The Transcriptomic Landscape of Pediatric Astrocytoma.

Central nervous system tumors are the most common solid neoplasia during childhood and represent one of the leading causes of cancer-related mortality. Tumors arising from astrocytic cells (astrocytomas) are the most frequently diagnosed, and according to their histological and pathological characteristics, they are classified into four categories. However, an additional layer of molecular classification considering the DNA sequence of the tumorigenesis-associated genes IDH1/2 and H3F3A has recently been incorporated into the classification guidelines. Although mutations in H3F3A are found exclusively in a subtype of grade IV pediatric astrocytoma, mutations in IDH1/2 genes are very rare in children under 14 years of age. The transcriptomic profiles of astrocytoma in adults and children have been extensively studied. However, there is scarce information on these profiles in pediatric populations considering the status of tumorigenesis-associated genes. Therefore, here we report the transcriptomic landscape of the four grades of pediatric astrocytoma by RNA sequencing. We found several well-documented biological functions associated with the misregulated genes in the four grades of astrocytoma, as well as additional biological pathways. Among the four grades of astrocytoma, we found shared misregulated genes that could have implications in tumorigenesis. Finally, we identified a transcriptional signature for almost all grades of astrocytoma that could be used as a transcription-based identification method.

Functional outcome after cord detethering in fecally incontinent patients with anorectal malformations.

PURPOSE: Tethered cord (TC) occurs in 36% of patients with anorectal malformations (ARMs), for whom the benefit of detethering surgery remains unclear regarding bowel and/or bladder function. This study aimed to examine whether cord detethering could improve fecal and urinary incontinence in these patients. METHODS: This was a retrospective study of TC patients (>3 years old) with fecal incontinence and ARMs, who underwent detethering surgery between 2016 and 2020 and were followed up for at least 6 months. RESULTS: Of the 27 included patients, 55% had sacral ratios between 0.4 and 0.7, and in 37% it was < 0.4; the remaining 8% was over 0.7; 52% suffered from colonic hypermotility. After detethering surgery, partial fecal continence was achieved in five patients (18%); total fecal continence, in ten patients (37%); 12 (44%) remained fecally incontinent. Partial urinary continence was obtained in four cases (14%), and the number of patients with total urinary continence rose from 7 (25%) to 15 (55%). Lower extremity symptoms were also improved in 72% of the cases. Patients with colonic hypomotility were found to have a better functional outcome than those with colonic hypermotility (69% vs. 43%, respectively). CONCLUSION: Our study demonstrated that detethering surgery led to remarkably improved bowel and bladder control in ARM patients with fecal incontinence, which, surprisingly, was not associated with sacral ratio.

Phrenic nerve neurotization utilizing half of the spinal accessory nerve to the functional restoration of the paralyzed diaphragm in high spinal cord injury secondary to brain tumor resection.

The authors present a case of functional improvement of diaphragmatic paralysis in high spinal cord injury, performing a neurotization of the phrenic nerve with accessory spinal nerve hemisection. A C1-C2 injury of the spinal cord was diagnosed in a 12-year-old male, secondary to resection of a brainstem glioma. The patient did not have diaphragmatic motility at the moment that the mechanical ventilation was removed; however, he presented apnea. The patient underwent neurotization of the right phrenic nerve with the right spinal accessory nerve, 5 months after the injury and 6 months after nerve transfer; he had complete mobilization of the right hemidiaphragm, nevertheless persisted with paralysis of the left hemidiaphragm. This achievement reduced the use of mechanical ventilation during the day.

Brain Connectivity in Ateles geoffroyi: Resting-State Functional Magnetic Resonance Imaging of Working Memory and Executive Control.

The objective of this research was to describe the organization and connectivity of the working memory (WM) and executive control (EC) networks in Ateles geoffroyi in resting-state conditions. Recent studies have shown that resting-state activity may underlie rudimentary brain functioning, showing that several brain regions can be tonically active at rest, maximizing the efficiency of information transfer while preserving a low physical connection cost. Whole-brain resting-state images were acquired from three healthy adult Ateles monkeys (2 females, 1 male; mean age 10.5 ± SD 2.5 years). Data were analyzed with independent component analysis, and results were grouped together using the GIFT software. The present study compared the EC and WM networks obtained with human data and with results found in the literature in other primate species. Nine resting-state networks were found, which were similar to resting networks found in healthy human adults in the prefrontal basal portion and frontopolar area. Additionally, components of the WM network were found to be extending into the hypothalamus and the olfactory areas. A key finding was the discovery of connections in the WM and EC networks to the hypothalamus, the motor cortex, and the entorhinal cortex, suggesting that information is integrated from larger brain areas. The correlated areas suggest that many elements of WM and EC may be conserved across primate species. Characterization of these networks in resting-state conditions in nonhuman primate brains is a fundamental prerequisite for understanding of the neural bases underlying the evolution and function of this cognitive system.

Endoscopic ventriculo-cisterno-ventricular approach in the treatment of bilateral trapped temporal horn related to fungal infection in a child: case report and review of the literature.

INTRODUCTION: Focal hydrocephalus including trapped temporal horn (TTH), isolated lateral and fourth ventricles, is caused by obstruction and/or adhesion related to various etiologies. With the advent of the neuroendoscope, endoscopic procedures have become an alternative in selected cases. CASE REPORT: A 2-year-old male from a rural town in México was referred to our institution because of multiple supra- and infra-tentorial abscesses and hydrocephalus. The patient had progressive deterioration and developed bilateral trapped temporal horn related to multi-septated hydrocephalus, so we performed an endoscopic ventricular-cistern-ventriculostomy through a single right temporal burr hole. POSTOPERATIVE COURSE: Bilateral TTH and multi-septated hydrocephalus were effectively treated with a single external ventricular drainage (EVD) catheter, from the right temporal horn to the left temporal horn through the interpeduncular cistern; after clamping the EVD for 3 days with no evidence of hydrocephalus, the EVD was removed. The size of the ventricles remained stable afterwards, and no clinical or radiological evidence of hydrocephalus was observed after 3 months of follow-up. DISCUSSION: Endoscopic ventriculocisternostomy is effective in selected cases of TTH. We know that dilatation of the temporal horn widens the window between the anterior choroidal artery and optic tract superiorly, and the posterior communicating and CN III inferiorly, making the described procedure feasible, even in the approach to the contralateral side. Even though this is a rare condition, we believe it is a safe and effective option to eliminate multiple shunts and/or to reduce the number of catheters needed to treat bilateral THH related to multi-septated hydrocephalus.

Expression of microRNAs in tumors of the central nervous system in pediatric patients in México.

PURPOSE: MicroRNAs were identified as molecules that participate in gene regulation; alterations in their expression characterize central nervous system (CNS). Information in pediatrics is scarce, so the objective of this work was to determine and then compare the patterns of expression of microRNAs in astrocytomas, ependymomas, and medulloblastomas, as well as in non-neoplastic brain. METHODS: Low-density arrays were utilized to evaluate 756 microRNAs in three samples of each type of tumor and non-neoplastic brain. The relative expression was calculated in order to identify the three microRNAs whose expression was modified notably. This was verified using RT-qPCR in more number of tumor samples. RESULTS: The microRNAs selected for testing were miR-100-5p, miR-195-5p, and miR-770-5p. A higher expression of miR-100-5p was observed in the astrocytomas and ependymomas compared to the medulloblastomas: on average 3.8 times (p < 0.05). MiR-770-5p was expressed less in medulloblastomas compared to astrocytomas four times (p = 0.0162). MiR-195-5p had a low expression in medulloblastomas compared to non-neoplastic cerebellum (p = 0.049). In all three tumor types, expression of miR-770-5p was lower than in non-neoplastic brain (p < 0.001). CONCLUSIONS: These microRNAs may represent potential markers in these tumors.

Epigenetic modifications in cell lines of human astrocytoma differentially regulate expression of apoptotic genes.

OBJECTS: Epigenetic alterations, known as epimutations, act by deregulating gene expression. These epimutations are reversible through the action of chromatin modifiers such as DNA methylation (DNA-met) and histone deacetylases (HDAC) inhibitors. The present study evaluated the effect of 5-azacitidine (5-aza) and sodium butyrate (NaBu) as inhibitors of DNA-met and HDAC, respectively, in the expression of genes involved in apoptosis. METHODS: D54-MG, U373-MG, and T98G cell lines were exposed to 8 mM of NaBu and 12 µM of 5-aza, as well as a combination of both, for 24 h. The expression of the Bcl-2, Bak-1, Bax, Caspase-3, and Caspase-9 genes was assessed by RT-PCR. RESULTS: They show that the Bcl-2, Caspase-3, and Caspase-9 genes were not expressed by the U373-MG and T98G lines, and that the D54-MG line did not express Bak-1. After treatment, however, these cell lines expressed all of the genes due to the effect of 5-aza on Bak-1 in D54-MG and Caspase-9 in T98G, which suggests repression by DNA-met. Meanwhile, Bcl-2, Caspase-3, and Caspase-9 were in the U373-MG and T98G lines expressed after NaBu treatment. The effect of 5-aza induced an increase in the expression of Bax and Bcl-2, while NaBu produced a similar effect on the Bak-1 and Bax genes. CONCLUSIONS: Results reveal that histone deacetylation is the principle mechanism for repressing these genes and that their basal expression is regulated primarily by this form of histone modification.

Reductions in the expression of miR-124-3p, miR-128-1, and miR-221-3p in pediatric astrocytomas are related to high-grade supratentorial, and recurrent tumors in Mexican children.

PURPOSE: Astrocytomas are the most frequent type of tumor of the central nervous system in children. Hence, it is important to describe markers that may improve our understanding of their behavior. Mature microRNAs (miRNAs) may be such biological markers. They are small molecules of RNA that regulate gene expression post-transcriptionally. Due to their importance in cancer, the objective of the present study was to determine the profile of expression of precursor and mature forms of miR-124-3p, miR-128-1, and miR-221-3p using RT-qPCR in pediatric samples. METHODS: A total of 57 astrocytomas embedded in paraffin were selected. As controls, the study included 13 samples of normal brain tissue. RESULTS: Three of eight miRNAs were selected after a preliminary screening. All the miRNAs showed higher levels of expression in normal brain tissue. The expression of miR-124-3p and miR-128-1 decreased in astrocytomas than in normal brain tissue in all grades (p < 0.05 in both cases), and this reduction was most evident in GIV (407- and 1,469-fold, respectively); however, the expression of the precursor forms pre-miR-128-1 and pre-miR-221 was higher in GIV (3.5-fold) than in GI. The levels of miR-128-1 were higher in infratentorial tumors than in supratentorial cases (p = 0.006). Finally, the expression of miR-221-3p was higher in non-recurrent tumors and live patients (p = 0.0185 and p = 0.0004, respectively). CONCLUSIONS: The low expression of these miRNAs may constitute a potential marker of astrocytomas that correlates with localization, possibly due to alterations in the maturation processes of these miRNAs that produced low mature forms in patients with recurrent pediatric astrocytomas.

Image Guided Interpedicular Screw Placement Simulation System for Training and Skill Evaluation. Proof of Concept.

BACKGROUND: The SpineST-01 system is an image-guided vertebrae cannulation training system. During task execution, the computer calculates performance-based metrics displaying different visual perspectives (lateral view, axial view, anteroposterior view) with the position of the instrument inside the vertebra. Finally, a report with the metrics is generated as performance feedback. METHODS: A training box holds a 3D printed spine section. The computer works with 2 orthogonally disposed cameras, tracking passive markers placed on the instrument. Eight metrics were proposed to evaluate the execution of the surgical task. A preliminary study with 25 participants divided into 3 groups (12 novices, 10 intermediates, and 3 expert) was conducted to determine the feasibility of the system and to evaluate and assess the performance differences of each group using Kruskal-Wallis analysis and Mann-Whitney U analysis. In both analyses, a P value ≤ 0.05 was considered statistically significant. RESULTS: When comparing experts versus novices and all 3 groups, statistical analysis showed significant differences in 6 of the 8 metrics: axial angle error (°), lateral angle error (°), average speed (mm/second), progress between shots (mm), Time (seconds), and shots. The metrics that did not show any statistically significant difference were time between shots (seconds), and speed between shots (mm/second). Also, the average result comparison placed the experts as the best performance group. CONCLUSIONS: Initial testing of the SpineST-01 demonstrated potential for the system to practice image-guided cannulation tasks on lumbar vertebrae. Results showed objective differences between experts, intermediates, and novices in the proposed metrics, making this system a feasible option for developing basic navigation system skills without the risk of radiation exposure and objectively evaluating task performance.

Single sagittal craniosynostosis surgical treatment with the "Peau d́ours" technique. Single-center experience in Mexico.

Scaphocephaly (SC) is defined as an elongation of the anteroposterior axis of the skull resulting from the abnormal fusion of the sagittal suture. This study describes the "Peau d'ours" technique and results for correcting SC. We conducted a consecutive and retrospective analysis of patients treated from 2011 to 2016. We evaluated the gender, age, and surgical outcomes. A total of 53 patients were enrolled with a mean age of 19 months old. The advantages of this technique are healthy coronal and lambdoid suture preservation and symmetrical parietal bone flap opening. This technique is safe and simple to reproduce, allowing good surgical outcomes with a low incidence of secondary craniosynostosis. This technique is ideal for patients older than six months old.

Integration of Comprehensive Metrics into the PsT1 Neuroendoscopic Training System.

OBJECTIVE: Metric-based surgical training can be used to quantify the level and progression of neurosurgical performance to optimize and monitor training progress. Here we applied innovative metrics to a physical neurosurgery trainer to explore whether these metrics differentiate between different levels of experience across different tasks. METHODS: Twenty-four participants (9 experts, 15 novices) performed 4 tasks (dissection, spatial adaptation, depth adaptation, and the A-B-A task) using the PsT1 training system. Four performance metrics (collision, precision, dissected area, and time) and 6 kinematic metrics (dispersion, path length, depth perception, velocity, acceleration, and motion smoothness) were collected. RESULTS: For all tasks, the execution time (t) of the experts was significantly lower than that of novices (P < 0.05). The experts performed significantly better in all but 2 of the other metrics, dispersion and sectional area, corresponding to the A-B-A task and dissection task, respectively, for which they showed a nonsignificant trend towards better performance (P = 0.052 and P = 0.076, respectively). CONCLUSIONS: It is possible to differentiate between the skill levels of novices and experts according to parameters derived from the PsT1 platform, paving the way for the quantitative assessment of training progress using this system. During the current coronavirus disease 2019 pandemic, neurosurgical simulators that gather surgical performance metrics offer a solution to the educational needs of residents.

The Role of Time as a Prognostic Factor in Pediatric Brain Tumors: a Multivariate Survival Analysis.

There is no evidence that prolonged pre diagnostic symptomatic intervals (PSI) increases the risk of death in pediatric brain tumors. When investigating the role of time previous research had not controlled for confounding variables or measured the pretreatment interval (PTI). We use the term global delay interval (GDI) to describe the sum of PSI and PTI. The aim of this research was to evaluate whether there was a decrease in the probability of survival in children with brain tumors due to a prolonged PSI, PTI and GDI, using a multivariate survival analysis. We retrospective review 127 clinical records labeled with the diagnosis of CNS tumors attended at a specialized pediatric center in Mexico City from January 2008 to December 2012. Patients with PSI and GDI diagnosed between 3 and 6 months showed statistical lower probability of surviving that those with intervals <3 months even when adjusting for age, sex, localization and tumor grade. When stratified for the place of residency and adjusted for sex, age, localization, grade of tumor, type of surgery and coadjuvant therapy, a GDI between 3 and 6 months showed to be a risk factor for the overall survival of brain tumors compared with an interval < 3 months. When analyzing the interaction, high grade tumors are at more risk of dying when GDI was between 3 and 6 months compared to <3 months. Prolonged PSI and GDI showed to be a potential prognostic factor for survival in CNS tumors, especially in high grade tumors. Future prospective research should measure the PSI, PTI and GDI and adjust for covariates in order to properly infer the effect of time in pediatric brain tumors.

Glioblastoma multiforme in children: experience at Hospital Infantil de Mexico Federico Gomez.

OBJECTIVE: To evaluate clinical evolution of pediatric patients diagnosed with glioblastoma multiforme (GBM) at Hospital Infantil de México Federico Gómez. METHODS: Cases of patients treated from January to May, 2007, were included in this study. Variables analyzed were: age, diagnosis, size of tumor, histopathological description, degree of resection, time of stay in hospital, complications and outcome using Pearson's chi-squared test and logistic regression. CONCLUSION: Sixteen patients were identified. Mean age of presentation was 8.8. An increased frequency of complications was observed in younger patients and longer survival rates in patients with greater resections; main mode of presentation was directly related to intracranial hypertension; size of tumor was not related to evolution or outcome. Modern histological classifications especially designed for children are deemed necessary to accurately diagnose GBM.

Pediatric pineal germinomas: Epigenetic and genomic approach.

OBJECTIVE: We identify and correlate chromosomal alterations, methylation patterns and gene expression in pediatric pineal germinomas. METHODS: CGH microarray, methylation and gene expression were performed through the Agilent platform. The results were analyzed with MatLab software, MapViewer, DAVID, GeneCards and Hippie. RESULTS: Amplifications were found in 1q24.2, 1q31.3, 2p11.2, 3p22.2, 7p13, 7p15.2, 8p22, 12p13.2, 14q24.3 y 22q12; and deletions were found in 1q21.2, 9p24.1, 10q11.22, 11q11, 15q11.2 and 17q21.31. In the methylation analysis, we observed 10,428 CpG Islands with a modified methylation status that may affect 11,726 genes. We identified 1260 overexpressed genes and 470 underexpressed genes. The genes RUNDC3A, CDC247, CDCA7L, ASAH1, TRA2A, LPL and NPC2 were altered among the three levels. CONCLUSIONS: We identified the 1q24.2 and 1q31.3 amplified regions and the 1q21.3 and 11q11 deleted regions as the most important aims. The genes NPC2 and ASAH1 may play an important role in the development, progression and tumor maintenance. The ASAH1 gene is an ideal candidate to identify drug responses. These genomic and epigenetic studies may help to characterize the formation of pineal germ cell tumors to determine prognostic markers and also to identify shared characteristics in gonadal and extragonadal tumors.

PsT1: A Low-Cost Optical Simulator for Psychomotor Skills Training in Neuroendoscopy.

BACKGROUND: Well-developed psychomotor skills are important for competence in minimally invasive surgery. Neuroendoscopy is no exception, and adaptation to different visual perspectives and careful handling of the surgical instruments are mandatory. Few training systems, however, focus on developing psychomotor skills for neuroendoscopy. Here, we introduce a new training system called PsT1 that provides visual feedback via the use of simple optics that emulate the endoscope at 0° and 30°. Time and error metrics are generated automatically with integrated software to ensure objective assessment. METHODS: Neuroendoscopic optics were emulated with a low-cost, commercially available universal serial bus 2.0 camera and a light-emitting diode light source. Visual feedback of 30° was obtained by displacing the optical axis of the universal serial bus camera by 30°, and metrics (time, precision, and errors) were generated automatically by the software. Three evaluation modules were developed (spatial adaptation, depth adaptation, and dissection), and 35 expert and nonexpert neurosurgeons performed an initial evaluation of the system. RESULTS: A total of 81% and 90% of surgeons agreed that the visuals were satisfactory and movement and control were accurately replicated, respectively. The advantages and disadvantages of the system were compared. CONCLUSIONS: Here, we present a novel, low-cost, and easy-to-implement training system for developing basic neuroendoscopic psychomotor skills. The use of objective metrics, surgical instruments, and emulation of the neuroendoscope at 0° and 30° are competitive advantages of the current system.

Evaluation of the melting temperature of TaqMan probes as a genotyping method for IDH1, IDH2, and H3F3A in pediatric astrocytomas / Evaluación del método de temperatura de disociación de sondas TaqMan para la genotipificación de IDH1, IDH2 y H3F3A en astrocitomas pediátricos

Abstract Background: Astrocytomas are cancer tumors of the central nervous system and represent the most common type of solid tumors during human childhood. In 2016, the World Health Organization established a molecular classification system to regroup tumor entities to achieve a more accurate diagnosis and a better clinical decision-making and selection of treatment in patients with these types of tumors. Methods: We evaluated a genotyping assay for rapid and cost-effective mutation detection in astrocytomas using TaqMan probes in an asymmetric polymerase chain reaction (PCR) assay. Results: Four diffuse astrocytomas (Grade II), three anaplastic astrocytomas (Grade III), and four glioblastomas (Grade IV) were sequenced, and all of them displayed the wild-type (WT) sequence. We tried to set up this melting analysis for the genotyping of pediatric astrocytomas by identifying the specific melting temperatures of the TaqMan probes due to the presence of the WT sequences in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) and H3.3 histone A genes (H3F3A). We used an IDH1-TaqMan probe to identify the WT status of IDH1 in two different WT deoxyribonucleic acid (DNA) templates (pilocytic and diffuse astrocytoma) and obtained four melting temperature values ranged from 65.6 to 92.2°C. Furthermore, only four out of 29 reactions displayed amplification of the DNA template. Sanger sequencing was faster and more reliable to detect the gene status in all the sequenced samples. Conclusions: We conclude that conventional Sanger sequencing remains the gold standard for the genotyping of pediatric astrocytomas.

Resumen Introducción: Los astrocitomas son un tipo de cáncer que afecta al sistema nervioso central y representan el tumor sólido más común durante la infancia. En el año 2016, la Organización Mundial de la Salud estableció un sistema de clasificación molecular para reagrupar tumores con identidades genéticas similares y lograr un diagnóstico más preciso, lo que lleva a tomar las decisiones clínicas idóneas al elegir el tratamiento de pacientes con este tipo de tumores. Métodos: Se evaluó un protocolo que involucra el uso de sondas TaqMan en un ensayo de reacción en cadena de la polimerasa asimétrica para la detección de mutaciones en astrocitomas. Se secuenciaron cuatro astrocitomas difusos (Grado II), tres astrocitomas anaplásicos (Grado III) y cuatro glioblastomas (Grado IV). Se intentó establecer las condiciones del análisis para la genotipificación de los astrocitomas pediátricos mediante la identificación de las temperaturas de disociación específicas de las sondas TaqMan producidas por la prescencia de las secuancias WT en los genes isocitrato deshidrogenasa 1 y 2 (IDH1, IDH2) y H3.3 histona A (H3F3A). Resultados: Los astrocitomas mostraron la secuencia wild type (WT) (silvestre) de los genes. Se utilizó una sonda TaqMan IDH1 para identificar el estado de este gen en dos templados WT de DNA (astrocitoma pilocítico y difuso) y se obtuvieron cuatro valores de temperatura de disociación (65.6-92.2 °C). Solo cuatro de las 29 reacciones mostraron amplificación de DNA. La secuenciación de Sanger fue más rápida y confiable para detectar el estado de los genes en todas las muestras. Conclusiones: La secuenciación de Sanger sigue siendo la técnica más práctica para la genotipificación de astrocitomas pediátricos.

The dawn of plastic surgery in Mexico: XVIth century.

An aspect of early Mexican surgery in the sixteenth century is presented. The treatment of facial wounds by Alonso Lopez de Hinojosos and Agustin Farfán is reviewed. Farfán proposed total nose reconstruction, with a cutaneous arm flap, 18 years before its description in De Curtorum Chirurgia, by Tagliacozzi, in 1597 in Venice, Italy. The chapter on facial wounds by Lopez de Hinojosos and Farfán shows their concern for the final aesthetic results and should be considered the first Mexican publication in the field of plastic surgery.

Holoprosencephaly in Mexico: first reported autopsy case by Dr. Agustín Arellano.

INTRODUCTION: Holoprosencephaly with cyclocephaly is an early disturbance of organogenesis and has been classified as a severe brain malformation starting in 1755 by Eller in Germany, then in 1822 by Etienne Geoffroy de Saint-Hilaire in France, and finally in 1828 by Tiedemann in Germany. In 1839, Dr. Arellano published in Mexico a necropsy case of holoprosencephaly. This was the fourth publication worldwide on this kind of pathological alteration. Furthermore, in reference to diaphragmatic herniation, Arellano's paper is the fourth world report, having appeared 9 years before Bochdalek's publication. We have not found any other report that appeared before 1839 in the Americas on this particular malformation, and we consider that Arellano's paper was the first of its kind on the American continent. CONCLUSION: As is well known, the publications of this Mexican medical researcher were, for his time, at the level of those of the most developed countries. It is also important to know that the medical journal where Arellano's work was published, the "Periódico de la Academia de Medicina de Mégico(sic)," founded and directed by Dr. Manuel Carpio in 1836, is the direct forerunner of the present Gaceta Médica de México, the oldest currently published journal in the Americas.