Paul Kongkham

Epigenomic alterations define lethal CIMP-positive ependymomas of infancy.

Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.

Complications in 622 Cases of Frame-Based Stereotactic Biopsy, a Decreasing Procedure

BACKGROUND Frame-based stereotactic brain biopsy has played an important role in the management of patients with suspected neoplastic intracranial lesions over the last three decades. We reviewed the surgical experience of one surgeon to determine the nature and frequency of complications associated with this procedure. METHODS Records were reviewed for 858 patients undergoing frame-based stereotactic procedures from January 1986 to May 2006. Data on each case were prospectively collected by the senior author. Procedures for Ommaya reservoir placement, brachytherapy, stereotactic craniotomy flap localization, shunt placement, or treatment of previously-diagnosed intracranial cystic lesions were excluded, leaving 614 patients in whom a total of 622 procedures were performed for purely diagnostic purposes. Complication rates and their association with clinical variables were sought. RESULTS Morbidity and mortality rates were 6.9% (43/622) and 1.3% (8/622), respectively. The risk of symptomatic hemorrhage (intracerebral hemorrhage [ICH], subarachnoid hemorrhage [SAH], intraventricular hemorrhage [IVH]) was 4.8%. The risks of transient or permanent neurological deficits were 2.9% (18/622) and 1.5% (9/622), respectively. Biopsy of deep-seated lesions was associated with increased overall complication rate, while biopsy of Glioblastoma Multiforme (GBM) was associated with perioperative mortality. CONCLUSIONS Overall, complication rates were comparable with those in previous reports. The subgroup of patients with deep-seated lesions or a histologic diagnosis of GBM may possess an elevated risk of overall complications or mortality, respectively, compared to other patients undergoing frame-based stereotactic brain biopsy.

The role of the membrane cytoskeleton cross-linker ezrin in medulloblastoma cells

Medulloblastoma is a highly malignant brain tumor that occurs predominantly in children. The molecular pathogenesis of medulloblastoma is under investigation. Previously, we used complementary DNA microarray analysis to compare patterns of gene expression in medulloblastoma samples versus normal cerebellum. The cytoskeletal protein ezrin was found to be overexpressed in medulloblastoma compared with normal cerebellum, an observation that was further validated by immunohistochemistry and real-time PCR analysis. To assess the role of ezrin in medulloblastoma, we studied ezrins role in medulloblastoma migration, invasion, and adhesion. Western blotting and immunofluorescence showed high expression of ezrin in four medulloblastoma cell lines, and ezrin was primarily localized to filopodia. Ezrin-specific small interfering RNA suppressed the formation of filopodia and in vitro migration, invasion, and adhesion. We also used a stably transfected medulloblastoma cell line to study the effect of ezrin overexpression. We showed that high expression of ezrin promotes filopodia formation and in vitro invasion. Finally, athymic mice implanted with ezrin-overexpressing DAOY medullo-blastoma cell clones in the cerebellum showed shortened survival compared with controls. These findings suggest that, in addition to other cytoskeletal proteins, ezrin plays an important role in medulloblastoma adhesion, migration, and invasion.

Mystery Case: Tanycytic ependymoma of the conus medullaris A rare cause of low back pain

A 25-year-old woman presented to the emergency department with low back pain radiating to the anterior aspect of both thighs, progressively worsening over 6 months. Her neurologic examination was unremarkable. MRI of the lumbar spine revealed an intradural extramedullary lesion located in the region of the conus medullaris (figure 1, A–D). The patient underwent bilateral T12 and L1 laminectomies and partial bilateral T11 laminectomy for resection of the intradural extramedullary tumor arising from the filum terminale. Her postoperative period was uneventful. The tumors location and imaging characteristics were suggestive of a myxopapillary ependymoma. However, histopathologic workup ultimately rendered the diagnosis of tanycytic ependymoma, a rare occurrence at this site (figure 2, A–D).1,2 This must be differentiated from schwannoma and astrocytoma due to therapeutic and prognostic implications.

Choroid Plexus Tumors

Choroid plexus tumors (CPTs) are rare, primary brain tumors arising from the neuroepithelium of the choroid plexus. Although they may be found in patients of any age, the vast majority occur in the pediatric population. Up to 70% of these neoplasms occur in children, with over half arising in children under 2 years of age [39]. The annual incidence for CPTs is low, with 0.3 cases/ million reported [23]. Despite this, the annual incidence in the pediatric age group is as high as 3–5%, and up to 12% in those children under 2 years of age [22, 25]. CPTs account for 0.4–0.8% of all brain tumors, between 0.9% and 3% of all primary pediatric brain tumors, and up to 10–20% of pediatric brain tumors during the first year of life [1, 10, 11, 46]. Case reports exist describing in utero findings of CPTs by ultrasound, or of the diagnosis of CPTs in the neonate, suggesting that some of these lesions may occur congenitally [3, 36, 55].

Oculoleptomeningeal Amyloidosis Secondary to the Rare Transthyretin c.381T>G (p.Ile127Met) Mutation

BACKGROUND Oculoleptomeningeal amyloidosis (OLMA) represents a rare subtype of familial transthyretin (TTR) amyloidosis, characterized by deposition of amyloid in cranial and spinal leptomeninges along with ocular involvement. Of >100 TTR mutations identified, few have been associated with OLMA. Herein we describe the first report of leptomeningeal amyloidosis associated with the c.381T>G (p.Ile127Met) TTR mutation, linking this variant to the OLMA phenotype. CASE DESCRIPTION A 53 year-old man presented with a 2-year history of progressive symptoms including upper and lower limb weakness, ataxia, and peripheral and autonomic neuropathy. Neuroimaging, including gadolinium-enhanced magnetic resonance imaging of the brain and spinal axis, identified diffuse leptomeningeal enhancement along the brainstem and spinal cord plus evidence of hemosiderosis. Pathologic and genetic analyses of biopsy material from enhancing intradural extramedullary tissue at the thoracolumbar junction was diagnostic of amyloidosis of a transthyretin type secondary to a TTR c.381T>G (p.Ile127Met) mutation. CONCLUSIONS OLMA represents a rare subtype of heritable transthyretin amyloidosis that may present with progressive neurological decline secondary to central nervous system leptomeningeal amyloid deposition. This case identifies the c.381T>G (p.Ile127Met) TTR mutation variant as being implicated in the OLMA phenotype.

Outcomes following stereotactic radiosurgery for small to medium-sized brain metastases are exceptionally dependent upon tumor size and prescribed dose

BACKGROUND At our institution, we have historically treated brain metastasis (BM) ≤2 cm in eloquent brain with a radiosurgery (SRS) lower prescription dose (PD) to reduce the risk of radionecrosis (RN). We sought to evaluate the impact of this practice on outcomes. METHODS We analyzed a prospective registry of BM patients treated with SRS between 2008 and 2017. Incidences of local failure (LF) and RN were determined and Cox regression was performed for univariate and multivariate analyses (MVAs). RESULTS We evaluated 1533 BM ≤2 cm. Median radiographic follow-up post SRS was 12.7 months (1.4-100). Overall, the 2-year incidence of LF was lower for BM treated with PD ≥21 Gy (9.3%) compared with PD ≤15 Gy (19.5%) (sub-hazard ratio, 2.3; 95% CI: 1.4-3.7; P = 0.0006). The 2-year incidence of RN was not significantly higher for the group treated with PD ≥21 Gy (9.5%) compared with the PD ≤15 Gy group (7.5%) (P = 0.16). MVA demonstrated that PD (≤15 Gy) and tumor size (>1 cm) were significantly correlated (P < 0.05) with higher rates of LF and RN, respectively. For tumors ≤1 cm, when comparing PD ≤15 Gy with ≥21 Gy, the risks of LF and RN are equivalent. However, for lesions >1 cm, PD ≥21 Gy is associated with a lower incidence of LF without significantly increasing the risk of RN. CONCLUSION Our results indicate that rates of LF or RN following SRS for BM are strongly correlated with size and PD. Based on our results, we now, depending upon the clinical context, consider increasing PD to 21 Gy for BM in eloquent brain, excluding the brainstem.

The relationship of study and authorship characteristics on trial sponsorship and self-reported conflicts of interest among neuro-oncology clinical trials

ProposeTo examine the association between trial sponsorship sources, self-reported conflicts of interest (COI), and study and author characteristics in central nervous system (CNS) oncology clinical trials (CT).MethodsMEDLINE search was performed for original CT on “Central Nervous System Neoplasms“[Mesh]. The investigators assessed for relationships between funding source (industry, academic or cooperative, none, not described), COI (presented, none, or not reported), CT, and author characteristics.ResultsFrom 2010 to 2015, 319 CT were considered eligible. The majority of the studies involved primary gliomas (55.2%) and were Phase II CT (59.2%). Drug therapy was investigated in 83.0% of the CT. The remaining studies investigated surgery or radiotherapy. A minority of papers were published in journals with impact factor (IF) higher than > 10 (16%) or in regions other than North America and Europe (20.4%). Overall, 83.1% of studies disclosed funding sources: 32.6% from industry alone, 33.9% from an academic or cooperative group, and 10.7% from a mixed funding model. COI data was reported by 85.9% of trials, of which 56.2% reported no COI and 43.8% reported a related COI. Significant predictors for sponsorship (industry and/or academia) on univariate analysis were study design, type of intervention, journal impact factor, study conclusion, transparency of COI and presence of COI. On multivariate analysis, type of intervention, (P < 0.001), journal impact factor (IF) (P = 0.003), presence of COI (P < 0.001) and study conclusion (P = 0.003) remained significant predictors of sponsorship. For predicting COI, significant variables on univariate analysis were disease type, type of intervention, journal IF, funding source, and intervention arm being related to sponsor. On multivariate analysis, disease type (P = 0.003), journal IF (P < 0.001), type of intervention (P = 0.001), and funding source (P = 0.008) remained significant.ConclusionsThe majority of CNS CT reported some external funding sources and non-related COI. We identified that drug trials, higher IF, presence of COI, and a neutral or negative study conclusion are associated with external funding. Likewise drug trials, higher IF, and glioma trials are associated with presence of COI.

Management and Outcomes in the Oldest-Old Population with Glioblastoma

OBJECTIVES Glioblastoma is a lethal disease in the elderly population. We aimed to evaluate disease and treatment outcomes in the oldest-old patients. METHODS Patients >80 years old with histologically confirmed glioblastoma treated between 2004 and 2009 were identified. We included patients managed with best supportive care (BSC), temozolomide (TMZ) alone, radiotherapy (RT) alone, or concomitantly with TMZ (CRT). Survival outcomes were analyzed using the Kaplan-Meier method. RESULTS Ultimately, 48 patients were analyzed. Median age and Eastern Cooperative Oncology Group (ECOG) Performance Status were 82 years and 2, respectively. The median Age-Adjusted Charlson Index (AAC) was 6. Gross total and subtotal resections were performed in 16.7% and 18.8% of patients, respectively. Biopsy followed by RT alone was the treatment modality for 23/48 (47.9%), while 17/48 (35.4%) received surgery followed by RT alone or CRT. A total of 8 (16.7%) were managed with BSC after biopsy. Median overall survival (OS) and progression-free survival (PFS) were 4.1 (95% confidence interval [95% CI] 3.3-4.9) and 2.7 (95% CI 1.5-3.9) months, respectively. Improved median OS was observed in those treated with surgical resection followed by RT alone or CRT (7.1 months), compared to biopsy followed by RT alone (4.2 months) or BSC (2.0 months; p=0.002). Surgical resection, age≤85, and AAC<6 were associated with better OS (p=0.032, p=0.031, and p=0.02, respectively). Cause of death was neurological progression in 56% of cases. RT was well-tolerated. CONCLUSIONS PFS and OS outcomes remain poor in the oldest-old patients (>80 years old). Younger age, lower AAC, surgical resection, and adjuvant treatment were associated with improved OS.

Neurofibromatosis Clinic: A Report on Patient Demographics and Evaluation of the Clinic.

BACKGROUND Neurofibromatosis type 1 (NF1) is a common single-gene disorder. A multidisciplinary approach to the management of NF1 patients is necessitated by the heterogeneity of clinical manifestations. Although multidisciplinary paediatric clinics have been well established, there is a dearth of such resources for adults with NF1. Herein we report our one-year institutional experience with a multidisciplinary adult NF1 clinic. METHODS A multidisciplinary team was assembled, and an NF Patient Registry Initiative questionnaire was adapted to collect patient-reported data during clinics. Multiple databases were searched to identify publications pertaining to the experience of other multidisciplinary NF1 clinics focusing on adult patients. Data on patient epidemiology and clinical staff were compared to our data. RESULTS A total of 77 patients were scheduled, and 68 attended the clinic, of whom 66 completed the intake questionnaire. The demographic and clinical data from this Canadian population are mostly consistent with previous reports, with some exceptions. Clinical data related to immune system involvement such as asthma, airway/breathing-related difficulties or allergies were striking in our NF1 population. Six relevant published reports of other NF1 clinics were identified. Reports from these studies pertained to periods ranging from 10 to 38 months, and the number of adults assessed ranged from 19 to 177 patients. CONCLUSIONS The structure of our clinic and the patient volume are comparable to those of other established centres found in the literature. Our data offer valuable cross-sectional prevalence statistics in the Canadian population. The patient-reported data concerning involvement of the immune system contribute to an emerging recognized medical concern within the NF1 population and warrant further clinical and basic investigation.