Summary
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.
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.
Abstract
Dysembryoplastic neuroepithelial tumors (DNT) lacking key diagnostic criteria are challenging to diagnose and sometimes fall into the broader category of mixed neuronal-glial tumors (MNGT) ...or the recently described polymorphous low-grade neuroepithelial tumor of the young (PLNTY). We examined 41 patients with DNT, MNGT, or PLNTY for histologic features, genomic findings, and progression-free survival (PFS). Genomic analysis included sequence and copy number variants and RNA-sequencing. Classic DNT (n = 26) was compared with those with diffuse growth without cortical nodules (n = 15), 6 of which exhibited impressive CD34 staining classifying them as PLNTY. Genomic analysis was complete in 33, with sequence alterations recurrently identified in BRAF, FGFR1, NF1, and PDGFRA, as well as 7 fusion genes involving FGFR2, FGFR1, NTRK2, and BRAF. Genetic alterations did not distinguish between MNGTs, DNTs, or PLNTYs; however, FGFR1 alterations were confined to DNT, and PLNTYs contained BRAF V600E or FGFR2 fusion genes. Analysis of PFS showed no significant difference by histology or genetic alteration; however, numbers were small and follow-up time short. Further molecular characterization of a PLNTY-related gene fusion, FGFR2-CTNNA3, demonstrated oncogenic potential via MAPK/PI3K/mTOR pathway activation. Overall, DNT-MNGT spectrum tumors exhibit diverse genomic alterations, with more than half (19/33) leading to MAPK/PI3K pathway alterations.
The surgical treatment of brain tumors has evolved over time, offering different strategies tailored to patients and their specific lesions. Among these strategies, Laser Interstitial Thermal Therapy ...(LITT) is one of the most recent advances in pediatric neurooncological surgery, and its results and evolution are still under assessment.
We retrospectively analyzed data from six pediatric patients with deep-seated brain tumors treated with LITT at a single center between November 2019 and June 2022. A total of four patients underwent a stereotaxic biopsy during the same operating session. The indications and preparation for LITT, technical issues, clinical and radiological follow-up, impact on quality of life, and oncological treatment are discussed.
The mean patient age eight years (ranging from 2 to 11 years). The lesion was thalamic in four patients, thalamo-peduncular in one, and occipital posterior periventricular in one. In total, two patients had been previously diagnosed with low-grade glioma (LGG). Biopsies revealed LGG in two patients, ganglioglioma grade I in one, and diffuse high-grade glioma (HGG) in one. Postoperatively, two patients presented with transient motor deficits. The mean follow-up period was 17 months (ranging from 5 to 32 months). Radiological follow-up showed a progressive reduction of the tumor in patients with LGG.
Laser interstitial thermal therapy is a promising, minimally invasive treatment for deep-seated tumors in children. The results of lesion reduction appear to be relevant in LGGs and continue over time. It can be used as an alternative treatment for tumors located at sites that are difficult to access surgically or where other standard treatment options have failed.
Craniopharyngioma (CP), although slow growing and histologically benign, has high morbidity, mostly related to hypothalamus-pituitary dysfunction and electrolyte imbalance. Increased risk of vascular ...complications has been described. However, data are still poor, especially in the paediatric population. The aim of our study was to evaluate the occurrence, timing, and predisposing factors of deep venous thrombosis (DVT) and other vascular alterations in neurosurgical paediatric CP patients.
In a single-centre, retrospective study, we investigated 19 CP patients (11 males, 8 females, mean age 10.5 ± 4.3 years), who underwent neurosurgery between December 2016 and August 2022, referred to Meyer Children's Hospital IRCCS in Florence.
Five patients (26.3%) presented vascular events, which all occurred in connection with sodium imbalances. Three DVT (two with associated pulmonary embolism, in one case leading to death) developed in the post-operative period, most frequently at 7-10 days. Elevated D-dimers, a reduced partial activated thrombin time and a prolonged C-reactive protein increase were highly related to thrombotic vascular events. One case of posterior cerebral artery pseudoaneurysm was described soon after neurosurgery, requiring vascular stenting. Superficial vein thrombophlebitis was a late complication in one patient with other predisposing factors.
CP patients undergoing neurosurgery are at risk of developing DVT and vascular alterations, thus careful follow-up is mandatory. In our study, we found that the phase of transition from central diabetes insipidus to a syndrome of inappropriate antidiuretic hormone secretion may be a period of significant risk for DVT occurrence. Careful vascular follow-up is mandatory in CP-operated patients.
Pediatric high-grade gliomas (pHGGs) encompass a heterogeneous group of tumors. Three main molecular types (H3.3 mutant, IDH mutant, and H3.3/IDH wild-type) and a number of subtypes have been ...identified. We provide an overview of pHGGs and present a mono-institutional series. We studied eleven non-related pHGG samples through a combined approach of routine diagnostic tools and a gene panel. TP53 and H3F3A were the most mutated genes (six patients each, 54%). The third most mutated gene was EGFR (three patients, 27%), followed by PDGFRA and PTEN (two patients each, 18%). Variants in the EZHIP, MSH2, IDH1, IDH2, TERT, HRAS, NF1, BRAF, ATRX, and PIK3CA genes were relatively infrequent (one patient each, 9%). In one case, gene panel analysis documented the presence of a pathogenic IDH2 variant (c.419G>A, p.Arg140Gln) never described in gliomas. More than one-third of patients carry a variant in a gene associated with tumor-predisposing syndromes. The absence of constitutional DNA did not allow us to identify their constitutional origin.
Abstract Background context Spinal tumors in childhood are rare and heterogeneous, and their treatment is very demanding. It is necessary to both manage the disease and preserve the spinal stability ...so that the spine can grow normally. As a consequence, results in terms of both mortality and morbidity are often suboptimal. Purpose The results of a single pediatric neurosurgery institution are reported to highlight the peculiarities and pitfalls of the management of this disease. Tumors are analyzed from the point of view of their localization, histology, and outcome in terms of mortality and morbidity, with a special focus on postoperative spinal deformity. Study design The study design was retrospective. Patient sample Between 1995 and 2011, 134 children (75 males and 59 females) were admitted for spinal tumors, accounting for 7.7% of all the patients admitted for central nervous system malignancies. The mean age was 8.5 years (14 days–26 years), and the mean follow-up was 28 months (3 months–13 years). Outcome measures Clinical and radiological outcomes were evaluated to assess mortality, morbidity, and surgical outcomes. A special interest was directed toward morbidity related to spinal deformity and neurologic deficits. Methods Patients were divided into four groups: intramedullary (46 patients), intradural extramedullary (25 patients), extradural (53 patients), and paravertebral tumors (10 patients). Data were obtained retrospectively from medical records and radiological archives. Results Low-grade glioma was the most common histology (14.1%). One hundred seventeen patients were surgically treated, with a total of 138 surgical procedures. A posterior approach was chosen in 111 cases, with osteoplastic laminotomy in 80. Radiotherapy was administered to 22 patients and chemotherapy to 26. At the last follow-up, 16 patients (11.9%) had died. A good control of the tumor with clinical improvement was reported in 100 patients (74.6%). Five patients developed a spinal instability (3.7%). Conclusions The goals of surgery should be histology, spine and nerve root decompression, and preservation of spinal stability. In our experience, osteoplastic laminotomy was a good surgical approach to perform the resection of the tumor with a low risk of secondary spinal instability.
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.
Dabrafenib plus trametinib is a promising new therapy for patients affected by
-mutant glioma, with high overall response and manageable toxicity. We described a complete and long-lasting response in ...a case of recurrent anaplastic pleomorphic xanthoastrocytoma CNS WHO-grade 3
mutated. Due to very poor prognosis, there are a few described cases of high-grade glioma (HGG) patients treated with the combined target therapy as third-line treatment. The emergence of optimized sequencing strategies and targeted agents, including multimodal and systemic therapy with dabrafenib plus trametinib, will continue to broaden personalized therapy in HGG improving patient outcomes.
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