Middle temporal gyrus approach to mesial temporal lobe tumours in children.

AIM OF THE STUDY: To assess whether the middle temporal gyrus (MTG) approach to mesial temporal lobe (MTL) tumours is an effective procedure for the treatment of epilepsy in children. CLINICAL RATIONALE FOR THE STUDY: MTL tumours are a common cause of drug-resistant epilepsy in children. There is as yet no consensus regarding their treatment. One possibility is resection via a MTG approach. MATERIAL AND METHODS: We assessed the medical records of patients treated at the Department of Neurosurgery, Children's Memorial Health Institute,Warsaw, Poland between 2002 and 2020. A prospectively maintained database including clinical, laboratory, and radiographic presentation, as well as pre- and post-operative course, was analysed. Patients with at least a one- -year follow-up were included. RESULTS: There were 14 patients aged 4-18 years who underwent a MTG approach for a MTL tumour. All presented with epileptic seizure, and none had neurological deficit on admission to hospital. Median follow-up was 2.5 years. Neuronavigation was used to adjust the approach, localise the temporal horn, and achieve radical resection of the tumour and the hippocampus. Gross total resection was performed in all cases. In most patients, histopathological examination revealed ganglioglioma. One patient had transient aphasia. Two patients developed hemiparesis after surgery, which later improved. One of them also experienced visual disturbances. Acute complications were more frequent in younger patients (p = 0.024). In all cases, MRI confirmed complete resection and there was no tumour recurrence during the follow-up period. 13/14 patients remained seizure-free (Engel class I). CONCLUSIONS AND CLINICAL IMPLICATIONS: The MTG approach to MTL tumours is an effective procedure for the treatment of epilepsy in children. It avoids removal of the lateral temporal lobe and poses only a minor risk of permanent neurological complications.

Exploring Novel Therapeutic Opportunities for Glioblastoma Using Patient-Derived Cell Cultures.

Glioblastomas (GBM) are the most common, primary brain tumors in adults. Despite advances in neurosurgery and radio- and chemotherapy, the median survival of GBM patients is 15 months. Recent large-scale genomic, transcriptomic and epigenetic analyses have shown the cellular and molecular heterogeneity of GBMs, which hampers the outcomes of standard therapies. We have established 13 GBM-derived cell cultures from fresh tumor specimens and characterized them molecularly using RNA-seq, immunoblotting and immunocytochemistry. Evaluation of proneural (OLIG2, IDH1R132H, TP53 and PDGFRα), classical (EGFR) and mesenchymal markers (CHI3L1/YKL40, CD44 and phospho-STAT3), and the expression of pluripotency (SOX2, OLIG2, NESTIN) and differentiation (GFAP, MAP2, ß-Tubulin III) markers revealed the striking intertumor heterogeneity of primary GBM cell cultures. Upregulated expression of VIMENTIN, N-CADHERIN and CD44 at the mRNA/protein levels suggested increased epithelial-to-mesenchymal transition (EMT) in most studied cell cultures. The effects of temozolomide (TMZ) or doxorubicin (DOX) were tested in three GBM-derived cell cultures with different methylation status of the MGMT promoter. Amongst TMZ- or DOX-treated cultures, the strongest accumulation of the apoptotic markers caspase 7 and PARP were found in WG4 cells with methylated MGMT, suggesting that its methylation status predicts vulnerability to both drugs. As many GBM-derived cells showed high EGFR levels, we tested the effects of AG1478, an EGFR inhibitor, on downstream signaling pathways. AG1478 caused decreased levels of phospho-STAT3, and thus inhibition of active STAT3 augmented antitumor effects of DOX and TMZ in cells with methylated and intermediate status of MGMT. Altogether, our findings show that GBM-derived cell cultures mimic the considerable tumor heterogeneity, and that identifying patient-specific signaling vulnerabilities can assist in overcoming therapy resistance, by providing personalized combinatorial treatment recommendations.

PD-L1/miR-155 Interplay in Pediatric High-Grade Glioma.

High-grade pediatric glioma (p-HGG-WHO 2021, formerly GBM-WHO 2016), as a common, aggressive, and highly lethal primary brain malignancy in adults, accounts for only 3-15% of primary brain tumors in pediatric patients. After leukemia, brain malignancies are the second most common in the pediatric population and first in incidences concerning solid tumors. This study was designed on the basis of 14 pediatric patients hospitalized at Children's Memorial Health Institute in Warsaw, Poland, due to p-HGG treatment. All the patients had a histopathological diagnosis performed by an experienced neuropathologist according to WHO guidelines (WHO 2016 Grade IV Glioblastoma). A significant correlation was found between the miR-155 concentration and the level of PD-L1 expression in p-HGG tumor tissue. Very few reports have indicated PD-L1 expression in pediatric patients.

Spinal muscular atrophy: epidemiology and health burden in children - a Polish national healthcare database perspective before introduction of SMA-specific treatment.

INTRODUCTION: Spinal muscular atrophy (SMA) is one of the most frequent autosomal recessive neuromuscular disorders. It leads to progressive muscle weakness, premature death or permanent ventilation. Significant disability, scoliosis, severe pulmonary infections and other problems require in- and outpatient medical care. Various approaches have been used to evaluate SMA epidemiology, healthcare burden and adherence to standard of care. The recent introduction of pharmacological treatment in a large SMA population will change the course of the disease and the healthcare requirements of patients. MATERIAL AND METHODS: We have used the National Health Fund database to identify children with SMA and the healthcare service they received in the pre-pharmacological treatment era. Pivotal phase II and III medical trials for nusinersen were conducted between 2013 and 2015. The National Treatment Programme of SMA patients with nusinersen in our country was started in January 2019. The year 2014 was used to evaluate incident cases. RESULTS: 51 new SMA cases (incidence 1:7,356) and 518 SMA patients younger than 18 were identified in 2014. 32 (6.2%) deaths were recorded, half in the first two years of life. 35 (6.8%) patients received palliative and 115 (22.2%) long-term care (including assisted ventilation). A total number of 3,057 days of hospital stay were reported. Only 65/518 (12.6%) patients did not receive publicly-funded healthcare service other than specialist or general practitioner's consultation. CONCLUSIONS: SMA caused significant mortality and morbidity in children. The National Health Fund database can be used to reliably record incident cases and track the care provided to paediatric SMA patients.

Magnetic Resonance Characteristics of Baló Concentric Sclerosis in Children.

BACKGROUND: Baló concentric sclerosis is a rare demyelinating disease with characteristic magnetic resonance appearance of multilayered ringlike lesions of demyelination. This disease is extremely rare in children. We present the clinical data, radiological appearance, and development of lesions in eight children. METHODS: We analyzed the clinical information of eight patients diagnosed between 2012 and 2020. Magnetic resonance brain and spinal cord examinations with contrast medium administration were performed using a 1.5-T scanner. RESULTS: All patients presented at least one typical Baló lesion on brain imaging. Four patients additionally had typical multiple sclerosis plaques. All primary Baló lesions had a characteristic appearance of concentric hyperintense rings on T2-weighted imaging and were round or ovoid. Cerebrospinal fluid analysis was performed in all patients. Oligoclonal bands were present in seven patients, and four of them had multiple sclerosis plaques on baseline brain magnetic resonance imaging. CONCLUSION: Baló concentric sclerosis in children is characterized by acute and severe onset with hemiparesis as a predominant symptom. The size, contrast enhancement, and restricted diffusion depend on the phase of the disease.

Mapping chromatin accessibility and active regulatory elements reveals pathological mechanisms in human gliomas.

Chromatin structure and accessibility, and combinatorial binding of transcription factors to regulatory elements in genomic DNA control transcription. Genetic variations in genes encoding histones, epigenetics-related enzymes or modifiers affect chromatin structure/dynamics and result in alterations in gene expression contributing to cancer development or progression. Gliomas are brain tumors frequently associated with epigenetics-related gene deregulation. We perform whole-genome mapping of chromatin accessibility, histone modifications, DNA methylation patterns and transcriptome analysis simultaneously in multiple tumor samples to unravel epigenetic dysfunctions driving gliomagenesis. Based on the results of the integrative analysis of the acquired profiles, we create an atlas of active enhancers and promoters in benign and malignant gliomas. We explore these elements and intersect with Hi-C data to uncover molecular mechanisms instructing gene expression in gliomas.

The Effects of Sampling Lateralization on Bilateral Inferior Petrosal Sinus Sampling for Pediatric Cushing's Disease-A Single Endocrinology Centre Experience and Review of the Literature.

Background: This study aims to analyze the diagnostic accuracy of bilateral inferior petrosal sinus sampling (BIPSS), the gold standard test for the differential diagnosis of ACTH-dependent Cushing's syndrome (CS) in a group of pediatric patients with Cushing's disease (CD). Methods: This is a retrospective analysis which include 12 patients with hypercortisolemia and inconclusive pituitary MRI, who underwent bilateral inferior petrosal sinus sampling (BIPSS) and transsphenoidal surgery (TSS) from 2004 to 2020 in the Children's Memorial Health Institute (CMHI) Warsaw, Poland. Pituitary origin of ACTH secretion was considered if baseline central to peripheral (C/P) ACTH level ratio was ≥ 2 or C/P ratio was ≥ 3 after human corticotropin-releasing hormone (hCRH) stimulation. The diagnosis was histologically confirmed in almost all cases after TSS. Results: The diagnostic accuracy of BIPSS reached 75% at baseline and 83.3% after CRH stimulation. The compatibility of localization of a microadenoma by BIPSS with the surgical location was 66.7%. Conclusions: Owing to its high diagnostic effectiveness, BIPSS remains the best test to differentiate CD from EAS. The indications for the procedure should be carefully considered, because EAS in the pediatric population, unlike in adults, is extremely rare. Moreover BIPSS has only limited value for indicating tumor localization.

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 (SEGAs) are slow-growing brain tumors that are a hallmark feature seen in 5-10% of patients with Tuberous Sclerosis Complex (TSC). Though histologically benign, they can cause serious neurologic symptoms, leading to death if untreated. SEGAs consistently show biallelic loss of TSC1 or TSC2. Herein, we aimed to define other somatic events beyond TSC1/TSC2 loss and identify potential transcriptional drivers that contribute to SEGA formation. Paired tumor-normal whole-exome sequencing was performed on 21 resected SEGAs from 20 TSC patients. Pathogenic variants in TSC1/TSC2 were identified in 19/21 (90%) SEGAs. Copy neutral loss of heterozygosity (size range: 2.2-46 Mb) was seen in 76% (16/21) of SEGAs (44% chr9q and 56% chr16p). An average of 1.4 other somatic variants (range 0-7) per tumor were identified, unlikely of pathogenic significance. Whole transcriptome RNA-sequencing analyses revealed 190 common differentially expressed genes in SEGA (n = 16, 13 from a prior study) in pairwise comparison to each of: low grade diffuse gliomas (n = 530) and glioblastoma (n = 171) from The Cancer Genome Atlas (TCGA) consortium, ganglioglioma (n = 10), TSC cortical tubers (n = 15), and multiple normal tissues. Among these, homeobox transcription factors (TFs) HMX3, HMX2, VAX1, SIX3; and TFs IRF6 and EOMES were all expressed >12-fold higher in SEGAs (FDR/q-value < 0.05). Immunohistochemistry supported the specificity of IRF6, VAX1, SIX3 for SEGAs in comparison to other tumor entities and normal brain. We conclude that SEGAs have an extremely low somatic mutation rate, suggesting that TSC1/TSC2 loss is sufficient to drive tumor growth. The unique and highly expressed SEGA-specific TFs likely reflect the neuroepithelial cell of origin, and may also contribute to the transcriptional and epigenetic state that enables SEGA growth following two-hit loss of TSC1 or TSC2 and mTORC1 activation.

Is there a common cause for paediatric Cushing's disease?

INTRODUCTION: According to recent literature, somatic mutations in the ubiquitin-specific protease 8 (USP8) gene are the most common changes in patients with Cushing's disease (CD). Data on the frequency of these mutations in the paediatric population are limited. The aim of the presented study was to determine the frequency of the USP8 gene mutations in a group of paediatric patients with CD treated at the Children's Memorial Health Institute (CMHI). MATERIAL AND METHODS: Eighteen patients (nine females) with CD were treated at CMHI, Warsaw, Poland between 1993 and 2019. All patients underwent transsphenoidal surgery (TSS) as a primary treatment for CD. The average age of all patients at TSS was 13.10 years (5.42-17.25). DNA was extracted from formalin-fixed paraffin-embedded resected tumour tissue. Sanger sequencing was performed on DNA sequence corresponding to the exon 14 of USP8 gene. RESULTS: The mean age at diagnosis of CD was 13.08 years, and the average duration of symptoms before diagnosis was 2.96 years. All patients were operated at CMHI by the same neurosurgeon. Fifteen out of 18 patients (83.33%) had initial biochemical remission after a single TSS procedure (post-operative serum cortisol < 1.8 µg/dL). The result of genetic testing was negative for all samples at the hotspot area of the USP8 gene. CONCLUSION: The current retrospective study demonstrates that mutations in the USP8 gene may not be as common a cause of paediatric Cushing's disease, as previously reported.

Predictive factors for the recurrence of Cushing's disease after surgical treatment in childhood.

INTRODUCTION: Cushing's disease (CD) is a rare cause of hypercortisolaemia caused by excessive adrenocorticotropic hormone (ACTH) excretion by a pituitary adenoma. Data on the predictive factors for the recurrence of the disease are limited in comparison with those for the adult population. The identification of the predictive factors for CD recurrence in patients after surgical treatment in childhood was the aim of the presented study. MATERIAL AND METHODS: A retrospective analysis of 26 CD patients, mean age at the time of diagnosis 13.46 years, treated at the Children's Memorial Health Institute (CMHI) in the years 1994-2018. Two time points were set at which the follow-up (FU) of patients was finished. The first time point (shorter FU, 24 patients) was set when the patients completed their treatment at the CMHI. The second time point (longer FU, 26 patients) was determined on the basis on the time when adult patients (previous CMHI patients) completed the author's questionnaire. In the case of the other patients (current CMHI paediatric patients and patients who did not respond to the questionnaire), the latest FU in this second time point was made during the last visit to the CMHI. The predictors of disease recurrence were evaluated by the construction of a logistic regression model and receiver operating characteristics. RESULTS: The average FU after transsphenoidal pituitary surgery (TSS) of 26 patients was 10.23 years (0.67-24.50). Recurrence of CD occurred in four out of 26 patients (15.4%) after an average time of 3.6 years (0.92-8.08) following definitive treatment. The results of the statistical analysis of potential predictive factors for CD recurrence were not conclusive, with no variables confirmed above the statistical significance threshold of p < 0.05. As regards the longer FU, two potential predictors: mean cortisol level at night (p = 0.10) and max. ACTH level after ovine corticotropin-releasing hormone (oCRH) test (p = 0.10), were the closest to meeting the assumed threshold of statistical significance. CONCLUSION: Recurrence of CD may be diagnosed even a long time after its effective treatment. It is possible that cortisol levels at night and ACTH values in oCRH test before TSS may be helpful to predict which patients may experience a recurrence after successful initial treatment. However, further studies on a larger sample are needed to confirm this hypothesis.

Long-term outcome in patients after treatment for Cushing's disease in childhood.

INTRODUCTION: Cushing's disease (CD) is a rare cause of hypercortisolemia presenting a major diagnostic and therapeutic challenge. Data on pituitary function in long-term follow-up after CD treatment in childhood is limited. AIM: Long-term assessment of patients of the Children's Memorial Health Institute (CMHI) after CD treatment in childhood. MATERIALS AND METHODS: Retrospective analysis of 29 CD patients, mean age at the time of diagnosis 13.46 yrs. The long-term follow-up (FU) was done by: 1) obtaining the data from a patient's questionnaire (75% of adult patients); 2) using the data from the last clinic visit for patients who did not respond to the questionnaire and for current CMHI patients. The average long-term FU from transsphenoidal pituitary surgery (TSS) was 10.23 yrs. RESULTS: At the latest FU: 18 patients (62%) had long-term disease remission after TSS1, 2 patients (6.9%) after TSS2, 1 patient (3.4%) after the post-TSS radiotherapy (XRT) cycle and 3 patients (10.3%) after bilateral adrenalectomy (BA). One patient (3.4%) died after TSS2 due to postoperative complications, 1 patient (3.4%) had persistent disease at latest FU, in 1 patient (3.4%) the long-term FU was not possible to perform. CD recurrence occurred in 4 out of 28 patients (14%) at an average time 3.6 yrs. from definitive treatment. One patient (3.4%) after BA was operated because of Nelson's syndrome. Two patients (6.9%) were suspected of relapse at latest assessment. At the time of the last evaluation, 17 patients (63%) were on levothyroxine therapy since definitive treatment, 16 patients (59%) were on hydrocortisone treatment, 10 patients (37%) were taking sex hormones replacement, 4 patients (15%)-antidiuretic hormone. CONCLUSIONS: Relatively large number of patients after CD treatment in childhood have hormonal pituitary deficits as well as mood and cognitive disorders. CD recurrence can occur even after a long time post effective treatment.

Hedgehog signalling network gene status analysis in paediatric intracranial germ cell tumours.

INTRODUCTION: Germ cell tumours (GCTs) in the children comprise a group of tumours that originate from primordial germ cells but their pathogenesis is not clear. Intracranial GCTs represent a special subset of these paediatric neoplasms. Hedgehog (Hh) pathway gene status in GCTs is generally unexplored, while Hh signalling is involved in germ cell biology. MATERIAL AND METHODS: Comparative genomic profiling analysis with a microarray-comparative genomic hybridization (CGH) + single nucleotide polymorphism (SNP) technique in a group of intracranial paediatric GCTs was performed. The analysis included evaluation of genes being ligands, receptors, regulators, effectors, and targets of Hh signalling. RESULTS: Chromosomal aberrations were found in 62% of examined tumours, showing their heterogeneity. A number of private genomic imbalances were observed, but only a few recurrent ones. The most common numerical changes were trisomies 19, 21 and monosomies 13, 18 while the most frequent structural aberration was gain/amplification of the chromosome 12p. The analysis of the gene status of Hh network elements showed imbalances in a proportion of tumours. PTCH1, GLI2, IHH and ZIC2 gene aberrations occurred most frequently. Moreover, six tumours had various copy gains or losses of several other genes involved in the pathway, including HHIP, GLI1, GLI3, DHH, SHH, SMO, PTCH2, and several genes from the WNT group. Interestingly, four cases showed losses of pathway repressors, with parallel gains of activators in two of them. Correlations with patho-clinical tumour features were not found, most probably due to the heterogeneity of the examined limited group. CONCLUSIONS: Our results show few genomic alterations related to the Hh signalling pathway genes in paediatric intracranial GCTs. Further analysis of Hedgehog pathway alterations can potentially disclose its biological significance and define new prognostic factors and/or therapeutic targets for high-risk patients.

Symptomatic Rathke cleft cyst in paediatric patients - clinical presentations, surgical treatment and postoperative outcomes - an analysis of 38 cases.

BACKGROUND: Rathke cleft cysts (RCC) are benign, epithelium-lined intrasellar and/or suprasellar cysts believed to originate from the remnants of the Rathke pouch. The aim of this study was to analyse the symptoms and surgical outcome of patients with the diagnosis of RCC verified in a histopathological examination of the postoperative material. METHODS: The study is a retrospective analysis of 38 cases of children who underwent a neurosurgical treatment due to RCC at the Children's Memorial Health Institute in Warsaw, Poland, between 1994 and 2015. RESULTS: At diagnosis, the mean age was 13 years and 8 months (6 years and 11 months-17 years and 10 months, sex ratio was 1:0.9 with a female prevalence). The most common symptoms were the following: headache (50%), hypothyroidism (50%), short stature and/or decreased growth velocity (47%), delayed puberty and menstrual abnormalities (37%), diabetes insipidus or polydipsia and polyuria (26%), adrenal dysfunction (26%), sleepiness and general weakness (13%) and visual disturbances (11%). Due to the gravity of symptoms and size of the lesion, all the patients underwent a surgical treatment. All but one were successful (one patient died due to postoperative neurosurgical complications). The most common postoperative complications were the following: adenohypopituitarism (67%) and diabetes insipidus (45%). CONCLUSIONS: RCC can present with serious symptoms that significantly deteriorate patients' quality of life. Despite a successful neurosurgical treatment in most of the analysed cases, patients required long-term pharmacological treatment.

Surgical treatment of neuronal-glial tumors of mesial-basal part of temporal lobe: Long term outcome and control of epilepsy in pediatric patients.

BACKGROUND: Neuronal-glial tumors (ganglioglioma and dysembryoplastic neuroepithelial tumor) are a frequent cause of focal, drug-resistant and epilepsy in children and young adults, that is amenable for surgical treatment. AIM OF PAPER: Assessment of late outcome of surgical treatment and degree of seizure control, as well as prognostic significance of selected clinical factors. MATERIAL AND METHOD: 52 Pediatric patients presenting with epilepsy, lesion of mesio-basal temporal lobe and histologically verified neuronal-glial tumor treated at our facility since 2000-2011. RESULTS: After the mean follow-up of 2.94 years, satisfactory treatment outcome (Engel classes I and II) was obtained in 92% of the patients (n=48). Poor outcome (Engel class III) was seen in 8% of patients (n=4). New neurological deficits appeared in 28% of the patients (n=20) but in most of them resolved over time. CONCLUSIONS: In patients with drug-resistant epilepsy and a lesion of mesial-basal part of temporal lobe suggestive of a glial-neuronal tumor, surgical treatment is strongly recommended, aiming at excision of tumor and elimination of seizures. Histological verification of the lesion is a pre-requisite for optimal treatment planning. In most patients, both treatment goals may be reached. Short duration of epilepsy prior to surgery and young age are favorable prognostic factors. Histological diagnosis of GG, co-existence of cortical dysplasia and location of tumor extending beyond mesial-basal temporal structures are associated with a higher risk of postoperative complications. These may out-weight expected benefits of surgery.

Epigenetics of Epileptogenesis-Evoked Upregulation of Matrix Metalloproteinase-9 in Hippocampus.

Enhanced levels of Matrix Metalloproteinase-9 (MMP-9) have been implicated in the pathogenesis of epilepsy in humans and rodents. Lack of Mmp-9 impoverishes, whereas excess of Mmp-9 facilitates epileptogenesis. Epigenetic mechanisms driving the epileptogenesis-related upregulation of MMP-9 expression are virtually unknown. The aim of this study was to reveal these mechanisms. We analyzed hippocampi extracted from adult and pediatric patients with temporal lobe epilepsy as well as from partially and fully pentylenetetrazole kindled rats. We used a unique approach to the analysis of the kindling model results (inclusion in the analysis of rats being during kindling, and not only a group of fully kindled animals), which allowed us to separate the molecular effects exerted by the epileptogenesis from those related to epilepsy and epileptic activity. Consequently, it allowed for a disclosure of molecular mechanisms underlying causes, and not consequences, of epilepsy. Our data show that the epileptogenesis-evoked upregulation of Mmp-9 expression is regulated by removal from Mmp-9 gene proximal promoter of the two, interweaved potent silencing mechanisms-DNA methylation and Polycomb Repressive Complex 2 (PRC2)-related repression. Demethylation depends on a gradual dissociation of the DNA methyltransferases, Dnmt3a and Dnmt3b, and on progressive association of the DNA demethylation promoting protein Gadd45ß to Mmp-9 proximal gene promoter in vivo. The PRC2-related mechanism relies on dissociation of the repressive transcription factor YY1 and the dissipation of the PRC2-evoked trimethylation on Lys27 of the histone H3 from the proximal Mmp-9 promoter chromatin in vivo. Moreover, we show that the DNA hydroxymethylation, a new epigenetic DNA modification, which is localized predominantly in the gene promoters and is particularly abundant in the brain, is not involved in a regulation of MMP-9 expression during the epileptogenesis in the rat hippocampus as well as in the hippocampi of pediatric and adult epileptic patients. Additionally, we have also found that despite of its transient nature, the histone modification H3S10ph is strongly and gradually accumulated during epileptogenesis in the cell nuclei and in the proximal Mmp-9 gene promoter in the hippocampus, which suggests that H3S10ph can be involved in DNA demethylation in mammals, and not only in Neurospora. The study identifies MMP-9 as the first protein coding gene which expression is regulated by DNA methylation in human epilepsy. We present a detailed epigenetic model of the epileptogenesis-evoked upregulation of MMP-9 expression in the hippocampus. To our knowledge, it is the most complex and most detailed mechanism of epigenetic regulation of gene expression ever revealed for a particular gene in epileptogenesis. Our results also suggest for the first time that dysregulation of DNA methylation found in epilepsy is a cause rather than a consequence of this condition.

Down-regulation of IKKß expression in glioma-infiltrating microglia/macrophages is associated with defective inflammatory/immune gene responses in glioblastoma.

Glioblastoma (GBM) is an aggressive malignancy associated with profound host immunosuppression. Microglia and macrophages infiltrating GBM acquire the pro-tumorigenic, M2 phenotype and support tumor invasion, proliferation, survival, angiogenesis and block immune responses both locally and systematically. Mechanisms responsible for immunological deficits in GBM patients are poorly understood. We analyzed immune/inflammatory gene expression in five datasets of low and high grade gliomas, and performed Gene Ontology and signaling pathway analyses to identify defective transcriptional responses. The expression of many immune/inflammatory response and TLR signaling pathway genes was reduced in high grade gliomas compared to low grade gliomas. In particular, we found the reduced expression of the IKBKB, a gene coding for IKKß, which phosphorylates IκB proteins and represents a convergence point for most signal transduction pathways leading to NFκB activation. The reduced IKBKB expression and IKKß levels in GBM tissues were demonstrated by qPCR, Western blotting and immunohistochemistry. The IKKß expression was down-regulated in microglia/macrophages infiltrating glioblastoma. NFκB activation, prominent in microglia/macrophages infiltrating low grade gliomas, was reduced in microglia/macrophages in glioblastoma tissues. Down-regulation of IKBKB expression and NFκB signaling in microglia/macrophages infiltrating glioblastoma correlates with defective expression of immune/inflammatory genes and M2 polarization that may result in the global impairment of anti-tumor immune responses in glioblastoma.

Ectopic virilising adrenocortical tumour in the spinal region in an 8 year-old boy: a case report and review of the literature.

INTRODUCTION: The adrenocortical rest tumours are the very rare entity in the pediatric population. They are usually found along the gonadal descent paths (celiac axis, the broad ligamen, the adnexa of the testes or the spermatic cord). They have been also described to occur at rare ectopic sites like intracranial locations, placenta, kidney, pancreas and liver. CLINICAL CASE: Here we present a unusual case of an ectopic, virilising, primary adrenocortical tumour localized in the spinal region in a 8 years-old-boy. DISCUSSION: This is the first case of functional ectopic, adrenocortical tumour localized in the spinal region in a pediatric population. We discuss here the clinical presentation and the diagnostic challenges and provide the review of the literature.

Angiocentric glioma: a rare intractable epilepsy-related tumour in children.

Angiocentric glioma is a low-grade tumour that occurs in children and young adults with a long-standing epilepsy. The typical histopathological features of this tumour is the presence of spindle-shaped cells, radially oriented around the cortical blood vessels. We present two teenage cases of the angiocentric variant of glioma: 1) a 15-year-old girl with a chronic and intractable partial epilepsy with cystic tumour located in the right temporal lobe and 2) a 14-year-old boy with intractable seizures and an extensive cortical lesion in the left parieto-occipital area. In both cases, the total tumours excision was performed. The histopathological findings revealed a characteristic angiocentric pattern that was composed of elongated cells arranging in pseudorosette-like structures around blood vessels. Moreover, schwannoma-like areas and subpial neoplastic infiltration with palisading of tumour cells at the brain surface were seen. The neoplastic cells displayed immunoreactivity for GFAP, S-100 protein and vimentin. A slight "dot-like" EMA staining, suggesting ependymal differentiation, was detected. The clinical and pathological picture allowed to establish the diagnosis of angiocentric gliomas. The patients were discharged home in a good condition and without seizures. During the 4-year follow-up, the tumour recurrence and seizures were not observed. The appropriate diagnosis of this peculiar type of usually low-grade glial tumour is important for adequate and successful treatment. The differential diagnosis requires the exclusion of other tumours with an angiocentric pattern, i.e. ependymoma, astroblastoma, which are associated with more aggressive biology.

Congenital subependymal giant cell astrocytomas in patients with tuberous sclerosis complex.

PURPOSE: Subependymal giant cell astrocytoma (SEGA) is a brain tumor associated with tuberous sclerosis complex (TSC). It usually grows in a second decade of life, but may develop in the first months of life. The aim of this work was to establish the incidence, clinical features, and outcome of congenital SEGA in TSC patients. METHODS: Cohort of 452 TSC patients was reviewed to identify cases with growing or hydrocephalus producing SEGAs in the first 3 months of life. Clinical presentation, size of the tumor, growth rate, mutational analysis, treatment applied, and outcome were analyzed. RESULTS: Ten (2.2 %) patients presented with SEGA in the first 3 months of life. All of them had documented SEGA growth and all developed hydrocephalus. In eight patients, mutational analysis was done, and in all of them, TSC2 gene mutations were identified. Mean maximum SEGA diameter at baseline was 21.8 mm. Mean SEGA growth rate observed postnatally was 2.78 mm per month and tended to be higher (5.43 mm per month) in patients with TSC2/PKD1 mutation than in other cases. Seven patients underwent SEGA surgery and surgery-related complications were observed in 57.1 % cases. One patient was successfully treated with everolimus as a primary treatment. CONCLUSIONS: Congenital SEGA develops 2.2 % of TSC patients. Patients with TSC2 mutations, and especially with TSC2/PKD1 mutations, are more prone to develop SEGA earlier in childhood and should be screened for SEGA from birth. In young infants with SEGA, both surgery and mTOR inhibitor should be considered as a treatment option.