Intrinsic Tumors Research Articles

The Safety and Feasibility of Intraoperative Ultrasound to Aid Intrinsic Tumour Resection: A Retrospective Case-Control Series

Objectives: Standard neuronavigation using preoperative imaging becomes increasingly inaccurate during tumour resection. Intraoperative imaging conveys a solution but to date magnetic resonance (MR) systems can be time-consuming and cumbersome. Intraoperative ultrasound (Sonowand™) provides real-time imaging and a three-dimensional image volume to update the neuronavigation dataset but its disadvantages have yet to be analyzed. We identified a cohort of patients with intrinsic tumours for which Sonowand™ had been used. Primary end points were (1) impact on operation duration and (2) postoperative complications.

Abstract 2791: Disruption of EB1 comets from microtubule “plus” ends and induction of microtubule catastrophes are intrinsic mechanisms of patupilone-induced inhibition of glioblastoma cell migration

Abstract Glioblastoma are the most frequent primary tumors of central nervous system. They are very aggressive, highly angiogenic and associated with very bad prognostic. One of the main biological features of a glioblastoma is the local invasion of its constituent neoplastic cells into the surrounding brain tissue. This invasive behavior represents a major obstacle to an effective treatment of intrinsic brain tumors. Therefore, it seems very important to target glioblastoma cell migration. Although many of the genetic alterations that deregulate the cell processes of growth and death, and are involved in tumor initiation have been elucidated in recent years, less progress has been done to understand the complex processes of migration. As a consequence, no specific therapeutic strategy against tumor cell migration is currently used to manage glioblastoma invasion. The Epothilones are a new class of microtubule (MT) stabilizing agents, which exert their cytotoxic activity by suppressing microtubule dynamics and that have strong anti-cancer activity both in vitro and in vivo. This drug family is active against cancer cells resistant to paclitaxel or to cells developing resistance to taxanes. Among the Epothilones, Patupilone (Epothilone B, EPO 906) is able to cross the blood-brain barrier since its activity is fully P-gp independent. Moreover, patupilone specifically targets αIII-tubulin, which is over expressed in glioblastomas. Here, we investigated the anti-migratory potential of patupilone through its effects on MT dynamics in glioblastoma cells. At non-cytotoxic concentrations, Patupilone inhibited glioblastoma cell migration, as shown by transwell cell migration, random motility and spheroids assay. This was associated with EB1 and related MT “plus” end tracking proteins comet shortening; and with MT catastrophes induction, without modification of any other MT dynamic instability parameters, including the microtubule growth rate. Such effect on MT catastrophes led to the disruption of MT stabilization at the leading edge. Evaluation of the effect of patupilone on EB comets and MT dynamics in a reconstituted in vitro system revealed that MT stabilizing drugs intrinsically induce MT catastrophes and disrupt EB comets at MT “plus” end. We have demonstrated that patupilone antagonizes glioblastoma cell migration by a new mechanism i.e. disruption of EB1 comets and induction of MT catastrophes distinct from its cytotoxic main mechanism i.e suppression of microtubule dynamic instability. Altogether, our results suggest that EB proteins may represent new potential target for anti-cancer therapy in highly invasive tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2791. doi:1538-7445.AM2012-2791

The paramedian supracerebellar-transtentorial approach to the entire length of the mediobasal temporal region: an anatomical and clinical study

The exploration of lesions in the mediobasal temporal region (MTR) has challenged generations of neurosurgeons to achieve an appropriate approach. To address this challenge, the extensive use of the paramedian supracerebellar-transtentorial (PST) approach to expose the entire length of the MTR, as well as the fusiform gyrus, was investigated. The authors studied the microsurgical aspects of the PST approach in 20 cadaver brains and 5 cadaver heads under the operating microscope. They evaluated the features, advantages, difficulties, and limitations of the PST approach and refined the surgical technique. They then used the PST approach in 15 patients with large intrinsic MTR tumors (6 patients), tumor in the posterior fusiform gyrus with mediobasal temporal epilepsy (MTE) (1 patient), cavernous malformations in the posterior MTR including the fusiform gyrus (2 patients), or intractable MTE with hippocampal sclerosis (6 patients) from December 2007 to May 2010. Patients ranged in age from 11 to 63 years (mean 35.2 years), and in 9 patients (60%) the lesion was located on the left side. In all patients with neuroepithelial tumors or cavernous malformations, the lesions were completely and safely resected. In all patients with intractable MTE with hippocampal sclerosis, the anterior two-thirds of the parahippocampal gyrus and hippocampus, as well as the amygdala, were removed selectively through the PST approach. There was no surgical morbidity or mortality in this series. Three patients (20%) with high-grade neuroepithelial tumors underwent postoperative radiotherapy and chemotherapy but needed a second surgery for recurrence during the follow-up period. In all patients with MTE, antiepileptic medication could be decreased to a single drug at lower doses, and no seizure activity has occurred until this point. The PST approach provides the surgeon precise anatomical orientation when exposing the entire length of the MTR, as well as the fusiform gyrus, for removing any lesion. This is a novel technique especially for removing tumors involving the entire MTR in a single session without damaging neighboring neural or vascular structures. This approach can also be a viable alternative for selective removal of the parahippocampal gyrus, hippocampus, and amygdala in patients with MTE due to hippocampal sclerosis.

Clinical status epilepticus due to anaplastic cortical ependymoma

1. IntroductionEpendymomas are glial tumors which arise from the ependy-mal lining of the cerebral ventricles and the central canal of thespinal cord.Duetomigrationfromperiventricularareastothecor-tex during the embryonal stage ependymal cells are also presentinside brain parenchyma.Ependymomas currently account for approximately 3–5% ofall intracranial malignancies in the United States, therefore mak-ing them the third most common brain tumor in children andyoung adults.Furthermore,African-Americansaremorecommonlyaffected than Caucasians.They aremorefrequentinchildren,wheretheymayaccountforabout 10% of all intrinsic brain tumors. In contrast this tumor typeis much rarer (1–2%) in adults. As a general rule, the prognosis inyoung patients seems to be worse than in adults.Anaplastic ependymomas are recognized as WHO grade III anddefined on the basis of their relative hypercellularity, cellularand nuclear pleomorphism, frequency of mitoses and endothe-lial proliferation. Only very little is known about the etiology ofependymomas, butapossibleinfectiousetiologyhasbeenhypoth-esized.This case highlights a rare clinical presentation due to anunusual localization of this type of tumor. The patient presented

Non-invasive detection of 2-hydroxyglutarate and other metabolites in IDH1 mutant glioma patients using magnetic resonance spectroscopy

Mutations of the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) are commonly found in primary brain cancers. We previously reported that a novel enzymatic activity of these mutations results in the production of the putative oncometabolite, R(-)-2-hydroxyglutarate (2-HG). Here we investigated the ability of magnetic resonance spectroscopy (MRS) to detect 2-HG production in order to non-invasively identify patients with IDH1 mutant brain tumors. Patients with intrinsic glial brain tumors (n = 27) underwent structural and spectroscopic magnetic resonance imaging prior to surgery. 2-HG levels from MRS data were quantified using LC-Model software, based upon a simulated spectrum obtained from a GAMMA library added to the existing prior knowledge database. The resected tumors were then analyzed for IDH1 mutational status by genomic DNA sequencing, Ki-67 proliferation index by immunohistochemistry, and concentrations of 2-HG and other metabolites by liquid chromatography-mass spectrometry (LC-MS). MRS detected elevated 2-HG levels in gliomas with IDH1 mutations compared to those with wild-type IDH1 (P = 0.003). The 2-HG levels measured in vivo with MRS were significantly correlated with those measured ex vivo from the corresponding tumor samples using LC-MS (r (2) = 0.56; P = 0.0001). Compared with wild-type tumors, those with IDH1 mutations had elevated choline (P = 0.01) and decreased glutathione (P = 0.03) on MRS. Among the IDH1 mutated gliomas, quantitative 2-HG values were correlated with the Ki-67 proliferation index of the tumors (r ( 2 ) = 0.59; P = 0.026). In conclusion, water-suppressed proton ((1)H) MRS provides a non-invasive measure of 2-HG in gliomas, and may serve as a potential biomarker for patients with IDH1 mutant brain tumors. In addition to 2-HG, alterations in several other metabolites measured by MRS correlate with IDH1 mutation status.

Diagnostic implications of histological analysis of neurosurgical aspirate in addition to routine resections

Many neurosurgical centers use surgical aspirators to remove brain tumor tissue. The resulting aspirate consists of fragmented viable tumor, normal or tumor-infiltrated brain tissue as well as necrotic tissue, depending on the type of tumor. Typically, such fragmented aspirate material is collected but discarded and not included when making the histopathological diagnosis. Whereas the general suitability of surgical aspirate for histological diagnosis and immunohistochemical staining has been reported previously, we have systematically investigated whether the collection and histological examination of surgical aspirate has an impact on diagnosis, in particular on the tumor grading, by providing additional features. Surgical and aspirate specimens from 85 consecutive neurosurgical procedures were collected and routinely processed. Sixty-five of the 85 specimens were intrinsic brain tumors and the remainder consisted of metastatic tumors, meningiomas, schwannomas and lymphomas. Important diagnostic features seen in surgical aspirate were microvascular proliferation (n = 3), more representative necrosis (n = 2), and gemistocytic component (n = 2). In one case, microvasular proliferations were seen in the aspirate only, leading to a change of diagnosis. Collection of surgical aspirate also generates additional archival material which can be microdissected and used for tissue microarrays or for molecular studies.

Intraparotid Facial Nerve Neurofibroma in Neurofibromatosis Type 1

Benign tumors of the nerve sheath are of 2 types: schwannoma and neurofibroma. Neurofibromas are most commonly found with neurofibromatosis type 1 and characterized by incorporation of the nerve fibers within their matrix. Both benign and malignant tumors can affect the facial nerve. These tumors can be intrinsic or extrinsic; in other words, it can originate from the facial nerve itself or from a contiguous structure or a metastatic disease. Actually, extrinsic tumors are far more common than intrinsic tumors. Intraparotid location of benign tumors of the facial nerve sheath is considered a rare event compared with intratemporal location.

Context-specific gene regulatory networks subdivide intrinsic subtypes of breast cancer

BackgroundBreast cancer is a highly heterogeneous disease with respect to molecular alterations and cellular composition making therapeutic and clinical outcome unpredictable. This diversity creates a significant challenge in developing tumor classifications that are clinically reliable with respect to prognosis prediction.ResultsThis paper describes an unsupervised context analysis to infer context-specific gene regulatory networks from 1,614 samples obtained from publicly available gene expression data, an extension of a previously published methodology. We use the context-specific gene regulatory networks to classify the tumors into clinically relevant subgroups, and provide candidates for a finer sub-grouping of the previously known intrinsic tumors with a focus on Basal-like tumors. Our analysis of pathway enrichment in the key contexts provides an insight into the biological mechanism underlying the identified subtypes of breast cancer.ConclusionsThe use of context-specific gene regulatory networks to identify biological contexts from heterogenous breast cancer data set was able to identify genomic drivers for subgroups within the previously reported intrinsic subtypes. These subgroups (contexts) uphold the clinical relevant features for the intrinsic subtypes and were associated with increased survival differences compared to the intrinsic subtypes. We believe our computational approach led to the generation of novel rationalized hypotheses to explain mechanisms of disease progression within sub-contexts of breast cancer that could be therapeutically exploited once validated.

Tratamiento de los tumores cerebrales intrínsecos de áreas motoras elocuentes: Resultados de un protocolo basado en la navegación, tractografía y monitorización neurofisiológica de estructuras corticales y subcorticales

The role of the microsurgical management of intrinsic brain tumors is to maximize the volumetric resection of the tumoral tissue minimizing the postoperative morbidity. The purpose of our paper has been to study the benefits of an original protocol developed for the microsurgical treatment of tumors located in eloquent motor areas where the navigation and electrical stimulation of motor subcortical pathways have been implemented. A total of 17 patients operated on for resection of cortical or subcortical tumors in motor areas were included in the series. Preoperative planning for multimodal navigation was done integrating anatomic studies, motor functional MRI (f-MRI) and subcortical pathways volumes generated by diffusion tensor imaging (DTI). Intraoperative neuromonitorization included motor mapping by direct cortical and subcortical electrical stimulation (CS and sCS) and localization of the central sulcus using cortical multipolar electrodes and the N20 wave inversion technique. The location of all cortical and subcortical stimulated points with positive motor response was stored in the navigator and correlated with the cortical or subcortical motor functional structures defined preoperatively. The mean tumoral volumetric resection was 89.1±14.2% of the preoperative volume, with a total resection (≥100%) in twelve patients. Preoperatively a total of 58.8% of the patients had some motor deficit, increasing 24 hours after surgery to 76.5% and decreasing to 41.1% a month later. There was a great correlation between anatomic and functional data, both cortically and subcortically. However, in six cases it was not possible to identify the central sulcus and in many cases fMRI gave contradictory information. A total of 52 cortical points submitted to CS had positive motor response, with a positive correlation of 83.7%. Also, a total of 55 subcortical points had positive motor response, being in these cases 7.3±3.1 mm the mean distance from the stimulated point to the subcortical tract. The integration of preoperative and intraoperative anatomic and functional studies allows a safe functional resection of the brain tumors located in eloquent areas, compared to the tumoral resection based on anatomic imaging studies. Multimodal navigation allows the integration and correlation among preoperative and intraoperative anatomic and functional data. Cortical motor functional areas are anatomically and functionally located preoperatively thanks to MRI and fMRI and subcortical motor pathways with TDI and tractography. Intraoperative confirmation is done with CS and N20 inversion wave for cortical structures and with sCS for subcortical pathways. With this protocol we achieved a mean of 90% of volumetric resection in cortical and subcortical tumors located in eloquent motor areas with an increase of neurological deficits in the immediate postoperative period that significantly decreased one month later. Ongoing studies will define the safe limits for functional resection taking into account the intraoperative brain shift. Finally, it must be demonstrated if this protocol has any benefit for patients concerning disease free or overall survival.

A Case of Brachial Plexus Neurofibroma

Tumors of the brachial plexus are relatively rare. The most common intrinsic tumors involving the brachial plexus are benign schwannomas and neurofibromas. Neurofibromas are usually associated with neurofibromatosis-1 (NF-1). Solitary neurofibromas unassociated with NF-1 are very uncommon. We report a 56 year-old man with brachial plexus solitary neurofibroma and reviews of literatures.

Age-Dependent Presentation of Tectal Plate Tumors: Preliminary Observations

Tectal plate tumors are intrinsic midbrain tumors that behave more like hamartomas than neoplasms. Postulating that the presentation depends on the age of the affected patients, the authors reassessed the presentation of 10 consecutive patients. All patients presented with headache and papilledema. Four children younger than 10 years presented with a short symptom interval, vomiting, and Parinaud's syndrome. The remaining 6 children presented with a long symptom interval, gait abnormalities, cognitive impairment, vision impairment, tremor, macrocephaly, impaired visual acuity, and ataxia and sometimes with pyramidal signs as well. The difference between groups was statistically significant. Tumor size was similar in the groups. It is therefore concluded that the presentation of tectal plate tumors varies with age.

Intraoperative magnetic resonance imaging–guided tractography with integrated monopolar subcortical functional mapping for resection of brain tumors

The object of this study was to describe the utility and safety of using a single probe for combined intraoperative navigation and subcortical mapping in an intraoperative MR (iMR) imaging environment during brain tumor resection. The authors retrospectively reviewed those patients who underwent resection in the iMR imaging environment, as well as functional electrophysiological monitoring with continuous motor evoked potential (MEP) and direct subcortical mapping combined with diffusion tensor imaging tractography. RESULTS As a navigational tool the monopolar probe used was safe and accurate. Positive subcortical fiber MEPs were obtained in 10 (83%) of the 12 cases. In 10 patients in whom subcortical MEPs were recorded, the mean stimulus intensity was 10.4 ± 5.2 mA and the mean distance from the probe tip to the corticospinal tract (CST) was 7.4 ± 4.5 mm. There was a trend toward worsening neurological deficits if the distance to the CST was short, and a small minimum stimulation threshold was recorded indicating close proximity of the CST to the resection margins. Gross-total resection (95%-100% tumor removal) was achieved in 11 cases (92%), whereas 1 patient (8%) had at least a 90% tumor resection. At the end of 3 months, 2 patients (17%) had persistent neurological deficits. The monopolar probe can be safely implemented in an iMR imaging environment both for navigation and stimulation purposes during the resection of intrinsic brain tumors. In this study there was a trend toward worsening neurological deficits if the distance from the probe to the CST was short (< 5 mm) indicating close proximity of the resection cavity to the CST. This technology can be used in the iMR imaging environment as a surgical adjunct to minimize adverse neurological outcomes.

DTI fiber tracking to differentiate demyelinating diseases from diffuse brain stem glioma

ObjectIntrinsic diffuse brainstem tumors and demyelinating diseases primarily affecting the brainstem can share common clinical and radiological features, sometimes making the diagnosis difficult especially at the time of first clinical presentation. To explore the potential usefulness of new MRI sequences in particular diffusion tensor imaging fiber tracking in differentiating these two pathological entities, we review a series of brainstem tumors and demyelinating diseases treated at our institution. Material and methodsThe clinical history including signs and symptoms and MRI findings of three consecutive demyelinating diseases involving the brainstem that presented with diagnostic uncertainty and three diffuse intrinsic brainstem tumors were reviewed, along with a child with a supratentorial tumor for comparison. Fiber tracking of the pyramidal tracts was performed for each patient using a DTI study at the time of presentation. Additionally Fractional Anisotropy values were calculated for each patient in the pons and the medulla oblongata. ResultsRoutine MR imaging was unhelpful in differentiating between intrinsic tumor and demyelination. In contrast, retrospective DTI fiber tracking clearly differentiated the pathology showing deflection of the pyramidal tracts posteriorly and laterally in the case of intrinsic brainstem tumors and, in the case of demyelinating disease, poorly represented and truncated fibers. Regionalized FA values were variable and of themselves were not predictive either pathology. ConclusionDTI fiber tracking of the pyramid tracts in patients with suspected intrinsic brainstem tumor or demyelinating disease presents two clearly different patterns that may help in differentiating between these two pathologies when conventional MRI and clinical data are inconclusive.

Multimodal navigation in the functional microsurgical resection of intrinsic brain tumors located in eloquent motor areas: role of tractography

Nowadays the role of microsurgical management of intrinsic brain tumors is to maximize the volumetric resection of the tumoral tissue, minimizing the postoperative morbidity. The purpose of this paper was to study the benefits of an original protocol developed for the microsurgical treatment of tumors located in eloquent motor areas where the navigation and electrical stimulation of motor subcortical pathways have been implemented. A total of 17 patients who underwent resection of cortical or subcortical tumors in motor areas have been included in the series. The preoperative planning for multimodal navigation was done by integrating anatomical studies, motor functional MR (fMR) imaging, and subcortical pathway volumes generated by diffusion tensor (DT) imaging. Intraoperative neuromonitoring included motor mapping by direct cortical stimulation (CS) and subcortical stimulation (sCS), and localization of the central sulcus by using cortical multipolar electrodes and the N20 wave inversion technique. The location of all cortically and subcortically stimulated points with positive motor response was stored in the navigator and correlated with the cortical and subcortical motor functional structures defined preoperatively. The mean tumoral volumetric resection was 89.1 +/- 14.2% of the preoperative volume, with a total resection (> or = 100%) in 8 patients. Preoperatively a total of 58.8% of the patients had some kind of motor neurological deficit, increasing 24 hours after surgery to 70.6% and decreasing to 47.1% at 1 month later. There was a great correlation between anatomical and functional data, both cortically and subcortically. A total of 52 cortical points submitted to CS had positive motor response, with a positive correlation of 83.7%. Also, a total of 55 subcortical points had positive motor response; in these cases the mean distance from the stimulated point to the subcortical tract was 7.3 +/- 3.1 mm. The integration of anatomical and functional studies allows a safe functional resection of the brain tumors located in eloquent areas. Multimodal navigation allows integration and correlation among preoperative and intraoperative anatomical and functional data. Cortical motor functional areas are anatomically and functionally located preoperatively thanks to MR and fMR imaging and subcortical motor pathways with DT imaging and tractography. Intraoperative confirmation is done with CS and N20 inversion wave for cortical structures and with sCS for subcortical pathways. With this protocol the authors achieved a good volumetric resection in cortical and subcortical tumors located in eloquent motor areas, with an increase in the incidence of neurological deficits in the immediate postoperative period that significantly decreased 1 month later. Ongoing studies must define the safe limits for functional resection, taking into account the intraoperative brain shift. Finally, it must be demonstrated whether this protocol has any long-term benefit for patients by prolonging the disease-free interval, the time to recurrence, or the survival time.

The selective amygdalohippocampectomy for intractable temporal limbic seizures

The proximal (anterior) transsylvian approach through a pterional craniotomy was developed by the senior author (M.G.Y.) in 1967 for the microsurgical treatment of saccular aneurysms of the circle of Willis, frontoorbital and temporobasal arteriovenous malformations, cavernomas, and extrinsic and intrinsic tumors. The acquired positive surgical experiences on this large series enabled the senior author, in 1973, to apply this approach for the selective amygdalohippocampectomy in patients with intractable mesial temporal lobe epilepsy. The proximal (anterior) transsylvian-transamygdala approach to the mesial temporal structures permits the selective two-thirds resection of the amygdala and hippocampus-parahippocampus in an anteroinferior to posteroinferior exploration axis along the base of the semicircular temporal horn. This strategy ensures preservation of the overlying neopallial temporal convolutions such as the T1, T2, T3, and T4 gyri as well as the related subcortical connective fiber systems and other essential components of the temporal white matter. The application of rigid brain self-retaining retractor systems was strictly avoided during the entire procedure. Computer-assisted navigation was never used. On routine postoperative CT scanning and MR imaging studies, infarction was not observed in any patient. The availability of tractography technology has proven that the connective fiber system around the resected mesial temporal area remains intact. The surgical outcome and results on neoplastic and vascular lesions of the mesiobasal temporal region have been presented in Volumes II, IIIB, and IVB of Microneurosurgery. The surgical outcomes and results in 102 patients with mesial temporal seizures who underwent surgery performed by the senior author in Zürich have been previously published. In this paper, 73 patients who underwent surgery between 1994 and September 2006 in Little Rock, Arkansas, are presented, and 13 other patients are excluded who underwent surgery after September 2006. Altogether, among 188 patients who underwent surgery, there was no surgical mortality or morbidity, and no neurological deficits, new neurocognitive dysfunction, or impairments of the preoperative incapacities. The surgical outcome in terms of seizures was rewarding in the majority of patients, particularly in those who exhibited the following irregularities on preoperative investigations: regular local dysfunctions on electroencephalography, dysmorphic changes in the mesiobasal temporal parenchyma on MR imaging studies, and hypometabolism in the anterior third of the temporal lobe on PET studies.

Abstract A178: Role of tumor and host-derived HGF in drug resistance to EGFR inhibitors in EGFR activating mutation-positive lung cancer

Abstract Background: Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)-activating mutations (EGFRmu) responds favorably to the EGFR tyrosine kinase inhibitors (EGFR-TKIs), gefitinib or erlotinib. However, 25–30% of patients with EGFRmu show intrinsic resistance, and the responders invariably acquire resistance to EGFR-TKIs. Here, we examined the role of hepatocyte growth factor (HGF), a specific ligand of MET, in gefitinib resistance of NSCLC with EGFRmu. Methods: NSCLC cells, PC-9 and HCC827, with EGFRmu, but not T790M second mutation in EGFR or MET amplification, were used in this study. Sensitivity to gefitinib was determined by MTT assay. Phosphorylation of MET, EGFR, ERBB3, and the PI3K/Akt pathway were examined by Western blotting. HGF expression in 20 tumors from 16 NSCLC patients with EGFRmu who were treated with gefitinib was determined by immunohistochemistry. Results: HGF induced resistance to gefitinib by restoring Akt phosphorylation independently of ErbB3. Specific down-regulation of MET, but not ErbB3, reversed gefitinib resistance and Akt phosphorylation induced by HGF. High levels of immunoreactivity for HGF were detected in cancer cells of 3 of 3 intrinsic resistant tumors and in one of 2 tumors with acquired resistance without T790M second mutation or MET amplification, suggesting HGF-induced resistance by autocrine mechanism. The lung cancer cells also became resistant to EGFR-TKIs when co-cultured in vitro with HGF-producing fibroblasts and co-injected into SCID mice. Importantly, combined use of gefitinib plus anti-HGF antibody or the HGF antagonist, NK4 successfully overcame the fibroblast-induced EGFR-TKI resistance both in vitro and in vivo. Co-localization of fibroblasts and HGF was detected in both xenograft tumors in mouse model and lung cancer patient specimens, suggesting HGF-induced resistance by paracrine mechanism. Conclusions: The findings indicate that HGF-mediated MET activation is a novel mechanism of intrinsic and acquired gefitinib-resistance in NSCLC with EGFRmu by both autocrine and paracrine mechanisms. Therefore, inhibition of HGF-MET signaling may be considerable strategy for more successful treatment with EGFR-TKIs. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A178.

Combinations of genetic mutations in the adult neural stem cell compartment determine brain tumour phenotypes

It has been suggested that intrinsic brain tumours originate from a neural stem/progenitor cell population in the subventricular zone of the post-natal brain. However, the influence of the initial genetic mutation on the phenotype as well as the contribution of mature astrocytes to the formation of brain tumours is still not understood. We deleted Rb/p53, Rb/p53/PTEN or PTEN/p53 in adult subventricular stem cells; in ectopically neurografted stem cells; in mature parenchymal astrocytes and in transplanted astrocytes. We found that only stem cells, but not astrocytes, gave rise to brain tumours, independent of their location. This suggests a cell autonomous mechanism that enables stem cells to generate brain tumours, whereas mature astrocytes do not form brain tumours in adults. Recombination of PTEN/p53 gave rise to gliomas whereas deletion of Rb/p53 or Rb/p53/PTEN generated primitive neuroectodermal tumours (PNET), indicating an important role of an initial Rb loss in driving the PNET phenotype. Our study underlines an important role of stem cells and the relevance of initial genetic mutations in the pathogenesis and phenotype of brain tumours.

Meta-analysis of glioblastoma multiforme versus anaplastic astrocytoma identifies robust gene markers

BackgroundAnaplastic astrocytoma (AA) and its more aggressive counterpart, glioblastoma multiforme (GBM), are the most common intrinsic brain tumors in adults and are almost universally fatal. A deeper understanding of the molecular relationship of these tumor types is necessary to derive insights into the diagnosis, prognosis, and treatment of gliomas. Although genomewide profiling of expression levels with microarrays can be used to identify differentially expressed genes between these tumor types, comparative studies so far have resulted in gene lists that show little overlap.ResultsTo achieve a more accurate and stable list of the differentially expressed genes and pathways between primary GBM and AA, we performed a meta-analysis using publicly available genome-scale mRNA data sets. There were four data sets with sufficiently large sample sizes of both GBMs and AAs, all of which coincidentally used human U133 platforms from Affymetrix, allowing for easier and more precise integration of data. After scoring genes and pathways within each data set, we combined the statistics across studies using the nonparametric rank sum method to identify the features that differentiate GBMs and AAs. We found >900 statistically significant probe sets after correction for multiple testing from the >22,000 tested. We also used the rank sum approach to select >20 significant Biocarta pathways after correction for multiple testing out of >175 pathways examined. The most significant pathway was the hypoxia-inducible factor (HIF) pathway. Our analysis suggests that many of the most statistically significant genes work together in a HIF1A/VEGF-regulated network to increase angiogenesis and invasion in GBM when compared to AA.ConclusionWe have performed a meta-analysis of genome-scale mRNA expression data for 289 human malignant gliomas and have identified a list of >900 probe sets and >20 pathways that are significantly different between GBM and AA. These feature lists could be utilized to aid in diagnosis, prognosis, and grade reduction of high-grade gliomas and to identify genes that were not previously suspected of playing an important role in glioma biology. More generally, this approach suggests that combined analysis of existing data sets can reveal new insights and that the large amount of publicly available cancer data sets should be further utilized in a similar manner.

In vivo assessment of high-grade glioma biochemistry using microdialysis: a study of energy-related molecules, growth factors and cytokines

Microdialysis enables measurement of the chemistry of the cerebral extracellular fluid. This study's objective was to utilise microdialysis to monitor levels of glucose, lactate, pyruvate, glutamate and glycerol in patients following surgery for intrinsic brain tumours, and to assess the concentration of growth factors, cytokines and other proteins involved in the pathogenesis of high-grade gliomas in vivo. Eight patients with suspected high-grade gliomas were studied. Seven of these underwent resection with one microdialysis catheter placed at the tumour resection margin and, in six of these seven cases, a second microdialysis catheter in macroscopically normal peritumour tissue. The remaining glioma patient had an image-guided biopsy with a single catheter inserted stereotactically at the tumour margin. Histology demonstrated WHO IV glioblastoma in five cases, WHO III anaplastic astrocytoma in two cases, and one cerebral lymphoma. In the high-grade gliomas (WHO IV and III), tumour margin microdialysates consistently showed significantly lower glucose, higher lactate/pyruvate (L/P) ratio, higher glutamate and higher glycerol, relative to peritumour microdialysates (P < 0.05). These results indicate that malignant glioma margin tissue is metabolically extremely active. There was great variability in the microdialysate concentrations of growth factors (TGFalpha, EGF, VEGF), cytokines (IL-1alpha, IL-1beta, IL-1ra, IL-6, IL-8), matrix metalloproteinases (MMP-2, MMP-9) and their endogenous inhibitors (TIMP-1, TIMP-2). Notably, microdialysates from the glioma resection margin demonstrated significantly higher IL-8 concentration and higher MMP-2/TIMP-1 ratio when compared to peritumour microdialysates (P < 0.05), suggesting an environment favouring invasion and angiogenesis at the tumour margin. Microdialysis is a promising technique to study in vivo glioma metabolism, and may assist in the development of new therapies.

Introduction: Surgery of limbic and paralimbic gliomas

In this issue of Neurosurgical Focus, a challenging neurosurgical entity, gliomas, which grow in the limbic and paralimbic system, is covered from various angles. It is still controversial whether intrinsic tumors in this area should be removed surgically or not. Temporomesial gliomas, and especially those of the insula and cingulate gyrus, are even now widely considered “unresectable.” The aim of this compilation of articles is to provide evidence to the contrary. On the basis of a thorough understanding of functional connectivity and knowledge of the topography, state-of-the-art imaging can be easily interpreted. This will aid in clear preoperative decision making with respect to resectability and imminent risks. It is clear that surgery that is aimed at complete removal has substantial but acceptable morbidity, which is most severe in insular and least severe in temporomesial gliomas. These tumors are closely related to epilepsy or seizures, a fact that is also acknowledged in this issue. Therefore, oncological and seizure aspects of outcome must be considered equally. In both aspects surgery is beneficial. The follow ing articles emphasize also that intraoperative monitoring is of utmost importance during surgery, and that surgery is part of a multimodality treatment concept. Since Yasargil and colleagues 3,4 reported their experience, our group has exhibited particular interest in