Luca Massimi

Hedgehog controls neural stem cells through p53-independent regulation of Nanog

Hedgehog (Hh) pathway has a pivotal function in development and tumorigenesis, processes sustained by stem cells (SCs). The transcription factor Nanog controls stemness acting as a key determinant of both embryonic SC self‐renewal and differentiated somatic cells reprogramming to pluripotency, in concert with the loss of the oncosuppressor p53. How Nanog is regulated by microenvironmental signals in postnatal SC niches has been poorly investigated. Here, we show that Nanog is highly expressed in SCs from postnatal cerebellum and medulloblastoma, and acts as a critical mediator of Hh‐driven self‐renewal. Indeed, the downstream effectors of Hh activity, Gli1 and Gli2, bind to Nanog‐specific cis‐regulatory sequences both in mouse and human SCs. Loss of p53, a key event promoting cell stemness, activates Hh signalling, thereby contributing to Nanog upregulation. Conversely, Hh downregulates p53 but does not require p53 to control Nanog. Our data reveal a mechanism for the function of Hh in the control of stemness that represents a crucial component of an integrated circuitry determining cell fate decision and involved in the maintenance of cancer SCs.

Radiation-induced brain tumours after central nervous system irradiation in childhood: a review.

ObjectsRadiation-induced cerebral tumours constitute a significant risk for subjects undergoing radiotherapy for the management of cerebral neoplasms. Age-related cerebral vulnerability could be a specific factor in the genesis of these complications.MethodsThe pertinent literature of both paediatric and adult series has been reviewed. Three personal cases were added.ResultsOne hundred forty-two paediatric second brain tumours were evaluated. Out of them, 69 were malignant gliomas, 33 meningiomas, 8 sarcomatous lesions and 13 low-grade astrocytomas. The average latency period for the appearance of the second tumour was 8xa0years. Among the second tumours occurring in adults, meningioma is the most common. In this subgroup, the latency period ranged between 16 and 30xa0years.ConclusionPaediatric radiation-induced brain tumours differ from the adult counterpart for both the histological subtypes. These figures indicate a specific vulnerability of the infantile brain demonstrated by the most frequent occurrence of highly malignant lesions.

ADAR2-editing activity inhibits glioblastoma growth through the modulation of the CDC14B/Skp2/p21/p27 axis.

Grade IV astrocytoma or glioblastoma multiforme (GBM) is one of the most aggressive and lethal tumors affecting humans. ADAR2-mediated A-to-I RNA editing, an essential post-transcriptional modification event in brain, is impaired in GBMs and astrocytoma cell lines. However, the role of ADAR2 editing in astrocytomas remains to be defined. Here, we show that ADAR2 editing rescue in astrocytomas prevents tumor growth in vivo and modulates an important cell cycle pathway involving the Skp2/p21/p27 proteins, often altered in glioblastoma. We demonstrate that ADAR2 deaminase activity is essential to inhibit tumor growth. Indeed, we identify the phosphatase CDC14B, which acts upstream of the Skp2/p21/p27 pathway, as a novel and critical ADAR2 target gene involved in glioblastoma growth. Specifically, ADAR2-mediated editing on CDC14B pre-mRNA increases its expression with a consequent reduction of the Skp2 target protein, as shown both in vitro and in vivo. We found that, compared to normal brain, both CDC14B editing and expression are progressively impaired in astrocytomas from grade I to IV, being very low in GBMs. These findings (1) demonstrate that post-transcriptional A-to-I RNA editing might be crucial for glioblastoma pathogenesis, (2) identify ADAR2-editing enzyme as a novel candidate tumor suppressor gene and (3) provide proof of principle that ADAR2 or its substrates may represent a suitable target(s) for possible novel, more effective and less toxic approaches to the treatment of GBMs.

Video-assisted microsurgical transoral approach to the craniovertebral junction: personal experience in childhood

PurposeThis paper outlines the perspectives of transoral craniosurgery for anterior craniovertebral junction (CVJ) compressive abnormalities in the specific subset of paediatric patients. In particular we analyzed the opportunity for endoscopic video-assisted approach to the CVJ along with neuronavigation for anterior decompression by the transoral approach in paediatric patients.MethodsAmong 30 patients ranging 6–78xa0years undergoing CVJ decompressive procedures, we operated transorally 3 paediatric patients (ranging 11–15xa0years) by using open access, microsurgical technique, neuronavigation, and endoscopy.ResultsThe microscope was the main stone of the transoral procedure; a complete CVJ decompression was accomplished in all the cases by using the 30-degree endoscope that allowed to identify residual compression not clearly visible by using the microscope alone. The use of an angled-lens endoscope can significantly improve the exposure of the clivus without splitting the soft palate.ConclusionsEndoscopically assisted transoral surgery represents an emerging alternative to the standard microsurgical approach to the anterior CVJ. Used in conjunction with traditional microsurgery and intraoperative fluoroscopy, endoscopy provides information for a better decompression with a reduced need for extensive soft-palate splitting, no need for hard-palate resection, or extended maxillotomy. Transoral video-assisted microsurgical approach should be considered the gold standard especially in the paediatric patient.

The role of inflammation in the genesis of the cystic component of craniopharyngiomas

BackgroundCraniopharyngioma accounts for 5–10% of childhood tumors and, despite of the benign histological features, its clinical course can be malignant because of critical anatomical relationships with neural and vascular structures and the possible morbidity associated to resection. Only a few studies have addressed the molecular characterization of the cyst fluid so far and the mechanisms of action of intracystic agents are not clearly understood yet.MethodsThe acidic soluble proteins contained in the cystic fluid of six patients with cystic craniopharyngioma, three of them treated with intratumoral interferon-α, were analyzed. A high performance liquid chromatography electrospray ionization mass spectrometry analysis was performed.FindingsThe antimicrobial peptides α-defensins 1–3 relevant for innate immunity were detected in the cystic fluid before the intratumoral treatment. Amount of peptides significantly decreased in cystic fluid during pharmacological treatment.InterpretationDetection of α-defensins 1–3 excludes that cyst fluid formation can derive from disruption of blood–brain barrier and suggests the involvement of innate immune response in pathology of craniopharyngioma cyst formation. The reduction of α-defensins could derive both from direct antitumoral effect of interferon-α on squamous epithelial cells of craniopharyngioma cyst and from its immuno-modulatory effects on the recruitment of cells of innate immune systems. Interestingly, the clinical patient outcome well correlates with the gradual reduction of α-defensins 1–3 amount. Additional studies will be necessary to establish the role of these molecules in the pathogenesis of craniopharyngioma, and further investigations will be necessary to confirm the efficacy of the antitumoral activity of interferon-α.

5‐YEAR‐OLD BOY WITH A CLIVAL MASS

Epithelioid sarcoma is a rare tumor originating from mesenchymal cells, usually involving the extremities of young adults and is found only sporadically in the head and neck region. Only one case involving the central nervous system has been described so far. We report a 5 year-old boy with a large solid, osteolytic lesion of the clivus with a wide soft tissue component expanding into the intracranial compartment and obliterating the prepontine cistern. Histopathological examination revealed epithelioid neoplastic cells with abundant eosinophilic cytoplasm, rounded nuclei and prominent nucleoli. Areas of geographic necrosis and numerous mitoses were present. Neoplastic cells immunostained for vimentin, cytokeratin, and epithelial membrane antigen (EMA). No immunostaining was observed for glial fibrillary associated protein (GFAP), S-100, PLAP, a-fetoprotein, CD 117, CD 34, CD 31, BAF-47 (INI1). The Ki67 proliferation index exceeded 40%. These histological findings favor a diagnosis of epithelioid sarcoma. This report adds epithelioid sarcoma to the differential diagnosis of both clival tumors and pediatric skull base tumors. Correspondence 526 Brain Pathology 19 (2009) 523–526

Sudden paraplegia in a case of apparently isolated frontal embryonal tumour with abundant neuropil and true rosettes

Abstract The exceptional case of a 19-month-old boy with an apparently isolated frontal lesion and a huge holocord neoplastic involvement, presenting with a subtly indolent preoperative course and a particularly tumultuous evolution, is reported. The diagnosis of embryonal tumour with abundant neuropil and true rosettes was posed.

Mini-invasive surgery for Chiari type I malformation.

Surgical treatment of Chiari I malformation and associated syringomyelia includes several different techniques with various degrees of invasiveness. Most extensive procedures may provide good long-term outcome in a good proportion of cases but are burdened by a quite high risk of postoperative complications. Thirty children operated on by simple bone decompression are retrospectively reviewed to assess the effectiveness of a less invasive technique. The present series comprises 30 children (18 females, 12 males; mean age: 68 months) treated from 1993 to 2005. All patients underwent foramen magnum decompression by means of suboccipital craniectomy and resection of the fibrous band at the level of foramen itself. Twenty-one children also required C1 laminectomy while a dural delamination was performed in 11 cases. The mean current follow-up is 4.3 years (1–12.6 years). Head and/or neck pain was the most frequent preoperative finding (56.7%), followed by upper and lower extremity weakness (20.0%), ataxia (20.0%) and vertigo (27.7%). Syringomyelia was present in 12 patients. A significant improvement of preoperative clinical symptoms and signs was observed in 28 patients (93.3%). Two children required adjunctive surgery. Neuroimaging revealed minor postoperative modifications in most cases regardless of tonsils location, while syringomyelia was reduced in size in 50% of the cases. Complication rate and length of hospital stay were significantly reduced compared with the literature data and our own experience using more invasive techniques. These data, compared with the literature, allow us to conclude that suboccipital craniectomy and Cl laminectomy (possibly integrated by dural delamination) is an effective and safe treatment for symptomatic children with Chiari I malformation and syringomyelia.

12‐YEAR‐OLD BOY WITH MULTIPLE BRAIN MASSES

The occurrence of more than one brain tumor in a single patient is not new, resulting from RT- or CT-induced neoplasms, syndromes or casual association. We report on the exceptional case of a 12-year-old boy harboring three different brain tumors with no definite correlation. The first MRI showed a medulloblastoma with signs of infratentorial and supratentorial tumor spreading, including a small frontal mass. Despite the good response to surgical and adjuvant treatment, the frontal mass remained unchanged and was excised, revealing a lipoastrocytoma. Finally, the possible local recurrence of the original medulloblastoma was a pilocytic astrocytoma with post-radiation alterations. Explanations of this very unusual association include radio-induced tumors, second tumors developing from remnants of medulloblastoma cancer stem cells, or the changing histology after adjuvant therapy.