Giant Cell Astrocytoma Research Articles

A Novel TSC2 Variant Associated with an Extremely Rare Magnetic Resonance Imaging Finding of Focal Megalencephaly

AbstractTuberous sclerosis complex (TSC) is a neurocutaneous syndrome with an autosomal dominant pattern of inheritance. It is a multisystem genetic disease caused by mutations in the TSC1 and TSC2 genes. The neuroradiographic findings of TSC include cortical dysplasia (cortical tubers and cerebral white matter radial migration lines), subependymal nodules, and subependymal giant cell astrocytoma. In this article, we describe an interesting case of TSC with an extremely rare radiographic finding of focal right megalencephaly. Molecular genetic testing detected a heterozygous c.3814+2T>G (p.?) variant, not previously described in the literature. As per the 2012 International Tuberous Sclerosis Complex Consensus Group guidelines and the findings of the genetic testing, this mutation most probably should be considered as a pathogenic variant. There are few cases of hemimegalencephaly (HME) reported in the literature, associated with TSC. To our knowledge focal megalencephaly is an extremely rare neuroradiographic finding in patients with TSC and has been previously reported only once by Griffiths et al based on clinical diagnostic criteria. Despite the uncommon association, TSC is the only neurocutaneous syndrome with similar histological appearance to HME. It is recognized that the pathological features in TSC and HME are due to abnormal cell proliferation, migration, and organization which could also be a possible mechanism for the development of focal megalencephaly. The uncommon association of HME and TSC with cytological similarities makes us wonder if there could be similarities in the pathogenesis of these two conditions. The advances in molecular genetic testing, increasing use of next-generation sequencing, and discovery of new pathogenic variants could answer some of these questions.

Therapy monitoring of mTOR-inhibitors using 3D reconstruction of SEGA volume, DTI and SVS

Objective: Subependymal giant cell astrocytomas (SEGAs) are WHO Grade I tumors, which occur in 5–10% of tuberous sclerosis complex (TSC) patients. Due to their location next to the foramen of Monroe, these tumors can lead to severe complications and to the risk of rapid neurological decline and death. Everolimus, a mTOR1-inhibitor, was approved in 2011 for the treatment of asymptomatic slowly growing SEGAs with risk of CSF – flow obstruction or inoperable SEGAs. However, the response is variable, and cessation of treatment is often associated with rapid tumor regrowth, necessitating life-long treatment, associated with unknown long-term toxicity. Advanced data on in vivo tumor behaviour utilizing state-of-the-art imaging methods, such as 3D reconstructed volumetry, DTI, and MRSI, do not yet exist. Our aim is to provide insight into growth patterns of these tumors. Methods: Between 2010 and 2016, 26 patients with SEGA had MRI scans at our center. 13 of these had treatment with mTOR-Inhibitors. Since 2015 we included Single-Voxel Spectroscopy and DTI to our MRI-protocol. SEGA volume was measured manually using the program ITK snap. Preliminary results: We analyzed 9 patients (4–19 years) with Everolimus treatment. Before treatment, the median SEGA volume was 707 mm³ (2372–71 mm³). After 12 months of therapy, SEGA volumes were reduced by median 40% (75–+38%). In 3 patients, treatment had to be stopped. In one of these patients the SEGA volume increased after cessation of treatment by 64%, in relation to the tumor volume under Everolimus treatment. The analysis of the entire patient group, the DTI and SVS are still ongoing. Conclusion: The 3D reconstruction of SEGA volume is a precise method to investigate the growth behavior of SEGA and the response to the therapy with Everolimus. However further research is required to predict tumor growth and treatment-response.

Everolimus alleviates obstructive hydrocephalus due to subependymal giant cell astrocytomas

Abstract Background Subependymal giant cell astrocytomas (SEGAs) are low-grade tumors affecting up to 20% of patients with tuberous sclerosis complex (TSC). Early neurosurgical resection has been the only standard treatment until few years ago when a better understanding of the molecular pathogenesis of TSC led to the use of mammalian target of rapamycin (mTOR) inhibitors. Surgical resection of SEGAs is still considered as the first line treatment in individuals with symptomatic hydrocephalus and intratumoral hemorrhage. We describe four patients with symptomatic or asymptomatic hydrocephalus who were successfully treated with the mTOR inhibitor everolimus. Methods We collected the clinical data of four consecutive patients presenting with symptomatic or asymptomatic hydrocephalus due to a growth of subependymal giant cell atrocytomas and who could not undergo surgery for different reasons. Results All patients experienced a clinically significant response to everolimus and an early shrinkage of the SEGA with improvement in ventricular dilatation. Everolimus was well tolerated by all individuals. Conclusions Our clinical series demonstrate a possible expanding indication for mTOR inhibition in TSC, which can be considered in patients with asymptomatic hydrocephalus or even when the symptoms already appeared. It offers a significant therapeutic alternative to individuals that once would have undergone immediate surgery. Everolimus might also allow postponement of a neurosurgical resection, making it elective with an overall lower risk.

Cerebellar lesions associated to Tuberous Sclerosis: New insights from an Italian paediatric series

Objectives: To evaluate: a) the cerebellar involvement in a pediatric population with tuberous sclerosis; b) the possible clinical and neuroradiological differences comparing patients with cerebellar lesions and those without; c) whether the cerebellar involvement may be considered a prognostic factor for neurological and neuropsychiatric outcomes in patients with tuberous sclerosis. Methods: Retrospective analysis of a pediatric population of 51 patients (21 males, 30 females) affected by tuberous sclerosis. For each patient we evaluated the clinical characteristics and in particular the neurological and neuropsychiatric phenotypes and all the available brain MRI. Results: 25.5% (13/51) of patients had cerebellar lesions (unilateral in 9/13 cases and bilateral in 4/13 cases). 91% of patients with cerebellar lesions had a TSC2 gene mutation (p=0.11) and in all cases mutations were de novo (p=0.02). Patients with cerebellar involvement compared to those without had a more severe phenotype (drug-resistant epilepsy: 46.2% vs 28.9%; intellectual disability: 61.5% vs 39.5%; neuropsychiatric disorders: 61.5% vs 50%; pervasive developmental disorder: 23.1% vs 10.5%; a higher brain tuber load tuberous, a higher frequency of subependymal nodules and subependymal giant cell astrocytomas). All cerebellar lesions involved the posterior lobe. Conclusions: A quarter of our patients with tuberous sclerosis have cerebellar lesions. Cases with cerebellar lesions, compared to those without, have more severe clinical phenotypes and neuroradiologic findings. The cerebellar lesions have a constant and peculiar localization in the posterior lobe of cerebellum, that is considered the seat of the cognitive functions of the cerebellum. Our data support the hypothesis that cerebellar lesions could represent a negative prognostic biomarker in patients with tuberous sclerosis. Their early detection could suggest to screen more carefully for neuropsychiatric disorders and neuropsychological problems and they could facilitate the selection of patients amenable to early treatment with mTOR inhibitors.

Clinical patterns and outcomes of status epilepticus in patients with tuberous sclerosis complex.

IntroductionRefractory epilepsy is a common clinical manifestation in patients with tuberous sclerosis complex (TSC), which can be complicated by many life-threatening conditions, such as status epilepticus (SE). However, very few reports mention the patterns and semiology of SE in those patients.ObjectiveTo study the clinical characteristics and outcomes of SE in TSC patients.Materials and methodsThis observational, prospective study was carried out on 36 Egyptian children with definite TSC. Clinical history, general and neurological examination and psychometric evaluation by standard questionnaires were used to explore characteristics of epileptic manifestations and clinical patterns of SE. All included patients were required to have long-term video electroencephalograms (EEGs) and brain MRI performed.ResultsA total of 32 attacks of SE were recorded in 21 patients (58.3%) in our cohort during a follow-up period of 2.8±1.1 years; of those patients, 15 had convulsive status, 7 had non-convulsive SE, 6 had refractory/super-refractory SE and 14 patients had a history of infantile spasms (epileptic spasms). The duration of status ranged from 40 to 150 min (mean ± standard deviation: 90±15). Fourteen patients with SE had severe mental retardation, 9 had autistic spectrum disorder and 22 had severe epileptogenic EEG findings. Patients with SE had higher tuber numbers (mean: 9.6), 5 patients had subependymal giant cell astrocytomas and 2 patients had their SE after receiving everolimus.ConclusionsThe incidence of SE in our patient sample is high (>50%); severe mental retardation, autistic features, history of infantile spasm (epileptic spasms) and high tuber burden are risk factors for developing SE.

Everolimus treatment in patient with tuberous sclerosis complex and giant cell astrocytoma (SEGA) – Kuwait experience

Objective: Tuberous sclerosis complex (TSC) is an autosomal dominant, genetic disorder caused by mutations in TSC1 or TSC2, which result in constitutive activation of the mammalian target of rapamycin complex 1 (mTORC1), causing benign tumors (hamartomas) most commonly in the brain, kidneys, lungs, and skin. SEGAs typically arise from subependymal nodules in the area of the foramen of Monro and occur in 5–20% of patients with TSC. Recent studies support the use of Everolimus for SEGA associated with TSC and suggest it might represent promising treatment. Methods: All three of our patient was treated with Everolimus according to our own protocol (adopted Novartis Pharmaceuticals Protocol, 2013) with starting a dose of 4.5 mg/m2 per day and titrated to a serum concentration between 5 and 15 ng/mL. Laboratory follow up included CBC, liver profile, electrolytes and lipid profile. First MRI brain done before Everolimus was started, and F/U MRI done at 3, 6, and 12 months after treatment onset, respectively. We evaluated seizure frequency, MRI finding and adverse effects including standard laboratory parameters. Results: Two of our patients became seizure free after Everolimus was started and 3rd one decreased seizure frequency. MRI finding reveled 30–50% size regression of SEGA in 2 patients, noted at 3 months F/U and no further decreasing after 1 year F/U was discerned. In 3rd one no size change of SEGA was achieved, but total resolution and regressive course of some tuberous nodules were found. No one side effect, except hypercholesterolemia was detected, with levels of 4.7–7.2 mmol/L, but have not required treatment withdrawal. One patient had previous cholesterol level on the higher side. Conclusion: Everolimus continues to demonstrate a sustained effect on SEGA tumor reduction. It remained well-tolerated with mild side effects such as hypercholesterolemia in all our patient and did not require medical treatment or reduction of Everolimus dosage.

Tuft of white hair dissappearance in a TSC patient treated with everolimus for SEGA

Objective: Tuberous sclerosis complex (TSC) predisposes to development of lesions within multiple organ systems, including brain, kidneys, heart, lungs, skin. Evidence supports and ongoing studies are further evaluating the role of mTOR inhibitors in the treatment of a wide spectrum of disease manifestations, including reduction in tumor volume (Subependimal giant cell astrocytomas - SEGAs, renal angiomyolipoma) and epilepsy improvement, lung function and skin manifestations, including facial angiofibromas. Methods: We report a 16 years old male with normal intellect who was diagnosed with definite TSC based on: multiple hypomelanic macules, facial angiofibromas, shagreen patch, cortical tubers, subependimal nodules, SEGA>1cm. The patient also has epilepsy with focal seizures (frequency 2 seizures/month). The patient also presented a tuft of white hair located in the vertex area of the head. He was treated with Everolimus for the growing subependimal giant cell astrocytoma (SEGA) associated to Tuberous Sclerosis Complex (TSC). Results: The results in this case were: SEGA volume reduction (brain MRI was repeated 3 months after the dose has been established) and cosmetic benefit – starting second day after treatment onset (angiofibromas became pale), consolidated at 3 month of treatment (almost not visible). Another good effect of Everolimus treatment was clinically relevant reduction in overall seizure frequency (one seizures/6 months). In the first 6 months of treatment the disappearance of the white hair tuft was noted. Conclusion: Everolimus provides a non-invasive method to treat SEGA or renal growing tumors associated to TSC. We describe a dermatologic positive effect of Everolimus – the disappearance of the tuft of white hair. This is a very rare clinical manifestation that may be associated to TSC clinical picture. In a PubMed search using the key words “everolimus dermatological effects”, “everolimus white hair”, “everolimus hair”, we did not find any other case reporting white hair disappearance under Everolimus treatment.

Clinical and imaging features of subependymal giant cell astrocytoma: report of 20 cases

BackgroundSubependymal giant cell astrocytoma (SEGA) is a clinically benign brain tumor associated with tuberous sclerosis complex (TSC). There are still controversies on early diagnosis of the tumor.MethodsCT and MR imaging of 20 patients with pathologically confirmed SEGA were retrospectively reviewed. Two radiologists evaluated the location, shape, size, number, edge, cerebral edema, homogeneous or heterogeneous appearance, attenuation and signal intensity, degree of enhancement and calcification of lesions. Their prognoses were based on clinical observations.ResultsSEGA showed similar features in imaging: an extra-axial, well-circumscribed, periventricular mass, isodense or slightly hyperdense on CT, hypointensity on T1-weighted imaging and isointensity to hyperintensity on T2-weighted imaging. The mass enhanced markedly and heterogeneously after the administration of contrast agent. Subependymal nodules were demonstrated in 5 cases. Remarkably, 17 patients (85%) showed ventricular dilatation and 14 patients (70%) showed calcification in CT and MR imaging. Moreover, perifocal edema was not significantly near the masses. Four cases are associated with tuberous sclerosis complex (TSC).ConclusionsAlthough there are no pathognomonic imaging findings for SEGA, the following clinical and imaging features might be helpful for the diagnosis, such as the initial age of first or second decade, typical location in the periventricular regions adjacent to the foramen of Monro, hydrocephalus accompanied with raised intracranial pressure, TSC and marked heterogeneous enhancement.

Hereditary tumor syndromes in neuropathology

Neoplasms in the central (CNS) and peripheral nervous system (PNS) in hereditary tumor syndromes play an important role in the neuropathological diagnostics. The benign and malignant PNS and CNS tumors that occur in the frequent neurofibromatosis type 1 (NF1) and type 2 (NF2) often represent essential factors for the course of the disease in those affected. Furthermore, certain clinical constellations (e.g. bilateral schwannomas of the auditory nerve, schwannomas at a young age and multiple meningiomas) can be important indications for a previously undiagnosed hereditary tumor disease. Other tumors occur practically regularly in association with certain germline defects, e.g. subependymal giant cell astrocytoma (SEGA) in tuberous sclerosis and dysplastic gangliocytoma of the cerebellum in Cowden's syndrome and can be indications in the diagnostics for an extended genetic counselling. This is not only important because many germline defects are based on new mutations, but also for the now established targeted therapy of certain tumors, e.g. inhibition of the mammalian target of rapamycin (mTOR) signaling pathway using temsirolimus for SEGA. Furthermore, knowledge about the possible constellations of genetic mosaics in hereditary tumor syndromes with the resulting (incomplete) syndrome manifestations is useful. This review article summarizes the most important hereditary tumor syndromes with involvement of the PNS and CNS.

Diagnosis, monitoring and treatment of tuberous sclerosis complex: A South African consensus response to international guidelines

Tuberous sclerosis complex (TSC) is a genetic disorder with multi-system manifestations and a high burden of disease. In 2013, an international panel of TSC experts revised the guidelines for the diagnosis, surveillance and treatment of the disorder. In South Africa (SA), a local multidisciplinary group of healthcare professionals and TSC researchers reviewed the international guidelines to generate an SA consensus clinical update on the identification, diagnosis, treatment and lifelong monitoring of individuals who live with TSC. We strongly endorse dissemination and use of the international guidelines for the assessment, monitoring and treatment of TSC. In addition, we strongly support access to genetic testing and to mTOR (mammalian target of rapamycin) inhibitors to treat subependymal giant cell astrocytomas not amenable to surgery and renal angiomyolipomas larger than 3 cm, and as adjunctive treatment for refractory focal seizures. We await with interest results from mTOR inhibitor trials of skin and TSC-associated neuropsychiatric disorders (TAND). With regard to training, we recommend the inclusion of TSC in undergraduate and postgraduate medical and health sciences curricula, and the promotion of other continuing professional development events to raise awareness about TSC. We also support the development of a TSC user/carer/parent organisation to provide an informal support network for families across SA. We acknowledge that some progress has been made in recent years in SA, but much remains to be done. We hope that this SA consensus clinical update based on the international guidelines will make a positive contribution to increase knowledge and improve clinical care for all patients who live with TSC in SA, and their families.

Abnormal Neural Progenitor Cells Differentiated from Induced Pluripotent Stem Cells Partially Mimicked Development of TSC2 Neurological Abnormalities.

SummaryTuberous sclerosis complex (TSC) is a disease featuring devastating and therapeutically challenging neurological abnormalities. However, there is a lack of specific neural progenitor cell models for TSC. Here, the pathology of TSC was studied using primitive neural stem cells (pNSCs) from a patient presenting a c.1444-2A>C mutation in TSC2. We found that TSC2 pNSCs had higher proliferative activity and increased PAX6 expression compared with those of control pNSCs. Neurons differentiated from TSC2 pNSCs showed enlargement of the soma, perturbed neurite outgrowth, and abnormal connections among cells. TSC2 astrocytes had increased saturation density and higher proliferative activity. Moreover, the activity of the mTOR pathway was enhanced in pNSCs and induced in neurons and astrocytes. Thus, our results suggested that TSC2 heterozygosity caused neurological malformations in pNSCs, indicating that its heterozygosity might be sufficient for the development of neurological abnormalities in patients.

Treatment of Renal Angiomyolipoma and Other Hamartomas in Patients with Tuberous Sclerosis Complex.

Tuberous sclerosis complex is an autosomal dominant genetic disease characterized by growth of benign tumors (hamartomas) in multiple organs, especially the kidneys, brain, heart, lungs, and skin. Tuberous sclerosis complex is usually caused by a mutation in either the tuberous sclerosis complex 1 or tuberous sclerosis complex 2 gene, resulting in constitutive activation of mammalian target of rapamycin signaling. Currently, mammalian target of rapamycin inhibitors are recommended in adult patients with tuberous sclerosis complex for the treatment of asymptomatic, growing renal angiomyolipoma that are >3 cm in diameter and pediatric or adult patients with brain lesions (subependymal giant cell astrocytoma) that either are growing or are not amenable to surgical resection. Clinical evidence suggests that systemic administration of a mammalian target of rapamycin inhibitor may provide concurrent improvements in multiple lesions and symptoms of tuberous sclerosis complex. With the major paradigm shift in consensus guidelines toward screening at diagnosis and ongoing monitoring and with the recent availability of an effective oral treatment, it is important that nephrologists have a thorough understanding of our role in the management of patients with tuberous sclerosis complex. Because the various manifestations of tuberous sclerosis complex typically emerge at different periods during patients' lifetimes, patients will need to be followed throughout their lives. Unlike brain and cardiac lesions, renal lesions are more likely to emerge as patients age and can grow at any time. Considerations regarding long-term medication administration for the potential control of multiple tuberous sclerosis complex manifestations will need to be addressed; these include the most appropriate starting dose, appropriate doses for tumor shrinkage versus prevention of regrowth, and management of adverse events. Best practices and potential obstacles for nephrologists treating patients with tuberous sclerosis complex who have multiple manifestations are considered.

Assessment of tumors in children with tuberous sclerosis: a single centre's experience.

As a result of mutations in TSC1 (9q34) and TSC2 (16p13.3) tumor supressor genes, the mammalian target of the rapamycin (mTor) signaling pathway is overactivated in patients with tuberous sclerosis. Abnormal cell proliferation and differentiation is responsible for the growth several different tumors. The aim of this study was to review tumors in our patients with tuberous sclerosis. Thirty-six patients with tuberous sclerosis were reviewed retrospectively in terms of age, sex, family history, clinical findings, presence of tumors, and treatments. Our study included 36 patients (18/18:M/F) aged between two days and 17 years with a median age of 6 years. There were hypopigmented spots in 30 patients, seizures in 28 patients, and a family history in 11 patients. Tumors related to tuberous sclerosis were renal angiomyolipomas in 21 patients, cardiac rhabdomyomas in 11, subependymal giant cell astrocytomas in seven, and non renal hamartoma in one patient. Everolimus treatment was used in only two patients because of hemodynamic instability. Tuberous sclerosis is a multisystemic disease characterized by the presence of various benign tumors and neurologic disorders. Renal angiomyolipomas, cardiac rhabdomyomas, and subependymal giant cell astrocytomas are commonly observed in patients with tuberous sclerosis. mTOR inhibitors such as everolimus and sirolimus have been increasingly used in the treatment of these tumors. However, the duration and optimal dose of mTOR inhibitors is still controversial and should be used in selected cases.

Risk factors for the development of autism spectrum disorder in children with tuberous sclerosis complex: protocol for a systematic review

BackgroundTuberous sclerosis complex (TSC) is an autosomal dominant condition, caused by mutations in either the TSC1 or TSC2 gene. It has widespread systemic manifestations and is associated with significant neurological morbidity. In addition to seizures and cerebral pathology including cortical tubers, subependymal nodules, subependymal giant cell astrocytoma and abnormal white matter, there are recognised neuropsychiatric difficulties including intellectual disability, autism spectrum disorder (ASD) and a range of learning and behaviour problems, recently conceptualised as “tuberous sclerosis-associated neuropsychiatric disorders”, or “TAND”. ASD in TSC is of particular importance because (1) it affects up to 50% of people with TSC and is a source of considerable difficulty for them and their families and (2) it provides a model for considering neurobiological pathways involved in ASD. Multiple factors are implicated in the development of ASD in TSC, including (1) seizures and related electrophysiological factors, (2) cerebral pathology, (3) genotype and (4) child characteristics. However, the neurobiological pathway remains unclear. We will conduct a systematic review to investigate and synthesise existing evidence about the role of these risk factors, individually and in combination, in leading to the development of ASD.MethodsOur review will report on all studies that include one or more of four predefined risk factors in the development of ASD in children with TSC. We will search five databases: MEDLINE, EMBASE, PubMed, The Cochrane Library and Web of Science (Conference Proceedings Citation Index). Studies will be selected for reporting after two authors independently (1) review all titles and abstracts, (2) read full text of all appropriate papers and (3) assess for bias using the Newcastle-Ottawa Scale recommended by the Guidelines for Meta-Analysis and Systematic Reviews of Observational Studies (MOOSE guidelines) and the ROBINS-I.DiscussionTo our knowledge, this is the first systematic review investigating multiple risk factors in the development of ASD in children with TSC. Clarifying the evidence in this area will be important to researchers in the field and to clinicians providing prognostic information to families.Systematic review registrationPROSPERO CRD42016042841

Thyroid transcription factor-1 distinguishes subependymal giant cell astrocytoma from its mimics and supports its cell origin from the progenitor cells in the medial ganglionic eminence

Subependymal giant cell astrocytoma is a benign brain tumor mostly associated with tuberous sclerosis complex. However, it may be misinterpreted as other high-grade brain tumors due to the presence of large tumor cells with conspicuous pleomorphism and occasional atypical features, such as tumor necrosis and endothelial proliferation. In this study, we first investigated thyroid transcription factor-1 (TTF-1) expression in a large series of subependymal giant cell astrocytomas and other histologic and locational mimics to validate the diagnostic utility of this marker. We then examined TTF-1 expression in non-neoplastic brain tissue to determine the cell origin of subependymal giant cell astrocytoma. Twenty-four subependymal giant cell astrocytoma specimens were subjected to tissue microarray construction. For comparison, a selection of tumors, including histologic mimics (21 gemistocytic astrocytomas and 24 gangliogliomas), tumors predominantly occurring at the ventricular system (50 ependymomas, 19 neurocytomas, and 7 subependymomas), and 134 astrocytomas (3 pleomorphic xanthoastrocytomas, 45 diffuse astrocytomas, 46 anaplastic astrocytomas, and 40 glioblastomas) were used. Immunohistochemical stain for TTF-1 was positive in all 24 subependymal giant cell astrocytomas, whereas negative in all astrocytomas, gangliogliomas, ependymomas, and subependymomas. Neurocytomas were positive for TTF-1 in 4/19 (21%) of cases using clone 8G7G3/1 and in 9/19 (47%) of cases using clone SPT24. In the three fetal brains that we examined, TTF-1 expression was seen in the medial ganglionic eminence, a transient fetal structure between the caudate nucleus and the thalami. There was no BRAFV600E mutation identified by direct sequencing in the 20 subependymal giant cell astrocytomas that we studied. In conclusion, TTF-1 is a useful marker in distinguishing subependymal giant cell astrocytoma from its mimics. Expression of TTF-1 in the fetal medial ganglionic eminence indicates that subependymal giant cell astrocytoma may originate from the progenitor cells in this region.

Clinicopathological features and microsurgical outcomes for giant pediatric intracranial tumor in 60 consecutive cases.

Giant pediatric intracranial tumor (GPIT) remains to be a challenging disease with high morbidity and mortality. The clinical data of 60 patients under 18years of age operated on with GPIT (≥5cm in diameter) were retrospectively analyzed. Gross total resection was achieved in 46 cases (77%) and subtotal resection was obtained in 14 cases (23%). Ninety percent (47/52) of the cases with obstructive hydrocephalus were resolved remarkably and only 10% (5/52) of the patients needed a ventriculoperitoneal shunt after tumor resection. Postoperative histopathological type revealed malignant brain tumors in 51 cases (85%). The most common neoplasm was medulloblastoma; other types include the following: ependymoma, pilocytic astrocytoma, mixed glioma, primitive neuroectoderm tumor (PNET), subependymal giant cell astrocytoma, gangliocytoma, gliosarcoma, choroid plexus carcinoma, and atypical teratoid rhabdoid tumor (AT/RT). Benign histopathological categories include the following: craniopharyngioma, choroid plexus papilloma, and meningioma. No death or serious complications occurred after the operation. However, transient subcutaneous effusion occurred in 14 patients postoperatively, nerve injury including the posterior cranial nerve in two cases and abduction nerve in one case, and mutism and pulmonary infection were observed in two cases, respectively. The follow-up period ranged from 1 to 72months, with an average of 32months. Poor prognosis occurred significantly in the high-grade malignant tumors and PNET, AT/RT, and gliosarcoma were implicated in the death of patients within 1year. To the best of our knowledge, the present study is the first description of clinicopathological features and the largest case analysis for GPIT. Optimal outcomes for GPIT were achieved by strict evaluation and perioperative management as well as microsurgical skills.

MicroRNA profiling of low-grade glial and glioneuronal tumors shows an independent role for cluster 14q32.31 member miR-487b

Low-grade (WHO I-II) gliomas and glioneuronal tumors represent the most frequent primary tumors of the central nervous system in children. They often have a good prognosis following total resection, however they can create many neurological complications due to mass effect, and may be difficult to resect depending on anatomic location. MicroRNAs have been identified as molecular regulators of protein expression/translation that can repress multiple mRNAs concurrently through base pairing, and have an important role in cancer, including brain tumors. Using the NanoString digital counting system, we analyzed the expression levels of 800 microRNAs in nine low-grade glial and glioneuronal tumor types (n=45). A set of 61 of these microRNAs were differentially expressed in tumors compared with the brain, and several showed levels varying by tumor type. The expression differences were more accentuated in subependymal giant cell astrocytoma, compared with other groups, and demonstrated the highest degree of microRNA repression validated by RT-PCR, including miR-129-2-3p, miR-219-5p, miR-338-3p, miR-487b, miR-885-5p, and miR-323a-3p. Conversely, miR-4488 and miR-1246 were overexpressed in dysembryoplastic neuroepithelial tumors compared with the brain and other tumors. The cluster 14q32.31 member miR-487b was variably under-expressed in pediatric glioma lines compared with human neural stem cells. Overexpression of miR-487b in a pediatric glioma cell line (KNS42) using lentiviral vectors led to a decrease in colony formation in soft agar (30%) (P<0.05), and decreased expression of known predicted targets PROM1 and Nestin (but not WNT5A). miR-487b overexpression had no significant effect on cell growth, proliferation, sensitivity to temozolomide, migration, or invasion. In summary, microRNA regulation appears to have a role in the biology of glial and glioneuronal tumor subtypes, a finding that deserves further investigation.

Unique findings of subependymal giant cell astrocytoma within cortical tubers in patients with tuberous sclerosis complex: a histopathological evaluation.

Tuberous sclerosis is associated with three central nervous system pathologies: cortical/subcortical tubers, subependymal nodules (SENs), and subependymal giant cell astrocytomas (SEGAs). Tubers are associated with epilepsy, which is often medication-resistant and often leads to resective surgery. Recently, mammalian target of rapamycin inhibitors (mTORi) have been shown to be effective reducing seizure burden in some patients with tuberous sclerosis complex (TSC)-related refractory epilepsy. mTORi have also been shown to be an alternative for surgery treating SEGAs. We describe several cases of resected tubers that contained SEGA tissue without an intraventricular SEGA. After institutional review board (IRB) protocol approval, we retrospectively reviewed the surgical-pathological data for all TSC patients who underwent cortical resections for treatment of refractory epilepsy at NYU Langone Medical Center and Tel Aviv Medical Center between 2003 and 2013. Data included demographics, epilepsy type, MRI characteristics, epilepsy outcome, and histopathological staining. We reviewed cortical resections from 75 patients with complete pathological studies. In three patients, cortical lesions demonstrated histopathological findings consistent with a SEGA within the resected tuber tissue, with no intraventricular SEGA. All lesions were cortically based and none had any intraventricular extension. No patient had been treated before surgery with an mTORi. Two of the three patients remain Engel grade I-II. All lesions stained positive for glial fibrillary acidic protein (GFAP), synaptophysin, and neuronal nuclear antigen (NeuN). This is the first description of cortical tubers harboring SEGA tissue. This observation though preliminary may suggest a subgroup of patients with intractable epilepsy in whom mTORi may be considered before surgical intervention.

TuberOus SClerosis registry to increase disease Awareness (TOSCA) \u2013 baseline data on 2093 patients

BackgroundTuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder. Many gaps remain in the understanding of TSC because of the complexity in clinical presentation. The TuberOus SClerosis registry to increase disease Awareness (TOSCA) is an international disease registry designed to address knowledge gaps in the natural history and management of TSC. Here, we present the baseline data of TOSCA cohort.MethodsPatients of any age diagnosed with TSC, having a documented visit for TSC within the preceding 12 months, or newly diagnosed individuals were included. The registry includes a “core” section designed to record detailed background information on each patient including disease manifestations, interventions, and outcomes collected at baseline and updated annually. “Subsections” of the registry recorded additional data related to specific features of TSC.ResultsBaseline “core” data from 2093 patients enrolled from 170 sites across 31 countries were available at the cut-off date September 30, 2014. Median age of patients at enrollment was 13 years (range, 0–71) and at diagnosis of TSC was 1 year (range, 0–69). The occurrence rates of major manifestations of TSC included – cortical tubers (82.2%), subependymal nodules (78.2%), subependymal giant cell astrocytomas (24.4%), renal angiomyolipomas (47.2%), lymphangioleiomyomatosis (6.9%), cardiac rhabdomyomas (34.3%), facial angiofibromas (57.3%), forehead plaque (14.1%), ≥ 3 hypomelanotic macules (66.8%), and shagreen patches (27.4%). Epilepsy was reported in 1748 (83.5%) patients, of which 1372 were diagnosed at ≤ 2 years (78%). Intellectual disability was identified in 451 (54.9%) patients of those assessed. TSC-associated neuropsychiatric disorders (TAND) were diagnosed late, and not evaluated in 30–50% of patients.ConclusionTOSCA is the largest clinical case series of TSC to date. It provided a detailed description of the disease trajectory with increased awareness of various TSC manifestations. The rates of different features of TSC reported here reflect the age range and referral patterns of clinics contributing patients to the cohort. Documentation of TAND and LAM was poor. A widespread adoption of the international TSC assessment and treatment guidelines, including use of the TAND Checklist, could improve surveillance. The registry provides valuable insights into the necessity for monitoring, timing, and indications for the treatment of TSC.

Everolimus Alleviates Obstructive Hydrocephalus due to Subependymal Giant Cell Astrocytomas

BackgroundSubependymal giant cell astrocytomas (SEGAs) are low-grade tumors affecting up to 20% of patients with tuberous sclerosis complex (TSC). Early neurosurgical resection has been the only standard treatment until few years ago when a better understanding of the molecular pathogenesis of TSC led to the use of mammalian target of rapamycin (mTOR) inhibitors. Surgical resection of SEGAs is still considered as the first line treatment in individuals with symptomatic hydrocephalus and intratumoral hemorrhage. We describe four patients with symptomatic or asymptomatic hydrocephalus who were successfully treated with the mTOR inhibitor everolimus. MethodsWe collected the clinical data of four consecutive patients presenting with symptomatic or asymptomatic hydrocephalus due to a growth of subependymal giant cell atrocytomas and who could not undergo surgery for different reasons. ResultsAll patients experienced a clinically significant response to everolimus and an early shrinkage of the SEGA with improvement in ventricular dilatation. Everolimus was well tolerated by all individuals. ConclusionsOur clinical series demonstrate a possible expanding indication for mTOR inhibition in TSC, which can be considered in patients with asymptomatic hydrocephalus or even when the symptoms already appeared. It offers a significant therapeutic alternative to individuals that once would have undergone immediate surgery. Everolimus might also allow postponement of a neurosurgical resection, making it elective with an overall lower risk.