Giant Cell Astrocytoma Research Articles

Diabetes in Individuals With Tuberous Sclerosis Complex Treated With mTOR Inhibitors

BackgroundTuberous sclerosis complex (TSC) is a genetic disorder that is manifested in multiple body systems. A mammalian target of rapamycin (mTOR) inhibitor (mTORi), either everolimus or sirolimus, is now routinely prescribed for multiple clinical manifestations of TSC, including subependymal giant cell astrocytoma and epilepsy. These medications are generally well tolerated. Side effects previously identified in well-designed clinical trials tend to be mild and readily manageable. Regulatory approvals for the treatment of TSC have expanded the use of everolimus and sirolimus clinically, enlarging clinician experience and enabling identification of potential treatment-related effects that are rarer than could be identified or recognized in previous clinical trials. MethodsThe medical records of clinical patients from our TSC center who were treated with an mTORi and later developed diabetes mellitus (DM) were analyzed and compared with those who were not treated with an mTORi. Eight individuals received detailed analysis, including laboratory results, concomitant medications, and body mass indices. ResultsAmong the 1576 individuals with TSC, 4% taking an mTORi developed diabetes compared with 0.6% of those not on mTORi, showing a significant interaction between DM and mTORi (chi-square = 18.1, P < 0.001). Details of eight patients who developed DM were presented. ConclusionsThe long-term use of mTORi agents in TSC may contribute to a risk of diabetes. Early detection can be critical in management. Additional studies are need to further investigate a causal relationship, but clinicians should be aware of this possible association when initiating and monitoring ongoing treatment.

CASE STUDY ON CIRCUMSCRIBED GLIOMAS, THEIR CLINICOPATHOLOGICAL CORRELATION IN A TERTIARY CARE CENTER

The histogenesis and biological behavior of primary tumors of the central nervous system(CNS) are very diverse. The majority of present gliomas as benign, slow growing lesions classied as by the WHO classicati grade I or II (Low grade gliomas) on of CNS tumors. However, a signicant fraction of gliomas develop over a short period of time and progress rapidly and are therefore classied as WHO grade III or IV(High grade gliomas). Astrocytomas are primary central nervous system tumours that can develop in adults or in children. They arise from the Astrocytes. They can be divided into diffuse that generally have a higher grade and poorer prognosis and those that are localised that tend to be of a lower grade and have a better prognosis. In this study, we outline the basic histological spectrum and features, epidemiological aspects and grade of circumscribed gliomas (localised) or other Astrocytic tumours according to WHO classication . These are the Pilocytic Astrocytoma, Pilomyxoid Astrocytoma, Subependymal giant cell Astrocytoma, Pleomorphic xanthoastrocytoma and Anaplastic astrocytoma . The knowledge of these tumours are important as they are one of the commonest cause of mortality and morbidity in both the young and old, accounting for about 60% of the glial tumours. Therefore neuropathological diagnosis and tumour characteristics will therefore profoundly inuence the impact of treatment strategies.

Experience using mTOR inhibitors for subependymal giant cell astrocytoma in tuberous sclerosis complex at a single facility

BackgroundSubependymal giant cell astrocytoma (SEGA) is occasionally seen in tuberous sclerosis complex (TSC). Two main options are currently available for treating SEGA: surgical resection or pharmacotherapy using mammalian target of rapamycin inhibitors (mTORi). We hypothesized that opportunities for surgical resection of SEGA would have reduced with the advent of mTORi.MethodsWe retrospectively reviewed the charts of patients treated between August 1979 and July 2020, divided into a pre-mTORi era group (Pre-group) of patients treated before November 2012, and a post-mTORi era group (Post-group) comprising patients treated from November 2012, when mTORi became available in Japan for SEGA. We compared groups in terms of treatment with surgery or mTORi. We also reviewed SEGA size, rate of acute hydrocephalus, recurrence of SEGA, malignant transformation and adverse effects of mTORi.ResultsIn total, 120 patients with TSC visited our facility, including 24 patients with SEGA. Surgical resection was significantly more frequent in the Pre-group (6 of 7 patients, 86 %) than in the Post-group (2 of 17 patients, 12 %; p = 0.001). Acute hydrocephalus was seen in 1 patient (4 %), and no patients showed malignant transformation of SEGA. The group treated using mTORi showed significantly smaller SEGA compared with the group treated under a wait-and-see policy (p = 0.012). Adverse effects of pharmacotherapy were identified in seven (64 %; 6 oral ulcers, 1 irregular menstruation) of the 11 patients receiving mTORi.ConclusionsThe Post-group underwent surgery significantly less often than the Pre-group. Since the treatment option to use mTORi in the treatment of SEGA in TSC became available, opportunities for surgical resection have decreased in our facility.

Bilateral renal angiomyolipomas and subependymal giant cell astrocytoma associated with tuberous sclerosis complex: A case report and review of the literature

Tuberous sclerosis complex (TSC) is an autosomal-dominant multi system disorder. The genetic basis of the disorder is mutations in the TSC1 or TSC2 gene, which leads to over activation of the mammalian target of rapamycin (mTOR) protein complex and results in development of benign tumors in different body systems such as brain, skin, lungs and kidney. The mTOR inhibitors are presently the main treatment option for patients with TSC. We here report a 21-year female patient with large bilateral angiomyolipoma (AML) in both kidneys with longest diameter more than 12.3 cm and subependymal giant cell astrocytoma (SEGA). Treatment with everolimus (EVE) was initiated at a dose of 10.0 mg/day and continued during the following 3 years. Magnetic resonance imaging (MRI) was performed before treatment with everolimus was initiated, and consequently at 12 and 36 months for follow-up of the efficacy of the treatment. After 3 years, the total size of largest AML decreased by ~24.0% in the longest diameter. A reduction of the total size of SEGA was also observed. The most common adverse effect of treatment was stomatitis grades 3 to 4 and one febrile episode associated with skin rash that required a reduced dose of EVE. In conclusion, the everolimus treatment improved even such a large renal AML and the effect persisted during the long-term administration with a small number of adverse effects. A positive effect was observed on the brain tumor as well.

The clinical and paraclinical manifestations of tuberous sclerosis complex in children.

Tuberous sclerosis complex (TSC) is an autosomal-dominant, multi-system, neurocutaneous disorder characterized by hamartomas in multiple organs. This study aimed to evaluate the clinical and paraclinical manifestations of children with TSC. The clinical and paraclinical characteristics of 79 children with TSC were evaluated and the possible correlations between the factors were calculated. Among the studied children which composed of 41 females (51.9%) and 38 males (48.1%), skin manifestations as hypopigmented macules as well as the brain involvement as cortical tubers in all (100%) cases, seizure in 74 (93.7%), and sub-ependymal nodules in 73 (92.4%) patients were the most common findings. The renal angiomyolipoma was diagnosed in 36 (70.6%) out of 51 patients. Subependymal giant cell astrocytoma in 25 (3/54%) out of 46 patients, retinal hamartoma in 15 (42.9%) out of 35 patients, and cardiac rhabdomyoma in 17 (41.3%) out of 46 patients were diagnosed. Furthermore, 50 (63.3%) out of 79 patients had psychological disorders that had a significant correlation with the prevalence of seizures (p = 0.002). Given the multi-systemic involvement of TSC, it is necessary that all organs of the patients even without any related clinical symptom or sign be examined regularly for proper therapeutic intervention and prevent disease progression. The growth of hamartomas in the brain and kidneys can be life-threatening; therefore, these organs have more importance to be regularly followed up and examined.

Endoscopic Management of Intra Ventricular Tumours

Objective: Neuroendoscopic removal of intraventricular tumors is difficult and time consuming because of the lack of an effective decompression system that can be used through the working channel of the endoscope. The authors report on the utilization of an endoscopic ultrasonic aspirator in the resection of intraventricular tumors. Methods: Seventeen pediatric patients (14 male, 3 female), ages 1-15 years old, underwent surgery via a purely endoscopic approach using a Gaab rigid endoscope and endoscopic ultrasonic aspirator. Ten patients presented with an intraventricular tumor, three with paraventricular, and 4 with suprasellar lesions. Histology analysis showed 6/17 glial tumors, 3/17 with subependymal giant cell astrocytomas (associated with tuberous sclerosis), two cases presented with intraventricular metastases from high-grade tumors (medulloblastoma, atypical teratoid rhabdoid tumor), 4/17 with suprasellar tumors (2 craniopharyngiomas and 2 optic pathway gliomas), and two with pineal region tumors (1 immature teratoma, 1 PNET). In all patients, the endoscopic trajectory and ventricular access were guided by electromagnetic neuronavigation. Fifteen patients underwent surgery via a precoronal bur hole while supine. In 1 case, surgery was performed through a frontal anterior bur hole and one patient underwent surgery via a posterior parietal approach to the trigone while in a lateral position. The endoscopic technique consisted of visualization of the tumor, ventricular washing to dilate the ventricles and to control bleeding, obtaining a tumor specimen with biopsy forceps, and ultrasonic aspiration of the tumor. Bleeding was controlled with irrigation, monopolar coagulation, and a thulium laser. Results/Discussion: In 9 cases, the resection was total or near total (more than 90% of lesion removed). In 8 cases, the resection was partial or biopsy. Histological evaluation of the collected material (withdrawn using biopsy forceps and aspirated with an ultrasonic aspirator) was diagnostic in all cases. The duration of surgery ranged from 30 to 120 minutes. One case was complicated by subdural hygroma requiring a subduro-peritoneal shunt implant. The dry field technique was used in cases with persistence of bleeding. Conclusion: Patients harboring intraventricular tumors are in most cases ideal candidates for endoscopy biopsy/resection. In this series, endoscopic ultrasonic aspiration proved to be a safe and reliable method for achieving extensive decompression or complete removal in the management of intra- and/or paraventricular lesions in pediatric patients.

Enhancing cyst-like lesions of the white matter in tuberous sclerosis complex: a novel neuroradiological finding.

Tuberous sclerosis complex (TSC) is an autosomal dominant condition clinically presenting with heterogenous clinical features. Multiple neuroradiological manifestations have been associated with TSC, such as tubers, radial migration lines, subependymal nodules, subependymal giant cell astrocytomas, and cyst-like lesions of the white matter (CLLWMs). The latter have been described as non-enhancing well-defined cysts whose pathogenesis is still unknown. We describe 2 TSC patients with CLLWM showing contrast enhancement after Gadolinium injection, a previously unreported entity.

The metformin in tuberous sclerosis (MiTS) study: A randomised double-blind placebo-controlled trial.

BackgroundTuberous Sclerosis Complex (TSC) is a genetic disorder characterised by the development of benign tumours secondary to loss of inhibitory regulation of the mTOR (mechanistic Target of Rapamycin) intracellular growth pathway. Metformin inhibits the mTOR pathway. We investigated whether metformin would reduce growth of hamartomas associated with tuberous sclerosis complex.MethodsIn this multicentre randomized, double-blind, placebo-controlled trial, patients with a clinical diagnosis of tuberous sclerosis, aged over 10 years and with at least one renal angiomyolipoma of greater than 1 cm in diameter were enrolled. Participants were randomly allocated (1:1) by a secure website to receive metformin or placebo for 12 months. The primary outcome was percentage volume change of renal angiomyolipomas (AML) at 12 months compared to baseline. Secondary outcomes were percentage change at 12 months from baseline in volume of cerebral Subependymal Giant Cell Astrocytomas (SEGA); appearance of facial and ungual hamartomas; frequency of epileptic seizures; and adaptive behaviour. The trial is registered with The International Standard Randomised Controlled Trial Number (ISRCTN), number 92545532, and the European Union Drug Regulating Authorities Clinical Trials (EUDRACT), number 2011-001319-30.FindingsBetween 1 November 2012 and 30 September 2015 72 patients were screened and 55 were randomly assigned to metformin (28) or placebo (27). Four participants withdrew between randomisation and starting treatment. All 51 patients who started therapy completed the trial and were assessed for outcome at 12 months. The median percentage change in angiomyolipoma (AML) volume was +7.6% (IQR -1.8% to +42.6%) for the placebo group and +8.9% (IQR 1.3% to 19.5%) for the metformin group (p = 0.28). Twenty-seven patients had SEGAs: 13 received placebo and 14 metformin. The median percentage change in SEGA volume was +3.0% (IQR -22.8% to +27.7%) for the placebo group and – 20.8% (IQR – 47.1% to - 5.0%) for the metformin group (p = 0.03). Twenty-one patients were assessed for seizure frequency: 9 received placebo and 12 received metformin. In the metformin group, a mean reduction of 43.7% from baseline in seizures was observed and in the placebo group a 3.1% mean reduction was observed, with a difference in response of 40.6% (95% CI -3.1% to +84.2%, p = 0.03). There were no significant differences between metformin and placebo groups for the other secondary outcomes. There were no deaths. Three serious adverse events (SAEs) occurred during the trial (all patients on metformin).InterpretationMetformin did not reduce AML volume. Metformin did reduce SEGA volume and seizure frequency compared with placebo. There may be a role for metformin in slowing or reversing growth of some life-threatening hamartomas in TSC and for reducing seizure frequency. Further study is justified.FundingThis study was funded by the National Institute for Health and Research (NIHR) through the The Research for Patient Benefit Programme (RfPB).

The Effect of Everolimus on Subependymal Giant Cell Astrocytoma (SEGA) in Children with Tuberous Sclerosis Complex.

Objective:Subependymal Giant Cell Astrocytomas (SEGAs) are slow-growing glioneuronal tumors typically found around the ventricles of the brain, particularly near the foramen of Monro in 15%-20% of patients with tuberous sclerosis complex (TSC). Surgical resection is the standard treatment for these symptomatic tumors. The mTOR inhibitor everolimus can be regarded as an alternative treatment for SEGAs due to the complications of surgery. The present study primarily aimed to specify the effect of everolimus on SEGA volume change before and after treatment. The secondary objective was to determine the effect of this drug on renal angiomyolipoma (AML), skin lesions, and seizures in TSC patients. Materials & Methods:This pre- and post-treatment clinical trial was performed on 14 children (eight females and six males with a mean age of 10 years) previously diagnosed with TSC based on the diagnostic criteria. The subjects received oral everolimus at a dose of 3 mg/m2 for at least six months. Results:Half of the patients had more than 30% of volume loss in SEGA, and in 28.5% of them, a ≥ 50% reduction in SEGA volume was observed (P=0.01). Moreover, 92.9% of the patients had a ≥ 50% decrease in the frequency of seizures (P=0.000). The response rate in AML and skin lesions was 14.2% and 50%, respectively. Conclusion:Everolimus significantly reduced the seizure frequency and SEGA volume in the subjects; hence, it can be used as a potential alternative treatment for symptomatic SEGA in TSC patients.

Mechanistic Target of Rapamycin (mTOR) Inhibitors.

Mechanistic target of rapamycin (mTOR) inhibitors are macrocyclic lactone antibiotics derived from Streptomyces hygroscopicus that prevent T lymphocyte activation and B cell differentiation. Unlike calcineurin inhibitors (CNIs) that inhibit cytokine production, mTOR inhibitors block the cytokine signal transduction to arrest cells in the G1 to S phase. This class of drugs is commonly used for post-transplantation and cancer management because of its immunosuppressive and antiproliferative properties, respectively. The potential uses of mTOR inhibitors are heavily explored because of their impact on cell growth and proliferation. However, mTOR inhibitors have a broad range of effects that can result in adverse reactions, but side effects can occur with other immunosuppressive agents as well. Thus, the performance of mTOR inhibitors is compared to the outcomes and adverse effects of other immunosuppressive drugs or the combination of other immunosuppressants and mTOR inhibitors. Because mTOR regulates many downstream pathways, mTOR inhibitors can affect these pathways to manage various diseases. Sirolimus (rapamycin) is approved by the Food and Drug Administration (FDA) to treat post-renal transplantation and lymphangioleiomyomatosis (LAM). Everolimus is approved by the FDA to treat postmenopausal advanced hormone receptor-positive, HER2-negative breast cancer in women, progressive neuroendocrine tumors of pancreatic origin (PNET), advanced renal cell carcinoma (RCC), renal angiomyolipoma (AML) and tuberous sclerosis complex (TSC), and subependymal giant cell astrocytoma (SEGA) associated with TSC as well as renal and liver transplantation. Temsirolimus is approved by the FDA to treat advanced RCC. Opportunities to use mTOR inhibitors as therapy for other transplantation, metabolic disease, and cancer management are being researched. mTOR inhibitors are often called proliferation signal inhibitors (PSIs) because of their effects on proliferation pathways.

Subependymal giant cell astrocytomas are characterized by mTORC1 hyperactivation, a very low somatic mutation rate, and a unique gene expression profile

Subependymal giant cell astrocytomas are characterized by mTORC1 hyperactivation, a very low somatic mutation rate, and a unique gene expression profile

Frequency and Topography of AstrocyticTumor: Experience of 567 Cases at Referral Neuroscience Hospital in Bangladesh

Background: Glioma is the most commonly occurring malignant brain tumor that varies by age, sex, race or ethnicity. A very few number of records on CNS tumors are available in Bangladesh. National Institute of Neurosciences and Hospital (NINS), Dhaka has a good number of CNS surgeries. Regularly both tumorous and non-tumorous ICSOL samples are examined here.&#x0D; Objective: The aim of the study was to see the subtypes, frequency and topography of Astrocytic tumors at NINS setting.&#x0D; Methodology: Data from the department of Neuropathology department of NINS since January 2013 to June 2019 were evaluated. Tissue were fixed in formalin, paraffin embedded, stained with H&amp;E. Histomorphology and WHO 2007 CNS tumor classification were used.&#x0D; Result: From 3945 routine sample 567 cases were sorted out as Astrocytic tumor. Total male were 61% (346) and female 39% (221), male to female ratio was 1.6:1. The mean age was 32.64 and ranged from 1 to 80 years. Sixty six percent (66%) tumors were in supratentorial compartment, 15% infratentorial, 6.3% spinal and 9.7% in midline areas like thalamus, hypothalamus and seller region. In this study 34.6% (196) cases were Glioblastoma, followed by Anaplastic Astrocytoma 8.3%(47), Diffuse Astrocytoma 29% (165), Pilocytic Astrocytoma 26.6% (151), Pilomyxoid Astrocytoma 0.4% (2), Subependymal giant cell Astrocytoma 0.9% (5) and Pleomorphic Xanthoastrocytoma 0.1 (0.1). Topographically 66% glial tumors are supratentorial. Among the glial tumors 34.6% is Glioblastoma, 8.3% Anaplastic Astrocytoma, 29% Diffuse Astrocytoma and 26.6% Pilocytic astrocytoma. Common age group of Glioblastoma is 41-60 (52%) years, diffuse astrocytoma is 21-40 years 60.60 and Pilocytic Astrocytoma is 1-20 years (66.88). Glioblastoma, Anaplastic Astrocytoma and Diffuse astrocytoma are more common in male than female.&#x0D; Conclusion: There is no gender difference in case of Pilocytic Astrocytoma.&#x0D; Journal of National Institute of Neurosciences Bangladesh, 2020;6(2): 91-95

NFB-16. mTOROPATHIES AND SUBEPENDYMAL GIANT CELL ASTROCYTOMAS: PREDICTIVE VALUE OF GERMINAL TSC1/2 MUTATIONS SCREENING IN FAMILIAL CASES

mTOR controls several important aspects of cell function particularly in the nervous system. Its hyperactivation has been involved in tuberous sclerosis complex (TSC) and other mTORopathies as well as drug-resistant epilepsy. Mutations in TSC1 and TSC2 genes cause loss of normal inhibition of mTORC1 complex, leading to cell overgrowth and disruptions in synaptogenesis. Many children and adults with TSC harbour neurologic defects especially subependymal giant cell astrocytomas (SEGAs) in the brain. Here, we have performed mutational analysis followed by a genetic counselling for a Tunisian family from Sfax town harboring epileptic seizures associated to a neurocutaneous disorder. Index cases were referred for renal angiolipomas (RAL) associated to seizures crisis and were diagnosed as having TSC. The first 26-year-old patient complained of epilepsy since the age of 22 with left temporal crisis related to cortical tubers near the Heschl’s gyrus. His brother, a 36-year-old man presented more severe epileptic crisis (since 15 years-old), multiples RAL, subependymal nodules, and a rapid evolution of his mTORopathy with tumoral progression of his renal and central nerve lesions: renal cell carcinoma and SEGAs. TSC1 gene mutation screening showed heterozygous two bp deletion at codons 213 and 214 of exon 5. SEGAs are rare, low-grade glioneuronal brain tumors that occur almost exclusively in TSC patients but can lead to nervous complications. We showed through this report, the predictive value of germinal TSC mutations screening in familial cases, because early recognition of the molecular defect may lead to appropriate management of the tumoral progression.

DDEL-06. DRUG INTERACTION BETWEEN EVEROLIMUS AND CANNABIDIOL IN PEDIATRIC PATIENTS WITH SUBEPENDYMAL GIANT CELL ASTROCYTOMAS: A SINGLE INSTITUTION EXPERIENCE

Tuberous sclerosis complex (TSC) is an autosomal recessive genetic disorder associated with clinical manifestations including subependymal giant cell astrocytomas (SEGA) and seizures. The combination of everolimus and Epidiolex, a purified form of cannabidiol, has become an increasingly common treatment regimen in this population. Everolimus is primarily metabolized via CYP3A4, which may be inhibited by cannabidiol. We seek to describe our institution’s experience with this drug interaction. METHODS: Investigators conducted a retrospective review of neuro-oncology patients with TSC and SEGA who were treated concurrently with everolimus and cannabidiol. Data collected included demographics, body surface area, everolimus dose, everolimus troughs, date of cannabidiol initiation, documented symptoms, liver and renal function tests, and reason for discontinuing therapy. RESULTS: Three patients (ages 11–17 years) met inclusion criteria. All patients were stable on everolimus doses ranging from 6.5 to 9.5 mg/m2/day and achieving trough goals of 5–10 ng/mL. Two to four weeks after initiating cannabidiol, everolimus trough concentrations rose 200–860% above goal. One patient reported new-onset involuntary movements, but no other toxicities were noted. Cannabidiol was discontinued in all cases due to caregiver concerns regarding drug interactions. All patients were able to achieve goal trough concentrations on previously stable doses of everolimus after discontinuing cannabidiol. CONCLUSIONS: Cannabidiol appears to modulate everolimus metabolism leading to significantly elevated serum concentrations. Additional research is required to determine the need for empiric dose adjustments upon cannabidiol initiation. Patient counseling, frequent trough monitoring, and surveillance for adverse effects are crucial for optimizing outcomes in patients prescribed this regimen.

LGG-32. CLINICAL OUTCOME OF PEDIATRIC GLIOMAS IN SINGLE INSTITUTION

Gliomas in children are rarer than in adult, then treatment strategies might vary from facility to facility. We report clinical features and outcome of pediatric glioma in our institution. Twenty-nine patients diagnosed with glioma, exclude ependymoma, 14 boys and 15 girls, among 98 pediatric brain tumor patients treated at Kagoshima University Hospital since 2006 were reviewed histopathology, extent of resection, adjuvant therapy and outcome, etc. Mean age at surgery was 10.4 (S.D. 5.6) years. Median follow-up period was 19.1 months. Histopathological diagnosis comprised 8 pilocytic astrocytoma, 3 ganglioglioma, 2 subependymal giant cell astrocytoma, 5 WHO grade Ⅱ astrocytoma, 8 glioblastoma, and desmoplastic infantile astrocytoma, anaplastic astrocytoma and astroblastoma were one case each. Tumor resection was performed in 24 cases, and 5 cases underwent biopsy. Chemotherapy was performed in 15 cases and irradiation was performed in 9 cases. Out of 5 WHO grade Ⅱ astrocytoma cases, 2 cases underwent biopsy following chemotherapy, 1 case underwent biopsy only and other 1 case underwent total resection. The four cases show long survival ranged from 71 to 136 months without irradiation. All of eight glioblastoma cases show poor prognosis ranged from 8.6 to 26.7 months regardless of chemo-radiotherapy. In management for pediatric brain tumor patients, irradiation is often laid over until recurrence. In WHO grade Ⅱ astrocytoma, the treatment strategy might be reasonable using appropriate chemotherapy even though biopsy cases.

SURG-14. ENDOSCOPIC SURGERY FOR PEDIATRIC INTRAVENTRICULAR TUMOR WITHOUT HYDROCEPHALUS: INDICATION, SURGICAL TECHNIQUE, AVOIDANCE OF COMPLICATION, AND ITS PROSPECT

INTRODUCTIONNeuroendoscopic surgery is useful for intraventricular tumors accompanied by ventriculomegaly. However, it is often challenging for cases with small ventricles. Our institution is actively performing surgeries for pediatric intraventricular tumors without frank ventriculomegaly.METHODSSeven cases of intraventricular tumors without ventriculomegaly (5 cases of subependymal giant cell astrocytoma (SEGA) and 2 cases of germ cell tumors (GCTs)) were analyzed. The age ranged between 3 and 14 years (median 5 years). The sizes of SEGA were between 10-27mm, and all the tumors showed an enlargement around the foramen of Monro, which was the indication for surgery. Biopsy and third ventriculostomy were performed for GCTs. For resection, after making a small craniotomy of 2 x 3 cm, ellipse-cone-like sheath with a diameter of 12mm or 17mm was inserted through it to the lateral ventricle, which enabled a wide surgical view. Under a rigid endoscope of 4mm diameter, 2 types of surgical instruments were employed, making the microsurgical procedure like under a microscope, with a wider view, possible. For the cases of tumor resection, septostomy and placement of a drain in the ventricle were performed at the end of surgery.RESULTSThe lesions were safely approached in all the cases. For resection, endoscopic microsurgery was possible, and tumor was totally removed in all the cases. No postoperative complication was observed in any of them.CONCLUSIONSOur experience shows that tumor resection can be safely achieved with the aid of endoscope even for cases without ventriculomegaly.

LINC-17. SIROLIMUS AS AN ALTERNATIVE TO SURGICAL RESECTION OF PEDIATRIC TUBEROUS SCLEROSIS COMPLEX-ASSOCIATED BILATERAL SUBEPENDYMAL GIANT CELL ASTROCYTOMAS: AN AFFORDABLE OPTION FOR PATIENTS FROM LOW-MIDDLE INCOME COUNTRIES

Subependymal giant cell astrocytomas (SEGA) may lead to significant neurological morbidity in children diagnosed with tuberous sclerosis complex (TSC). Surgical resection is warranted for SEGAs demonstrating continuous growth, causing hydrocephalus and increased intracranial pressure. mTOR inhibitors (sirolimus and everolimus) are alternatives to surgery and have shown efficacy in stabilizing and shrinking SEGAs. Everolimus showed stronger evidence in efficacy, but its cost poses a limitation for this treatment among patients from low-middle income countries. We explored sirolimus as a potentially more cost-effective alternative in our setting. We present a 10-year-old Filipino child with TSC admitted due to headache, vomiting, and increased sleeping time. Neuroimaging revealed large bilateral SEGAs involving the frontal horns and foramina of Monro, causing moderate obstructive hydrocephalus. Surgical excision was offered, but parents opted for medical treatment. Bilateral posterior parietal ventriculoperitoneal shunts were inserted to decrease intracranial pressure. Due to the cost of everolimus, the patient was started on sirolimus at 1mg/m2/day. Imaging done 6 months after initiating therapy demonstrated significant decrease in size of both SEGAs (right: 82.5%, left: 64.1%). Sirolimus levels were maintained at 15.7ng/ml and minimal elevations on cholesterol and triglyceride levels were observed and treated with simvastatin. Results of this case and review of related data suggest that sirolimus can be used as a conservative approach in inducing regression of large bilateral SEGAs, and an affordable alternative to everolimus for pediatric TSC patients from low-middle income countries. Prospective studies and clinical trials are needed to further establish its efficacy, safety and cost-effectiveness in our setting.

Familial Nervous System Tumor Syndromes.

Although sporadic primary neoplasms account for the majority of nervous system tumors, familial nervous system tumor syndromes are important and clinically relevant conditions for the neurologist to understand. This article reviews common inherited nervous system tumor syndromes including neurofibromatosis type 1, neurofibromatosis type 2, schwannomatosis, tuberous sclerosis complex, and von Hippel-Lindau syndrome. The epidemiology, genetics, approach to diagnosis, neurologic and nonneurologic manifestations, and management options are reviewed. Awareness of the more common and clinically relevant familial nervous system tumor syndromes is important. These conditions teach us about the underlying biology that drives tumor development in the central and peripheral nervous systems including peripheral nerve sheath tumors (eg, neurofibroma, schwannoma), meningioma, vestibular schwannoma, subependymal giant cell astrocytoma, and hemangioblastoma. Knowledge of the clinical manifestations ensures that the neurologist will be able to diagnose these conditions, recommend appropriate surveillance, refer to specialists, and support optimal management. Important discoveries in the role of the underlying genetics have contributed to the launch of several novel drug trials for these tumors, which are changing therapeutic options for patients. Familial nervous system tumor syndromes are uncommon conditions that require specialized surveillance and management strategies. Coordination across a multidisciplinary team that includes neurologists, neuro-oncologists, radiologists, neurosurgeons, radiation oncologists, otolaryngologists, pathologists, neuropsychologists, physical medicine and rehabilitation specialists, and geneticists is necessary for the optimal treatment of these patients.

Tuberous sclerosis: a review of the past, present, and future

Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem disorder that is characterized by cellular and tissue dysplasia in several organs. With the advent of genetic and molecular techniques, mutations in the TSC1 or TSC2 genes were discovered to be responsible for mTOR overactivation, which is the underlying mechanism of pathogenesis. TSC is a highly heterogenous clinical entity with variable presentations and severity of disease. The brain, heart, skin, eyes, kidneys, and lungs are commonly involved in this syndrome, with neurologic symptoms comprising a significant source of morbidity and mortality. In 2012, the diagnostic criteria for TSC were revised by the International Tuberous Sclerosis Complex Consensus panel, and genetic testing was incorporated into the guidelines. Early detection of cardiac rhabdomyomas or TSC-associated skin lesions can suggest the diagnosis and underlie the importance of clinical vigilance. Animal studies have demonstrated the benefit of using mTOR inhibitors for various symptoms of TSC, and they have been successfully translated into clinical trials with significant improvement in symptom burden. Subependymal giant cell astrocytomas, renal angiomyolipomas, and epilepsy are the three FDA-approved indications in relation to TSC for the use of everolimus, which is a first generation mTOR inhibitor. Rapamycin has been FDA approved for lymphangioleiomyomatosis. Other TSC symptoms that could potentially benefit from this class of medication are currently under investigation. TSC constitutes a unique combination of protean physical symptoms and neurobehavioral abnormalities. TSC associated neuropsychiatric disorders (TAND), including intellectual disability, mood disorders, and autism spectrum disorder, represent significant challenges but remain underdiagnosed and undertreated. The TAND checklist is a useful tool for routine use in the clinical evaluation of TSC patients. A multidisciplinary treatment plan, based on the specific problems and needs of individuals, is the key to management of this genetic condition. Ongoing research studies have been providing promising leads for developing novel mechanistic strategies to address the pathophysiology of TSC.

Solitary subependymal giant cell astrocytoma: Case report and review of the literature

Tuberous sclerosis complex (TSC) is a multisystem autosomal dominant hamartoma syndrome caused by mutations in TSC1 or TSC2 genes, leading to upregulation of cell growth signalling pathways. Subependymal giant cell astrocytomas (SEGAs) are seen almost exclusively in TSC patients. We report a ‘solitary SEGA’ in an adult patient, with confirmed deletion of the entire TSC2 gene on tumour tissue DNA, in the absence of detectable constitutional mutation or clinical manifestations of TSC. These rare cases may be secondary to somatic mosaicism and provide an opportunity to explore the genetic basis of the syndrome and its related tumours.