Radiomic- and dosiomic-based clustering development for radio-induced neurotoxicity in pediatric medulloblastoma.

BACKGROUND: Texture analysis extracts many quantitative image features, offering a valuable, cost-effective, and non-invasive approach for individual medicine. Furthermore, multimodal machine learning could have a large impact for precision medicine, as texture biomarkers can underlie tissue microstructure. This study aims to investigate imaging-based biomarkers of radio-induced neurotoxicity in pediatric patients with metastatic medulloblastoma, using radiomic and dosiomic analysis. METHODS: This single-center study retrospectively enrolled children diagnosed with metastatic medulloblastoma (MB) and treated with hyperfractionated craniospinal irradiation (CSI). Histological confirmation of medulloblastoma and baseline follow-up magnetic resonance imaging (MRI) were mandatory. Treatment involved helical tomotherapy (HT) delivering a dose of 39 Gray (Gy) to brain and spinal axis and a posterior fossa boost up to 60 Gy. Clinical outcomes, such as local and distant brain control and neurotoxicity, were recorded. Radiomic and dosiomic features were extracted from tumor regions on T1, T2, FLAIR (fluid-attenuated inversion recovery) MRI-maps, and radiotherapy dose distribution. Different machine learning feature selection and reduction approaches were performed for supervised and unsupervised clustering. RESULTS: Forty-eight metastatic medulloblastoma patients (29 males and 19 females) with a mean age of 12 ± 6 years were enrolled. For each patient, 332 features were extracted. Greater level of abstraction of input data by combining selection of most performing features and dimensionality reduction returns the best performance. The resulting one-component radiomic signature yielded an accuracy of 0.73 with sensitivity, specificity, and precision of 0.83, 0.64, and 0.68, respectively. CONCLUSIONS: Machine learning radiomic-dosiomic approach effectively stratified pediatric medulloblastoma patients who experienced radio-induced neurotoxicity. Strategy needs further validation in external dataset for its potential clinical use in ab initio management paradigms of medulloblastoma.

Paediatric endoscopic endonasal middle skull base reconstruction: retrospective analysis of 78 patients treated in a single tertiary care paediatric center.

INTRODUCTION: Skull base pathologies in the paediatric population are rare and require treatment by multiple qualified specialists. The endoscopic endonasal approach has revolutionized surgical treatment because it is less invasive than existing treatments.The goal of this study was to retrospectively review our experience with the reconstruction of paediatric skull middle base defects and associated complications. MATERIALS AND METHODS: We analysed medical records from patients aged ≤ 18 years who were treated at our centre between 2013 and 2021. Patients treated with an endoscopic skull base approach and reconstruction, and who had complete clinical and radiological documentation and a minimum follow-up of 12 months, were included in the analysis. Personal data, reconstructive techniques, and complications were analysed. RESULTS: A total of 78 patients met the inclusion criteria and were enrolled in the study. Of these patients, 32 were male and 46 were female, and the mean age was 11.5 years. The main signs and symptoms were as follows: bitemporal hemianopsia in 53 cases, visual impairment in 23 cases, and headache in 30 cases. The most frequent aetiologies were craniopharyngioma (38 cases), pituitary adenoma (23 cases), and clivus chordoma (4 cases). All patients were treated via a pure endoscopic approach. For reconstruction, a multilayer technique was used in 18 cases, naso-septal flap in 43 cases, Gasket-Seal technique in 12 cases, and heterologous reconstruction in 5 cases. Only six patients presented a major complication: two had a postoperative cerebral spinal fluid leak, one developed a brain abscess, and three had diabetes insipidus.The mean follow-up period was 23.4 months.There were no statistically significant differences in postoperative CSF leak in relation to different reconstructive techniques. CONCLUSION: Endoscopic endonasal skull base surgery is a safe and effective treatment for paediatric middle skull base pathologies. Reconstruction techniques have a high success rate of 96.5-100%, and the rate of associated complications is < 3%.

Loculated hydrocephalus: is neuroendoscopy effective and safe? A 90 patients' case series and literature review.

INTRODUCTION: Loculated hydrocephalus is a complex condition in which different non-communicating compartments form within the ventricular system due to different etiology, mainly intraventricular hemorrhage and infection. Since the end of the twentieth century, neuroendoscopy has been explored as a therapeutic option for loculated hydrocephalus with non-univocal results. METHODS: We performed a retrospective analysis of 90 patients who underwent endoscopic treatment for loculated hydrocephalus from January 1997 to January 2021 (mean age: 2 years, range 7-21). We included 37 (41.1%) children with multiloculated hydrocephalus, 37 (41.1%) with isolated lateral ventricle, 13 (14.4%) with excluded temporal horn, and 3 (3.3%) with isolated fourth ventricle. We compared our results with those available in literature. RESULTS: A mean of 1.91 endoscopic procedure/patient were performed (only one endoscopy in 42.2% of cases). Complications of neuroendoscopy and of shunt surgeries were recorded in 17 (18.9%) and 52 (57.8%) children, respectively. Twenty-six (28.9%) children were shunt-free at the last follow-up, 47.8% have only one shunt. DISCUSSION: The first goal of neuroendoscopy is to increase the rate of shunt-free patients but, when it is not possible, it aims at simplifying shunt system and reducing the number of surgical procedures. In our series, neuroendoscopy was able to achieve both these goals with an acceptable complication rate. Thus, our results confirmed neuroendoscopy as a valid tool in the long-term management of loculated hydrocephalus. Neuronavigation and intraoperative ultrasound could increase the success rate in cases with distorted anatomy.

Distinct DNA Methylation Patterns of Subependymal Giant Cell Astrocytomas in Tuberous Sclerosis Complex.

Tuberous sclerosis complex (TSC) is a monogenic disorder caused by mutations in either the TSC1 or TSC2 gene, two key regulators of the mechanistic target of the rapamycin complex pathway. Phenotypically, this leads to growth and formation of hamartomas in several organs, including the brain. Subependymal giant cell astrocytomas (SEGAs) are low-grade brain tumors commonly associated with TSC. Recently, gene expression studies provided evidence that the immune system, the MAPK pathway and extracellular matrix organization play an important role in SEGA development. However, the precise mechanisms behind the gene expression changes in SEGA are still largely unknown, providing a potential role for DNA methylation. We investigated the methylation profile of SEGAs using the Illumina Infinium HumanMethylation450 BeadChip (SEGAs n = 42, periventricular control n = 8). The SEGA methylation profile was enriched for the adaptive immune system, T cell activation, leukocyte mediated immunity, extracellular structure organization and the ERK1 & ERK2 cascade. More interestingly, we identified two subgroups in the SEGA methylation data and show that the differentially expressed genes between the two subgroups are related to the MAPK cascade and adaptive immune response. Overall, this study shows that the immune system, the MAPK pathway and extracellular matrix organization are also affected on DNA methylation level, suggesting that therapeutic intervention on DNA level could be useful for these specific pathways in SEGA. Moreover, we identified two subgroups in SEGA that seem to be driven by changes in the adaptive immune response and MAPK pathway and could potentially hold predictive information on target treatment response.

Clinical-pathological study of 28 glial and mixed neuronal-glial tumors diagnosed within the first year of life.

Our purpose was to investigate the incidence of gliomas and neuronal-glial tumors, their outcome, and H3.3K27M, BRAFV600E, and IDH status in children within 1 year of age affected by CNS tumor. We collected 28 consecutive gliomas and mixed tumors. Immunohistochemistry and/or molecular analyses were performed on formalin-fixed/paraffin-embedded specimens. 24 (86%) tumors were supratentorial. 15 (54%) tumors were astrocytomas (5 glioblastomas, 1 anaplastic astrocytoma, 1 pilocytic astrocytoma, 3 pilomixoid astrocytomas, 2 subependymal giant cell astrocytomas, 3 astrocytomas not otherwise specified (NOS)), 4 (14%) were anaplastic ependymomas, and 9 (32%) were mixed tumors (5 gangliogliomas, 2 gangliocytomas, 2 desmoplastic infantile gangliogliomas (DIGs)). Alive patients were: 4 (67%) affected by high-grade astrocytoma (mean follow-up 64 months), 4 (67%) affected by low-grade astrocytoma (mean follow-up 83 months), 2 (67%) affected by astrocytoma NOS (mean follow-up 60 months), 1 (25%) affected by anaplastic ependymoma (follow-up 12 months), and 9 (100%) affected by mixed tumors (mean follow-up 74 months). H3.3K27M and IDH were not-mutated in any tumor (100%). BRAFV600E mutation was documented in 6 (21%) tumors (4 gangliogliomas, 1 gangliocytoma, and 1 astrocytoma NOS resulted as anaplastic pleomorphic xanthoastrocytoma 8 years later). Gliomas and mixed tumors diagnosed within 1 year of age are morphologically heterogeneous. Moreover, analogously to those affecting older children, they are IDH1-2 and H3.3K27M (when located outside midline) not-mutated while BRAFV600E mutation is typical of gangliogliomas/gangliocytomas and pleomorphic xanthoastrocytomas. High-grade astrocytomas have a more favorable prognosis compared with the same lesions occurring later in life while ependymomas have a poorer outcome.

Airgun Wound with Superior Sagittal Sinus Involvement in a Child: Case Report and Review of the Literature.

INTRODUCTION: Although still considered quite harmless, nonpowder guns (NPG) may cause severe head injuries in children. We present the case of a depressed skull fracture with superior sagittal sinus involvement following NPG injury. Decision-making and surgical management are discussed, and the current literature concerning NPG-related pediatric head injuries is reviewed. CASE PRESENTATION: A 4-year-old boy hit by a compressed-air rifle came to our center. CT scan showed a depressed skull fracture of the occipital bone on the midline and intracranial penetration of some fragments of the pellet. CT angiography documented a compression of the superior sagittal sinus without thrombosis. Soon after hospital admission, the patient showed deterioration of the neurological status suggesting intracranial hypertension. Surgery was performed with fracture elevation, removal of metal fragments, and wound debridement. The patient had a full recovery without subsequent neurological deficits. DISCUSSION/CONCLUSION: Modern airguns may produce severe penetrating head injuries in children. Parents and physicians should be aware of the danger of NPG. Depressed skull fracture and dural venous sinus involvement can occur, and even a stable neurological condition may worsen. In such instances, a thorough preoperative assessment including vascular imaging is mandatory. The surgical risk is not negligible due to the possible injury of the sinus wall and subsequent intraoperative bleeding. This has to be weighted against potential complications of the penetrating injury, such as infection, sinus thrombosis, and intracranial hypertension. Our case suggests that prompt surgical treatment can be a safe and effective option.

Endoscopic Endonasal Treatment of Intra-Axial Ventral Brainstem Cavernomas: Case Experience and Literature Review.

INTRODUCTION: Cavernous malformations of the ventral brainstem are a challenging disease to treat. From an anatomical perspective, the best surgical options are endoscopic endonasal approaches. The first reports of their usage for this purpose date back to 2012. In this study, we gathered data on the subject, share our experience, and outline technical notes and tips for this surgery. CASE PRESENTATION: We report a 14-year-old female with a ventral pons cavernoma, treated using an endoscopic endonasal transclival approach and followed-up for 5.9 years. This is the longest reported follow-up for this condition to date. Written informed consent was obtained from the patient for publication of this case report and the accompanying images. DISCUSSION: An endoscopic endonasal transclival approach was used. The skull base was reconstructed using the multilayer grafting technique and a nasoseptal flap. There was no postoperative cerebrospinal fluid leakage. In a literature review, we identified 8 patients who were treated endoscopically: 1 transplanum-transtuberculum, 1 transtuberculum-transclival, and 6 transclival approaches were employed. Skull base closure was achieved using multilayer grafting and a nasoseptal flap in 4 cases, a gasket seal technique combined with nasoseptal flap in 3 cases and a periumbilical fat graft, fibrin sealant patch, and fibrin glue in 1 case. There were 2 cases of leakage, which resolved completely with revision surgery. CONCLUSION: Endoscopic surgery is a reliable alternative to traditional open surgery. It may be the preferred choice for intra-axial ventral brain cavernomas.

Chiari 1 malformation and exome sequencing in 51 trios: the emerging role of rare missense variants in chromatin-remodeling genes.

Type 1 Chiari malformation (C1M) is characterized by cerebellar tonsillar herniation of 3-5 mm or more, the frequency of which is presumably much higher than one in 1000 births, as previously believed. Its etiology remains undefined, although a genetic basis is strongly supported by C1M presence in numerous genetic syndromes associated with different genes. Whole-exome sequencing (WES) in 51 between isolated and syndromic pediatric cases and their relatives was performed after confirmation of the defect by brain magnetic resonance image (MRI). Moreover, in all the cases showing an inherited candidate variant, brain MRI was performed in both parents and not only in the carrier one to investigate whether the defect segregated with the variant. More than half of the variants were Missense and belonged to the same chromatin-remodeling genes whose protein truncation variants are associated with severe neurodevelopmental syndromes. In the remaining cases, variants have been detected in genes with a role in cranial bone sutures, microcephaly, neural tube defects, and RASopathy. This study shows that the frequency of C1M is widely underestimated, in fact many of the variants, in particular those in the chromatin-remodeling genes, were inherited from a parent with C1M, either asymptomatic or with mild symptoms. In addition, C1M is a Mendelian trait, in most cases inherited as dominant. Finally, we demonstrate that modifications of the genes that regulate chromatin architecture can cause localized anatomical alterations, with symptoms of varying degrees.

The coding and non-coding transcriptional landscape of subependymal giant cell astrocytomas.

Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited neurocutaneous disorder caused by inactivating mutations in TSC1 or TSC2, key regulators of the mechanistic target of rapamycin complex 1 (mTORC1) pathway. In the CNS, TSC is characterized by cortical tubers, subependymal nodules and subependymal giant cell astrocytomas (SEGAs). SEGAs may lead to impaired circulation of CSF resulting in hydrocephalus and raised intracranial pressure in patients with TSC. Currently, surgical resection and mTORC1 inhibitors are the recommended treatment options for patients with SEGA. In the present study, high-throughput RNA-sequencing (SEGAs n = 19, periventricular control n = 8) was used in combination with computational approaches to unravel the complexity of SEGA development. We identified 9400 mRNAs and 94 microRNAs differentially expressed in SEGAs compared to control tissue. The SEGA transcriptome profile was enriched for the mitogen-activated protein kinase (MAPK) pathway, a major regulator of cell proliferation and survival. Analysis at the protein level confirmed that extracellular signal-regulated kinase (ERK) is activated in SEGAs. Subsequently, the inhibition of ERK independently of mTORC1 blockade decreased efficiently the proliferation of primary patient-derived SEGA cultures. Furthermore, we found that LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5 were overexpressed at both gene and protein levels in SEGA compared to control tissue. Taken together LAMTOR1-5 can form a complex, known as the 'Ragulator' complex, which is known to activate both mTORC1 and MAPK/ERK pathways. Overall, this study shows that the MAPK/ERK pathway could be used as a target for treatment independent of, or in combination with mTORC1 inhibitors for TSC patients. Moreover, our study provides initial evidence of a possible link between the constitutive activated mTORC1 pathway and a secondary driver pathway of tumour growth.

Exclusive Neurogenic Bladder and Fecal Incontinency in an Achondroplasic Child Successfully Treated with Lumbar Foraminal Decompression.

INTRODUCTION: Achondroplasia is a genetic disorder characterized by defects in the development of endochondral bone resulting in skeletal abnormalities like stenosis of the foramen magnum and of the spine, shortened limb bones, and macrocephaly. Congenital spinal stenosis is frequent and due to premature fusion of the pedicles to the laminae. CASE PRESENTATION: We report a case of neurogenic bladder and fecal incontinence due to lumbar stenosis successfully treated with L1-L5 partial laminectomy and foraminotomy in a 7-year-old achondroplasic child. DISCUSSION/CONCLUSION: To our knowledge, this is the first case report of exclusive neurogenic bladder and fecal incontinence in an achondroplasic child. Neurogenic bladder and fecal incontinence without motor impairment may be early and exclusive clinical findings of lumbar stenosis in children with achondroplasia.

Dysembryoplastic neuroepithelial tumors: A single-institutional series with special reference to glutamine synthetase expression.

Dysembryoplastic neuroepithelial tumors (DNT) is a benign (World Health Organisation, WHO, grade I) glioneuronal tumor and it represent one of the most frequent neoplasm in patient affected by seizures. The epileptic neuronal activity can be determined by abnormal synchronization, excessive glutamate excitation and\or inadequate GABA inhibition. Increasing evidence suggests that the astrocytes might be involved in this process even if neurons play a relevant role. In particular astrocytes promote the clearance of glutamate, a potent excitatory neurotransmitter of the central nervous system. Indeed, elevated concentrations of extracellular glutamate may determine iper-excitability and seizures as well as other neurological disorders. So, astrocytes, converting glutamate into glutamine via the enzyme glutamine synthetase (GS), could play a protective anti-seizures role. In the present study, we analyzed the immunohistochemical expression of GS in 20 DNTs specimens documenting a constant immunoistochemical expression of GS in astrocytes of the lesional tissue and of the cerebral cortex.

Neurosurgical treatment of subependymal giant cell astrocytomas in tuberous sclerosis complex: a series of 44 surgical procedures in 31 patients.

BACKGROUND: Subependymal giant cell astrocytomas (SEGA) are benign tumors characteristic of tuberous sclerosis complex (TSC) that may cause hydrocephalus. Various treatments are nowadays available as mTOR inhibitors or surgery. Surgery is still a valid option especially for symptomatic and larger tumors. METHODS: From January 1994 to December 2015, 31 TSC patients harboring SEGA underwent surgery at the Department of Neurosurgery of the Meyer Pediatric Hospital, Florence. Indications for surgery were tumor size and location, growth and cystization/hemorrhage, and hydrocephalus. Clinical data, preoperative and postoperative MRI, recurrence rate, further surgical procedures, and related complications were analyzed. RESULTS: A total of 44 surgeries were performed in 31 TSC patients affected by SEGA, achieving gross total removal (GTR) and subtotal removal (STR), respectively, in 36 and 8 patients. Recurrences occurred in 11 patients; 9 of them underwent further surgical procedures and 2 were treated with mTOR pathway inhibitors. Surgical morbidity and mortality were, respectively, 22.7% and 2.3%. After a mean follow-up of 4.9 years, 90% of patients were tumor-free with good neurological status in 93.3%; twelve (40%) had a ventriculo-peritoneal shunt (VPS) for hydrocephalus. CONCLUSIONS: The present series confirms that the surgical approach, combined with mTOR inhibitors, is still a valid option for the treatment of SEGAs.

Post-mortem histopathology of a pediatric brain after bilateral DBS of GPI for status dystonicus: case report and review of the literature.

PURPOSE: To investigate the effects of deep brain stimulation (DBS) electrodes on the brain of a dystonic pediatric patient submitted to bilateral DBS of the globus pallidus internus (GPI). METHODS: An 8-year-old male patient underwent bilateral DBS of GPI for status dystonicus. He died 2 months later due to multiorgan failure triggered by bacterial pneumonia. A post-mortem pathological study of the brain was done. RESULTS: At visual inspection, no grossly apparent softening, hemorrhage, or necrosis of the brain adjacent to the DBS lead tracts was detected. High-power microscopic examination of the tissue surrounding the electrode trajectories showed lymphocyte infiltration, astrocytic gliosis, microglia, macrophages, and clusters of multinucleate giant cells. Significant astrocytosis was confirmed by GFAP staining in the electrode site. The T cell lymphocyte activity was overexpressed with activated macrophages detected with CD3, CD20, CD45, and CD68 stains respectively. There was no gliosis or leukocyte infiltration away from the surgical tracks of the electrodes. CONCLUSION: This is the first post-mortem examination of a child's brain after bilateral DBS of GPI. The comparison with adult post-mortem reports showed no significant differences and confirms the safety of DBS implantation in the pediatric population too.

Outcome after hemispherotomy in patients with intractable epilepsy: Comparison of techniques in the Italian experience.

OBJECTIVE: The objective of the study was to evaluate clinical characteristics and outcome of hemispherotomy in children and adolescents with hemispheric refractory epilepsy in an Italian cohort of patients. METHODS: We retrospectively evaluated the clinical course and outcome of 92 patients with refractory epilepsy who underwent hemispherotomy in three Italian epilepsy centers between 2006 and 2016. Three different approaches for hemispherotomy were used: parasagittal, modified parasagittal, and lateral. RESULTS: Mean age at epilepsy onset was 1.8 ±â€¯2.51 years, and mean duration of epilepsy prior to surgery was 7.4 ±â€¯5.6 years. Mean age at surgery was 9.2 ±â€¯8.0 years. After a mean follow-up of 2.81 ±â€¯2.4 years, 66 of 90 patients (two lost from follow-up, 73.3%) were seizure-free (Engel class I). The etiology of epilepsy was related to acquired lesions (encephalomalacia or gliosis) in 44 patients (47.8%), congenital malformations (cortical dysplasia, hemimegalencephaly, other cortical malformations) in 38 (41.3%), and progressive conditions (Rasmussen or Sturge-Weber syndrome) in 10 patients (10.9%). Regarding seizure outcome, we could not identify statistically significant differences between vertical and lateral approaches (p = 0.154). Seizure outcome was not statistically different in patients with congenital vs acquired or progressive etiologies (p = 0.43). Acute postoperative seizures (APOS) correlated with poor outcome (p < 0.05). On multivariate analysis, presurgical focal to bilateral tonic-clonic seizures (Odds Ratio (OR) = 3.63, 95% Confidence Interval (CI): 1.86-15.20, p = 0.048) independently predicted seizure recurrence. Twenty-one patients (22.8%) exhibited postoperative complications, with no unexpected and persistent neurological deficit. More than 50% of the patients completely tapered drugs. SIGNIFICANCE: Our data confirm hemispherotomy to be a safe and effective procedure in patients with drug resistant epilepsies due to hemispheric lesions. Presurgical focal to bilateral tonic-clonic seizures are the strongest predictor of seizure recurrence after surgery, independently from the type of hemispherotomy.

The use of opioids in children receiving intrathecal baclofen therapy.

PURPOSE: We hypothesized that children on chronic intrathecal baclofen therapy (ITB) may require less analgesics for postoperative pain control and are at higher risk of developing opioid-induced respiratory depression postoperatively. The aims of this study are to review children on chronic intrathecal baclofen therapy receiving opioids after major surgery and to determine the incidence complications in this population. METHOD: We conducted a retrospective cohort study comparing 13 children on ITB, who underwent posterior spinal fusion surgery, to 17 children with spina bifida that received the same surgery. RESULTS: On postoperative day 0 (POD 0), four children (40%) had respiratory depression in the baclofen group compared to none in the control group. Desaturation was significantly more frequent in children in the ITB group compared to those of the control group on POD 0; oversedation was recorded in 8 (80%) children in the baclofen group vs. 3 (17.6%) in the control group. Desaturation, respiratory depression, and oversedation were significantly more frequent on POD 0 in children in the baclofen group compared with children in the control group. CONCLUSIONS: The findings of the current study suggest that children on chronic intrathecal baclofen therapy require lesser amounts of opioids for postoperative pain control and are at a greater risk of developing postoperative respiratory depression and excessive sedation compared to patients without baclofen therapy.

Pediatric intracranial ependymoma: correlating signs and symptoms at recurrence with outcome in the second prospective AIEOP protocol follow-up.

PURPOSE: The aims of patients' radiological surveillance are to: ascertain relapse; apply second-line therapy; accrue patients in phase 1/2 protocols if second-line therapy is not standardized/curative; and assess/treat iatrogenic effects. To lessen the emotional and socioeconomic burdens for patients and families, we ideally need to establish whether scheduled radiological surveillance gives patients a better outcome than waiting for symptoms and signs to appear. METHODS: We analyzed a prospective series of 160 newly-diagnosed and treated pediatric/adolescent patients with intracranial ependymoma, comparing patients with recurrent disease identified on scheduled MRI (the RECPT group; 34 cases) with those showing signs/symptoms of recurrent disease (the SYMPPT group; 16 cases). The median follow-up was 67 months. RESULTS: No significant differences emerged between the two groups in terms of gender, age, tumor grade/site, shunting, residual disease, or type of relapse (local, distant, or concomitant). The time to relapse (median 19 months; range 5-104) and the MRI follow-up intervals did not differ between the SYMPPT and RECPT groups. The presence of signs/symptoms was an unfavorable factor for overall survival (OS) after recurrence (5-year OS: 8% vs. 37%, p = 0.001). On multivariable analysis, an adjusted model confirmed a significantly worse OS in the SYMPPT than in the RECPT patients. CONCLUSIONS: Symptomatic relapses carried a significantly worse survival for ependymoma patients than recurrences detected by MRI alone. It would therefore be desirable to identify recurrences before symptoms develop. Radiological follow-up should be retained in ependymoma patient surveillance because there is a chance of salvage treatment for relapses found on MRI.

Glioblastoma Chemoresistance: The Double Play by Microenvironment and Blood-Brain Barrier.

For glioblastoma, the tumor microenvironment (TME) is pivotal to support tumor progression and therapeutic resistance. TME consists of several types of stromal, endothelial and immune cells, which are recruited by cancer stem cells (CSCs) to influence CSC phenotype and behavior. TME also promotes the establishment of specific conditions such as hypoxia and acidosis, which play a critical role in glioblastoma chemoresistance, interfering with angiogenesis, apoptosis, DNA repair, oxidative stress, immune escape, expression and activity of multi-drug resistance (MDR)-related genes. Finally, the blood brain barrier (BBB), which insulates the brain microenvironment from the blood, is strongly linked to the drug-resistant phenotype of glioblastoma, being a major physical and physiological hurdle for the delivery of chemotherapy agents into the brain. Here, we review the features of the glioblastoma microenvironment, focusing on their involvement in the phenomenon of chemoresistance; we also summarize recent advances in generating systems to modulate or bypass the BBB for drug delivery into the brain. Genetic aspects associated with glioblastoma chemoresistance and current immune-based strategies, such as checkpoint inhibitor therapy, are described too.

Vagus nerve stimulation: Surgical technique of implantation and revision and related morbidity.

Indications for vagus nerve stimulation (VNS) therapy include focal, multifocal epilepsy, drop attacks (tonic/atonic seizures), Lennox-Gastaut syndrome, tuberous sclerosis complex (TSC)-related multifocal epilepsy, and unsuccessful resective surgery. Surgical outcome is about 50-60% for seizures control, and may also improve mood, cognition, and memory. On this basis, VNS has also been proposed for the treatment of major depression and Alzheimer's' disease. The vagus nerve stimulator must be implanted with blunt technique on the left side to avoid cardiac side effects through the classic approach for anterior cervical discectomy. The actual device is composed of a wire with three helical contacts (two active contacts, one anchoring) and a one-pin battery. VNS is usually started 2 weeks after implantation with recommended settings of stimulation (1.0-2.0 mA; 500 µs pulse width; 20-30 Hz; 30 s ON, 5 min OFF). The complications of VNS therapy are early (related to surgery) and late (related to the device and to stimulation of the vagus nerve). Early complications include the following: intraoperative bradycardia and asystole during lead impedance testing, peritracheal hematoma, infections (3-8%), and vagus nerve injury followed by hoarseness, dyspnea, and dysphagia because of left vocal cord paralysis. Delayed morbidity due to the device includes late infections or problems in wound healing; other more rare events are due to late injury of the nerve. Late complications due to nerve stimulation include delayed arrhythmias, laryngopharyngeal dysfunction (hoarseness, dyspnea, and coughing), obstructive sleep apnea, stimulation of phrenic nerve, tonsillar pain mimicking glossopharyngeal neuralgia, and vocal cord damage during prolonged endotracheal intubation. The laryngopharyngeal dysfunction occurs in about 66% of patients and is usually transitory and due to the stimulation of the inferior (recurrent) laryngeal nerve. A true late paralysis of the left vocal cord is often partial and rare (1-2.7%), and usually transitory, and may be caused by previous surgical trauma (i.e., damage of nerve fibers and/or of their blood supply) or to a supposed chronic denervation during stimulation. Surgery for complete removal or revision and replacement of the device is to be considered in cases of device malfunction (4-16.8%), failure of VNS therapy, intolerable side effects, or because of patient's specific request. As described in the literature, the surgical techniques of lead revision and replacement are two: sharp and blunt dissection of helical electrodes and replacement; and blunt dissection combined with ultrasharp low-voltage cautery dissection. The incidence of left vocal cord palsy after vagus nerve stimulator replacement/revision is slightly higher than that of first implantation (4.9% vs. 3.8%). A de novo implantation in a naive segment of the left or right vagus nerve may be considered in specific cases; the use of the right vagus nerve is a rare exception that may be chosen with an acceptable result.

Cognitive outcome after epilepsy surgery in children: A controlled longitudinal study.

OBJECTIVE: To analyze the determinants of cognitive outcome two years after surgery for drug-resistant epilepsy in a cohort of 31 children when compared to a control group of 14 surgical candidates who had yet to undergo surgery two years after the first neuropsychological assessment. METHODS: Controlled longitudinal study including three evaluations of IQ (Intelligence Quotient) scores or GDQ (General Developmental Quotient) for each group depending on the patient's age: prior to surgery (T0), one year (T1) and two years (T2) after surgery for the surgical group; baseline (T0) and one year (T1) and 2years (T2) after the first evaluation for the control-group. At follow-up, 25 children (80%) of the surgical group were seizure free, while seizure outcome was unsatisfactory in the remaining six (20%). To analyze language, visuomotor skills, memory, reading, visual attention, and behavior, we selected 11 school age children in the surgical group and nine controls. We reported performance prior to (T0) and one year after surgery (T1). RESULTS: There was a significant correlation between earlier age at seizure onset and lower IQ/GDQ at T0 (r=0.39; p=0.03) in the overall cohort. IQ/GDQ scores did not significantly differ between the surgical and control groups when analyzed at T0 and T2. However, they evolved differently with an improved developmental trajectory becoming identifiable only in the surgical group (F1,31=5.33 p=0.028; η2=0.15). There was also a significant increase of forward digit span (Z=2.33; p=0.02) and Rey recall scores (Z=1.97; p=0.049) in the surgical school age subgroup at T1 versus T0. SIGNIFICANCE: We identified significantly different developmental trajectories in operated versus non- operated children with improved IQ/GDQ scores in operated children only. We also observed a significant increase of digit span scores and Rey recall scores a year after surgery. Further studies including larger samples with longer follow-ups are needed to confirm these preliminary findings.

Subependymal giant cell astrocytoma: a lesion with activated mTOR pathway and constant expression of glutamine synthetase.

Subependymal giant-cell astrocytoma (SEGA) is a rare tumor associated with tuberous sclerosis complex (TSC). TSC mainly involves the central nervous system (CNS) where SEGA, subependymal nodules, and cortical tubers may be present. First studies suggested the astrocytic nature of SEGA while successive studies demonstrated the mixed glio-neuronal nature. There are similarities between TSC-associated CNS lesions and type IIb focal cortical dysplasia (FCD). In all these pathologies, mammalian target of rapamycin (mTOR) pathway activation has been demonstrated. Recent data evidenced that balloon cells in FCD IIb express glutamine synthetase (GS). GS is involved in the clearance of glutamate. Cells expressing GS might exert an antiepileptic role. We evaluated by immunohistochemistry the glial fibrillary acidic protein (GFAP), neurofilaments (NF), and GS expression and the mTOR status (mTOR and phosphorylated ribosomal protein S6) in 16 SEGAs and 2 cortical tubers. Our purpose was to emphasize the mixed nature of SEGA and to further investigate the similarities between TSC-related CNS lesions (in particular SEGA) and FCD IIb. We confirm the glio-neuronal nature and the common activation of the mTOR pathway in SEGAs. In addition, we report for the first time that these tumors, analogously to FCD IIb, commonly express GS. Notably, the expression of mTOR, phosphorylated ribosomal protein S6, and GS was restricted to gemistocytic-like GFAP-negative cells. GS expression and mTOR pathway activation were also documented in cortical tubers. Further studies are necessary to understand the significance of GS expression in SEGAs as well as in cortical tubers.