Robert J. Bollo

The transcriptional network for mesenchymal transformation of brain tumours

The inference of transcriptional networks that regulate transitions into physiological or pathological cellular states remains a central challenge in systems biology. A mesenchymal phenotype is the hallmark of tumour aggressiveness in human malignant glioma, but the regulatory programs responsible for implementing the associated molecular signature are largely unknown. Here we show that reverse-engineering and an unbiased interrogation of a glioma-specific regulatory network reveal the transcriptional module that activates expression of mesenchymal genes in malignant glioma. Two transcription factors (C/EBPβ and STAT3) emerge as synergistic initiators and master regulators of mesenchymal transformation. Ectopic co-expression of C/EBPβ and STAT3 reprograms neural stem cells along the aberrant mesenchymal lineage, whereas elimination of the two factors in glioma cells leads to collapse of the mesenchymal signature and reduces tumour aggressiveness. In human glioma, expression of C/EBPβ and STAT3 correlates with mesenchymal differentiation and predicts poor clinical outcome. These results show that the activation of a small regulatory module is necessary and sufficient to initiate and maintain an aberrant phenotypic state in cancer cells.

Epilepsy surgery and tuberous sclerosis complex: special considerations

Epilepsy surgery for medically refractory seizures among patients with tuberous sclerosis complex (TSC) is a well-accepted treatment option. Many epilepsy centers around the world have published their experience over the past several years, supporting the idea that the best seizure control is obtained when a single tuber and associated epileptogenic zone is documented and targeted surgically. Recent advances in imaging and physiological techniques that reveal the epileptogenic zone have been used successfully in children with TSC who are being evaluated for surgery. As a result, a number of different surgical strategies have emerged, each reflecting the experience, strengths, and referral biases of the individual treating teams. Experience suggests that some patients with TSC who present with seizures that are difficult to localize and do not meet the classic selection criteria for epilepsy surgery may, nevertheless, benefit from surgery. Tuberectomy alone is often not sufficient for obtaining seizure control. Intracranial electrode recordings performed in a large number of children with TSC undergoing epilepsy surgery have raised new questions about the relationship of the cortical tuber to the epileptogenic zone in TSC. A careful assessment of the risks and benefits of any surgical strategy, compared with those associated with continued refractory epilepsy, should be considered by the treating team in conjunction with the patients family. Epilepsy surgery has not only benefited many children with TSC, but it also facilitates the understanding of epileptogenesis in TSC.

Endoscopic endonasal odontoidectomy in a child with chronic type 3 atlantoaxial rotatory fixation: case report and literature review

IntroductionAlthough the transoral transpharyngeal approach has been the standard approach to decompress the odontoid process, it bears some disadvantages including risk of infection, prolonged intubation or tracheostomy, need for nasogastric tube feeding, extended hospitalization, and possible effects of phonation. The endoscopic transnasal approach is a viable alternative, managing to avoid some of the pitfalls of the more accepted transoral transpharyngeal approach. However, there have only been a handful of adult cases and only three pediatric cases.Case reportWe present the case of a 10-year-old girl with a chronic type 3 atlantoaxial rotator fixation and significant spinal cord compression from basilar invagination and a displaced odontoid process. We performed an endoscopic endonasal odontoidectomy prior to posterior occiptocervical fusion on the patient. She was neurologically intact with a well-healed wound at 7-month follow-up.

Currarino syndrome and spinal dysraphism.

Currarino syndrome is a rare constellation of congenital anomalies characterized by the triad of sacral dysgenesis, presacral mass, and anorectal malformation. It is frequently associated with other congenital anomalies, often including occult spinal dysraphism. Mutations in the MNX1 gene are identified in the majority of cases. The authors report a rare case of Currarino syndrome in an infant with tethered cord syndrome and a dorsal lipomyelomeningocele continuous with a presacral intradural spinal lipoma, in addition to an imperforate anus and a scimitar sacrum. They review the literature to highlight patterns of occult spinal dysraphism in patients with Currarino syndrome and their relationship to tethered cord syndrome. Approximately 60% of the patients with Currarino syndrome reported in the literature have an occult spinal dysraphism. Published studies suggest that the risk of tethered cord syndrome may be higher among patients with a lipoma and lower among those with a teratoma or anterior meningocele.

Spinal arteriovenous fistulas in children with hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant angiodysplasia with high penetrance and variable expression. The manifestations of HHT are often age related, and spinal arteriovenous fistula (AVF) may be the initial presentation of HHT in young children. Because spinal AVFs are rarely reported, however, screening is not incorporated into current clinical recommendations for the treatment of patients with HHT. The authors describe 2 cases of children younger than 2 years of age with acute neurological deterioration in the context of a spinal AVF and in whom HHT was subsequently diagnosed. One patient presented with intraventricular and subarachnoid hemorrhage and the other with acute thrombosis of an intramedullary varix. These cases highlight the potential for significant neurological morbidity from a symptomatic AVF in very young children with HHT. Given the lack of data regarding the true incidence and natural history of these lesions, these cases raise the question of whether spinal cord imaging should be incorporated into screening recommendations for patients with HHT.

Extraventricular subependymal giant cell tumor in a child with tuberous sclerosis complex.

Subependymal giant cell tumors (SGCTs) are observed in 5-20% of patients with tuberous sclerosis complex (TSC) but account for approximately 25% of neurological morbidity. The authors report the case of a 7-year-old girl with TSC and multiple cortical tubers who presented with worsening seizures in the context of the rapid growth of a cystic, calcified, extraventricular SGCT in the right frontal lobe, initially thought to represent a cortical tuber. The tumor and surrounding tubers were excised, and clinical seizures resolved. This is the first report of an extraventricular SGCT in a child with TSC outside the neonatal period.

Osteosarcoma of the cranial vault and skull base in pediatric patients

Cranial osteosarcoma is very rare in children, rendering the development of optimal treatment algorithms challenging. The authors present 3 cases of pediatric cranial osteosarcoma: a primary calvarial tumor, a cranial metastasis, and a primary osteosarcoma of the cranial base. A review of the literature demonstrates significant variation in the management of cranial osteosarcomas and the outcome for patients with these tumors. This series and literature review is presented to improve the understanding of pediatric cranial osteosarcoma and to reinforce the importance of maximal resection in optimizing outcome.

A Novel Quantitative Method for Evaluating Surgical Outcomes in Craniosynostosis: Pilot Analysis for Metopic Synostosis

Objective assessment of head shape has been an elusive goal in the management of craniosynostosis patients. Clinical judgment, craniometric indices, and computed tomography scans are the primary means through which a surgeon assesses this patient population. The purpose of this study was to examine and discuss the utility of the STARscanner for evaluation of surgical outcomes in metopic synostosis patients. A retrospective chart review of patients with metopic synostosis who underwent fronto-orbital advancement with pre- and postoperative STARscanner imaging at Texas Childrens Hospital was performed. Two patients were identified and evaluation and discussion of the data produced by the STARscanner was undertaken. A novel symmetry index created by the authors, called the anterior–posterior volume ratio (APVR), was discussed for use in metopic synostosis patients. The postoperative growth metrics demonstrated an interval increase compared with the preoperative data. The anterior symmetry ratio, posterior symmetry ratio, overall symmetry ratio, cranial vault volumes, cranial vault asymmetry index, and cephalic ratio were not found to be useful in evaluating resolution of dysmorphology after fronto-orbital advancement in metopic synostosis. The APVR does not characterize dysmorphology, but may help show degree of expansion of the anterior cranial vault after fronto-orbital advancement. The STARscanner imaging device does not appear to have significant utility in characterizing head shape for surgical outcomes assessment in metopic synostosis. The minor utility of this device may be that it is a safe and fast way to derive growth parameters for both short-term and long-term follow-up of cranial vault remodeling.

Stereotactic endoscopic placement of third ventricle catheter for long-term infusion of baclofen in patients with secondary generalized dystonia.

Continuous infusion of baclofen is a treatment option for severe generalized dystonia. Catheter insertion within the third ventricle has been described as an alternative to standard intrathecal placement to maximize intracranial concentrations of baclofen. The authors describe their experience with a novel technique for stereotactic endoscopic insertion of baclofen infusion catheters in the third ventricle in 3 patients with severe secondary generalized dystonia. Insertion was successful in all 3 patients, and all of them experienced significant improvement in dystonia scores on the Barry-Albright Dystonia Scale. Follow-up ranged from 5.5 to 7 months (mean 6 months), and no mechanical complications or CSF leaks were observed. The stereotactic endoscopic insertion of a baclofen infusion catheter into the third ventricle appears to be a safe method for continuous intraventricular baclofen infusion in patients with generalized secondary dystonia.

Resting-State Functional MRI in Pediatric Epilepsy Surgery

Resting-state functional MRI (rs-fMRI) identifies resting-state networks (RSN) in the human brain by analyzing the connectivity of anatomically remote neuronal populations with synchronous low-frequency fluctuation in blood oxygen level-dependent (BOLD) signal. Network analysis has informed the understanding of functional brain organization and is beginning to reveal the impact that neurological disorders such as epilepsy may have on the developing cerebral cortex. Among children undergoing epilepsy surgery, mapping the brain networks supporting language, sensorimotor and visual function is a critical part of the preoperative evaluation. However, task-based functional mapping techniques are particularly difficult in immature patients and those with severe impairment. Functional mapping of RSN is a promising tool that may help circumvent the challenges of adequate cooperation and limited abilities of developmentally disabled children to perform age-appropriate functions. We discuss the current methodology of rs-fMRI in the pediatric population, review the literature of rs-fMRI in pediatric epilepsy and present our experience of using rs-fMRI for functional network mapping in children undergoing epilepsy surgery.