Report of two cases

PI3K/Akt signalling pathway and cancer ☆

Pediatric brain tumors are significant causes of morbidity and mortality. It has been hypothesized that they derive from self-renewing multipotent neural stem cells. Here, we tested whether different pediatric brain tumors, including medulloblastomas and gliomas, contain cells with properties similar to neural stem cells. We find that tumor-derived progenitors form neurospheres that can be passaged at clonal density and are able to self-renew. Under conditions promoting differentiation, individual cells are multipotent, giving rise to both neurons and glia, in proportions that reflect the tumor of origin. Unlike normal neural stem cells, however, tumor-derived progenitors have an unusual capacity to proliferate and sometimes differentiate into abnormal cells with multiple differentiation markers. Gene expression analysis reveals that both whole tumors and tumor-derived neurospheres express many genes characteristic of neural and other stem cells, including CD133, Sox2, musashi-1, bmi-1, maternal embryonic leucine zipper kinase, and phosphoserine phosphatase, with variation from tumor to tumor. After grafting to neonatal rat brains, tumor-derived neurosphere cells migrate, produce neurons and glia, and continue to proliferate for more than 4 weeks. The results show that pediatric brain tumors contain neural stem-like cells with altered characteristics that may contribute to tumorigenesis. This finding may have important implications for treatment by means of specific targeting of stem-like cells within brain tumors.

https://www.pnas.org/content/pnas/100/25/15178.full.pdf

Cancerous stem cells can arise from pediatric brain tumors

The new edition of the World Health Organization (WHO) book on 'Histological Typing of Tumours of the Central Nervous System' reflects the progress in brain tumour classification which has been achieved since publication of the first edition in 1979. Several new tumour entities have been added, including the pleomorphic xanthoastrocytoma, central neurocytoma, the infantile desmoplastic astrocytoma/ganglioglioma, and the dysembryoplastic neuroepithelial tumour. The list of histological variants has also been expanded. In line with recent morphological and molecular data on glioma progression, the glioblastoma is now grouped together with astrocytic tumours. The classification of childhood tumours has been largely retained, the diagnosis primitive neuroectodermal tumour (PNET) only being recommended as a generic term for cerebellar medulloblastomas and neoplasms that are histologically indistinguishable from medulloblastoma but located in the CNS at sites other than the cerebellum. The WHO grading scheme was revised and adapted to new entities but its use, as before, remains optional.

The new WHO classification of brain tumours.

The health-care facility environment is rarely implicated in disease transmission, except among patients who are immunocompromised. Nonetheless, inadvertent exposures to environmental pathogens (e.g., Aspergillus spp. and Legionella spp.) or airborne pathogens (e.g., Mycobacterium tuberculosis and varicella-zoster virus) can result in adverse patient outcomes and cause illness among health-care workers. Environmental infection-control strategies and engineering controls can effectively prevent these infections. The incidence of health-care--associated infections and pseudo-outbreaks can be minimized by 1) appropriate use of cleaners and disinfectants; 2) appropriate maintenance of medical equipment (e.g., automated endoscope reprocessors or hydrotherapy equipment); 3) adherence to water-quality standards for hemodialysis, and to ventilation standards for specialized care environments (e.g., airborne infection isolation rooms, protective environments, or operating rooms); and 4) prompt management of water intrusion into the facility. Routine environmental sampling is not usually advised, except for water quality determinations in hemodialysis settings and other situations where sampling is directed by epidemiologic principles, and results can be applied directly to infection-control decisions. This report reviews previous guidelines and strategies for preventing environment-associated infections in health-care facilities and offers recommendations. These include 1) evidence-based recommendations supported by studies; 2) requirements of federal agencies (e.g., Food and Drug Administration, U.S. Environmental Protection Agency, U.S. Department of Labor, Occupational Safety and Health Administration, and U.S. Department of Justice); 3) guidelines and standards from building and equipment professional organizations (e.g., American Institute of Architects, Association for the Advancement of Medical Instrumentation, and American Society of Heating, Refrigeration, and Air-Conditioning Engineers); 4) recommendations derived from scientific theory or rationale; and 5) experienced opinions based upon infection-control and engineering practices. The report also suggests a series of performance measurements as a means to evaluate infection-control efforts.

Recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee (HICPAC)

We describe the clinical and imaging findings of brain stem tumours in patients with neurofibromatosis type 1 (NF1). The NF1 patients imaged between January 1984 and January 1996 were reviewed and 25 patients were identified with a brain stem tumour. Clinical, radiographical and pathological results were obtained by review of records and images. Brain stem tumour identification occurred much later than the clinical diagnosis of NF1. Medullary enlargement was most frequent (68 %), followed by pontine (52 %) and midbrain enlargement (44 %). Patients were further subdivided into those with diffuse (12 patients) and those with focal (13 patients) tumours. Treatment for hydrocephalus was required in 67 % of the first group and only 15 % of the second group. Surgery was performed in four patients and revealed fibrillary astrocytomas, one of which progressed to an anaplastic astrocytoma. In 40 % of patients both brain stem and optic pathway tumours were present. The biological behaviour of brain stem tumours in NF1 is unknown. Diffuse tumours in the patients with NF1 appear to have a much more favourable prognosis than patients with similar tumours without neurofibromatosis type 1.

Neurofibromatosis type 1: brain stem tumours.

We studied 14 young people with newly diagnosed hemisphere tumors, aged from 3 to 20 years (average 10 years). All underwent surgery following MR imaging (MRI) and spectroscopy (MRS). The tumors studied were three glioblastomas, one each of ganglio-glioblastoma, primitive neuroectodermal tumor (PNET), rhabdoid teratoid tumor, pilocytic astrocytoma, ependymoma, anaplastic ependymoma, and gliomatosis cerebri, and four gangliogliomas. Four patients died; ten patients are alive (five with stable residual tumor, five with no evident tumor). Images and spectra were acquired on a 1.5-T imager. Proton MRS was performed before gadolinium injection in all but one case. Single-voxel techniques were utilized in all cases, using a spin-echo or STEAM sequence with a long echo time (135 or 270 ms). Peak areas of N -acetyl aspartate (NAA), choline (Cho), and creatine and phosphocreatine (Cr) were assessed. The NAA/Cho peak-area ratio was very low in the patients who died (mean ± s. d. 0.20 ± 0.14), and higher in the patients who are alive (0.74 ± 0.47; P = 0.007 by two-tailed t -test). The Cr/Cho peak-area ratio also followed a similar trend for the two groups (mean ± s. d. 0.17 ± 0.07 and 0.49 ± 0.30, respectively; P = 0.01 by two-tailed t -test).

Prognostic value of proton MR spectroscopy of cerebral hemisphere tumors in children

To investigate the effects of hypothermia on the rate of change and degree of recovery of brain adenosine triphosphate and phosphocreatine concentrations and intracellular pH, we have developed a model that allows phosphorus nuclear magnetic resonance spectroscopy of the intact piglet brain during circulatory arrest.

Three groups of piglets were studied. Three control animals underwent cardiopulmonary bypass at normothermia for 1 hour; five group 1 animals underwent bypass at a brain temperature of 15 degrees C, followed by a period of circulatory arrest such that adenosine triphosphate was absent for 21 minutes, followed by 1 hour of reperfusion; and five group 2 animals underwent bypass at a brain temperature of 37 degrees C, followed by a period of circulatory arrest such that adenosine triphosphate was absent for 21 minutes, followed by reperfusion for 1 hour.

Control animals showed no significant metabolic effects of bypass. Group 1 animals showed a slower decay of the adenosine triphosphate and phosphocreatine concentrations than group 2 animals, consistent with a lower metabolic rate, and had a higher pH at the onset of ischemia. Recovery of the adenosine triphosphate concentration was significantly better in group 1 animals (95%) than in group 2 animals (30%) (p less than 0.02), and recovery of the phosphocreatine concentration was also better in group 1 animals (93%) than in group 2 animals (32%) (p less than 0.02). Intracellular pH recovered in group 1 animals, but not in group 2 animals. Regional biochemical assays of metabolites performed in the group 2 piglets and in five pilot piglets exposed to deep hypothermia generally confirmed the spectroscopic findings but demonstrated considerable regional variation, specially in the group 2 piglets' brains.

We conclude that hypothermia exerts a protective effect on the piglet brain during global ischemia even after the adenosine triphosphate pool has been completely depleted.

https://www.ahajournals.org/doi/pdf/10.1161/01.STR.22.12.1567

Global cerebral ischemia in piglets under conditions of mild and deep hypothermia.

Myelomeningocele (MMC) is one of the most common serious congenital malformations. Typically this condition has been treated with closure of the MMC defect shortly after birth. In general, surgery for MMC aims to provide a multilayered closure to provide protection to the neural elements, prevent leakage of spinal fluid and reduce infection risks. A randomized controlled trial, the Management of Myelomeningocele Study (MOMS), has shown that closure during the fetal period can be performed relatively safely and can result in significant benefit to the child. Whereas the surgical technique of prenatal closure of an MMC defect is similar to a postnatal closure, there are some important technical differences. The goal of this paper is to describe the technique of fetal closure of MMC defects, highlight the unique steps that are needed for this surgery and delineate some potential pitfalls.

/pdf/fetal-myelomeningocele-closure-technical-considerations-5anrgarf9v.pdf

Fetal myelomeningocele closure: technical considerations

Deletions of chromosome 22 have been identified in 3 types of childhood primary brain tumor: meningiomas, rhabdoid or atypical teratoid tumors (ATT) and ependymomas. This implicates the involvement of tumor suppressor genes on chromosome 22 in the genesis of these rare tumors. One such candidate tumor suppressor gene is the recently cloned neurofibromatosis 2 (NF2) locus. The purpose of our study was to determine the frequency of germ-line and somatic NF2 mutations in a selected group of brain tumors in children. Using single-strand conformation polymorphism (SSCP) assays we screened 17 exons of the NF2 gene in 13 pediatric brain tumors and 9 matched normal blood DNA samples. Tumors included 3 meningiomas, 2 rhabdoid or ATTs, 7 ependymomas and 1 malignant tumor of glial lineage. In addition, lymphoblastoid cell lines from 3 patients with rhabdoid/ATT in whom no tumor tissue was available were analyzed for germ-line mutations. Migration shifts were not detected in any of the normal DNA samples analyzed. Of the 13 tumors screened by SSCP, 1 meningioma with monosomy 22 produced a migration shift in exon 13. DNA sequencing of exon 13 revealed a deletion of a single guanine nucleotide (base 1397) in codon 466, causing a frame shift. While not all mutations might have been picked up by this technique, the data suggest that, similar to adult sporadic meningiomas, some pediatric meningiomas may result from somatic mutations in the NF2 gene. For rhabdoid tumors and ependymomas it appears that a locus distinct from NF2 might be responsible for tumorigenesis.

Leslie N. Sutton

Papers

Neurofibromatosis type 1: brain stem tumours.

Prognostic value of proton MR spectroscopy of cerebral hemisphere tumors in children

Global cerebral ischemia in piglets under conditions of mild and deep hypothermia.

Fetal myelomeningocele closure: technical considerations

Exon scanning for mutations of the NF2 gene in pediatric ependymomas, rhabdoid tumors and meningiomas.