Ash Singhal

Personalizing the treatment of pediatric medulloblastoma: Polo-like kinase 1 as a molecular target in high-risk children.

Medulloblastoma is the most common malignant brain tumor in children. This disease is heterogeneous and is composed of four subtypes of medulloblastoma [WNT, Sonic Hedgehog (SHH), Group 3, and Group 4]. An immediate goal is to identify novel molecular targets for the most aggressive forms of medulloblastoma. Polo-like kinase 1 (PLK1) is an oncogenic kinase that controls cell cycle and proliferation, making it a strong candidate for medulloblastoma treatment. In this study, pediatric medulloblastomas were subtyped in two patient cohorts (discovery cohort, n = 63 patients; validation cohort, n = 57 patients) using NanoString nCounter analysis and PLK1 mRNA was assessed. We determined that the SHH and Group 3 subtypes were independently associated with poor outcomes in children as was PLK1 using Cox regression analyses. Furthermore, we screened a library of 129 compounds in clinical trials using a model of pediatric medulloblastoma and determined that PLK1 inhibitors were the most promising class of agents against the growth of medulloblastoma. In patient-derived primary medulloblastoma isolates, the PLK1 small-molecule inhibitor BI2536 suppressed the self-renewal of cells with high PLK1 but not low PLK1 expression. PLK1 inhibition prevented medulloblastoma cell proliferation, self-renewal, cell-cycle progression, and induced apoptosis. In contrast, the growth of normal neural stem cells was unaffected by BI2536. Finally, BI2536 extended survival in medulloblastoma-bearing mice with efficacy comparable with Headstart, a standard-of-care chemotherapy regimen. We conclude that patients with medulloblastoma expressing high levels of PLK1 are at elevated risk. These preclinical studies pave the way for improving the treatment of medulloblastoma through PLK1 inhibition.

Polo‐Like Kinase 1 Inhibition Kills Glioblastoma Multiforme Brain Tumor Cells in Part Through Loss of SOX2 and Delays Tumor Progression in Mice

Glioblastoma multiforme (GBM) ranks among the deadliest types of cancer and given these new therapies are urgently needed. To identify molecular targets, we queried a microarray profiling 467 human GBMs and discovered that polo‐like kinase 1 (PLK1) was highly expressed in these tumors and that it clustered with the proliferative subtype. Patients with PLK1‐high tumors were more likely to die from their disease suggesting that current therapies are inactive against such tumors. This prompted us to examine its expression in brain tumor initiating cells (BTICs) given their association with treatment failure. BTICs isolated from patients expressed 110‐470 times more PLK1 than normal human astrocytes. Moreover, BTICs rely on PLK1 for survival because the PLK1 inhibitor BI2536 inhibited their growth in tumorsphere cultures. PLK1 inhibition suppressed growth, caused G2/M arrest, induced apoptosis, and reduced the expression of SOX2, a marker of neural stem cells, in SF188 cells. Consistent with SOX2 inhibition, the loss of PLK1 activity caused the cells to differentiate based on elevated levels of glial fibrillary acidic protein and changes in cellular morphology. We then knocked glial fibrillary acidic protein (GFAP) down SOX2 with siRNA and showed that it too inhibited cell growth and induced cell death. Likewise, in U251 cells, PLK1 inhibition suppressed cell growth, downregulated SOX2, and induced cell death. Furthermore, BI2536 delayed tumor growth of U251 cells in an orthotopic brain tumor model, demonstrating that the drug is active against GBM. In conclusion, PLK1 level is elevated in GBM and its inhibition restricts the growth of brain cancer cells. STEM CELLS2012;30:1064–1075

Third ventricular shape: a predictor of endoscopic third ventriculostomy success in pediatric patients

OBJECT The criteria for identifying patients in whom endoscopic third ventriculostomy (ETV) provides control of hydrocephalus remain in evolution. In particular, it is not clear when ETV would be effective if intraventricular obstruction is not found preoperatively. The authors postulated that 1) displacement of the third ventricle floor inferiorly into the interpeduncular cistern and displacement of the lamina terminalis anteriorly into the lamina terminalis cistern could predict clinical success of ETV, and 2) improvement in these displacements would correlate with the success of ETV. METHODS Magnetic resonance imaging in 38 consecutive patients treated between 2004 and 2010 was reviewed to assess displacement of the lamina terminalis and third ventricular floor prior to and following ETV. Displacements of the floor and lamina terminalis were judged qualitatively and quantitatively, using a newly created index, the Third Ventricular Morphology Index (TVMI). The association between the aforementioned morphological features and clinical success of ETV was analyzed. RESULTS Ninety-six percent of patients in whom the authors preoperatively observed displacement of the lamina terminalis and the third ventricular floor were successfully treated with ETV. Displacements of the third ventricular floor and lamina terminalis, as judged qualitatively, correlated with the clinical success of ETV. The TVMI correlated with the qualitative assessments of displacement. Postoperative decrease in the TVMI occurred in the majority of successfully treated patients. Changes in third ventricular morphology preceded changes in other measures of third and lateral ventricular volume following ETV. CONCLUSIONS Assessment of third ventricular floor and lamina terminalis morphology is useful in predicting clinical success of ETV and in the follow-up in treated patients. The TVMI provided a quantitative assessment of the third ventricular morphology, which may be useful in equivocal cases and in research studies.

Natural history of untreated syringomyelia in pediatric patients

OBJECT The natural history of syringomyelia in pediatric patients remains uncertain. Although symptomatic and operative cases of syringomyelia are well studied, there are fewer articles in the literature on the nonoperative syrinx and its clinical and radiological course. The purpose of this research was to analyze the natural history of untreated syringomyelia in pediatric patients presenting with minimal neurological symptoms. METHODS A review of the neurosurgery database at British Columbias Childrens Hospital identified all pediatric patients (< 18 years of age) with syringes identified on MR imaging. Patients were included in this study if they had at least 2 MR images of the spine, at least 1 year apart, while receiving nonoperative treatment. Magnetic resonance imaging was used to determine changes in the size of the syrinx over time. Clinic notes were analyzed to establish demographic and clinical features and to determine any clinical changes over time. RESULTS A total of 17 patients were included in the study. Symptoms at presentation were often mild and included limb numbness (3 cases), headaches (2 cases), mild sensory deficits (2 cases), mild motor deficits (3 cases), and intermittent incontinence (7 cases). The consultant neurosurgeon believed that the syrinx was not contributing to the symptoms in these 17 patients. The syrinx either remained unchanged (7 cases) or diminished in size (8 cases) in a total of 15 patients (88%). In the remaining 2 patients the authors noted an increase in syrinx size, in 1 of whom the clinical course also worsened. Both of these patients had a Chiari malformation and subsequently underwent craniocervical decompression. Overall, the mean change was -0.7 mm of maximal axial diameter (range -2.6 to +2.7 mm). Sixteen patients (94%) exhibited no worsening of symptoms over time. CONCLUSIONS Syringomyelia often remains stable in patients receiving nonoperative treatment. However, given that 2 (12%) of 17 syringes in this series enlarged, it is likely appropriate to include periodic imaging in the follow-up of these cases.

Possible differentiation of cerebral glioblastoma into pleomorphic xanthoastrocytoma: an unusual case in an infant

The authors describe an infant girl who, at 10 months of age, presented with a large right parietooccipital tumor causing increased intracranial pressure, mass effect, and midline shift. The tumor was completely resected, and the entirety of the histology was consistent with glioblastoma. She was subsequently placed on adjuvant high-dose chemotherapy consisting of carboplatin, vincristine, and temozolomide, according to Head Start III, Regimen C. Three months after the complete resection, tumor recurrence was noted on MR imaging, during the third cycle of chemotherapy, and biopsy revealed malignant astrocytoma. Given the recurrence and the patients intolerance to chemotherapy, a palliative course was pursued. Unexpectedly, the patient was alive and had made significant developmental improvements 18 months into palliation. Subsequently, however, signs of increased intracranial pressure developed and imaging demonstrated a very large new tumor growth at the site of prior resection. The recurrence was again fully resected, but microscopy surprisingly revealed pleomorphic xanthoastrocytoma throughout. The clinicopathological and genetic features of this girls unusual neoplasm are detailed and potential pathogenic hypotheses are explored in this report.

Consensus definitions of complications for accurate recording and comparisons of surgical outcomes in pediatric neurosurgery.

OBJECT Monitoring and recording of complications in pediatric neurosurgery are important for quality assurance and in particular for improving outcomes. Lack of accurate or mutually agreed upon definitions hampers this process and makes comparisons between centers, which is an important method to improve outcomes, difficult. Therefore, the Canadian Pediatric Neurosurgery Study Group created definitions of complications in pediatric neurosurgery with consensus among 13 Canadian pediatric neurosurgical centers. METHODS Definitions of complications were extracted from randomized trials, prospective data collection studies, and the medical literature. The definitions were presented at an annual meeting and were subsequently recirculated for anonymous comment and revision, assembled by a third party, and re-presented to the group for consensus. RESULTS Widely used definitions of shunt failure were extracted from previous randomized trials and prospective studies. Definitions for wound infections were extracted from the definitions from the Centers for Disease Control and Prevention. Postoperative neurological deficits were based on the Pediatric Stroke Outcome Measure. Other definitions were created and modified by consensus. These definitions are now currently in use across the Canadian Pediatric Neurosurgery Study Group centers in Morbidity and Mortality data collection and for subsequent comparison studies. CONCLUSIONS Coming up with consensus definitions of complications in pediatric neurosurgery is a first step in improving the quality of outcomes. It is a dynamic process, and further refinements are anticipated. Center to center comparison will hopefully allow significant variations in outcomes to be identified and acted upon.

Conventional and Diffusion-Weighted Magnetic Resonance Imaging Findings in a Pediatric Patient with a Posterior Fossa Brain Tumor and Papilledema

We present a case report of a 21-month-old female patient to highlight magnetic resonance (MR) imaging findings associated with papilledema in a pediatric patient with an intracranial tumor. The MR findings included optic disc elevation, dilated perioptic subarachnoid spaces, optic nerve tortuosity and restricted diffusion in the optic nerve heads, all of which resolved upon resolution of raised intracranial pressure (ICP) and papilledema. The case demonstrates that both conventional and diffusion-weighted MR imaging findings can detect the presence, and follow posttreatment resolution, of increased ICP and papilledema in a pediatric tumor patient. The postoperative resolution of optic disc elevation clearly indicates the intracranial tumor etiology.

Intracystic interferon-α treatment leads to neurotoxicity in craniopharyngioma: case report.

Craniopharyngioma is a benign, cystic suprasellar tumor that can be treated with intracystic chemotherapy. Interferon-α (IFN-α) has been gaining popularity as an intracystic treatment for craniopharyngioma because of its efficacy and supposed benign neurotoxicity profile. In this case report the authors describe a patient who, while receiving intracystic IFN-α, suffered a neurological event, which was believed to be related to drug leakage outside the cyst. This is the first report of a focal neurological deficit potentially attributable to intracystic IFN-α therapy, highlighting the fact that IFN-α may have neurotoxic effects on the central nervous system. Given this case and the results of a literature review, the authors suggest that a positive leak test is a relative contraindication to intracystic IFN-α treatment.

Manifestations of Tuberous Sclerosis Complex: The Experience of a Provincial Clinic.

BACKGROUND Tuberous sclerosis complex (TSC) is a neurocutaneous disorder with a wide spectrum of manifestations. Recent consensus recommendations stress the importance of multidisciplinary management of children with TSC. The objective of this study was to examine the manifestations of TSC at a large referral centre to determine the care needs of this population. METHODS A retrospective, systematic chart review was performed of children with TSC managed at British Columbia Childrens Hospital. Patients were identified through epilepsy and clinical neurophysiology databases. RESULTS The study population comprised 81 patients, born between 1987 and 2014, who were a median of 10 years (range, 0.2-23.2) at most recent follow-up. Epilepsy occurred in 91% of patients, including 32% with a history of infantile spasms. Nineteen patients underwent epilepsy surgery, nine (47%) of whom were seizure-free at most recent follow-up. Overall, 61% of epilepsy patients had been seizure-free for at least 1 year at the time of last follow-up. Neuropsychiatric disorders were diagnosed in 49% of children, with autism (25%), attention deficit hyperactivity order (19%) and anxiety (16%) being the most common. Cardiac rhabdomyomata occurred in 35% of children and renal angiomyolipomas were seen in 43%. A total of 91% had skin manifestations. CONCLUSION This study outlines the multisystem manifestations of TSC, observed through a large pediatric referral center. Epilepsy and neuropsychiatric disorders are the major source of morbidity in this age group and provide many challenges to the treating clinician. Because a subset of the study population is still quite young, the prevalence of neuropsychiatric disorders is likely underestimated.

Regression of ventriculomegaly following medical management of a patient with Hurler syndrome

Hurler syndrome is the most severe form of mucopolysaccharidosis (MPS) Type 1. Progressive neurocognitive decline in this condition can be accompanied by macrocephaly, ventriculomegaly, and/or periventricular signal changes on MRI, which often leads to a neurosurgical referral. In this case, the authors describe a 2-year-old boy with ventriculomegaly and periventricular T2 signal changes, both of which decreased following medical management of Hurler syndrome. The authors discuss the possible mechanisms for this finding and the implications for neurosurgical treatment of this condition.