Diffuse midline gliomas, H3 K27M-mutant are associated with less peritumoral edema and contrast enhancement in comparison to glioblastomas, H3 K27M-wildtype of midline structures.

PURPOSE: The entity 'diffuse midline glioma, H3 K27M-mutant (DMG)' was introduced in the revised 4th edition of the 2016 WHO classification of brain tumors. However, there are only a few reports on magnetic resonance imaging (MRI) of these tumors. Thus, we conducted a retrospective survey focused on MRI features of DMG compared to midline glioblastomas H3 K27M-wildtype (mGBM-H3wt). METHODS: We identified 24 DMG cases and 19 mGBM-H3wt patients as controls. After being retrospectively evaluated for microscopic evidence of microvascular proliferations (MVP) and tumor necrosis by two experienced neuropathologists to identify the defining histological criteria of mGBM-H3wt, the samples were further analyzed by two experienced readers regarding imaging features such as shape, peritumoral edema and contrast enhancement. RESULTS: The DMG were found in the thalamus in 37.5% of cases (controls 63%), in the brainstem in 50% (vs. 32%) and spinal cord in 12.5% (vs. 5%). In MRI and considering MVP, DMG were found to be by far less likely to develop peritumoral edema (OR: 0.13; 95%-CL: 0.02-0.62) (p = 0.010). They, similarly, were associated with a significantly lower probability of developing strong contrast enhancement compared to mGBM-H3wt (OR: 0.10; 95%-CL: 0.02-0.47) (P = 0.003). CONCLUSION: Despite having highly variable imaging features, DMG exhibited markedly less edema and lower contrast enhancement in MRI compared to mGBM-H3wt. Of these features, the enhancement level was associated with evidence of MVP.

Recycling drug screen repurposes hydroxyurea as a sensitizer of glioblastomas to temozolomide targeting de novo DNA synthesis, irrespective of molecular subtype.

Background: Glioblastoma (GBM) is the most common and most aggressive primary malignant brain tumor. Standard-of-care treatment involves maximal surgical resection of the tumor followed by radiation and chemotherapy (temozolomide [TMZ]). The 5-year survival rate of patients with GBM is <10%, a colossal failure that has been partially attributed to intrinsic and/or acquired resistance to TMZ through O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status in the tumor. Methods: A drug screening aimed at evaluating the potential recycling and repurposing of known drugs was conducted in TMZ-resistant GBM cell lines and primary cultures of newly diagnosed GBM with different MGMT promoter methylation status, phenotypic/genotypic background and subtype, and validated with sphere formation, cell migration assays, and quantitative invasive orthotopic in vivo models. Results: We identified hydroxyurea (HU) to synergize with TMZ in GBM cells in culture and in vivo, irrespective of MGMT promoter methylation status, subtype, and/or stemness. HU acts specifically on the S-phase of the cell cycle by inhibiting the M2 unit of enzyme ribonucleotide reductase. Knockdown of this enzyme using RNA interference and other known chemical inhibitors exerted a similar effect to HU in combination with TMZ both in culture and in vivo. Conclusions: We demonstrate preclinical efficacy of repurposing hydroxyurea in combination with TMZ for adjuvant GBM therapy. This combination benefit is of direct clinical interest given the extensive use of TMZ and the associated problems with TMZ-related resistance and treatment failure.

Diagnostic challenges of primary thalamic gliomas-identification of a minimally enhancing neuroradiological subtype with aggressive neuropathology and poor clinical outcome.

AIM: To evaluate neuropathology and neuroradiology in the diagnosis and clinical outcome of a retrospective cohort of thalamic gliomas. METHODS: Neuropathological and neuroradiological review was undertaken in 25 cases of radiologically suspected thalamic glioma (excluding childhood pilocytic astrocytoma) over an 8 year period (2004-2012) at Frenchay Hospital and compared to the clinical outcome. RESULTS: In 12/25 (48%) there was a difference in neuropathological and suspected neuroradiological grading of the lesion of one or more grades. In 5/12 (42%) cases, the neuroradiology was lower grade than the pathology. In 4/5 (80%) of these cases, we identified a minimally enhancing subtype where the neuroradiology was predicted to be of lower grade than neuropathology. In 4/12, (33%) the suspected neuroradiology grade was higher than the final pathology. In 3/4, (75%) of these cases the suspected neuroradiology grade was higher than the neuropathology possibly because of unusual differentiation within the thalamic glioma (central neurocytoma, anaplastic oligoastrocytoma, and diffuse astrocytoma with pilocytic features). In 3/12 (25%) the biopsy was non-diagnostic. Neuropathology was a better predictor of clinical outcome than neuroradiology. 9/10 (90%) WHO Grade 4 gliomas and 8/9 (88%) Grade 3 gliomas on neuropathology were dead between 3-7 years after diagnosis. 3/3 (100%) Grade 2 gliomas on neuropathology were alive 3-7 years after diagnosis. 2/3 (67%) of the non-diagnostic cases were alive 3-7 years after biopsy. In 1/3 (33%) of the non-diagnostic cases the outcome was unknown. CONCLUSIONS: Diagnosis of primary thalamic glioma is challenging. We have identified that in the thalamus, a pattern of diffuse infiltration with minimal enhancement on imaging may often represent high-grade glioma. Neuropathology is overall the best predictor of clinical outcome.

Occipital WHO grade II gliomas: oncological, surgical and functional considerations.

BACKGROUND: Diffuse WHO grade II glioma (GIIG) involving the occipital lobe is a rare entity. Its surgical resection remains controversial as it implies inducing a permanent visual deficit. For the first time to our knowledge, we report a consecutive surgical series of patients who underwent an occipital lobectomy for an LGG invading visual structures. METHOD: Six right-handed patients harboring a GIIG revealed by seizures (normal examination except a quadrantanopsia in one case) and located within the occipital lobe (4 left and 2 right tumors) were submitted to surgery. Before making this decision, the benefit-to-risk ratio of the resection was extensively discussed with the patient and his/her family, especially concerning the price to pay to remove the tumor, that is, to voluntarily generate a permanent hemianopsia. All the procedures were performed under awake condition using intraoperative electrostimulation, in order to pursue the resection until sensory-motor and/or language structures were encountered. FINDINGS: An extensive occipital lobectomy was achieved in the six patients, with identification and preservation of sensory-motor pathways in the two cases with a right tumor and detection of language pathways in the four cases with a left tumor. The mean extent of resection was 93% (range: 91-100%). All patients experienced an expected postoperative deficit of the visual field (homonymous hemianopsia). Nonetheless, the six patients resumed a normal social and professional life (KPS at 90 in the 6 cases) with a mean follow-up of 58 months (range: 3-147 months)--with adjuvant treatment in three cases (in addition to a reoperation in two of them). CONCLUSIONS: Our findings suggest that, despite a definitive hemianopsia, an extensive surgical resection can be considered in the rare cases of occipital GIIG involving the primary visual structures, with patients able to maintain a normal life--except regarding the medico-legal problem of driving.

Classification of peritumoral fiber tract alterations in gliomas using metabolic and structural neuroimaging.

UNLABELLED: The aims of this study were to investigate and categorize peritumoral fiber tract alterations while considering changes in metabolism and integrity of fiber structures using multimodal neuroimaging-that is, PET with O-(2-(18)F-fluoroethyl)-l-tyrosine and diffusion tensor imaging evaluated by fiber density mapping-and to correlate categories of fiber alterations with preoperative neurologic deficits and postoperative course. METHODS: We examined 26 patients with cerebral gliomas. Fiber density data were used to segment peritumoral fiber structures and were coregistered to anatomic MR images and PET data. Fiber density and O-(2-(18)F-fluoroethyl)-l-tyrosine uptake values were evaluated as ipsilateral-to-contralateral ratios. Four metabolic categories were defined on the basis of O-(2-(18)F-fluoroethyl)-l-tyrosine values: tumor-infiltrated tissue, reactive tissue (astrogliosis and microglial activation), normal brain tissue, and tissue with attenuated amino acid metabolism. Fiber density values were grouped in 3 categories for structural integrity: compressed, normal, and attenuated fibers. RESULTS: We evaluated and classified 103 peritumoral fiber structures with 10 patterns of fiber tract alterations. Fiber structures in tumor-infiltrated, reactive, and normal brain tissue showed compressed fibers, displaced fibers, and (partly) destroyed fibers, respectively. Attenuated amino acid metabolism was associated only with attenuated fiber density. Thirteen patients showed white matter-related neurologic deficits (paresis, hypoesthesia, aphasia, or anopia) as initial symptoms. Three patients showed tumor infiltration in the corresponding fiber tracts; all the others had reactive or normal brain tissue. Fiber structures were compressed or attenuated but not normal. The 3 patients with tumor infiltration in the corresponding fiber tracts and 1 with compressed fibers in normal brain showed no improvements or worsening of the deficits in the postoperative course. Eight patients with the corresponding fiber tracts in reactive or normal brain areas showed improvement of deficits. One patient underwent biopsy only. CONCLUSION: Our multimodal neuroimaging approach provides complementary information and more detailed understanding of peritumoral fiber tract alterations in gliomas which are more complex as described so far. We presented a classification model for systematic assessment of these alterations that may be helpful for treatment planning and prediction of patients' prognoses.

Thalamic high-grade gliomas in children: a distinct clinical subset?

Pediatric high-grade gliomas (HGGs) of the thalamic region account for up to 13% of pediatric HGGs and usually result in only anecdotal long-term survival. Because very little is known about these tumors, we aimed to further characterize them. In our series of 99 pediatric thalamic HGGs, there were no significant differences in survival between patients with tumors affecting the thalamus alone (including bithalamic lesions) and patients with tumors affecting the thalamus plus adjacent structures. Tumor resection (event-free survival/overall survival) and an early treatment response to radiotherapy/chemotherapy (event-free survival) had independent prognostic significance, as shown by Kaplan-Meier and multivariate Cox regression analyses. When we compared clinical characteristics and outcomes of pediatric thalamic HGG with those of pediatric (nonthalamic) supratentorial (n = 177) as well as pediatric pontine HGG (including diffuse intrinsic pontine gliomas; n = 234), we found that thalamic HGG shared more similarities with pontine than with supratentorial HGG, but overall, it appeared to represent a clinically distinct subgroup of pediatric HGG. The varying extent of tumor resection in the different tumor localizations may play some role in the observed clinical differences, as shown by multivariate Cox regression analyses, but the tumor site itself was also identified as an independent prognostic parameter. Thus, an additional location-specific effect on survival and/or tumor biology, despite different neurosurgical accessibility, has to be considered. Therefore, future investigations should try to further characterize the obviously site-specific heterogeneity of pediatric HGG on a molecular genetic basis.

Advances in translational research in neuro-oncology.

During the last decade, we have witnessed several key advances in the field of neuro-oncology. First, there were conceptual advances in the molecular and cell biology of malignant gliomas including the discovery in 2004 of brain tumor stem cells. Second, the Cancer Genome Atlas project has been extremely useful in the discovery of new molecular markers, including mutations in the IDH1 gene, and has led to a new classification of gliomas based on the differentiation status and mesenchymal transformation. In addition, use of the 1p/19q marker and O6-methylguanine-DNA methyltransferase methylation status have been identified as guides for patient selection for therapies and represent the first steps toward personalized medicine for treating gliomas. Finally, progress has been made in treatment strategies including the establishment of temozolomide as the criterion standard for treating gliomas, the adoption of bevacizumab in the clinical setting, and developments in experimental biological therapies including cancer vaccines and oncolytic adenoviruses.

[Modern approach to WHO grade II glioma classification and treatment--review of the literature]. / Nowe spojrzenie na klasyfikacje i terapie nowotworów glejowych II stopnia zlosliwosci wg WHO--przeglad pismiennictwa.

Although WHO grade II gliomas are slowly growing tumours, they inevitably show local recurrence and progression to higher grade counterparts. Progressive trials become time-consuming and troublesome because of relatively long survival and multimodal therapy. Recent discoveries in molecular pathology have divided patients into subgroups with different prognosis and expected response to therapy. Development did not omit surgical techniques, in particular intraoperative imaging and electrostimulation. The aim of radiotherapy development is preservation of the surroundings of the region of interest. Chemotherapy yields promising results notably with the possibility to choose patients with the best expected response. We present the current state of knowledge regarding these neoplasms.

Resection of World Health Organization Grade II gliomas involving Broca's area: methodological and functional considerations.

OBJECTIVE: Advances in functional mapping have enabled us to extend the indications of surgery for low-grade gliomas (LGGs) within eloquent regions. However, to our knowledge, no study has been specifically dedicated to the resection of LGGs within Broca's area. We report the first surgical series of LGGs involving this area by focusing on methodological and functional considerations. METHODS: Seven patients harboring an LGG in Broca's area (revealed by partial seizures) had a language functional magnetic resonance imaging scan and then underwent operation while awake using intrasurgical electrical mapping. RESULTS: The neurological examination was normal in all patients despite mild language disturbances shown using the Boston Diagnosis Aphasia Examination. Both pre- and intraoperative cortical mapping found language reorganization with recruitment of the ventral and dorsal premotor cortices, orbitofrontal cortex, and insula, whereas no or few language sites were detected within Broca's area. Subcortically, electrostimulation allowed the identification and preservation of four structures still functional, including the arcuate fasciculus, fronto-occipital fasciculus, fibers from the ventral premotor cortex, and head of the caudate. Postoperatively, after transient language worsening, all patients recovered and returned to a normal socioprofessional life. The resection was total in three cases, subtotal in three, and partial in one patient (operated twice). CONCLUSION: Our results indicate that, in patients with no aphasia despite LGGs within Broca's area, thanks to brain plasticity, the tumor can be removed while involving this "unresectable" structure without inducing sequelae and even improving the quality of life when intractable epilepsy is relieved on the condition that subcortical language connectivity is preserved.

Mouse models of brain tumors and their applications in preclinical trials.

Primary brain tumors, including gliomas and medulloblastomas, often represent the most devastating and difficult-to-treat tumors, and are thought to arise from glial cells and/or their precursors or the external granule cell layer, respectively. The majority of genetic alterations characteristic of the human brain tumors are thought to occur in genes encoding proteins involved in signal transduction or cell cycle regulation. Accurate recapitulation of these genetic alterations using genetically engineered mouse models allows for in vivo modeling of brain tumors with similar histopathology, etiology, and biology. These mouse models, in turn, increase our understanding of brain tumor initiation, formation, progression, and metastasis, providing an experimental system to discover novel therapeutic targets and test various therapeutic agents.

Análisis de 50 casos de tumores hipofisiarios operados / Analisys of 55 cases in operated pituitary tumors

Se presenta el análisis de 50 casos de tumores hipofisiarios operados en el Servicio de Neurocirugía de Valdivia, tanto por vía subfrontal, como por vía transesfenoidal, sus características clínicas, radiológicas, complicaciones, evolución y resultados. Se hace hincapié en las dificultades y facilidades que ofrecen ambas vías, acentuadas con los problemas que presenta la Neurocirugía en provincias.

Basal ganglia and thalamic tumours: an imaging approximation.

INTRODUCTION: Among brain tumours, those arising from the deep brain are rare. In many cases they are low-grade astrocytomas. But primitive neuroectodermal tumours, ganglion cell tumours, oligodendrogliomas, lymphomas, and germinal neoplasms can also grow up from the basal ganglia and thalamic region. In other occasions peripheral neoplasms developing in neighbouring structures like the cerebral lobes, the ventricular walls, choroidal plexus, pineal gland and the hypothalamic-chiasmatic-suprasellar region can spread to the deep brain. IMAGING: Imaging cannot reliably indicate that a histological picture for a tumour of this kind should be suspected. Although the macro- and microscopical characteristics of brain tumours are often the basis of the imaging findings, these data usually overlap and are only useful as an approximation tool. CONCLUSIONS: Nonetheless, whilst radiologists and clinicians must always be cautious when evaluating the macroscopic peculiarities of a brain tumour, the value of imaging cannot be overestimated when any sort of pathology is encountered. Moreover, besides the classic CT and MRI findings, new MRI-related techniques, such as magnetic resonance spectroscopy (MRS), are able to extract a different kind of information from cerebral neoplasms, and they could be important widespread diagnostic alternatives in the very near future.

Risk factors for gliomas and meningiomas in males in Los Angeles County.

Detailed job histories and information about other suspected risk factors were obtained during interviews with 272 men aged 25-69 with a primary brain tumor first diagnosed during 1980-1984 and with 272 individually matched neighbor controls. Separate analyses were conducted for the 202 glioma pairs and the 70 meningioma pairs. Meningioma, but not glioma, was related to having a serious head injury 20 or more years before diagnosis [odds ratio (OR) = 2.3; 95% confidence interval (CI) = 1.1-5.4], and a clear dose-response effect was observed relating meningioma risk to number of serious head injuries (P for trend = 0.01; OR for greater than or equal to 3 injuries = 6.2; CI = 1.2-31.7). Frequency of full-mouth dental X-ray examinations after age 25 related to both glioma (P for trend = 0.04) and meningioma risk (P for trend = 0.06). Glioma, but not meningioma risk, related to duration of prior employment in jobs likely to involve high exposure to electric and magnetic fields (P for trend = 0.05). This risk was greatest for astrocytoma (OR for employment in such jobs for greater than 5 years = 4.3; CI = 1.2-15.6). More glioma cases had worked in the rubber industry (discordant pairs 6/1) and more worked in hot processes using plastics (9/1). More meningioma cases had jobs that involved exposure to metal dusts and fumes (discordant pairs 13/5), and six of these cases and two controls worked as machinists. Finally, there was a protective effect among glioma pairs relating to frequency of use of vitamin C and other vitamin supplements (P for trend = 0.004); the OR for use at least twice a day was 0.4 (CI = 0.2-0.8).