Glioblastoma Multiforme

DTI-015 (BCNU dissolved in ethanol) utilizes solvent facilitated perfusion (SFP) for intratumoral drug delivery. A phase II clinical trial of DTI-015 and fractionated external beam radiotherapy on newly diagnosed, malignant gliomas investigated early changes in tumour physiology and metabolism, clinical outcome and safety. Pre-and post DTI-015 injection neuro-imaging included computed tomography (CT) cerebral blood flow and volume, glucose and thallium single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Clinical status was determined before and after DTI-015, prior to radiotherapy and 3 monthly thereafter until progression (defined by Macdonald criteria). Primary endpoint was radiographic response. Secondary endpoints were progression free (PFS) and overall survival (OS). Twelve patients were enrolled; eight glioblastoma multiforme (GBM), four anaplastic astrocytoma (AA). Three days after DTI-015 injection, mean tumour blood flow (Paired t-test; P \ 0.001) and blood volume (Paired t-test; P = 0.001) were significantly reduced. There was a significant decrease in glucose utilization (Paired t-test; P \ 0.001) and thallium uptake (Paired ttest; P \ 0.001) at 6 days. Tumour blood volume had a sustained reduction (Paired t-test; P = 0.001) at 26 days after DTI-015. There were two serious adverse events. Two patients with AA achieved a partial response. Median PFS was 39 weeks for AA and 27 weeks for GBM; median OS for GBM was 47 weeks and 132 weeks for AA. The imaging data forms a biological basis for understanding the effects of high dose BCNU delivered intratumorally by SFP, and suggests early effects on tumour vasculature and metabolism.

Background Despite possible advantages, few surgical series report specifically on awake craniotomy for intrinsic brain tumors in eloquent brain areas. Objectives Primary: To evaluate the safety and efficacy of fully awake craniotomy (FAC) for the resection of primary supratentorial brain tumors (PSBT) near or in eloquent brain areas (EBA) in a developing country. Secondary: To evaluate the impact of previous surgical history and different treatment modalities on outcome. Patients and methods From 1998 to 2007, 79 consecutive FACs for resection PSBT near or in EBA, performed by a single surgeon, were prospectively followed. Two groups were defined based on time period and surgical team: group A operated on from March 1998 to July 2004 without a multidisciplinary team and group B operated on from August 2004 to October 2007 in a multidisciplinary setting. For both time periods, two groups were defined: group I had no previous history of craniotomy, while group II had undergone a previous craniotomy for a PSBT. Forty-six patients were operated on in group A, 46 in group B, 49 in group I and 30 in group II. Psychological assessment and selection were obligatory. The preferred anesthetic procedure was an intravenous high-dose opioid infusion (Fentanil 50 μg, bolus infusion until a minimum dose of 10 μg/kg). Generous scalp and periosteous infiltrations were performed. Functional cortical mapping was performed in every case. Continuous somato-sensory evoked potentials (SSEPs) and phase reversal localization were available in 48 cases. Standard microsurgical techniques were performed and monitored by continuous clinical evaluation. Results Clinical data showed differences in time since clinical onset (p<0.001), slowness of thought (p=0.02) and memory deficits (p<0.001) between study periods and also time since recent seizure onset for groups I and II (p=0.001). Mean tumor volume was 51.2±48.7 cm 3 and was not different among the four groups. The mean extent of tumor reduction was 90.0±12.7% and was similar for the whole series. A trend toward a larger incidence of glioblastoma multiforme occurred in group B (p=0.05) and I (p=0.04). Recovery of previous motor deficits was observed in 75.0% of patients, while motor worsening in 8.9% of cases. Recovery of semantic language deficits, control of refractory seizures and motor worsening were statistically more frequent in group B (p=0.01). Satisfaction with the procedure was reported by 89.9% of patients, which was similar for all groups. Clinical complications were minimal, and surgical mortality was 1.3%. Conclusions These data suggest that FAC is safe and effective for the resection of PSBT in EBA as the main technique, and in a multidisciplinary context is associated with greater clinical and physiological monitoring. The previous history of craniotomy for PSBT did not seem to influence the outcome.

The combination of irradiation with angiogenic inhibition is increasingly being investigated for treatment of glioblastoma multiforme (GBM). We investigated whether vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitor DC101 affects morbidity and tumor growth in irradiated and non-irradiated intracerebral GBM-bearing mice, controlled with sham treatments. End-points were toxicity, morbidity and histology. Irradiation either or not combined, reduced tumor size strongly, whereas DC101 mono-treatment reduced tumor size by 64%. Irradiation delayed morbidity from 5.8 weeks in sham-treated mice to 10.3 weeks. Morbidity after combined treatment occurred after 5.9 weeks. Treatment with angiogenesis inhibitor DC101 delays tumor growth but it induces morbidity, by itself or combined with irradiation.

In this paper the results of two coordinated biomedical research projects are presented. The first project involves the determination of the average values of elements in normal human brain (20 individuals, age-group 65-75). 21 brain parts were selected from both hemispheres. Determinations were carried out by ICP-AES and INAA methods. The main (Na, K, Mg, Ca, Fe, P, S) and trace elements (A1, B, Ba, Co, Cr, Mn, Ni, Pb, Sr, Zn) were investigated. Quality control was ensured by using NBS Bovine Liver SRMs. On the basis of our investigations the regional distribution of elements can be given. The second goal was to detect the possible trace element changes in histopathologically selected brain regions from patients with glioblastoma multiforme. The majority of elements displayed no statistically significant differences between the studied groups, except the reduced levels of B and Zn and the increased level of Sr compared to the tissue from control individuals.

Boron neutron capture therapy (BNCT) is increasingly being used in the treatment of several aggressive cancers, including cerebral glioblastoma multiforme. The main requirement for this therapy is selective targeting of tumor cells by sufficient quantities of 10 B atoms required for their capture/irradiation with lowenergy thermal neutrons. The low content of boron targeting species in glioblastoma multiforme accounts for the difficulty in selective targeting of this very malignant cerebral tumor by this radiation modality. In the present study, we have used for the first time boron nitride nanotubes as carriers of boron atoms to overcome this problem and enhance the selective targeting and ablative efficacy of BNCT for these tumors. Following their dispersion in aqueous solution by noncovalent coating with biocompatible poly-L-lysine solutions, boron nitride nanotubes were functionalized with a fluorescent probe (quantum dots) to enable their tracking and with folic acid as selective tumor targeting ligand. Initial in vitro studies have confirmed substantive and selective uptake of these nanovectors by glioblastoma multiforme cells, an observation which confirms their potential clinical application for BNCT therapy for these malignant cerebral tumors.

P.108. UPDATED RESULTS OF A PHASE II TRIAL OF BEVACIZUMAB AND IRINOTECAN IN RELAPSED HIGH-GRADE GLIOMA
V. F. Keyrouz 1, E. Elias 1, G. Y. Chahine 1,2, Y. G. Comair 3, H. Dimassi 4, and F. G. Kamar 1,5; 1CHU Notre Dame des Secours – Universite ́ Saint Esprit Kaslik, Byblos, Lebanon; 2CHU Hotel Dieu De France – Universite ́ Saint Joseph, Beirut, Lebanon; 3Baylor College of Medicine, Houston, TX, United States; 4Lebanese American University, Beirut, Lebanon; 5Clemenceau Medical Center – Johns Hopkins International, Beirut, Lebanon
BACKGROUND: Relapsed glioblastoma multiforme (GBM) has a poor response to current chemotherapy and prognosis of patients with recurrent disease is dismal, with a median survival of 3–6 months. Numeral trials using bevacizumab, a humanized IgG1 monoclonal antibody to vascular endothelial growth factor (VEGF), with or without chemotherapy, have reported excellent response rates using 10 mg/kg or 15 mg/kg every 2 weeks, and allowed expedite FDA approval for its use as a second-line treat- ment in relapsed GBM. We performed a phase II trial of bevacizumab using 5 mg/kg only, with irinotecan (CPT 11) every 2 weeks as reported in the initial presentation by Stark Vance. In our interim analysis, we had demon- strated excellent response rates and similar results to others. This is an update of the final results. PATIENTS AND METHODS: This phase II trial accrued 30 patients with recurrent GBM who received bevacizumab at 5 mg/kg and CPT 11 at 125 mg/m2 every 2 weeks, after failing radiation therapy and adjuvant TMZ. All patients on antiepileptic drugs (AEDs) had their regimen changed to nonenzyme-inducing antiepileptic drugs (NEIAEDs) prior to receiving CPT 11. Patients with KPS ≥50% were allowed regardless of prior relapses. Patients were evaluated clinically and with contrast-enhanced MRI scan every 4 treatments of bevacizumab until pro- gression. RESULTS: All 30 patients were evaluable. Responses were assessed radiographically according to the MacDonald criteria and comparing T2 or Flair weighed Sequences; 19 patients (63%) had a documented response (CR + PR), 6 patients (20%) had stable disease (SD) and 5 patients (19%) progressed (PD). The average number of bevacizumab treatments received was 5.6 (1 – 20). The 6-month progression-free survival was 33.4%; 6-month overall survival was 66.7%, median overall survival was 8.7 months (36.3 weeks); median progression-free survival was 5 months (22.8 weeks). Several complications were reported: 3 DVTs and 2 PEs requir- ing IVC filter placement, 2 intracranial hemorrhages and one nonneurosur- gical complication. All patients had a clinical benefit and were taken off steroids rapidly after starting bevacizumab regardless of radiological response. Clinical and radiographic responses correlated well. Failures were mostly local progression in 12 cases, infiltrative nonenhancing (glioma- tosis like) in 10 cases and multifocal including subependymal and leptome- ningeal in 8 patients. CONCLUSION: Bevacizumab-based regimen for relapsed GBM demonstrates superior activity when compared with historical treatments. It is safe and improves overall quality of life in this patients’ cat- egory. Our results were as attractive as previously reported series despite lower KPS on enrollment, and using lower doses of bevacizumab.

Background: A shift from respiration to fermentation is a common metabolic hallmark of cancer cells. As a result, glucose and glutamine become the prime fuels for driving the dysregulated growth of tumors. The simultaneous occurrence of " Press-Pulse " disturbances was considered the mechanism responsible for reduction of organic populations during prior evolutionary epochs. Press disturbances produce chronic stress, while pulse disturbances produce acute stress on populations. It was only when both disturbances coincide that population reduction occurred.

Cannabinoids, the active components of Cannabis sativa L., act in the body by mimicking endogenous substances — the endocannabinoids — that activate specific cell surface receptors. Cannabinoids exert various palliative effects in cancer patients. In addition, cannabinoids inhibit the growth of different types of tumor cells, including glioma cells, in laboratory animals. They do so by modulating key cell signaling pathways, mostly the endoplasmic reticulum stress response, thereby inducing antitumoral actions such as the apoptotic death of tumor cells and the inhibition of tumor angiogenesis. Of interest, cannabinoids seem to be selective antitumoral compounds as they kill glioma cells but not their nontransformed astroglial counterparts. On the basis of these preclinical findings, a pilot clinical study of Δ9-tetrahydrocannabinol (Δ9-THC) in patients with recurrent glioblastoma multiforme has been recently run. The fair safety profile of Δ9-THC, together with its possible growth-inhibiting action on tumor cells, may set the basis for future trials aimed at evaluating the potential antitumoral activity of cannabinoids.

Background. Glioblastoma multiforme infrequently metastasizes to the leptomeninges and even more rarely to the spinal cord. Moreover, very few patients with intracranial glioblastoma develop symptoms from spinal dissemination, with most patients not surviving long enough for spinal disease to become clinically evident.

Malignant gliomas such as glioblastoma multiforme (GBM) present some of the greatest challenges in the management of cancer patients worldwide, despite notable recent achievements in oncology. Even with aggressive surgical resections using state-of-the-art preoperative and intraoperative neuroimaging, along with recent advances in radiotherapy and chemotherapy, the prognosis for GBM patients remains dismal: median survival after diagnosis is about 14 months. Established good prognostic factors are limited, but include young age, high Karnofsky Performance Status (KPS), high mini-mental status examination score, O6-methylguanine methyltransferase promoter methylation, and resection of > 98% of the tumor. Standard treatment includes resection, followed by concurrent chemotherapy and radiotherapy. GBM research is being conducted worldwide at a remarkable pace, with some of the more recent promising studies focused on identification of aberrant genetic events and signaling pathways, tumor stem cell identification and characterization, modulation of tumor immunological responses, combination therapies, and understanding of the rare long-term survivors. Past treatment strategies have failed for various reasons; however, newer strategies in trials today and on the horizon encourage optimism. To help illustrate 'where we have been' with this fatal disease and 'where we are going' with contemporary studies, we include in this review a detailed history of Phase III clinical trials for GBM, with a final emphasis on exciting new treatment strategies that offer hope for future GBM therapy.

We aimed to evaluate the feasibility and tolerability of the newly developed thermotherapy using magnetic nanoparticles on recurrent glioblastoma multiforme. Fourteen patients received 3-dimensional image guided intratumoral injection of aminosilane coated iron oxide nanoparticles. The patients were then exposed to an alternating magnetic field to induce particle heating. The amount of fluid and the spatial distribution of the depots were planned in advance by means of a specially developed treatment planning software following magnetic resonance imaging (MRI). The actually achieved magnetic fluid distribution was measured by computed tomography (CT), which after matching to pre-operative MRI data enables the calculation of the expected heat distribution within the tumor in dependence of the magnetic field strength.

Glioblastoma multiforme (GBM) is a malignant tumor within the brain. Generally classified as primary and secondary with several different subtypes, ample molecular biomarkers have risen throughout the years which have garnered the attention of researchers. The advancements in genomics and proteomics have allowed researchers to gather prominent molecular biomarkers. All these biomarkers are gathered by means of biopsy or bodily fluid sample collection and are quantitatively analyzed by polymerase chain reaction coupled with other computational technologies. This review highlights the significance, regulation and prevalence of molecular biomarkers such as O6 -methylguanine-DNA methyltransferase, epidermal growth factor receptor vIII, isocitrate dehydrogenase mutation and several others which expressed differently in different types and molecular subtypes of GBM. The discoveries and roles of GBM-specific microRNAs including miR-21 and miR-10b as biomarkers with promising prognostic values were also delineated. The role and mechanism of biomarkers in GBM tumorigenesis are essential in the development of therapy for patients suffering from the disease itself. Thus, this review also discusses the mechanisms, effects and limitations of therapy such as temozolomide, viral gene transfer, biomarker-based vaccines or even engineered T cells for more specific responses. Biomarkers have displayed a high value and could eventually be utilized as drug targets. It is hoped that by combining different aspects of the disease which present with different biomarkers could lead to the development of a robust, effective and innovative take on GBM therapy.

Glioblastoma multiforme (GBM) is the most frequent primary brain tumor in adults with a 5-year survival rate of 5% despite intensive research efforts. The poor prognosis is due, in part, to aggressive invasion into the surrounding brain parenchyma. Invasion is a complex process mediated by cell-intrinsic pathways, extrinsic microenvironmental cues, and biophysical cues from the peritumoral stromal matrix. Recent data have attributed GBM invasion to the glioma stem-like cell (GSC) subpopulation. GSCs are slowly dividing, highly invasive, therapy resistant, and are considered to give rise to tumor recurrence. GSCs are localized in a heterogeneous cellular niche, and cross talk between stromal cells and GSCs cultivates a fertile environment that promotes GSC invasion. Pro-migratory soluble factors from endothelial cells, astrocytes, macrophages, microglia, and non-stem-like tumor cells can stimulate peritumoral invasion of GSCs. Therefore, therapeutic efforts designed to target the invasive GSCs may enhance patient survival. In this review, we summarize the current understanding of extrinsic pathways and major stromal and immune players facilitating GSC maintenance and survival.

Galectins form a family of carbohydrate-binding proteins defined by their affinity for -galactosides containing glycoconjugates. The carbohydrate recognition domain (CRD) is responsible for the specificity of galectins for saccharides. This binding may result in modulated cell proliferation, cell death and cell migration, three processes that are intimately involved in cancer initiation and progression. Galectins can also display protein-protein types of interactions with their binding partners. Certain galectins directly involved in cancer progression seem to be promising targets for the development of novel therapeutic strategies to combat cancer. Indeed, migrating cancer cells resistant to apoptosis still constitute the principal target for the cytotoxic drugs used to treat cancer patients. Reducing the levels of migration in apoptosis-resistant cancer cells can restore certain levels of sensitivity to apoptosis (and so to pro-apoptotic drugs) in restrictedmigration cancer cells. Anti-galectin agents can restrict the levels of migration of several types of cancer cell and should therefore be used in association with cytotoxic drugs to combat metastatic cancer. We provide experimental proof in support of this concept. While the present review focuses on various experimental strategies to impair cancer progression by targeting certain types of galectins, it pays particular attention to glioblastomas, which constitute the ultimate level of malignancy in primary brain tumors. Glioblastomas form the most common type of malignant brain tumor in children and adults, and no glioblastoma patient has been cured to date.

The outcomes for glioblastoma (GBM) patients remain dismal despite significant increases in our understanding of treatment-naïve disease biology and increased focus on clinical trials. Almost all patients experience disease recurrence. If we hope to develop more durable responses in this aggressive disease cohort, a better understanding of resistance mechanisms and drivers of GBM tumour recurrence will be needed. Here we review the findings todate of current advances in therapeutic development and biology of recurrent GBM, highlighting recent research and clinical trials breakthroughs.

Glioblastoma (GBM) is a deadly cancer in which cancer stem cells (CSCs) sustain tumor growth and contribute to therapeutic resistance. Protein arginine methyltransferase 5 (PRMT5) has recently emerged as a promising target in GBM. Using two orthogonal-acting inhibitors of PRMT5 (GSK591 or LLY-283), we show that pharmacological inhibition of PRMT5 suppresses the growth of a cohort of 46 patient-derived GBM stem cell cultures, with the proneural subtype showing greater sensitivity. We show that PRMT5 inhibition causes widespread disruption of splicing across the transcriptome, particularly affecting cell cycle gene products. We identify a GBM splicing signature that correlates with the degree of response to PRMT5 inhibition. Importantly, we demonstrate that LLY-283 is brain-penetrant and significantly prolongs the survival of mice with orthotopic patient-derived xenografts. Collectively, our findings provide a rationale for the clinical development of brain penetrant PRMT5 inhibitors as treatment for GBM.

The purpose of this study was to determine the safety of tinzaparin for deep vein thrombosis prophylaxis in newly diagnosed grade III-IV malignant glioma patients. Patients were initiated on daily tinzaparin at a fixed dose of 4,500 IU subcutaneously between 48 h and 4 weeks post-operative for planned duration of 12 months. During chemotherapy cycles, blood counts were monitored weekly and tinzaparin was held if the platelet count decreased to \50,000 and was re-initiated at a platelet count [100,000. Forty patients were enrolled into the study, 35 with glioblastoma multiforme and 5 with anaplastic astrocytoma. Possible attributable toxicity was limited to two patients who developed CNS hemorrhages (one grade 1 and one grade 2) and one patient with an increase in liver enzymes (grade 3). There were no patients with a grade 4 or 5 CNS hemorrhages or systemic hemorrhages Cgrade 2. The median time on prophylactic tinzaparin was 161 days (range of 5 to 601 days). One patient developed a deep venous thrombosis while taking tinzaparin, and three patients developed thromboembolic complications while off tinzaparin. Tinzaparin at a fixed prophylactic dose is safe and may decrease the incidence of thromboembolic complications in brain tumor patients.

In the central nervous system (CNS), liver-type glutaminase (LGA) shows a unique nuclear localization suggesting its role in the regulation of transcription rather than in the cellular glutamine metabolism. RT-PCR analysis of RNA derived from postoperative tissue samples revealed the absence or only traces of LGA mRNA in all (9) cases of malignant gliomas (astrocytoma anaplasticum, AA, WHO grade III; glioblastoma multiforme, WHO grade IV) examined. The RNA was strongly expressed in the non-neoplastic tissue derived from the same patients (6 cases), and in most of the brain metastases from different organs (5 out of 7 cases). By contrast, the mRNAs coding for the kidney-type glutaminase (KGA) and its less ubiquitous isoform GAC, which catalyze degradation of the cytoplasmic pool of Gln, were expressed in all the tissues examined. The lack of LGA may be thus considered as a useful negative diagnostic marker of highly malignant gliomas in situ.

Glioblastoma multiforme (GBM) is the most common primary brain tumour in adults and one of the most aggressive cancers in man. Despite technological advances in surgical management, combined regimens of radiotherapy with new generation chemotherapy, the median survival for these patients is 14.6 months. This is largely due to a highly deregulated tumour genome with opportunistic deletion of tumour suppressor genes, amplification and/or mutational hyper-activation of receptor tyrosine kinase receptors. The net result of these genetic changes is augmented survival pathways and systematic defects in the apoptosis signalling machinery. The only randomised, controlled phase II trial conducted targeting the epidermal growth factor receptor (EGFR) signalling with the small molecule inhibitor, erlotinib, has showed no therapeutic benefit. Survival signalling and apoptosis resistance in GBMs can be viewed as two sides of the same coin. Targeting increased survival is unlikely to be efficacious without at the same time targeting apoptosis resistance. We have critically reviewed the literature regarding survival and apoptosis signalling in GBM, and highlighted experimental, preclinical and recent clinical trials attempting to target these pathways. Combined therapies simultaneously targeting apoptosis and survival signalling defects might shift the balance from tumour growth stasis to cytotoxic therapeutic responses that might be associated with greater therapeutic benefits.

Using single nucleotide polymorphic (SNP) allele arrays, we analyzed 28 pediatric gliomas consisting of 14 high-grade gliomas and 14 low-grade gliomas. Most of the low-grade gliomas had no detectable loss of heterozygosity (LOH) in any of the 11,562 SNP loci; exceptions were two gangliogliomas (3q and 9p), one astrocytoma (6q), and two subependymal giant cell astrocytomas (16p and 21q). On the other hand, all high-grade gliomas had various degrees of LOH affecting 52 to 2,168 SNP loci on various chromosomes. LOH occurred most frequently in regions located at 4q (54%), 6q (46%), 9p (38%), 10q (38%), 11p (38%), 12 (38%), 13q (69%), 14q (54%), 17 (38%), 18p (46%), and 19q (38%). We also detected amplifications of epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor a (PDGFRa) in a few of the 13 cases of glioblastoma multiforme analyzed. Interestingly, the amplified EGFR and PDGFRa were located within regions of LOH. SNP loci with LOH and copy number changes were validated by sequencing and quantitative PCR, respectively. Our results indicate that, in some pediatric glioblastoma multiforme, one allele each of EGFR and PDGFRa was lost but the remaining allele was amplified. This may represent a new molecular mechanism underlying tumor progression.

Temozolomide (TMZ) is a cytotoxic agent of the imidazotetrazine class, chemically related to dacarbazine. Its use poses higher risks of lymphopenia and opportunistic infections. Prophylaxis for Pneumocystis jiroveci must be considered up to 12 months after treatment discontinuation. The due literature (MEDLINE) makes no mention of a possible connection between the use of TMZ and tuberculosis (TB). A female patient, aged 59, featuring glioblastoma multiforme and having undergone solely a brain biopsy, was submitted to TMZ along with radiotherapy. After the first TMZ maintenance cycle, the referred patient was admitted displaying a background of a 40-day afternoon fever and productive coughing. She was thus submitted to a bronchoscopy and LBA, which resulted BAAR 1?/4?. TMZ was then suspended, and rifampicin, isoniazid, and pyrazinamide introduced. Considerations on prophylaxis with isoniazide in cancer patients are long-lived and scarce. Some subgroups are likely to benefit from the prophylactic administration of isoniazide during TMZ treatment, such as those patients under high doses of corticoids, patients with past medical history of TB, the malnourished, patients from endemic regions, and patients with highly reactive tuberculinic tests. That, nevertheless, must not restrict the administration of TMZ, but, rather, stand for a warning about its possible toxicity, and thus mitigate complications.

Recurrent glioblastoma multiforme is a lethal disease with currently available treatment options having a limited impact on outcome. In this article, current and novel therapeutic approaches in the treatment of recurrent glioblastoma multiforme, including chemotherapy, targeted molecular agents, virotherapy/gene therapy and immunotherapy and challenges in developing novel therapeutic agents for glioblastoma multiforme will be discussed.

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.

Present standard treatment planning (TP) for glioblastoma multiforme (GBM -a kind of brain tumor), used in all boron neutron capture therapy (BNCT) trials, requires the construction (based on CT and/or MRI images) of a 3D model of the patient head, in which several regions, corresponding to different anatomical structures, are identified. The model is then employed by a computer code to simulate radiation transport in human tissues. The assumption is always made that considering a single value of boron concentration for each specific region will not lead to significant errors in dose computation. The concentration values are estimated ''indirectly'', on the basis of previous experience and blood sample analysis.

Purpose: A Monte Carlo-based treatment planning code for boron neutron capture therapy (BNCT), called =AN, has been developed in support of the New England Medical Center-Massachusetts Institute of Technology program in BNCT. This code has been used to plan BNCT irradiations in an ongoing peripheral melanoma BNCT protocol. The concept and design of the code is described and illustrative applications are presented. Methods and Materials: NCTPLAN uses thin-slice Computed Tomography (CT) image data to automatically create a heterogeneous multimaterlal mathematical model of the relevant body part, which is then used as input to a Monte Carlo simulation code, MCNP, to derive dose distributions within the model. Results are displayed as isocontours superimposed on precisely corresponding CT images of the body part. Currently the computational slowness of the dose calculations precludes efficient treatment planning per se, but does provide the radiation oncologist with a preview of the doses that will be delivered to tumors and to various normal tissues, and permits neutron irradiation times in Megawatt-minutes (MW-mln) to be calculated for specliic dose prescriptions. The validation of the NCTPLAN results by experimental mixed-field dosimetry is presented. A typical application involving a cranial parallel-opposed epithermal neutron beam irradiation of a human subject with a gliohlastoma multiforme is illustrated showing relative biological effectiveness-isodose (RBE) distributions in normal CNS structures and in brain tumors. Parametric curves for the MITR-II M67 epithermal neutron beam, showing the gain factors (gain factor = minimum tumor dose/maximum normal brain dose) for various combinations of boron concentrations in tumor and in normal brain, are presented. Results: The NCTPLAN code provides good computational agreement with experimental measurements for all dose components along the neutron beam central axis in a head phantom. For the M67 epithermal beam the gain factor for 1, boronophenylalanme for a small midline brain tumor under typical distribution assumptions is 1.4-1.8~. Implementation of the code under clinical conditions is demonstrated. Conclusion: The NCTPLAN code has been shown to be well suited to treatment-planning applications in BNCT. Comparison of computationally derived dose distributions in a phantom compared with experimental measurements demonstrates good agreement. Automatic superposition of isodose contours with corresponding CT image data provides the ability to evaluate BNCT doses to tumor and to normal structures. Calculation of gain factors suggests that for the M67 epithermal neutron beam, more advantage is gained from increasing boron concentrations in tumor than from increasing the boron tumor-to-normal brain ratio.

Neural stem cells (NSCs) offer great potential for regenerative medicine due to their excellent ability to differentiate into various specialized cell types of the brain. In the central nervous system (CNS), NSC renewal and differentiation are under strict control by the regulation of the pivotal SLIT-ROBO Rho GTPase activating protein 2 (SRGAP2)—Family with sequence similarity 72 (FAM72) master gene (i.e., |-SRGAP2–FAM72-|) via a divergent gene transcription activation mechanism. If the gene transcription control unit (i.e., the intergenic region of the two sub-gene units, SRGAP2 and FAM72) gets out of control, NSCs may transform into cancer stem cells and generate brain tumor cells responsible for brain cancer such as glioblastoma multiforme (GBM). Here, we discuss the surveillance of this |-SRGAP2–FAM72-| master gene and its role in GBM, and also in light of FAM72 for diagnosing various types of cancers outside of the CNS.

Abstract: Glioblastoma multiforme (GBM) is the most common and lethal type of brain cancer. To identify the genetic alterations in GBMs, we sequenced 20,661 protein coding genes, determined the presence of amplifications and deletions using high-density oligonucleotide arrays, and performed gene expression analyses using next-generation sequencing technologies in 22 human tumor samples. This comprehensive analysis led to the discovery of a variety of genes that were not known to be altered in GBMs. Most ...

Purpose: A Phase I trial of cranial neutron capture therapy (NCT) was conducted at Harvard-MIT. The trial was designed to determine maximum tolerated NCT radiation dose to normal brain. Methods and Materials: Twenty-two patients with brain tumors were treated by infusion of boronophenylalanine-fructose (BPA-f) followed by exposure to epithermal neutrons. The study began with a prescribed biologically weighted dose of 8.8 RBE (relative biologic effectiveness) Gy, escalated in compounding 10% increments, and ended at 14.2 RBE Gy. BPA-f was infused at a dose 250 -350 mg/kg body weight. Treatments were planned using MacNCTPlan and MCNP 4B. Irradiations were delivered as one, two, or three fields in one or two fractions. Results: Peak biologically weighted normal tissue dose ranged from 8.7 to 16.4 RBE Gy. The average dose to brain ranged from 2.7 to 7.4 RBE Gy. Average tumor dose was estimated to range from 14.5 to 43.9 RBE Gy, with a mean of 25.7 RBE Gy.

Background Despite possible advantages, few surgical series report specifically on awake craniotomy for intrinsic brain tumors in eloquent brain areas. Objectives Primary: To evaluate the safety and efficacy of fully awake craniotomy (FAC) for the resection of primary supratentorial brain tumors (PSBT) near or in eloquent brain areas (EBA) in a developing country. Secondary: To evaluate the impact of previous surgical history and different treatment modalities on outcome. Patients and methods From 1998 to 2007, 79 consecutive FACs for resection PSBT near or in EBA, performed by a single surgeon, were prospectively followed. Two groups were defined based on time period and surgical team: group A operated on from March 1998 to July 2004 without a multidisciplinary team and group B operated on from in a multidisciplinary setting. For both time periods, two groups were defined: group I had no previous history of craniotomy, while group II had undergone a previous craniotomy for a PSBT. Forty-six patients were operated on in group A, 46 in group B, 49 in group I and 30 in group II. Psychological assessment and selection were obligatory. The preferred anesthetic procedure was an intravenous high-dose opioid infusion (Fentanil 50 μg, bolus infusion until a minimum dose of 10 μg/kg). Generous scalp and periosteous infiltrations were performed. Functional cortical mapping was performed in every case. Continuous somato-sensory evoked potentials (SSEPs) and phase reversal localization were available in 48 cases. Standard microsurgical techniques were performed and monitored by continuous clinical evaluation.

Normal tissue toxicity limits the efficacy of current treatment modalities for glioblastoma multiforme (GBM). We evaluated the influence of cannabinoids on cell proliferation, death, and morphology of human GBM cell lines and in primary human glial cultures, the normal cells from which GBM tumors arise. The influence of a plant derived cannabinoid agonist, Δ9-tetrahydrocannabinol Δ9-THC), and a potent synthetic cannabinoid agonist, WIN 55,212-2, were compared using time lapse microscopy. We discovered that Δ9-THC decreases cell proliferation and increases cell death of human GBM cells more rapidly than WIN 55,212-2. Δ9-THC was also more potent at inhibiting the proliferation of GBM cells compared to WIN 55,212-2. The effects of Δ9-THC and WIN 55,212-2 on the GBM cells were partially the result of cannabinoid receptor activation. The same concentration of Δ9-THC that significantly inhibits proliferation and increases death of human GBM cells has no significant impact on human primary glial cultures. Evidence of selective efficacy with WIN 55,212-2 was also observed but the selectivity was less profound, and the synthetic agonist produced a greater disruption of normal cell morphology compared to Δ9-THC.

SYSTEMIC THERAPY IN PATIENTS WITH RELAPSED GLIOBLASTOMA: For patients with relapsed GBM there is currently no standard systemic therapy. Wick et al. treated 64 patients with TMZ 150 mg/m(2), one week on, one week off and observed PFS-6 of 43.8%, and OAS of 8.4 months after the diagnosis of relapse. Strik et al. reported on 13 patients treated 5 days in a week and observed a PFS-6 of 39%, OAS of 7.8 months, Perry et al. reported on 50 mg/m(2). Vredenburgh et al. reported prospectively rapid symptomatic relief, PFS-6 of 46% and OAS of 8 months in 35 patients with relapsed GBM. The BRAIN study evaluated 167 patients with Avastin/Irinotecan vs. Avastin alone in patients with relapsed GBM, showing PFS-6 of 50 vs. 42% and OAS of 8.7 vs. 9.2 months. More than 40 drugs are currently investigated in patients with relapsed gliomas. Should be part of all interactions with a neuro-oncologist. Thorough consideration of the individual patient&#39;s characteristics to evaluate the best fitted trea...

Introduction Conventional magnetic resonance (MR) imaging has limited capacity to differentiate between glioblastoma multiforme (GBM) and metastasis. The purposes of this study were: (1) to compare microvascular leakage (MVL), cerebral blood volume (CBV), and blood flow (CBF) in the distinction of metastasis from GBM using dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging (DSC-MRI), and (2) to estimate the diagnostic accuracy of perfusion and permeability MR imaging.

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Simple Summary: Glioblastoma multiforme (GBM) is a serious and aggressive cancer disease
that has not allowed scientists to rest for decades. In this review, we consider the new gene pair
|-SRGAP2–FAM72-| and discuss its role in the cell cycle and the possibility of defining new therapeutic
approaches for the treatment of GBM and other cancers via this gene pair |-SRGAP2–FAM72-|.
Abstract: Neural stem cells (NSCs) offer great potential for regenerative medicine due to their
excellent ability to differentiate into various specialized cell types of the brain. In the central nervous
system (CNS), NSC renewal and differentiation are under strict control by the regulation of the
pivotal SLIT-ROBO Rho GTPase activating protein 2 (SRGAP2)—Family with sequence similarity
72 (FAM72) master gene (i.e., |-SRGAP2–FAM72-|) via a divergent gene transcription activation
mechanism. If the gene transcription control unit (i.e., the intergenic region of the two sub-gene units,
SRGAP2 and FAM72) gets out of control, NSCs may transform into cancer stem cells and generate
brain tumor cells responsible for brain cancer such as glioblastoma multiforme (GBM). Here, we
discuss the surveillance of this |-SRGAP2–FAM72-| master gene and its role in GBM, and also in
light of FAM72 for diagnosing various types of cancers outside of the CNS.
Keywords: brain cancer; cell cycle; differentiation; glioblastoma; proliferation; RAS; SRGAP2; stem
cell; TP53

In this paper, models are described which have been developed to model both the way in which a population of cells respond to radiation and the way in which a population of patients respond to radiotherapy to assist the conduct of clinical trials in silico. Population balance techniques have been used to simulate the age distribution of tumour cells in the cell cycle. Sensitivity to radiation is not constant round the cell cycle and a single fraction of radiation changes the age distribution. Careful timing of further fractions of radiation can be used to maximize the damage delivered to the tumour while minimizing damage to normal tissue. However, tumour modelling does not necessarily predict patient outcome. A separate model has been established to predict the course of a brain cancer called glioblastoma multiforme (GBM). The model considers the growth of the tumour and its effect on the normal brain. A simple representation is included of the health status of the patient and hence the type of treatment offered. It is concluded that although these and similar models have a long way yet to be developed, they are beginning to have an impact on the development of clinical practice.

Malignant brain tumors represent one of the most devastating forms of cancer with abject survival rates that have not changed in the past 60 years. This is partly because the brain is a critical organ, and poses unique anatomical , physiological, and immunological barriers. The unique interplay of these barriers also provides an opportunity for creative engineering solutions. Cancer immunotherapy, a means of harnessing the host immune system for anti-tumor efficacy, is becoming a standard approach for treating many cancers. However, its use in brain tumors is not widespread. This review discusses the current approaches, and hurdles to these approaches in treating brain tumors, with a focus on immunotherapies. We identify critical barriers to immunoengineering brain tumor therapies and discuss possible solutions to these challenges.

Glioblastoma multiforme (GBM) is the most common and deadliest primary brain tumor, driving patients to death within 15 months after diagnosis (short term survivors, ST), with the exception of a small fraction of patients (long term survivors, LT) surviving longer than 36 months. Here we present deep sequencing data showing that peritumoral (P) areas differ from healthy white matter, but share with their respective frankly tumoral (C) samples, a number of mRNAs and microRNAs representative of extracellular matrix remodeling, TGFβ and signaling, of the involvement of cell types different from tumor cells but contributing to tumor growth, such as microglia or reactive astrocytes. Moreover, we provide evidence about RNAs differentially expressed in ST vs LT samples, suggesting the contribution of TGF-β signaling in this distinction too. We also show that the edited form of miR-376c-3p is reduced in C vs P samples and in ST tumors compared to LT ones. As a whole, our study provides new insights into the still puzzling distinction between ST and LT tumors, and sheds new light onto that " grey " zone represented by the area surrounding the tumor, which we show to be characterized by the expression of several molecules shared with the proper tumor mass.

Glioblastoma multiforme is the most malignant form of brain tumor. Despite treatment including surgical resection, adjuvant chemotherapy, and radiation, these tumors typically recur. The recurrent tumor is often resistant to further therapy with the same agent, suggesting that the surviving cells that repopulate the tumor mass have an intrinsic genetic advantage. We previously demonstrated that cells selected for resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) are near-diploid, with over-representation of part or all of chromosomes 7 and 22. While cells from untreated gliomas often have over-representation of chromosome 7, chromosome 22 is typically under-represented. We have analyzed cells from primary and recurrent tumors from the same patient before and after in vitro selection for resistance to clinically relevant doses of BCNU. Karyotypic analyses were done to demonstrate the genetic makeup of these cells, and fluorescent in situ hybridization analyses have defined th...

Clinically detected extra-cranial metastases from glioblastoma multiforme (GBM) are quite rare, with an incidence of <2% reported in the published literature. Among the various reported sites of systemic metastases from GBM, there are few cases of clinically symptomatic bone marrow metastasis. The case of a patient developing systemic dissemination of a GBM is described. A 60-year-old man with GBM who developed back pain, thrombocytopenia and subsequently neurological deficits was found to have extensive bony and bone marrow metastases. Previously reported cases of extra-cranial systemic spread of GBM and attempts made in the literature to explain the possible routes of extra-neural dissemination are reviewed.

Background The term of low-grade glioma addresses a favorable clinical outcome with indolent histological features in general consideration; however, recent studies underline the inconsistency, which originates from the accumulation of different histologic subtypes in this terminology. The malignant transformation of a low-grade glioma is unusual but presents a poor prognosis. Case history We report a case of a 12-year-old boy, who was referred for complaints of recurrent seizures. His physical examination was unremarkable, but it was learned that a peripheral mass lesion located on the left posterior parietal lobe-which had been thought to be a low-grade glioma-had been detected on a magnetic resonance imaging 2 years ago at a different hospital. The patient was then treated with valproate and carbamazepine for the seizures and advised to be followed up without any additional diagnostic and therapeutic studies for his suspected low-grade glioma. A recent magnetic resonance imaging study showed enlargements of the mass and surrounding edema with additional necrosis. Surgical excision of the tumor was performed. After the diagnosis of glioblastoma multiforme, the patient received radiation therapy and chemotherapy with a good clinical recovery without any evidence of residue or recurrence at 12-month follow-up. Conclusion The first line treatment modality in the management of low-grade glioma-especially in suitable patients-is clearly surgery. The gross total resection guarantees the distinguishing of the histological types of the low-grade gliomas and reflects the biologic behavior of these tumors. Observation without surgery must be reserved for selected unoperable cases.