Abstract: Routine and nonselective use of awake and outpatient craniotomy for supratentorial tumors has been shown to be safe and effective from a medical standpoint. In this study the authors aim was to explore patients' perceptions about awake and outpatient craniotomy.
Abstract: Tumor-initiating cells with stem cell properties are believed to sustain the growth of gliomas, but proposed markers such as CD133 cannot be used to identify these cells with sufficient specificity. We report an alternative isolation method purely based on phenotypic qualities of glioma-initiating cells (GICs), avoiding the use of molecular markers. We exploited intrinsic autofluorescence properties and a distinctive morphology to isolate a subpopulation of cells (FL1(+)) from human glioma or glioma cultures. FL1(+) cells are capable of self-renewal in vitro, tumorigenesis in vivo and preferentially express stem cell genes. The FL1(+) phenotype did not correlate with the expression of proposed GIC markers. Our data propose an alternative approach to investigate tumor-initiating potential in gliomas and to advance the development of new therapies and diagnostics.
Abstract: Schwannomas, although benign, can be fatal or give rise to significant morbidity due to an unpredictable growth rate. They can reoccur after surgery or radiation, current treatments each with significant inherent risks. These risks are further amplified in neurofibromatosis type 2 (NF2), a germ line predisposition syndrome characterized by multiple schwannomas, underlying the need for biological targeted therapies. Gleevec (STI571, imatinib mesylate), in addition to the bcr-abl oncogene in chronic myelogenous leukemia, inhibits c-kit and platelet-derived growth factor receptor (PDGFR) signaling, thereby expanding its use to several malignant and benign human diseases. In the present study, we show that human sporadic and NF2-associated schwannomas have increased expression along with activation of PDGFR-alpha, PDGFR-beta, and c-kit receptors, compared with normal or traumatic nerve. Using the human NF2-null HEI-193 schwannoma cell line, Gleevec inhibited schwannoma viability, proliferation, and anchorage-independent growth, as well as induced apoptosis in a dose-dependent manner (IC(50) 5-10 micromol/L). These antitumorigenic effects were correlated to inhibition of PDGFR-alpha, PDGFR-beta, and c-kit activation/phosphorylation and major downstream signaling pathways. Lack of robust xenograft or transgenic models of schwannomas prevents extension of these studies in vivo. However, the established long track record and tolerable toxicity of Gleevec already in clinical use and our preclinical data lead us to propose that Gleevec should be evaluated in human schwannomas with shown progressive growth.
Abstract: In human gliomas, self-renewing and tumor-initiating cells are characterized by the expression marker CD133. Although, widely used, the validity of CD133 is debated as recent data show that CD133(+) and CD133(-) cells share similar stemness and tumorigenic properties. To clarify this "CD133 controversy", we reexamined the methods of purification and the stem behavior of both CD133 compartments in fresh gliomas and gliomasphere cultures. Using human anti-CD133-coupled microbeads and magnetic activated cell sorting, we observed a nonspecific sorting of glioma cells irrespective of their CD133 expression. In contrast, when purified by fluorescence activating cell sorting, a specific expression and enrichment of CD133 was successfully observed in fresh human gliomas and gliomasphere cultures. However, neither the expression of stemness genes nor the long-term self-renewal capacities of CD133(+) and CD133(-) cells were significantly different, even after fresh isolation. Altogether, our data show that purification of CD133(+) glioma cells using hCD133-microbeads presents a lack of specificity and demonstrate that the use of CD133 as a unique glioma stem cell marker is likely not sufficient to tag the whole self-renewing tumor cell reservoir.
Abstract: The prion consists essentially of PrP(Sc), a misfolded and aggregated conformer of the cellular protein PrP(C). Whereas PrP(C) deficient mice are clinically healthy, expression of PrP(C) variants lacking its central domain (PrP(DeltaCD)), or of the PrP-related protein Dpl, induces lethal neurodegenerative syndromes which are repressed by full-length PrP. Here we tested the structural basis of these syndromes by grafting the amino terminus of PrP(C) (residues 1-134), or its central domain (residues 90-134), onto Dpl. Further, we constructed a soluble variant of the neurotoxic PrP(DeltaCD) mutant that lacks its glycosyl phosphatidyl inositol (GPI) membrane anchor. Each of these modifications abrogated the pathogenicity of Dpl and PrP(DeltaCD) in transgenic mice. The PrP-Dpl chimeric molecules, but not anchorless PrP(DeltaCD), ameliorated the disease of mice expressing truncated PrP variants. We conclude that the amino proximal domain of PrP exerts a neurotrophic effect even when grafted onto a distantly related protein, and that GPI-linked membrane anchoring is necessary for both beneficial and deleterious effects of PrP and its variants.
Abstract: The treatment for the pineal region tumors depends on tumor histology. Nowadays, germinomas can be cured by radiotherapy and chemotherapy without surgical resection but the other pineal region tumors should be primary treated by surgery. Two microsurgical approaches, the infratentorial supracerebellar and the occipital transtentorial, are accepted as the main standard accesses to the pineal region. For benign pineal tumors (pineocytoma, meningioma, mature teratomas, symptomatic pineal cysts, etc.) radical surgical resection can be curative. For malignant tumors radical surgical resection is not an objective. Serum and CSF markers contribute to the diagnosis of pineal parenchymal tumors. b-HCG is mainly positive in choriocarcinomas, embryonal carcinomas and mixed germ cell tumors and AFP is expressed by yolk sac tumors, embryonic carcinomas, immature teratomas and mixed germ cell tumors, b-HCG is usually low in germinomas which are often positive for PLAP on immunohistochemistry. Fifty-one pineal region tumors were surgically treated by senior author (NdT). Only 17 of them were the neoplasms originating from pineal body (pineal tumors). In conclusion it can be stressed that management of pineal tumors requires a multidisciplinary cooperation. With the exception of germinoma where only a biopsy is needed, the role of the surgeons still remains prominent as resection of pineal tumors requires high technical skill and experience as well as precise clinical judgment.
Abstract: Overexpression of the polycomb group protein enhancer of zeste homologue 2 (EZH2) occurs in diverse malignancies, including prostate cancer, breast cancer, and glioblastoma multiforme (GBM). Based on its ability to modulate transcription of key genes implicated in cell cycle control, DNA repair, and cell differentiation, EZH2 is believed to play a crucial role in tissue-specific stem cell maintenance and tumor development. Here, we show that targeted pharmacologic disruption of EZH2 by the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep), or its specific downregulation by short hairpin RNA (shRNA), strongly impairs GBM cancer stem cell (CSC) self-renewal in vitro and tumor-initiating capacity in vivo. Using genome-wide expression analysis of DZNep-treated GBM CSCs, we found the expression of c-myc, recently reported to be essential for GBM CSCs, to be strongly repressed upon EZH2 depletion. Specific shRNA-mediated downregulation of EZH2 in combination with chromatin immunoprecipitation experiments revealed that c-myc is a direct target of EZH2 in GBM CSCs. Taken together, our observations provide evidence that direct transcriptional regulation of c-myc by EZH2 may constitute a novel mechanism underlying GBM CSC maintenance and suggest that EZH2 may be a valuable new therapeutic target for GBM management.
Abstract: Different surgical approaches to and through the lamina terminalis (LT) have been proposed to treat pathologies of the anterior third ventricle. Moreover, the opening of the LT is a standard adjunct in ruptured aneurysm surgery. However, the endoscopic anatomy and approach to the LT have not been extensively described. In the following study we performed an endoscopic subfrontal approach to the LT on 10 human cadaveric specimens through a supraorbital minicraniotomy. We discuss the endoscopic anatomy of the LT region and its fenestration through such an approach. The clinical potential use of this alternative third ventriculostomy is also pointed out.
Abstract: Cancer stem cells are rare tumor cells characterized by their ability to self-renew and to induce tumorigenesis. They are present in gliomas and may be responsible for the lethality of these incurable brain tumors. In the most aggressive and invasive type, glioblastoma multiforme (GBM), an average of about one year spans the period between detection and death [1]. The resistence of gliomas to current therapies may be related to the existence of cancer stem cells [2-6]. We find that human gliomas display a stemness signature and demonstrate that HEDGEHOG (HH)-GLI signaling regulates the expression of stemness genes in and the self-renewal of CD133(+) glioma cancer stem cells. HH-GLI signaling is also required for sustained glioma growth and survival. It displays additive and synergistic effects with temozolomide (TMZ), the current chemotherapeutic agent of choice. TMZ, however, does not block glioma stem cell self-renewal. Finally, interference of HH-GLI signaling with cyclopamine or through lentiviral-mediated silencing demonstrates that the tumorigenicity of human gliomas in mice requires an active pathway. Our results reveal the essential role of HH-GLI signaling in controlling the behavior of human glioma cancer stem cells and offer new therapeutic possibilities.
Abstract: The PTEN hamartoma tumor syndrome, manifestations of which include Cowden disease and Bannayan-Riley-Ruvalcaba syndrome, is caused by various mutations of the PTEN gene located at 10q23. Its major criteria are macrocephaly and a propensity to develop breast and thyroid cancers as well as endometrial carcinoma. Minor diagnostic criteria include hamartomatous intestinal polyps, lipomas, fibrocystic disease of the breasts, and fibromas. Mutations of PTEN can also be found in patients with Lhermitte-Duclos disease (dysplastic gangliocytoma of the cerebellum). The authors report the case of a 17-year-old girl who had a severe cyanotic cardiac malformation for which surgery was not advised and a heterozygous missense mutation (c.406T>C) in exon 5 of PTEN resulting in the substitution of cysteine for arginine (p.Cysl36Arg) in the protein, which was also found in her mother and sister. The patient presented in the pediatric emergency department with severe spastic paraparesis. A magnetic resonance imaging study of the spine showed vertebral hemangiomas at multiple levels, but stenosis and compression were maximal at level T5-6. An emergency T5-6 laminectomy was performed. The decompression was extremely hemorrhagic because the rapid onset of paraparesis necessitated prompt treatment, and there was no time to perform preoperative embolization. The patient's postoperative course was uneventful with gradual recovery. This represents the first report of an association of a PTEN mutation and multiple vertebral angiomas. The authors did not treat the remaining angiomas because surgical treatment was contraindicated without previous embolization, which in itself would present considerable risk in this patient with congenital cyanotic heart disease.
Abstract: Dumbbell tumours are those with an intraspinal and a paraspinal component, connected through a frequently enlarged and eroded intervertebral foramen. Most dumbbell tumours are located in the thoracic spine, and most of them are schwannomas. The extraspinal tumour extension is usually larger than the intraspinal tumour part, but the intraspinal tumour component commonly causes the typical symptoms: local pain and symptoms from spinal cord compression in the thoracic spine. Diagnosis is best established by magnetic resonance imaging with and without contrast agent injection. Controversy exists as to whether to remove thoracic dumbbell tumours using a single posterior approach with posterolateral extension or using a combined posterior and transthoracic approach. We report the removal of a dumbbell neurinoma at T6/7 using a single posterior midline approach with laminectomy and costo-transversectomy and review the literature regarding the approaches to thoracic dumbbell tumours.
Abstract: Nijmegen breakage syndrome (NBS), ataxia telangiectasia and ataxia telangiectasia-like disorder (ATLD) show overlapping phenotypes such as growth retardation, microcephaly, cerebellar developmental defects and ataxia. However, the molecular pathogenesis of these neurological defects remains elusive. Here we show that inactivation of the Nbn gene (also known as Nbs1) in mouse neural tissues results in a combination of the neurological anomalies characteristic of NBS, ataxia telangiectasia and ATLD, including microcephaly, growth retardation, cerebellar defects and ataxia. Loss of Nbn causes proliferation arrest of granule cell progenitors and apoptosis of postmitotic neurons in the cerebellum. Furthermore, Nbn-deficient neuroprogenitors show proliferation defects (but not increased apoptosis) and contain more chromosomal breaks, which are accompanied by ataxia telangiectasia mutated protein (ATM)-mediated p53 activation. Notably, depletion of p53 substantially rescues the neurological defects of Nbn mutant mice. This study gives insight into the physiological function of NBS1 (the Nbn gene product) and the function of the DNA damage response in the neurological anomalies of NBS, ataxia telangiectasia and ATLD.
Abstract: The cellular prion protein PrP(C) confers susceptibility to transmissible spongiform encephalopathies, yet its normal function is unknown. Although PrP(C)-deficient mice develop and live normally, expression of amino proximally truncated PrP(C) (DeltaPrP) or of its structural homolog Doppel (Dpl) causes cerebellar degeneration that is prevented by coexpression of full-length PrP(C). We now report that mice expressing DeltaPrP or Dpl suffer from widespread leukoencephalopathy. Oligodendrocyte-specific expression of full-length PrP(C) under control of the myelin basic protein (MBP) promoter repressed leukoencephalopathy and vastly extended survival but did not prevent cerebellar granule cell (CGC) degeneration. Conversely, neuron-specific PrP(C) expression under control of the neuron-specific enolase (NSE) promoter antagonized CGC degeneration but not leukoencephalopathy. PrP(C) was found in purified myelin and in cultured oligodendrocytes of both wild-type and MBP-PrP transgenic mice but not in NSE-PrP mice. These results identify white-matter damage as an extraneuronal PrP-associated pathology and suggest a previously unrecognized role of PrP(C) in myelin maintenance.
Abstract: The histopathology and the epidemiology of human cancers, as well as studies of animal models of tumorigenesis, have led to a widely accepted notion that multiple genetic and epigenetic changes have to accumulate for progression to malignancy. Formation of new blood vessels (tumor angiogenesis) has been recognized, in addition to proliferative capabilities and ability to down-modulate cell death (apoptosis), as essential for the progressive growth and expansion of solid tumors. Mice overexpressing activated forms of oncogenes or carrying targeted mutations in tumor suppressor genes have proven extremely useful for linking the function of these genes with specific tumor features such as continuous proliferation, escape from apoptosis, invasion and neo-angiogenesis. The interbreeding of these mice allows for studying the extent of cooperativity between different genetic lesions in disease progression, leading to a greater understanding of multi-stage nature of tumorigenesis.
Abstract: Differentiation between posttherapy radiation necrosis and recurrent tumor in humans with brain tumor is still a difficult diagnostic task. The new PET tracers (18)F-fluoro-ethyl-l-tyrosine (FET) and (18)F-fluorocholine (N,N-dimethyl-N-(18)F-fluoromethyl-2-hydroxyethylammonium [FCH]) have shown promise for improving diagnostic accuracy. This study assessed uptake of these tracers in experimental radiation injury.
Abstract: Patients suffering from multiple endocrine neoplasia type 1 (MEN1) are predisposed to multiple endocrine tumors. The MEN1 gene product, menin, is expressed in many embryonic, as well as adult tissues, and interacts with several proteins in vitro and in vivo. However, the biological function of menin remains largely unknown. Here we show that disruption of the Men1 gene in mice causes embryonic lethality at E11.5-E13.5. The Men1 null mutant embryos appeared smaller in size, frequently with body haemorrhages and oedemas, and a substantial proportion of them showed disclosure of the neural tube. Histological analysis revealed an abnormal development of the nervous system and heart hypotrophy in some Men1 null embryos. Furthermore, Men1 null livers generally displayed an altered organization of the epithelial and hematopoietic compartments associated with enhanced apoptosis. Chimerism analysis of embryos generated by injection of Men1 null ES cells, showed that cells lacking menin do not seem to have a general cell-autonomous defect. However, primary Men1 null embryonic fibroblasts entered senescence earlier than their wild-type counterparts. Despite normal proliferation ability, Men1 null ES cells exhibited a deficiency to form embryoid bodies, suggesting an impaired differentiation capacity in these cells. The present study demonstrates that menin plays an important role in the embryonic development of multiple organs in addition to its proposed role in tumor suppression.
Abstract: Interactions of CD70, a tumor necrosis factor-related cell surface ligand and its receptor, CD27, are thought to play an important role for T-, B-, and natural killer-cell activation. However, ligation of CD27 can also induce apoptosis. Human glioblastoma is paradigmatic for cancer-associated immunosuppression. We identified CD70 as a radioinducible gene in U87 MG glioma cells. A screening of a panel of human glioma cell lines revealed that 11 of 12 cell lines expressed CD70 mRNA and protein. Two human neuroblastoma cell lines did not express CD70. CD70 mRNA expression was enhanced by irradiation in 8 of 12 glioma cell lines in a p53-independent manner. No alteration in CD70 expression was observed after glioma cell exposure to cytotoxic drugs such as lomustine. CD70 protein was also detected by immunocytochemistry in 5 of 12 glioblastomas and 3 of 4 anaplastic astrocytomas in vivo. CD27 expression was not detected in any glioma cell line, and there was no evidence for autocrine or backward signaling of the CD70 system in human glioma cells. Unexpectedly, CD70 expressed on glioma cells did not increase the immunogenicity of glioma cells in vitro. In contrast, CD70-positive glioma cells induced apoptosis in peripheral blood mononuclear cells (PBMCs) in a CD70-dependent manner. Neutralization of CD70 expressed on glioma cells prevented apoptosis and enhanced the release of tumor necrosis factor-alpha in cocultures of glioma cells and PBMCs. The effects of CD70-expressing glioma cells on PBMCs were mimicked by agonistic CD27 antibodies. Conversely, the shedding of CD27 by PBMCs was identified as a possible escape mechanism from glioma cell-induced CD70-dependent apoptosis. Thus, induction of B-cell and T-cell apoptosis via interactions of CD70 expressed on glioma cells and CD27 expressed on B and T cells may be a novel way for the immune escape of malignant gliomas.
Abstract: The Mouse Models of Cancer Consortium of the NCI sponsored a meeting of neuropathologists and veterinary pathologists in New York City in November of 2000. A rapidly growing number of genetically engineered mice (GEM) predisposed to tumors of the nervous system have led to a concomitant need for neuropathological evaluation and validation of these models. A panel of 13 pathologists reviewed material representing most of the available published and unpublished GEM models of medulloblastoma, primitive neuroectodermal tumor, astrocytoma, oligodendroglioma, mixed glioma, and tumors of the peripheral nerve. The GEM tumors were found to have many similarities and some distinct differences with respect to human disease. After review of the biology and pathology for all models presented, participants were split into groups reflective of clinical expertise in human pathology, tumor biology, neuroimaging, or treatment/intervention. Recommendations were made detailing an extensive and complete neuropathological characterization of animals. Importance was placed on including information on strains, tumor clonality, and examination for genetic mutation or altered gene expression characteristics of the corresponding human malignancy. Specific proposals were made to incorporate GEM models in emerging neuroradiological modalities. Recommendations were also made for preclinical validation of these models in cancer therapeutics, and for incorporation of surrogate markers of tumor burden to facilitate preclinical evaluation of new therapies.
