenic disease with IBD-like morphology.
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Parente P, Macciomei MC, Buccoliero AM, Santoro L, Cafferata B, Bifano D, Ferro J, Vanoli A, Fassan M, Angerilli V, Alaggio R, Mastracci L, D'Armiento M, Grillo F, and Francalanci P
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- Child, Humans, Retrospective Studies, Endoscopy, Gastrointestinal, Colitis, Ulcerative diagnosis, Colitis, Ulcerative pathology, Crohn Disease diagnosis, Crohn Disease pathology, Upper Gastrointestinal Tract pathology, Inflammatory Bowel Diseases diagnosis, Inflammatory Bowel Diseases pathology
- Abstract
Aims: Very early-onset inflammatory bowel disease (VEO-IBD) is a clinical umbrella term referring to IBD-like symptoms arising in children before the age of 6 years, encompassing both 'pure' IBD, such as ulcerative colitis (UC) and Crohn's disease (CD) and monogenic diseases (MDs), the latter often involving genes associated with primary immunodeficiencies. Moreover, histological features in gastrointestinal (GI) biopsies in MD can also have IBD-like morphology, making differential diagnosis difficult. Correct diagnosis is fundamental, as MDs show a more severe clinical course and their inadequate/untimely recognition leads to inappropriate therapy., Methods and Results: Biopsy samples from the lower and upper GI tract of 93 clinically diagnosed VEO-IBD children were retrospectively selected in a multicentre cohort and histologically re-evaluated by 10 pathologists blinded to clinical information. Each case was classified according to morphological patterns, including UC-like; CD-like; enterocolitis-like; apoptotic; eosinophil-rich; and IBD-unclassified (IBD-U). Nine (69%) MD children showed IBD-like morphology; only the IBD-U pattern correlated with MD diagnosis (P = 0.02) (available in 64 cases: 51 non-MD, true early-onset IBD/other; 13 MD cases). MD patients showed earlier GI symptom onset (18.7 versus 26.9 months) and were sent to endoscopy earlier (22 versus 37 months), these differences were statistically significant (P < 0.05). Upper GI histology was informative in 37 biopsies., Conclusions: The diagnosis of the underlying cause of VEO-IBD requires a multidisciplinary setting, and pathology, while being one of the fundamental puzzle pieces, is often difficult to interpret. A pattern-based histological approach is therefore suggested, thus aiding the pathologist in VEO-IBD reporting and multidisciplinary discussion., (© 2023 The Authors. Histopathology published by John Wiley & Sons Ltd.)
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- 2024
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14. External auditory canal ectopic atypical meningioma: A case report and brief literature review.
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Nozzoli F, Buccoliero AM, Massi D, Santoro R, and Pecci R
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- Humans, Ear Canal pathology, Meningioma pathology, Meningeal Neoplasms pathology
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Meningiomas are tumours typically derived from the meningothelial cells of the arachnoid mater. They most often arise in intracranial, intraspinal, or orbital locations. Ectopic meningiomas, described as primary meningiomas with no intracranial involvement, are definitely unconventional. In fact, most of the extracranial meningiomas described in the literature, particularly in the outer ear, are effectively spreads of disease with primary intracranial localization. We describe a case of a primary external auditory canal meningioma with demonstrated absence of intracranial involvement, and we provide a full radiological, histological, immunohistochemical and molecular characterization of the lesion., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)
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- 2024
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15. Leat-associated seizures the possible role of EAAT2, pyruvate carboxylase and glutamine synthetase.
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Buccoliero AM, Caporalini C, Moscardi S, Cetica V, Mei D, Conti V, Nozzoli F, Bonaudo C, Battista F, Giordano F, Mura R, Spacca B, Mussa F, D'Onofrio V, Guerrini R, Genitori L, and Scagnet M
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- Child, Humans, Glutamate-Ammonia Ligase, Glutamates, Pyruvate Carboxylase, Seizures complications, Astrocytoma complications, Astrocytoma metabolism, Astrocytoma pathology, Brain Neoplasms metabolism, Epilepsy etiology, Ganglioglioma metabolism, Glioma genetics, Neoplasms, Neuroepithelial
- Abstract
Background: Drug-resistant epilepsy is a common condition in patients with brain neoplasms. The pathogenesis of tumor-associated seizures is poorly understood. Among the possible pathogenetic mechanisms, the increase in glutamate concentration has been proposed. Glutamate transporters, glutamine synthetase and pyruvate carboxylase are involved in maintaining the physiological concentration of glutamate in the intersynaptic spaces. In our previous research on angiocentric gliomas, we demonstrated that all tumors lacked the expression of the main glutamate transporter EAAT2, while the expression of glutamine synthetase and pyruvate carboxylase was mostly preserved., Methods: In the present study, we evaluated the immunohistochemical expression of EAAT2, glutamine synthetase and pyruvate carboxylase in a heterogeneous series of 25 long-term epilepsy-associated tumors (10 dysembryoplastic neuroepithelial tumors, 7 gangliogliomas, 3 subependymal giant cell astrocytomas, 3 rosette forming glioneuronal tumors, 1 diffuse astrocytoma MYB- or MYBL1-altered and 1 angiocentric glioma). In order to evaluate the incidence of variants in the SLC1A2 gene, encoding EAAT2, in a large number of central nervous system tumors we also queried the PedcBioPortal., Results: EAAT2 protein expression was lost in 9 tumors (36 %: 3 dysembryoplastic neuroepithelial tumors, 1 ganglioglioma, 3 subependymal giant cell astrocytomas, 1 diffuse astrocytoma MYB- or MYBL1-altered and 1 angiocentric glioma). Glutamine synthetase protein expression was completely lost in 2 tumors (8 %; 1 ganglioglioma and 1 diffuse astrocytoma MYB- or MYBL1-altered). All tumors of our series but rosette forming glioneuronal tumors (in which neurocytic cells were negative) were diffusely positive for pyruvate carboxylase. Consultation of the PedcBioPortal revealed that of 2307 pediatric brain tumors of different histotype and grade, 20 (< 1%) had variants in the SLC1A2 gene. Among the SLC1A2-mutated tumors, there were no angiocentric gliomas or other LEATs CONCLUSIONS: In conclusion, unlike angiocentric gliomas where the EAAT2 loss is typical and constant, the current study shows the loss of EAAT2 expression only in a fraction of the LEATs. In these cases, we may hypothesize some possible epileptogenic role of the EAAT2 loss. The retained expression of pyruvate carboxylase may contribute to determining a pathological glutamate excess unopposed by glutamine synthetase that resulted expressed to a variable extent in the majority of the tumors. Furthermore, we can assume that the EAAT2 loss in brain tumors in general and in LEATs in particular is more conceivably epigenetic., (Copyright © 2023 Elsevier B.V. All rights reserved.)
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- 2024
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16. Childhood-onset Erdheim-Chester disease in the molecular era: clinical phenotypes and long-term outcomes of 21 patients.
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Pegoraro F, Mazzariol M, Trambusti I, Bakhshi S, Mallick S, Dunkel IJ, van den Bos C, Tezol Ö, Shan S, Ocak S, Giordano F, De Fusco C, Gaspari S, Buccoliero AM, Coniglio ML, Buti E, Romagnani P, Picarsic J, Donadieu J, Diamond EL, Emile JF, Sieni E, Haroche J, and Vaglio A
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- Humans, Child, Phenotype, Erdheim-Chester Disease diagnostic imaging, Erdheim-Chester Disease genetics
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- 2023
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17. Bevacizumab-Irinotecan combination therapy in recurrent low-grade glioma, previously treated with chemo-radiotherapy: a case report.
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Castelli B, Fonte C, Guidi M, Tellini M, Di Nicola M, Iacono A, Buccoliero AM, Greto D, Genitori L, and Sardi I
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Low grade gliomas (LGGs) of pineal region are usually difficult to remove and they frequently relapse or progress after front line chemotherapy. Bevacizumab-Irinotecan (BEVIRI) combination has been successfully attempted in children with recurrent LGGs, in most cases not previously irradiated. The efficacy of bevacizumab has also been described in radiation necrosis. Considering the possible overlapping of radiation treatment effect and disease progression and difficulty in differentiating, we report on the use of BEVIRI in a case of a recurrent relapsing low-grade glioma of the pineal region, subjected to multiple neurosurgical interventions, also treated with a carboplatin-etoposide regimen and a radiation course, at present at one-year follow-up showing a stable response, with no adverse events., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Castelli, Fonte, Guidi, Tellini, Di Nicola, Iacono, Buccoliero, Greto, Genitori and Sardi.)
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- 2023
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18. Brief report: pediatric high-grade gliomas treated with vinorelbine and valproic acid added to temozolomide.
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Guidi M, Giunti L, Buccoliero AM, Fonte C, Scoccianti S, Censullo ML, Caporalini C, Tellini M, Di Nicola M, Castelli B, Greto D, Giordano F, Genitori L, and Sardi I
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Children and young adult with high grade gliomas (HGG) have dismal prognoses and treatment options remain limited. We present 19 patients diagnosed with anaplastic astrocytoma (AA) or glioblastoma (GBM) treated with concomitant and adjuvant 20-30 mg/m
2 /dose of vinorelbine and 30 mg/kg/day valproic acid (VA) in combination to consolidated TMZ and focal RT after maximal surgery. We evaluated the feasibility of treating children diagnosed with HGG. The median follow-up time was 51.4 months (range, 6.2-106.6 months). The 5-year OS was 57.9% (CI 95%, 33.2-76.3) and the 5-year PFS was 57.9% (CI 95%, 33.2-76.3). Eight patients (42.1%) have progressed so far, with a median time to progression of 9 months from diagnosis (range, 4.6-34.7 months). All of them died for disease progression. At time of analysis, 11 patients were still alive with no evidence of disease. It is notable that all events occurred within 35 months from the start of therapy. All 19 treated patients reported low-grade drug-related adverse events (AEs). The treatment was well tolerated in our limited cohort of patients without significant toxicity. Further studies of the efficacy and safety of combination of vinorelbine/VA to consolidated RT/TMZ therapy in children with HGG are underway in a clinical trial setting., Competing Interests: None., (AJCR Copyright © 2023.)- Published
- 2023
19. SMARCE1-related meningiomas: A clear example of cancer predisposing syndrome.
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Fiorentini E, Giunti L, Di Rita A, Peraio S, Fonte C, Caporalini C, Buccoliero AM, Censullo ML, Gori G, Noris A, Pasquariello R, Battini R, Pavone R, Giordano F, Giglio S, and Rinaldi B
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- Adolescent, Female, Humans, Chromosomal Proteins, Non-Histone genetics, DNA-Binding Proteins genetics, Germ-Line Mutation, Loss of Heterozygosity, Transcription Factors genetics, Meningeal Neoplasms genetics, Meningeal Neoplasms diagnosis, Meningeal Neoplasms pathology, Meningioma genetics, Meningioma diagnosis, Meningioma pathology
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We report the case of a 16-year-old girl presenting with spinal clear-cell multiple meningiomas (CCMs). In view of this presentation, we sequenced a bioinformatic panel of genes associated with susceptibility to meningioma, identifying a germline heterozygous variant in SMARCE1. Somatic DNA investigations in the CCM demonstrated the deletion of the wild-type allele (loss of heterozygosity, LOH), supporting the causative role of this variant. Family segregation study detected the SMARCE1 variant in the asymptomatic father and in the asymptomatic sister who, nevertheless, presents 2 spinal lesions. Germline heterozygous loss-of-function (LoF) variants in SMARCE1, encoding a protein of the chromatin-remodeling complex SWI/SNF, have been described in few familial cases of susceptibility to meningioma, in particular the CCM subtype. Our case confirms the role of NGS in investigating predisposing genes for meningiomas (multiple or recurrent), with specific regard to SMARCE1 in case of pediatric CCM. In addition to the age of onset, the presence of familial clustering or the coexistence of multiple synchronous meningiomas also supports the role of a genetic predisposition that deserves a molecular assessment. Additionally, given the incomplete penetrance, it is of great importance to follow a specific screening or follow-up program for symptomatic and asymptomatic carriers of pathogenic variants in SMARCE1., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)
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- 2023
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20. Myxoid glioneuronal tumor: Histopathologic, neuroradiologic, and molecular features in a single center series.
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Caporalini C, Scagnet M, Giunti L, Cetica V, Mei D, Conti V, Moscardi S, Macconi L, Giordano F, D'Incerti L, Genitori L, Guerrini R, and Buccoliero AM
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- Child, Humans, Magnetic Resonance Imaging, Septum Pellucidum pathology, Mutation, Receptor Protein-Tyrosine Kinases genetics, Disease Progression, Brain Neoplasms pathology
- Abstract
Background: Myxoid glioneuronal tumor (MGT) is a benign glioneuronal neoplasm recently introduced in the World Health Organization (WHO) classification of the central nervous system (CNS) tumors. MGTs are typically located in the septum pellucidum, foramen of Monro or periventricular white matter of the lateral ventricle. They were previously diagnosed as dysembryoplastic neuroepithelial tumors (DNT), showing histological features almost indistinguishable from classical cortical DNT. Despite that, MGTs have been associated with a specific dinucleotide substitution at codon 385 in the platelet-derived growth factor receptor alpha (PDGFRA) gene, replacing a lysine residue with either leucine or isoleucine (p. LysK385Leu/Iso). This genetic variation has never been described in any other CNS tumor., Materials and Methods: Thirty-one consecutive tumors, previously diagnosed as DNTs at the Meyer Children's Hospital IRCCS between January 2010 and June 2021 were collected for a comprehensive study of their clinical, imaging, pathological features, and molecular profile., Results: In six out of the thirty-one tumors we had previously diagnosed as DNTs, we identified the recurrent dinucleotide mutation in the PDGFRA. All six tumors were typically located within the periventricular white matter of the lateral ventricle and in the septum pellucidum. We then renamed these lesions as MGT, according to the latest WHO CNS classification. In all patients we observed an indolent clinical course, without recurrence., Conclusion: MGT represent a rare but distinct group of neoplasm with a typical molecular profiling, a characteristic localization, and a relative indolent clinical course., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier Inc.)
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- 2023
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21. Dysplasia and tumor discrimination in brain tissues by combined fluorescence, Raman, and diffuse reflectance spectroscopies.
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Baria E, Giordano F, Guerrini R, Caporalini C, Buccoliero AM, Cicchi R, and Pavone FS
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Identification of neoplastic and dysplastic brain tissues is of paramount importance for improving the outcomes of neurosurgical procedures. This study explores the combined application of fluorescence, Raman and diffuse reflectance spectroscopies for the detection and classification of brain tumor and cortical dysplasia with a label-free modality. Multivariate analysis was performed to evaluate classification accuracies of these techniques-employed both in individual and multimodal configuration-obtaining high sensitivity and specificity. In particular, the proposed multimodal approach allowed discriminating tumor/dysplastic tissues against control tissue with 91%/86% sensitivity and 100%/100% specificity, respectively, whereas tumor from dysplastic tissues were discriminated with 89% sensitivity and 86% specificity. Hence, multimodal optical spectroscopy allows reliably differentiating these pathologies using a non-invasive, label-free approach that is faster than the gold standard technique and does not require any tissue processing, offering the potential for the clinical translation of the technology., Competing Interests: The authors declare no conflicts of interest., (© 2023 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement.)
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- 2023
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22. The children's brain tumor network (CBTN) - Accelerating research in pediatric central nervous system tumors through collaboration and open science.
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Lilly JV, Rokita JL, Mason JL, Patton T, Stefankiewiz S, Higgins D, Trooskin G, Larouci CA, Arya K, Appert E, Heath AP, Zhu Y, Brown MA, Zhang B, Farrow BK, Robins S, Morgan AM, Nguyen TQ, Frenkel E, Lehmann K, Drake E, Sullivan C, Plisiewicz A, Coleman N, Patterson L, Koptyra M, Helili Z, Van Kuren N, Young N, Kim MC, Friedman C, Lubneuski A, Blackden C, Williams M, Baubet V, Tauhid L, Galanaugh J, Boucher K, Ijaz H, Cole KA, Choudhari N, Santi M, Moulder RW, Waller J, Rife W, Diskin SJ, Mateos M, Parsons DW, Pollack IF, Goldman S, Leary S, Caporalini C, Buccoliero AM, Scagnet M, Haussler D, Hanson D, Firestein R, Cain J, Phillips JJ, Gupta N, Mueller S, Grant G, Monje-Deisseroth M, Partap S, Greenfield JP, Hashizume R, Smith A, Zhu S, Johnston JM, Fangusaro JR, Miller M, Wood MD, Gardner S, Carter CL, Prolo LM, Pisapia J, Pehlivan K, Franson A, Niazi T, Rubin J, Abdelbaki M, Ziegler DS, Lindsay HB, Stucklin AG, Gerber N, Vaske OM, Quinsey C, Rood BR, Nazarian J, Raabe E, Jackson EM, Stapleton S, Lober RM, Kram DE, Koschmann C, Storm PB, Lulla RR, Prados M, Resnick AC, and Waanders AJ
- Subjects
- Adult, Humans, Child, Quality of Life, Brain Neoplasms therapy
- Abstract
Pediatric brain tumors are the leading cause of cancer-related death in children in the United States and contribute a disproportionate number of potential years of life lost compared to adult cancers. Moreover, survivors frequently suffer long-term side effects, including secondary cancers. The Children's Brain Tumor Network (CBTN) is a multi-institutional international clinical research consortium created to advance therapeutic development through the collection and rapid distribution of biospecimens and data via open-science research platforms for real-time access and use by the global research community. The CBTN's 32 member institutions utilize a shared regulatory governance architecture at the Children's Hospital of Philadelphia to accelerate and maximize the use of biospecimens and data. As of August 2022, CBTN has enrolled over 4700 subjects, over 1500 parents, and collected over 65,000 biospecimen aliquots for research. Additionally, over 80 preclinical models have been developed from collected tumors. Multi-omic data for over 1000 tumors and germline material are currently available with data generation for > 5000 samples underway. To our knowledge, CBTN provides the largest open-access pediatric brain tumor multi-omic dataset annotated with longitudinal clinical and outcome data, imaging, associated biospecimens, child-parent genomic pedigrees, and in vivo and in vitro preclinical models. Empowered by NIH-supported platforms such as the Kids First Data Resource and the Childhood Cancer Data Initiative, the CBTN continues to expand the resources needed for scientists to accelerate translational impact for improved outcomes and quality of life for children with brain and spinal cord tumors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. David S. Ziegler is a consultant, or on the advisory board, of Bayer, AstraZeneca, Accendatech, Novartis, Day One, FivePhusion, Amgen, Alexion, and Norgine. Angela J. Waanders is on the advisory board of Alexion and Day One., (Copyright © 2022. Published by Elsevier Inc.)
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- 2023
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23. Distinct DNA Methylation Patterns of Subependymal Giant Cell Astrocytomas in Tuberous Sclerosis Complex.
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Bongaarts A, Mijnsbergen C, Anink JJ, Jansen FE, Spliet WGM, den Dunnen WFA, Coras R, Blümcke I, Paulus W, Gruber VE, Scholl T, Hainfellner JA, Feucht M, Kotulska K, Jozwiak S, Grajkowska W, Buccoliero AM, Caporalini C, Giordano F, Genitori L, Söylemezoğlu F, Pimentel J, Jones DTW, Scicluna BP, Schouten-van Meeteren AYN, Mühlebner A, Mills JD, and Aronica E
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- Humans, DNA Methylation genetics, Sirolimus therapeutic use, Astrocytoma metabolism, Tuberous Sclerosis complications, Tuberous Sclerosis genetics, Tuberous Sclerosis pathology
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Tuberous sclerosis complex (TSC) is a monogenic disorder caused by mutations in either the TSC1 or TSC2 gene, two key regulators of the mechanistic target of the rapamycin complex pathway. Phenotypically, this leads to growth and formation of hamartomas in several organs, including the brain. Subependymal giant cell astrocytomas (SEGAs) are low-grade brain tumors commonly associated with TSC. Recently, gene expression studies provided evidence that the immune system, the MAPK pathway and extracellular matrix organization play an important role in SEGA development. However, the precise mechanisms behind the gene expression changes in SEGA are still largely unknown, providing a potential role for DNA methylation. We investigated the methylation profile of SEGAs using the Illumina Infinium HumanMethylation450 BeadChip (SEGAs n = 42, periventricular control n = 8). The SEGA methylation profile was enriched for the adaptive immune system, T cell activation, leukocyte mediated immunity, extracellular structure organization and the ERK1 & ERK2 cascade. More interestingly, we identified two subgroups in the SEGA methylation data and show that the differentially expressed genes between the two subgroups are related to the MAPK cascade and adaptive immune response. Overall, this study shows that the immune system, the MAPK pathway and extracellular matrix organization are also affected on DNA methylation level, suggesting that therapeutic intervention on DNA level could be useful for these specific pathways in SEGA. Moreover, we identified two subgroups in SEGA that seem to be driven by changes in the adaptive immune response and MAPK pathway and could potentially hold predictive information on target treatment response., (© 2021. The Author(s).)
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- 2022
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24. Pleomorphic Xanthoastrocytoma: a single institution retrospective analysis and a review of the literature.
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Detti B, Scoccianti S, Maragna V, Lucidi S, Ganovelli M, Teriaca MA, Caini S, Desideri I, Agresti B, Greto D, Buccoliero AM, Puppa AD, Sardi I, and Livi L
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- Adult, Child, Follow-Up Studies, Humans, Proto-Oncogene Proteins B-raf genetics, Retrospective Studies, Astrocytoma diagnostic imaging, Astrocytoma genetics, Astrocytoma therapy, Brain Neoplasms diagnostic imaging, Brain Neoplasms therapy
- Abstract
Background: Pleomorphic xanthoastrocytoma (PXA) is a rare low-grade brain tumor. To date, limited studies have analyzed factors affecting survival outcomes and defined the therapeutic strategy. The aim of this retrospective analysis was to investigate the clinicopathologic characteristics of PXA and identify factors associated with outcomes., Methods: We retrospectively analyzed a cohort of 16 adult and children patients with PXA who underwent primary resection from 1997 to 2019, referred to our Radiation Oncology Unit and to Meyer's Paediatric Hospital. We also reviewed the relevant literature., Results: All patients underwent primary surgical resection; 10 patients received adjuvant radiation treatment course, ranging from DTF 54 to 64 Gy; 8 of them received, in addition, concurrent adjuvant chemotherapy; 6 patients underwent only radiological follow-up. After a median follow up was 60 months: median OS was 34.9 months (95% CI 30-218), 1-year OS 87%, 5-years OS 50%, 10-years OS 50%; median PFS 24.4 months (95% CI 13-156), 1-year PFS 80%, 5-years PFS 33%, 10-years PFS 33%. A chi-square test showed a significant association between OS and recurrent disease (p = 0.002) and with chemotherapy adjuvant treatment (p = 0.049). A borderline statistical significant association was instead recognized with BRAF mutation (p = 0.058)., Conclusions: Despite our analysis did not reveal a strong prognostic or predictive factor able to address pleomorphic xanthoastrocytoma management; however, in selected patients could be considered the addition of adjuvant radiation chemotherapy treatment after adequate neurosurgical primary resection. Furthermore, recurrent disease evidenced a detrimental impact on survival., (© 2022. The Author(s).)
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- 2022
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25. Brain low-grade gliomas with high-grade spinal localization: report of a clinical case and systematic literature review.
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Battista F, Muscas G, Scoccianti S, Buccoliero AM, Gadda D, and Della Puppa A
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- Adult, Aged, Brain pathology, Humans, Middle Aged, Neoplasm Grading, Survival Rate, Brain Neoplasms pathology, Brain Neoplasms surgery, Glioma pathology
- Abstract
Introduction: Oncological aggressiveness and the ability to present distant localizations are known in high-grade gliomas (HGGs), but the knowledge about the possible aggressiveness of LGGs is scarce, especially concerning possible spinal localization., Evidence Acquisition: A systematic search of low-grade gliomas (LGGs) with spinal localization on the three primary online databases (PubMed/MEDLINE, Embase, and Cochrane) was conducted. We included adult patients with histological diagnosis of intracranial LGG and specified WHO grade showing a remote spinal localization during follow-up. Additionally, we present a case of a left temporal LGG presenting a spinal localization fourteen years after the first appearance. We compared the survival rates of LGGs in our series with those of LGGs without spinal localizations., Evidence Synthesis: Seven articles dealing with the subject and eight patients were considered (including our case), with a mean age at diagnosis of 42.25 years (range 26-69 years). The mean latency between a diagnosis of intracranial LGGs and a spinal localization occurrence was 7.37 years (range 2-14 years), and an increased WHO grade of the spinal localization compared to the brain LGG was observed in all patients. There was no sign of intracranial progression at the time of spinal glioma diagnosis in four cases, including ours. Survival at ten years was 28% against a 10-year survival rate of 65-71% for LGGs without distant localization, as reported in the literature., Conclusions: Spinal metastasis of intracranial LGGs is an adverse prognostic factor. Surgical violation of ventricles can play a role in the pathophysiology of CSF spread of tumor cells in LGGs.
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- 2022
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26. Primary Intracerebral Alveolar Soft Part Sarcoma: Report of a Case and Review of the Literature.
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Caporalini C, Giordano F, Moscardi S, Di Stefano G, Lenge M, Di Giacomo G, Basile M, Zin A, Mura R, Scagnet M, Alaggio R, Sardi I, Genitori L, and Buccoliero AM
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- Adolescent, Diagnosis, Differential, Female, Humans, Sarcoma, Alveolar Soft Part diagnosis, Sarcoma, Alveolar Soft Part pathology, Sarcoma, Alveolar Soft Part surgery, Soft Tissue Neoplasms pathology
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Alveolar soft part sarcomas (ASPSs) are rare malignant tumors representing ∼1% of all soft tissue sarcomas. Most ASPS occurring in the central nervous system are metastases. In contrast, primary intracranial ASPSs are extremely rare and only 8 cases have been previously reported in English literature. Here, we report a case of primary alveolar soft part sarcoma in a 16-year-old female patient with no evidence of primary extracranial tumors. Histologically this case fulfilled the criteria of ASPS, and a molecular confirmation has been archived. To date, only 9 primary intracranial ASPS cases, including ours, have been reported in the literature. This report highlights the clinical and pathological characteristics, differential diagnosis, and molecular analysis of primary ASPS of the central nervous system.
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- 2022
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27. Pediatric High Grade Glioma Classification Criteria and Molecular Features of a Case Series.
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Buccoliero AM, Giunti L, Moscardi S, Castiglione F, Provenzano A, Sardi I, Scagnet M, Genitori L, and Caporalini C
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- Child, Humans, Glioma genetics, Glioma pathology
- Abstract
Pediatric high-grade gliomas (pHGGs) encompass a heterogeneous group of tumors. Three main molecular types (H3.3 mutant, IDH mutant, and H3.3/IDH wild-type) and a number of subtypes have been identified. We provide an overview of pHGGs and present a mono-institutional series. We studied eleven non-related pHGG samples through a combined approach of routine diagnostic tools and a gene panel. TP53 and H3F3A were the most mutated genes (six patients each, 54%). The third most mutated gene was EGFR (three patients, 27%), followed by PDGFRA and PTEN (two patients each, 18%). Variants in the EZHIP, MSH2, IDH1, IDH2, TERT, HRAS, NF1, BRAF, ATRX, and PIK3CA genes were relatively infrequent (one patient each, 9%). In one case, gene panel analysis documented the presence of a pathogenic IDH2 variant (c.419G>A, p.Arg140Gln) never described in gliomas. More than one-third of patients carry a variant in a gene associated with tumor-predisposing syndromes. The absence of constitutional DNA did not allow us to identify their constitutional origin.
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- 2022
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28. A Unique Case of Primary Cutaneous Adenoid Cystic Carcinoma Associated with Aplasia Cutis Congenita in a Four-Year-Old Female: A Case Report.
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Zulli A, Martin A, Facchini F, Coletta R, Tamburini A, Oranges T, Filippeschi C, Bassi A, Buccoliero AM, and Morabito A
- Abstract
Introduction: Primary cutaneous adenoid-cystic carcinoma (PCACC) is a rare malignant tumour reported in only about 450 cases in the literature, with only two adolescent cases reported. PCACC seems to occur between the fifth and seventh decade of life, and the most frequent regions involved are head and neck (46%). Aplasia cutis congenita (ACC) has an incidence of 1:10,000, and it seems to be rarely associated with neoplastic lesions. Interestingly, the association between PCACC and ACC has, so far, never been described., Methods: We report a case of PCACC in the scalp associated with ACC in a four-year-old patient., Discussion: The patient was under follow-up at the dermatology unit, but suddenly a red lesion appeared within the ACC. This red, ulcerated area increased rapidly over six months, so it was surgically removed, and the pathological examination results were suggestive for cribriform PCACC. According to the guidelines for skin tumours, the patient underwent widening resection, and an advancement-sliding skin flap was performed to recreate the scalp. After one year of follow-up, the patient has no local or widespread recurrence of the PCACC, and the surgical scar appears to have healed well., Conclusions: This clinical case is the first known patient with PCACC associated with ACC. A skin excision biopsy should be performed with wide margins to avoid a second widening resection of skin in a similar scenario. Genetic studies may help to identify the origin of this rare association.
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- 2022
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29. New insights in gastrointestinal "pediatric" neoplasms in adult patients: pancreatoblastoma, hepatoblastoma and embryonal sarcoma of the liver. A practical approach by GIPPI-GIPAD Groups.
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Tsvetkova V, Magro G, Broggi G, Luchini C, Cappello F, Caporalini C, Buccoliero AM, and Santoro L
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- Child, Female, Humans, Pregnancy, Hepatoblastoma diagnosis, Hepatoblastoma epidemiology, Hepatoblastoma therapy, Liver Neoplasms therapy, Pancreatic Neoplasms therapy, Sarcoma diagnosis, Sarcoma therapy
- Abstract
Pediatric solid neoplasms are rare and very different from those observed in adults. The majority of them are referred to as embryonal because they arise as a result of alterations in the processes of organogenesis or normal growth and are characterized by proliferation of primitive cells, reproducing the corresponding tissue at various stages of embryonic development. This review will focus on embryonal gastrointestinal pediatric neoplasms in adult patients, including pancreatoblastoma, hepatoblastoma, and embryonal sarcoma of the liver. Although they are classically considered pediatric neoplasms, they may (rarely) occur in adult patients. Hepatoblastoma represents the most frequent liver neoplasm in the pediatric population, followed by hepatocellular carcinoma and embryonal sarcoma of the liver; while pancreatoblastoma is the most common malignant pancreatic tumor in childhood. Both in children and adults, the mainstay of treatment is complete surgical resection, either up front or following neoadjuvant chemotherapy. Unresectable and/or metastatic neoplasms may be amenable to complete delayed surgery after neoadjuvant chemotherapy. However, these neoplasms display a more aggressive behavior and overall poorer prognosis in adults than in children, probably because they are diagnosed in later stages of diseases., (Copyright © 2022 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)
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- 2022
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30. Clinical-pathological study of 28 glial and mixed neuronal-glial tumors diagnosed within the first year of life.
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Buccoliero AM, Caporalini C, Moscardi S, Spacca B, Scagnet M, Castiglione F, Sardi I, Giunti L, and Genitori L
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- Adolescent, Child, Humans, Astrocytoma diagnosis, Astrocytoma genetics, Brain Neoplasms diagnosis, Brain Neoplasms genetics, Ganglioglioma diagnosis, Ganglioglioma genetics, Glioblastoma, Glioma diagnosis, Glioma genetics
- Abstract
Our purpose was to investigate the incidence of gliomas and neuronal-glial tumors, their outcome, and H3.3K27M, BRAFV600E, and IDH status in children within 1 year of age affected by CNS tumor. We collected 28 consecutive gliomas and mixed tumors. Immunohistochemistry and/or molecular analyses were performed on formalin-fixed/paraffin-embedded specimens. 24 (86%) tumors were supratentorial. 15 (54%) tumors were astrocytomas (5 glioblastomas, 1 anaplastic astrocytoma, 1 pilocytic astrocytoma, 3 pilomixoid astrocytomas, 2 subependymal giant cell astrocytomas, 3 astrocytomas not otherwise specified (NOS)), 4 (14%) were anaplastic ependymomas, and 9 (32%) were mixed tumors (5 gangliogliomas, 2 gangliocytomas, 2 desmoplastic infantile gangliogliomas (DIGs)). Alive patients were: 4 (67%) affected by high-grade astrocytoma (mean follow-up 64 months), 4 (67%) affected by low-grade astrocytoma (mean follow-up 83 months), 2 (67%) affected by astrocytoma NOS (mean follow-up 60 months), 1 (25%) affected by anaplastic ependymoma (follow-up 12 months), and 9 (100%) affected by mixed tumors (mean follow-up 74 months). H3.3K27M and IDH were not-mutated in any tumor (100%). BRAFV600E mutation was documented in 6 (21%) tumors (4 gangliogliomas, 1 gangliocytoma, and 1 astrocytoma NOS resulted as anaplastic pleomorphic xanthoastrocytoma 8 years later). Gliomas and mixed tumors diagnosed within 1 year of age are morphologically heterogeneous. Moreover, analogously to those affecting older children, they are IDH1-2 and H3.3K27M (when located outside midline) not-mutated while BRAFV600E mutation is typical of gangliogliomas/gangliocytomas and pleomorphic xanthoastrocytomas. High-grade astrocytomas have a more favorable prognosis compared with the same lesions occurring later in life while ependymomas have a poorer outcome.
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- 2022
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31. Corrigendum to 'Angiocentric glioma-associated seizures: The possible role of EATT2, pyruvate carboxylase and glutamine synthetase [Seizure: European Journal of Epilepsy 86 (2021) 152-154].
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Buccoliero AM, Caporalini C, Scagnet M, Mussa F, Giordano F, Sardi I, Migliastro I, Moscardi S, Conti V, Barba C, Antonelli M, Gianno F, Rossi S, Diomedi-Camassei F, Gessi M, Donofrio V, Bertero L, Giangaspero F, Santi M, Aronica E, Genitori L, and Guerrini R
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- 2021
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32. Dysembryoplastic neuroepithelial tumors: A single-institutional series with special reference to glutamine synthetase expression.
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Caporalini C, Scagnet M, Moscardi S, Di Stefano G, Baroni G, Giordano F, Mussa F, Barba C, Sardi I, Genitori L, and Buccoliero AM
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- Adolescent, Astrocytes metabolism, Astrocytes pathology, Brain Neoplasms pathology, Child, Child, Preschool, Female, Glioma pathology, Humans, Immunohistochemistry methods, Male, Neoplasms, Neuroepithelial pathology, Neurons pathology, Young Adult, Brain Neoplasms metabolism, Glioma metabolism, Glutamate-Ammonia Ligase metabolism, Neoplasms, Neuroepithelial metabolism
- Abstract
Dysembryoplastic neuroepithelial tumors (DNT) is a benign (World Health Organisation, WHO, grade I) glioneuronal tumor and it represent one of the most frequent neoplasm in patient affected by seizures. The epileptic neuronal activity can be determined by abnormal synchronization, excessive glutamate excitation and\or inadequate GABA inhibition. Increasing evidence suggests that the astrocytes might be involved in this process even if neurons play a relevant role. In particular astrocytes promote the clearance of glutamate, a potent excitatory neurotransmitter of the central nervous system. Indeed, elevated concentrations of extracellular glutamate may determine iper-excitability and seizures as well as other neurological disorders. So, astrocytes, converting glutamate into glutamine via the enzyme glutamine synthetase (GS), could play a protective anti-seizures role. In the present study, we analyzed the immunohistochemical expression of GS in 20 DNTs specimens documenting a constant immunoistochemical expression of GS in astrocytes of the lesional tissue and of the cerebral cortex., (Copyright © 2021 Elsevier Inc. All rights reserved.)
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- 2021
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33. Analysis of the mutational status of SIX1/2 and microRNA processing genes in paired primary and relapsed Wilms tumors and association with relapse.
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Ciceri S, Montalvão-de-Azevedo R, Tajbakhsh A, Bertolotti A, Spagnuolo RD, Boschetti L, Capasso M, D'Angelo P, Serra A, Diomedi-Camassei F, Meli M, Nantron M, Quarello P, Buccoliero AM, Tamburini A, Ciniselli CM, Verderio P, Collini P, Radice P, Spreafico F, and Perotti D
- Subjects
- Humans, Mutation, Survival Analysis, Wilms Tumor mortality, Homeodomain Proteins genetics, Homeodomain Proteins metabolism, MicroRNAs genetics, Nerve Tissue Proteins genetics, Wilms Tumor genetics
- Abstract
Whereas 90% of patients with Wilms tumor (WT) reach cure, approximately half of patients developing a recurrent tumor die of the disease. Therefore, to disclose events leading to recurrence represents a clinical need. To study paired primary/recurrent tumor samples, being aware of the intra-tumoral heterogeneity, might help finding these answers. We previously suggested that mutations in SIX1 and DROSHA underlie WT recurrence. With the aim to better investigate this scenario, we collected 19 paired primary/recurrent tumors and 10 primary tumors from relapsing patients and searched for mutations in the SIX1/2 genes and microRNA processing genes (miRNAPGs). We found SIX1 mutation in one case, miRNAPGs mutations in seven cases, and the co-occurrence of SIX1 and miRNAPG mutations in one case. We could observe that, whereas in primary tumors the mutations could be heterogeneously present, in all cases they were positively selected and homogeneously present in the recurrent disease, as also indicated by a "moderate" and "almost perfect" agreement (according to the Landis and Koch classification criteria) between paired samples. Analysis of SIX1/2 genes and miRNAPGs in 50 non-relapsing WTs disclosed SIX2 mutation in one case and miRNAPGs mutations in seven. A borderline statistically significant association was observed between miRNAPGs mutations and the occurrence of relapse (p value: 0.05). These data suggest that SIX1 and miRNAPGs mutations may provide an advantage during tumor progression to recurrence and can represent oncogenic drivers in WT development., (© 2020. The Author(s), under exclusive licence to Springer Nature America, Inc. part of Springer Nature.)
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- 2021
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34. Genetic signature and treatment of pediatric high-grade glioma.
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Guidi M, Giunti L, Buccoliero AM, Caporalini C, Censullo ML, Galli L, Genitori L, and Sardi I
- Abstract
Pediatric high-grade glioma (HGG) is a type of malignancy that carries a poor prognosis. The genetic analysis of HGGs has previously identified useful mutations, the targeting of which has improved prognosis. Thus, further research into the more common mutations, such as H3 histone variants (HIST1H3B and H3F3A) and BRAF V600E, may be useful in identifying tumors with different prognoses, as the mutations are considered to drive two distinct oncogenic programs. The present study performed a retrospective analysis of pediatric HGGs. In total, 42 cases of HGG, including 32 cases (76.1%) of anaplastic astrocytoma and 10 cases (23.8%) of glioblastoma multiforme (GBM), were assessed. The median age of the patients was 7 years (range, 0-32 years). Mutations on histone H3, in particular the K27M and G34R mutations in the distinct variants HIST1H3B and H3F3A, in addition to the presence of the BRAF V600E mutation, were analyzed in 24 patients. The H3F3A K27M mutation was identified in 7 patients (29.1%), while the HIST1H3B K27M mutation was only observed in 1 patient with GBM. In addition, 5 patients harbored a BRAF V600E mutation (21%), while the H3F3A G34R mutation was not recorded in any of the patients. The overall survival of the wild-type patients at 20 months was 68% [confidence interval (CI): 38-85%] compared with 28% (CI: 0.4-60%) in patients with the H3F3A K27M mutation. These results suggested that patients with the H3F3A K27M mutation had a worse prognosis compared with wild-type patients (P=0.0045). Moreover, 3/5 patients with the BRAF V600E mutation had HGGs that were derived from a previous low-grade glioma (LGG; P=0.001). In conclusion, these results suggested that histone H3 mutations may help predict the outcome in patients with HGG. In addition, the BRAF V600E mutation was found to be associated with an increased risk of anaplastic progression. The novel data of the present study may help better define the clinical and radiological characteristics of glioma., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2020, Spandidos Publications.)
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- 2021
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35. Clinical and dermoscopic polymorphisms in agminated Spitz nevi: Ugly presentation but benign behavior.
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De Giorgi V, Venturi F, Scarfì F, Trane L, Silvestri F, Savarese I, Facchini F, Buccoliero AM, and Massi D
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- Cafe-au-Lait Spots, Child, Dermoscopy, Humans, Male, Nevus, Epithelioid and Spindle Cell diagnosis, Nevus, Epithelioid and Spindle Cell genetics, Skin Neoplasms diagnosis
- Abstract
Agminated Spitz nevi are an uncommon entity, and their management is challenging due not only the young age of the patients but also the tumor's uncertain malignant potential and the variability in the dermoscopic and clinical presentation. We report a case of a 6-year-old boy with multiple agminated Spitz nevi on a café au lait macule with different atypical clinical patterns and dermoscopic features., (© 2021 Wiley Periodicals LLC.)
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- 2021
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36. Alternative lengthening of telomeres in molecular subgroups of paediatric high-grade glioma.
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Minasi S, Baldi C, Gianno F, Antonelli M, Buccoliero AM, Pietsch T, Massimino M, and Buttarelli FR
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- Child, Humans, Mutation genetics, Telomere genetics, Telomere Homeostasis genetics, X-linked Nuclear Protein genetics, Brain Neoplasms genetics, Glioma genetics
- Abstract
Purpose: The maintenance of telomere length prevents cancer cell senescence and occurs via two mutually exclusive mechanisms: (a) reactivation of telomerase expression and (b) activation of alternative lengthening of telomeres (ALT). ALT is frequently related to alterations on ATRX, a chromatin-remodelling protein. Recent data have identified different molecular subgroups of paediatric high-grade glioma (pHGG) with mutations of H3F3A, TERTp and ATRX; however, differences in telomere length among these molecular subgroups were not thoroughly examined., Methods: We investigated which genetic alterations trigger the ALT mechanism in 52 IDH-wildtype, 1p/19q-wildtype pHGG. Samples were analysed for telomere length using Tel-FISH. ATRX nuclear loss of expression was assessed by IHC, H3F3A and TERTp mutations by DNA sequencing, and TERTp methylation by MS-PCR., Results: Mutant H3.3 was found in 21 cases (40.3%): 19.2% with K27M mutation and 21.1% with G34R mutation. All H3.3G34R-mutated cases showed the ALT phenotype (100%); on the opposite, only 40% of the H3.3K27M-mutated showed ALT activation. ATRX nuclear loss was seen in 16 cases (30.7%), associated sometimes with the G34R mutation, and never with the K27M mutation. ATRX nuclear loss was always related to telomere elongation. TERTp C250T mutations were rare (5.4%) and were not associated with high intensity Tel-FISH signals, as TERTp hyper-methylation detected in 21% of the cases. H3.3/ATRX/TERTp-wildtype pHGG revealed all basal levels of telomere length., Conclusion: Our results show a strong association between H3.3 mutations and ALT, and highlight the different telomeric profiles in histone-defined subgroups: H3.3-G34R mutants always trigger ALT to maintain telomere length, irrespective of ATRX status, whereas only some H3.3-K27M tumours activate ALT. These findings suggest that acquiring the gly34 mutation on H3.3 might suffice to trigger the ALT mechanism.
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- 2021
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37. Angiocentric glioma-associated seizures: The possible role of EATT2, pyruvate carboxylase and glutamine synthetase.
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Buccoliero AM, Caporalini C, Scagnet M, Mussa F, Giordano F, Sardi I, Migliastro I, Moscardi S, Conti V, Barba C, Antonelli M, Gianno F, Rossi S, Diomedi-Camassei F, Gessi M, Donofrio V, Bertero L, Giangaspero F, Santi M, Aronica E, Genitori L, and Guerrini R
- Subjects
- Glutamate-Ammonia Ligase, Glutamic Acid, Humans, Pyruvate Carboxylase, Glioma complications, Seizures etiology
- Abstract
Purpose: Our purpose was to better understand the pathogenesis of seizures associated with angiocentric glioma. Angiocentric glioma is an indolent and rare low-grade glioma. Its typical clinical presentation is with epileptic seizures. The pathogenesis of tumor-associated seizures is poorly understood. Among the possible pathomechanisms, the increased neurotoxic concentrations of the glutamate has been proposed. Glutamate transporters, pyruvate carboxylase and glutamine synthetase are involved in maintaining the physiological concentration of glutamate in the inter synaptic spaces., Methods: We evaluated the immunohistochemical expression of EAAT2 (the most important glutamate transporter), pyruvate carboxylase and glutamine synthetase in 17 angiocentric gliomas., Results: EAAT2 was never expressed (0%) in the neoplastic cells in none of the cases studied. Pyruvate carboxylase was expressed in the cytoplasm of the neoplastic cells in 16/17 cases (94 %). Glutamine synthetase was expressed in the cytoplasm of the neoplastic cells in 15/17 cases (88 %)., Conclusion: The net result of this enzymatic expression, in particular considering the loss of EAAT2, could be an increased glutamate concentration in the synaptic clef, which might increase local network excitability initially involving intratumoral neurons. The observation that the angiocentric glioma-associated epilepsy might be at least in part related to EAAT2 deficiency opens up interesting therapeutic perspectives., (Copyright © 2021 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)
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- 2021
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38. Correlation Between Immunohistochemistry and Sequencing in H3G34-Mutant Gliomas.
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Gianno F, Antonelli M, Di Dio T, Minasi S, Donofrio V, Buccoliero AM, Gardiman MP, Pollo B, Diomedi Camassei F, Rossi S, Novello M, Giangaspero F, Arcella A, Gessi M, and Buttarelli FR
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Female, Humans, Immunohistochemistry, Infant, Male, Mutation, Polymerase Chain Reaction, Sensitivity and Specificity, Young Adult, Biomarkers, Tumor analysis, Biomarkers, Tumor genetics, Brain Neoplasms genetics, Glioma genetics, Histones genetics
- Abstract
Recurrent glycine-to-arginine/valine alterations at codon 34 (G34R/V) within H3F3A gene characterize a subset of hemispheric high-grade gliomas (HGG) affecting children and young adults. These tumors, defined as G34R/V-mutant gliomas, are histologically heterogenous, with microscopic features of either HGG or embryonal tumors (primitve neuroectodermal tumor-like features). To assess the value of immunohistochemistry (IHC) to detect G34R/V-mutated cases, we tested anti-histone G34V (clone 329E5) and anti-histone G34R (clone RM240) antibodies in a series of 28 formalin-fixed and paraffin-embedded samples. A total of 28 cases of hemispheric, IDH-wt HGG mainly affecting children and young adults were evaluated by IHC and by sequencing. The median age of patients at diagnosis was 17 years (0.1 to 26 y). By IHC, 10 of the 28 cases showed nuclear positivity for G34R and 3 of the 28 cases for G34V. Molecular analysis of G34R/V-mutation status was successful in 24 of the 28 cases. Mutation at glycine 34 of the H3F3A gene was identified in 9 of the 24 tumors (37%) by direct sequencing, revealing 7 of 9 positive case by sequencing and 2 of 9 false negative cases by IHC. Two of 15 negative case by sequencing demonstrated a false positivity by IHC. In total, in 4 (16.6%) of 24 cases, IHC and mutational results were discordant: 2 tumors were negative by IHC (false negative) but harbored G34R mutation by sequencing, and 2 cases were positive by IHC (false positive by IHC) but wild type by sequencing. Moreover, most mutated cases showed loss of ATRX expression and/or p53 expression. The positivity by IHC with specific antibody tested is not highly predictive for presence of G34R/V mutation, but confirmation by sequencing is mandatory; G34R/V mutations should be suspected in all hemispheric tumor IDH1/2 wild type, showing loss of OLIG2 and ATRX and/or p53 expression., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2021
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39. Somatic Focal Copy Number Gains of Noncoding Regions of Receptor Tyrosine Kinase Genes in Treatment-Resistant Epilepsy.
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Vasudevaraja V, Rodriguez JH, Pelorosso C, Zhu K, Buccoliero AM, Onozato M, Mohamed H, Serrano J, Tredwin L, Garonzi M, Forcato C, Zeck B, Ramaswami S, Stafford J, Faustin A, Friedman D, Hidalgo ET, Zagzag D, Skok J, Heguy A, Chiriboga L, Conti V, Guerrini R, Iafrate AJ, Devinsky O, Tsirigos A, Golfinos JG, and Snuderl M
- Subjects
- Adolescent, Adult, Child, Drug Resistant Epilepsy metabolism, ErbB Receptors metabolism, Female, Humans, In Situ Hybridization, Fluorescence, Male, Middle Aged, Retrospective Studies, Young Adult, Brain metabolism, DNA Copy Number Variations, DNA Methylation, Drug Resistant Epilepsy genetics, ErbB Receptors genetics
- Abstract
Epilepsy is a heterogenous group of disorders defined by recurrent seizure activity due to abnormal synchronized activity of neurons. A growing number of epilepsy cases are believed to be caused by genetic factors and copy number variants (CNV) contribute to up to 5% of epilepsy cases. However, CNVs in epilepsy are usually large deletions or duplications involving multiple neurodevelopmental genes. In patients who underwent seizure focus resection for treatment-resistant epilepsy, whole genome DNA methylation profiling identified 3 main clusters of which one showed strong association with receptor tyrosine kinase (RTK) genes. We identified focal copy number gains involving epidermal growth factor receptor (EGFR) and PDGFRA loci. The dysplastic neurons of cases with amplifications showed marked overexpression of EGFR and PDGFRA, while glial and endothelial cells were negative. Targeted sequencing of regulatory regions and DNA methylation analysis revealed that only enhancer regions of EGFR and gene promoter of PDGFRA were amplified, while coding regions did not show copy number abnormalities or somatic mutations. Somatic focal copy number gains of noncoding regulatory represent a previously unrecognized genetic driver in epilepsy and a mechanism of abnormal activation of RTK genes. Upregulated RTKs provide a potential avenue for therapy in seizure disorders., (© 2020 American Association of Neuropathologists, Inc. All rights reserved.)
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- 2021
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40. Is Focal Cortical Dysplasia/Epilepsy Caused by Somatic MTOR Mutations Always a Unilateral Disorder?
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Guerrini R, Cavallin M, Pippucci T, Rosati A, Bisulli F, Dimartino P, Barba C, Garbelli R, Buccoliero AM, Tassi L, and Conti V
- Abstract
Objective: To alert about the wide margin of unpredictability that distribution of somatic MTOR mosaicism may have in the brain and the risk for independent epileptogenesis arising from the seemingly healthy contralateral hemisphere after complete removal of epileptogenic focal cortical dysplasia (FCD)., Methods: Clinical, EEG, MRI, histopathology, and molecular genetics in 2 patients (1 and 2) treated with focal resections and subsequent complete hemispherectomy for epileptogenic FCD due to somatic MTOR mutations. Autoptic brain study of bilateral asymmetric hemispheric dysplasia and identification of alternative allele fraction (AAF) rates for AKT1 (patient 3)., Results: The strongly hyperactivating p.Ser2215Phe (patient 1) and p.Leu1460Pro (patient 2) MTOR mutations were at low-level AAF in the dysplastic tissue. After repeated resections and eventual complete hemispherectomy, both patients manifested intractable seizures arising from the contralateral, seemingly healthy hemisphere. In patient 3, the p.Glu17Lys AKT1 mutation exhibited random distribution and AAF rates in different tissues with double levels in the more severely dysplastic cerebral hemisphere., Conclusions: Our understanding of the distribution of somatic mutations in the brain in relation to the type of malformation and its hypothesized time of origin may be faulty. Large studies may reveal that the risk of a first surgery being disappointing might be related more to the specific somatic mammalian target of rapamycin mutation identified than to completeness of resection and that the advantages of repeated resections after a first unsuccessful operation should be weighed against the risk of the contralateral hemisphere becoming in turn epileptogenic., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
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- 2020
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41. A misdiagnosed vesicobullous recurrent eruption in a 7-year-old girl.
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Tersigni C, Filippeschi C, Buccoliero AM, Antiga E, Oranges T, De Martino M, and Bassi A
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- Child, Diagnostic Errors, Female, Humans, Recurrence, Skin Diseases, Vesiculobullous pathology
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- 2020
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42. Post-mortem histopathology of a pediatric brain after bilateral DBS of GPI for status dystonicus: case report and review of the literature.
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Giordano F, Caporalini C, Peraio S, Mongardi L, Buccoliero AM, Cavallo MA, Genitori L, Lenge M, Mura R, Melani F, L'Erario M, Lelli L, and Pennica M
- Subjects
- Autopsy, Child, Humans, Male, Treatment Outcome, Deep Brain Stimulation, Globus Pallidus
- Abstract
Purpose: To investigate the effects of deep brain stimulation (DBS) electrodes on the brain of a dystonic pediatric patient submitted to bilateral DBS of the globus pallidus internus (GPI)., Methods: An 8-year-old male patient underwent bilateral DBS of GPI for status dystonicus. He died 2 months later due to multiorgan failure triggered by bacterial pneumonia. A post-mortem pathological study of the brain was done., Results: At visual inspection, no grossly apparent softening, hemorrhage, or necrosis of the brain adjacent to the DBS lead tracts was detected. High-power microscopic examination of the tissue surrounding the electrode trajectories showed lymphocyte infiltration, astrocytic gliosis, microglia, macrophages, and clusters of multinucleate giant cells. Significant astrocytosis was confirmed by GFAP staining in the electrode site. The T cell lymphocyte activity was overexpressed with activated macrophages detected with CD3, CD20, CD45, and CD68 stains respectively. There was no gliosis or leukocyte infiltration away from the surgical tracks of the electrodes., Conclusion: This is the first post-mortem examination of a child's brain after bilateral DBS of GPI. The comparison with adult post-mortem reports showed no significant differences and confirms the safety of DBS implantation in the pediatric population too.
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- 2020
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43. Dysregulation of the MMP/TIMP Proteolytic System in Subependymal Giant Cell Astrocytomas in Patients With Tuberous Sclerosis Complex: Modulation of MMP by MicroRNA-320d In Vitro.
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Bongaarts A, de Jong JM, Broekaart DWM, van Scheppingen J, Anink JJ, Mijnsbergen C, Jansen FE, Spliet WGM, den Dunnen WFA, Gruber VE, Scholl T, Hainfellner JA, Feucht M, Borkowska J, Kotulska K, Jozwiak S, Grajkowska W, Buccoliero AM, Caporalini C, Giordano F, Genitori L, Scicluna BP, Schouten-van Meeteren AYN, van Vliet EA, Mühlebner A, Mills JD, and Aronica E
- Subjects
- Adolescent, Adult, Astrocytoma genetics, Astrocytoma pathology, Brain metabolism, Brain pathology, Cells, Cultured, Child, Child, Preschool, Female, Humans, Infant, Male, Matrix Metalloproteinases genetics, MicroRNAs genetics, Tissue Inhibitor of Metalloproteinases genetics, Tuberous Sclerosis genetics, Tuberous Sclerosis pathology, Young Adult, Astrocytoma metabolism, Matrix Metalloproteinases metabolism, MicroRNAs biosynthesis, Proteolysis, Tissue Inhibitor of Metalloproteinases metabolism, Tuberous Sclerosis metabolism
- Abstract
Tuberous sclerosis complex (TSC), a rare genetic disorder caused by a mutation in the TSC1 or TSC2 gene, is characterized by the growth of hamartomas in several organs. This includes the growth of low-grade brain tumors, known as subependymal giant cell astrocytomas (SEGA). Previous studies have shown differential expression of genes related to the extracellular matrix in SEGA. Matrix metalloproteinases (MMPs), and their tissue inhibitors (TIMPs) are responsible for remodeling the extracellular matrix and are associated with tumorigenesis. This study aimed to investigate the MMP/TIMP proteolytic system in SEGA and the regulation of MMPs by microRNAs, which are important post-transcriptional regulators of gene expression. We investigated the expression of MMPs and TIMPs using previously produced RNA-Sequencing data, real-time quantitative PCR and immunohistochemistry in TSC-SEGA samples and controls. We found altered expression of several MMPs and TIMPs in SEGA compared to controls. We identified the lowly expressed miR-320d in SEGA as a potential regulator of MMPs, which can decrease MMP2 expression in human fetal astrocyte cultures. This study provides evidence of a dysregulated MMP/TIMP proteolytic system in SEGA of which MMP2 could be rescued by microRNA-320d. Therefore, further elucidating microRNA-mediated MMP regulation may provide insights into SEGA pathogenesis and identify novel therapeutic targets., (© 2020 American Association of Neuropathologists, Inc.)
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- 2020
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44. Neurosurgical treatment of subependymal giant cell astrocytomas in tuberous sclerosis complex: a series of 44 surgical procedures in 31 patients.
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Giordano F, Moscheo C, Lenge M, Biagiotti R, Mari F, Sardi I, Buccoliero AM, Mongardi L, Aronica E, Guerrini R, and Genitori L
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- Child, Humans, Neoplasm Recurrence, Local, Retrospective Studies, Astrocytoma complications, Astrocytoma diagnostic imaging, Astrocytoma surgery, Brain Neoplasms complications, Brain Neoplasms diagnostic imaging, Brain Neoplasms surgery, Tuberous Sclerosis complications, Tuberous Sclerosis diagnostic imaging, Tuberous Sclerosis surgery
- Abstract
Background: Subependymal giant cell astrocytomas (SEGA) are benign tumors characteristic of tuberous sclerosis complex (TSC) that may cause hydrocephalus. Various treatments are nowadays available as mTOR inhibitors or surgery. Surgery is still a valid option especially for symptomatic and larger tumors., Methods: From January 1994 to December 2015, 31 TSC patients harboring SEGA underwent surgery at the Department of Neurosurgery of the Meyer Pediatric Hospital, Florence. Indications for surgery were tumor size and location, growth and cystization/hemorrhage, and hydrocephalus. Clinical data, preoperative and postoperative MRI, recurrence rate, further surgical procedures, and related complications were analyzed., Results: A total of 44 surgeries were performed in 31 TSC patients affected by SEGA, achieving gross total removal (GTR) and subtotal removal (STR), respectively, in 36 and 8 patients. Recurrences occurred in 11 patients; 9 of them underwent further surgical procedures and 2 were treated with mTOR pathway inhibitors. Surgical morbidity and mortality were, respectively, 22.7% and 2.3%. After a mean follow-up of 4.9 years, 90% of patients were tumor-free with good neurological status in 93.3%; twelve (40%) had a ventriculo-peritoneal shunt (VPS) for hydrocephalus., Conclusions: The present series confirms that the surgical approach, combined with mTOR inhibitors, is still a valid option for the treatment of SEGAs.
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- 2020
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45. Use of High-Dose Chemotherapy in Front-Line Therapy of Infants Aged Less Than 12 Months Treated for Aggressive Brain Tumors.
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Guidi M, Giunti L, Buccoliero AM, Santi M, Spacca B, De Masi S, Genitori L, and Sardi I
- Abstract
Introduction: Malignant brain tumors in infants less than 12 months of age are extremely rare, and they have poor prognosis. We evaluated genetic characteristics and response rates of infants with congenital brain tumors subjected to high-dose chemotherapy and autologous stem cell transplant after gross total tumor resection. Materials and Methods: In total, 10 infants, aged less than 12 months, were enrolled in this study. The median age was 56 days (range: 1-279 days). Pathological examination demonstrated the following: four anaplastic astrocytomas, two glioblastomas, two central nervous system (CNS) embryonal tumors, not otherwise specified (NOS), and two atypical teratoid/rhabdoid tumors. Results: All patients were exposed to induction chemotherapy regimen, two high-dose chemotherapy courses, and autologous stem cell transplant after maximal surgery. At 1-3-5 years, the global overall survival (OS) was 90, 70, and 70% and the progression-free survival (PFS) was 80-60 and 60%. In all the patients, the copy number variants (CNVs) profile was analyzed using the SNP/CGH array approach. To investigate the clinical relevance of germline SMARCB1 mutation in AT/RT patients, we performed sequence analysis of the coding regions. The two patients with AT/RT were found to have germline SMARCB1 mutations. No BRAF mutations were found, and only NTRK gene fusion was present in one patient. We also have examined the association with OS and PFS and different histological subtypes of infant CNS proving that high-grade astrocytoma has better overall survival than other tumor types ( p : 0.007 and p : 0.0590). Conclusion: High-dose chemotherapy regimen represents a valid therapeutic approach for congenital brain tumors with a high rate of response. The molecular analysis has to be analyzed in all infants' brain tumor types. High-grade gliomas are characterized by a better prognosis than other histologies of infant CNS., (Copyright © 2020 Guidi, Giunti, Buccoliero, Santi, Spacca, De Masi, Genitori and Sardi.)
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- 2020
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46. Infantile inflammatory myofibroblastic tumors: clinicopathological and molecular characterization of 12 cases.
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Lopez-Nunez O, John I, Panasiti RN, Ranganathan S, Santoro L, Grélaud D, Wu T, Buccoliero AM, Casanova M, Alaggio R, and Surrey LF
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- Antineoplastic Agents therapeutic use, Biomarkers, Tumor analysis, Crizotinib therapeutic use, Female, Gene Fusion, Gene Rearrangement, Genetic Predisposition to Disease, Humans, Infant, Infant, Newborn, Italy, Kinesins, Male, Myofibroblasts drug effects, Myofibroblasts enzymology, Neoplasms, Muscle Tissue drug therapy, Neoplasms, Muscle Tissue enzymology, Phenotype, Philadelphia, Protein Kinase Inhibitors therapeutic use, Registries, Soft Tissue Neoplasms drug therapy, Soft Tissue Neoplasms enzymology, Biomarkers, Tumor genetics, Myofibroblasts pathology, Neoplasms, Muscle Tissue genetics, Neoplasms, Muscle Tissue pathology, Soft Tissue Neoplasms genetics, Soft Tissue Neoplasms pathology
- Abstract
Inflammatory myofibroblastic tumors arising in infants are rare, poorly investigated and mostly reported as isolated cases or as a part of larger series thus, their clinicopathological and molecular features are essentially unknown. Archival files from two large pediatric institutions and a tumor registry were queried for pediatric inflammatory myofibroblastic tumors. Available material from patients ≤12 months of age was reviewed. Additional immunostains (ALK-1, D240, WT1) and ALK-FISH studies were performed as needed. Targeted anchored multiplex PCR with next-generation sequencing was done in all cases. A total of 12 of 131 infantile cases (mean 5.5 months) were identified (M:F of 2:1). Anatomic locations included intestinal/mesenteric (n = 6), head/neck (n = 3), and viscera (n = 3). Half of tumors showed a hypocellular myxoid pattern, perivascular condensation, and prominent vasculature with vague glomeruloid structures present in four of them. The remaining cases exhibited a more cellular pattern with minimal myxoid component. ALK-1 immunohistochemistry was positive in most cases (11/12) with cytoplasmic-diffuse (n = 6), cytoplasmic-granular (n = 2), and dot-like (n = 3) staining patterns. ALK fusion partners identified in five cases included EML4, TPM4, RANBP2, and a novel KLC1. Three inflammatory myofibroblastic tumors showed fusions with other kinases including TFG-ROS1 and novel FN1-ROS1 and RBPMS-NTRK3 rearrangements. Favorable outcome was documented in most cases (10/11) with available follow-up (median 17 months) while three patients were successfully treated with crizotinib. In summary, infantile inflammatory myofibroblastic tumors are rare and can exhibit paucicellular, extensively myxoid/vascular morphology with peculiar immunophenotype mimicking other mesenchymal or vascular lesions. All tumors harbored kinase fusions involving ALK, ROS1, and NTRK3 including three novel fusion partners (KLC1, FN1, and RBPMS, respectively). A favorable response to crizotinib seen in three cases supports its potential use in infants as seen in older patients. Awareness of these unusual morphologic, immunophenotypic, and molecular features is critical for appropriate diagnosis and optimized targeted therapy.
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- 2020
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47. Transcriptional profiling of medulloblastoma with extensive nodularity (MBEN) reveals two clinically relevant tumor subsets with VSNL1 as potent prognostic marker.
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Korshunov A, Okonechnikov K, Sahm F, Ryzhova M, Stichel D, Schrimpf D, Ghasemi DR, Pajtler KW, Antonelli M, Donofrio V, Mastronuzzi A, Rossi S, Camassei FD, Buccoliero AM, Haberler C, Slavc I, Dahiya S, Casalini B, Sievers P, Meyer J, Kumirova E, Zheludkova O, Golanov A, Jones DTW, Pfister SM, Kool M, and von Deimling A
- Subjects
- Adolescent, Cerebellar Neoplasms pathology, Child, Child, Preschool, Female, Gene Expression Profiling, Humans, Infant, Infant, Newborn, Male, Medulloblastoma pathology, Prognosis, Transcriptome, Biomarkers, Tumor metabolism, Cerebellar Neoplasms genetics, Medulloblastoma genetics, Neurocalcin metabolism
- Abstract
Medulloblastoma with extensive nodularity (MBEN) is one of the few central nervous system (CNS) tumor entities occurring in infants which is traditionally associated with good to excellent prognosis. Some MBEN, however, have been reported with an unfavorable clinical course. We performed an integrated DNA/RNA-based molecular analysis of a multi-institutional MBEN cohort (n = 41) to identify molecular events which might be responsible for variability in patients' clinical outcomes. RNA sequencing analysis of this MBEN cohort disclosed two clear transcriptome clusters (TCL) of these CNS tumors: "TCL1 MBEN" and "TCL2 MBEN" which were associated with various gene expression signatures, mutational landscapes and, importantly, prognosis. Thus, the clinically unfavorable "TCL1 MBEN" subset revealed transcriptome signatures composed of cancer-associated signaling pathways and disclosed a high frequency of clinically relevant germline PTCH1/SUFU alterations. In contrast, gene expression profiles of tumors from the clinically favorable "TCL2 MBEN" subgroup were associated with activation of various neurometabolic and neurotransmission signaling pathways, and germline SHH-pathway gene mutations were extremely rare in this transcriptome cluster. "TCL2 MBEN" also revealed strong and ubiquitous expression of VSNL1 (visinin-like protein 1) both at the mRNA and protein level, which was correlated with a favorable clinical course. Thus, combining mutational and epigenetic profiling with transcriptome analysis including VSNL1 immunohistochemistry, MBEN patients could be stratified into clinical risk groups of potential value for subsequent treatment planning.
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- 2020
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48. Extraskeletal Chondroma: A Rare Cause of Trigger Finger in Children.
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Salvatori G, Abati CN, Bettuzzi C, Buccoliero AM, Caporalini C, Zanardi A, and Lampasi M
- Abstract
Introduction: Trigger finger is ten times less common than trigger thumb in infants and children and, unlike trigger thumb, may arise from a variety of underlying causes. To our knowledge, we describe the first case of pediatric trigger finger secondary to an extraskeletal chondroma., Case Presentation: We report the case of an 11-year-old girl presenting with a typical history of triggering of the fourth finger, in whom a nodule attached to the flexor digitorum superficialis was found; clinical, ultrasound, and operative findings are described. Histological analysis was diagnostic of extraskeletal chondroma, also known as chondroma of soft tissues., Conclusion: This is a very uncommon benign cartilaginous tumor, mostly reported in patients aged 30 to 60 years (just one pediatric extraskeletal chondroma of the hand has been described), and presentation with trigger finger has been reported just once, in a 76-year-old man. This condition should be considered in the differential diagnosis of pediatric trigger finger., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2020 Giada Salvatori et al.)
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- 2020
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49. β3-adrenoreceptor blockade reduces tumor growth and increases neuronal differentiation in neuroblastoma via SK2/S1P 2 modulation.
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Bruno G, Cencetti F, Pini A, Tondo A, Cuzzubbo D, Fontani F, Strinna V, Buccoliero AM, Casazza G, Donati C, Filippi L, Bruni P, Favre C, and Calvani M
- Subjects
- Animals, Carcinogenesis drug effects, Carcinogenesis genetics, Cell Differentiation drug effects, Cell Proliferation drug effects, Gene Expression Regulation, Neoplastic drug effects, Heterografts, Humans, Lysophospholipids metabolism, Mice, Neuroblastoma genetics, Neuroblastoma pathology, Neurons drug effects, Propanolamines pharmacology, Signal Transduction drug effects, Sphingosine analogs & derivatives, Sphingosine metabolism, Tumor Hypoxia drug effects, Adrenergic beta-3 Receptor Antagonists pharmacology, Neuroblastoma drug therapy, Receptors, Adrenergic, beta-3 genetics, Small-Conductance Calcium-Activated Potassium Channels genetics, Sphingosine-1-Phosphate Receptors genetics
- Abstract
Neuroblastoma (NB) is the most frequently observed among extracranial pediatric solid tumors. It displays an extreme clinical heterogeneity, in particular for the presentation at diagnosis and response to treatment, often depending on cancer cell differentiation/stemness. The frequent presence of elevated hematic and urinary levels of catecholamines in patients affected by NB suggests that the dissection of adrenergic system is crucial for a better understanding of this cancer. β3-adrenoreceptor (β3-AR) is the last identified member of adrenergic receptors, involved in different tumor conditions, such as melanoma. Multiple studies have shown that the dysregulation of the bioactive lipid sphingosine 1-phosphate (S1P) metabolism and signaling is involved in many pathological diseases including cancer. However, whether S1P is crucial for NB progression and aggressiveness is still under investigation. Here we provide experimental evidence that β3-AR is expressed in NB, both human specimens and cell lines, where it is critically involved in the activation of proliferation and the regulation between stemness/differentiation, via its functional cross-talk with sphingosine kinase 2 (SK2)/S1P receptor 2 (S1P
2 ) axis. The specific antagonism of β3-AR by SR59230A inhibits NB growth and tumor progression, by switching from stemness to cell differentiation both in vivo and in vitro through the specific blockade of SK2/S1P2 signaling.- Published
- 2020
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50. The coding and non-coding transcriptional landscape of subependymal giant cell astrocytomas.
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Bongaarts A, van Scheppingen J, Korotkov A, Mijnsbergen C, Anink JJ, Jansen FE, Spliet WGM, den Dunnen WFA, Gruber VE, Scholl T, Samueli S, Hainfellner JA, Feucht M, Kotulska K, Jozwiak S, Grajkowska W, Buccoliero AM, Caporalini C, Giordano F, Genitori L, Coras R, Blümcke I, Krsek P, Zamecnik J, Meijer L, Scicluna BP, Schouten-van Meeteren AYN, Mühlebner A, Mills JD, and Aronica E
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Adolescent, Adult, Astrocytes drug effects, Astrocytes metabolism, Astrocytoma etiology, Astrocytoma metabolism, Brain Neoplasms complications, Brain Neoplasms metabolism, Butadienes pharmacology, Child, Child, Preschool, Enzyme Inhibitors pharmacology, Extracellular Signal-Regulated MAP Kinases antagonists & inhibitors, Extracellular Signal-Regulated MAP Kinases metabolism, Female, Gene Expression Profiling, Guanine Nucleotide Exchange Factors genetics, Guanine Nucleotide Exchange Factors metabolism, High-Throughput Nucleotide Sequencing, Humans, Infant, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Male, Mechanistic Target of Rapamycin Complex 1, Nitriles pharmacology, RNA-Seq, Sequence Analysis, RNA, Tuberous Sclerosis complications, Tuberous Sclerosis Complex 1 Protein genetics, Tuberous Sclerosis Complex 2 Protein genetics, Tumor Cells, Cultured, Young Adult, Astrocytoma genetics, Brain Neoplasms genetics, Extracellular Signal-Regulated MAP Kinases genetics, MAP Kinase Signaling System genetics, MicroRNAs metabolism, RNA, Messenger metabolism, Tuberous Sclerosis genetics
- Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited neurocutaneous disorder caused by inactivating mutations in TSC1 or TSC2, key regulators of the mechanistic target of rapamycin complex 1 (mTORC1) pathway. In the CNS, TSC is characterized by cortical tubers, subependymal nodules and subependymal giant cell astrocytomas (SEGAs). SEGAs may lead to impaired circulation of CSF resulting in hydrocephalus and raised intracranial pressure in patients with TSC. Currently, surgical resection and mTORC1 inhibitors are the recommended treatment options for patients with SEGA. In the present study, high-throughput RNA-sequencing (SEGAs n = 19, periventricular control n = 8) was used in combination with computational approaches to unravel the complexity of SEGA development. We identified 9400 mRNAs and 94 microRNAs differentially expressed in SEGAs compared to control tissue. The SEGA transcriptome profile was enriched for the mitogen-activated protein kinase (MAPK) pathway, a major regulator of cell proliferation and survival. Analysis at the protein level confirmed that extracellular signal-regulated kinase (ERK) is activated in SEGAs. Subsequently, the inhibition of ERK independently of mTORC1 blockade decreased efficiently the proliferation of primary patient-derived SEGA cultures. Furthermore, we found that LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5 were overexpressed at both gene and protein levels in SEGA compared to control tissue. Taken together LAMTOR1-5 can form a complex, known as the 'Ragulator' complex, which is known to activate both mTORC1 and MAPK/ERK pathways. Overall, this study shows that the MAPK/ERK pathway could be used as a target for treatment independent of, or in combination with mTORC1 inhibitors for TSC patients. Moreover, our study provides initial evidence of a possible link between the constitutive activated mTORC1 pathway and a secondary driver pathway of tumour growth., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.)
- Published
- 2020
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