Phase II study of temozolomide, thalidomide, and celecoxib for newly diagnosed glioblastoma in adults.

We conducted a phase II study of the combination of temozolomide and angiogenesis inhibitors for treating adult patients with newly diagnosed glioblastoma. Patients who had stable disease following standard radiation therapy received temozolomide for 5 days in 28-day cycles, in combination with daily thalidomide and celecoxib. Patients were treated until tumor progression or development of unacceptable toxicity. Four-month progression-free survival (PFS) from study enrollment was the primary end point, and overall survival (OS) was the secondary end point. In addition, we sought to correlate response with O(6)-methylguanine-DNA methyltransferase promoter methylation status and serum levels of angiogenic peptides. Fifty patients with glioblastoma were enrolled (18 women, 32 men). Median age was 54 years (range, 29-78) and median KPS score was 90 (range, 70-100). From study enrollment, median PFS was 5.9 months (95% confidence interval [CI]: 4.2-8.0) and 4-month PFS was 63% (95% CI: 46%-75%). Median OS was 12.6 months (95% CI: 8.5-16.4) and 1-year OS was 47%. Of the 47 patients evaluable for best response, none had a complete response, five (11%) had partial response, four (9%) had minor response, 22 (47%) had stable disease, and 16 (34%) had progressive disease. Analysis of serial serum samples obtained from 47 patients for four angiogenic peptides failed to show a significant correlation with response or survival for three of the peptides; higher vascular endothelial growth factor levels showed a trend toward correlation with decreased OS (p=0.07) and PFS (p=0.09). The addition of celecoxib and thalidomide to adjuvant temozolomide was well tolerated but did not meet the primary end point of improvement of 4-month PFS from study enrollment.

Marked genomic differences characterize primary and secondary glioblastoma subtypes and identify two distinct molecular and clinical secondary glioblastoma entities.

Glioblastoma is classified into two subtypes on the basis of clinical history: "primary glioblastoma" arising de novo without detectable antecedent disease and "secondary glioblastoma" evolving from a low-grade astrocytoma. Despite their distinctive clinical courses, they arrive at an indistinguishable clinical and pathologic end point highlighted by widespread invasion and resistance to therapy and, as such, are managed clinically as if they are one disease entity. Because the life history of a cancer cell is often reflected in the pattern of genomic alterations, we sought to determine whether primary and secondary glioblastomas evolve through similar or different molecular pathogenetic routes. Clinically annotated primary and secondary glioblastoma samples were subjected to high-resolution copy number analysis using oligonucleotide-based array comparative genomic hybridization. Unsupervised classification using genomic nonnegative matrix factorization methods identified three distinct genomic subclasses. Whereas one corresponded to clinically defined primary glioblastomas, the remaining two stratified secondary glioblastoma into two genetically distinct cohorts. Thus, this global genomic analysis showed wide-scale differences between primary and secondary glioblastomas that were previously unappreciated, and has shown for the first time that secondary glioblastoma is heterogeneous in its molecular pathogenesis. Consistent with these findings, analysis of regional recurrent copy number alterations revealed many more events unique to these subclasses than shared. The pathobiological significance of these shared and subtype-specific copy number alterations is reinforced by their frequent occurrence, resident genes with clear links to cancer, recurrence in diverse cancer types, and apparent association with clinical outcome. We conclude that glioblastoma is composed of at least three distinct molecular subtypes, including novel subgroups of secondary glioblastoma, which may benefit from different therapeutic strategies.

Phase II study of metronomic chemotherapy for recurrent malignant gliomas in adults.

Preclinical evidence suggests that continuous low-dose daily (metronomic) chemotherapy may inhibit tumor endothelial cell proliferation (angiogenesis) and prevent tumor growth. This phase II study evaluated the feasibility of this antiangiogenic chemotherapy regimen in adults with recurrent malignant gliomas. The regimen consisted of low-dose etoposide (35 mg/m2 [maximum, 100 mg/day] daily for 21 days), alternating every 21 days with cyclophosphamide (2 mg/kg [maximum, 100 mg/day] daily for 21 days), in combination with daily thalidomide and celecoxib, in adult patients with recurrent malignant gliomas. Serum and urine samples were collected for measurement of angiogenic peptides. Forty-eight patients were enrolled (15 female, 33 male). Twenty-eight patients had glioblastoma multiforme (GBMs), and 20 had anaplastic gliomas (AGs). Median age was 53 years (range, 33-74 years), and median KPS was 70 (range, 60-100). Therapy was reasonably well tolerated in this heavily pretreated population. Two percent of patients had partial response, 9% had a minor response, 59% had stable disease, and 30% had progressive disease. For GBM patients, median progression-free survival (PFS) was 11 weeks, six-month PFS (6M-PFS) was 9%, and median overall survival (OS) was 21 weeks. For AG patients, median PFS was 14 weeks, 6M-PFS was 26%, and median OS was 41.5 weeks. In a limited subset of patients, serum and urine angiogenic peptides did not correlate with response or survival (p > 0.05). Although there were some responders, this four-drug, oral metronomic regimen did not significantly improve OS in this heavily pretreated group of patients who were generally not eligible for conventional protocols. While metronomic chemotherapy may not be useful in patients with advanced disease, further studies using metronomic chemotherapy combined with more potent antiangiogenic agents in patients with less advanced disease may be warranted.

Predicting survival of children with CNS tumors using proton magnetic resonance spectroscopic imaging biomarkers.

Using brain proton magnetic resonance spectroscopic imaging (MRSI) in children with central nervous system (CNS) tumors, we tested the hypothesis that combining information from biologically important metabolites, at diagnosis and prior to treatment, would improve prediction of survival. We evaluated brain proton MRSI exams in 76 children (median age at diagnosis: 74 months) with brain tumors. Important biomarkers, choline-containing compounds (Cho), N-acetylaspartate (NAA), total creatine (tCr), lipids and/or lactate (L), were measured at the "highest Cho region" and normalized to the tCr of surrounding healthy tissue. Neuropathological grading was performed using World Health Organization (WHO) criteria. Fifty-eight of 76 (76%) patients were alive at the end of the study period. The mean survival time for all subjects was 52 months. Univariate analysis demonstrated that Cho, L, Cho/NAA and tumor grade differed significantly between survivors and non-survivors (P< or =0.05). Multiple logistic regression and stepwise multivariate Cox regression indicated that Cho + 0.1L was the only independent predictor of survival (likelihood ratio test = 10.27, P<0.001; Cox regression, P=0.004). The combined index Cho + 0.1L was more accurate and more specific predictor than Cho or Cho/NAA. Accuracy and specificity for Cho + 0.1L were 80% and 86%, respectively. We conclude that brain proton MRSI biomarkers predict survival of children with CNS tumors better than does standard histopathology. More accurate prediction using this non-invasive technique represents an important advance and may suggest more appropriate therapy, especially when diagnostic biopsy is not feasible.

Temozolomide-mediated radiation enhancement in glioblastoma: a report on underlying mechanisms.

PURPOSE: In this study, we investigated the mechanisms by which temozolomide enhances radiation response in glioblastoma cells. EXPERIMENTAL DESIGN: Using a panel of four primary human glioblastoma cell lines with heterogeneous O(6)-methylguanine-DNA methyltransferase (MGMT) protein expression, normal human astrocytes, and U87 xenografts, we investigated (a) the relationship of MGMT status with efficacy of temozolomide-based chemoradiation using a panel of in vitro and in vivo assays; (b) underlying mechanisms by which temozolomide enhances radiation effect in glioblastoma cells; and (c) strategies to overcome resistance to radiation + temozolomide. RESULTS: Temozolomide enhances radiation response most effectively in glioblastomas without detectable MGMT expression. On concurrent radiation + temozolomide administration in MGMT-negative glioblastomas, there seems to be decreased double-strand DNA (dsDNA) repair capacity and enhanced dsDNA damage compared either with radiation alone or with sequentially administered temozolomide. Our data suggest that O(6)-benzylguanine can enhance the antitumor effects of concurrent radiation + temozolomide in MGMT-positive cells by enhancing apoptosis and the degree of dsDNA damage. O(6)-Benzylguanine was most effective when administered concurrently with radiation + temozolomide and had less of an effect when administered with temozolomide in the absence of radiation or when administered sequentially with radiation. Our in vivo data using U87 xenografts confirmed our in vitro findings. CONCLUSIONS: The present study shows that temozolomide enhances radiation response most effectively in MGMT-negative glioblastomas by increasing the degree of radiation-induced double-strand DNA damage. In MGMT-positive glioblastomas, depletion of MGMT by the addition of O(6)-benzylguanine significantly enhances the antitumor effect of concurrent radiation + temozolomide. These are among the first data showing mechanisms of synergy between radiation and temozolomide and the effect of MGMT.

Therapy of hematogenous melanoma brain metastases with endostatin.

PURPOSE: Cerebral metastases represent the most common type of brain tumors. This study investigated the effects of endogenous endostatin on hematogenous cerebral melanoma metastases. EXPERIMENTAL DESIGN: Murine K1735 melanoma cells were transfected with the mouse endostatin cDNA. Experimental tumors were induced either by s.c. injection, intracerebral implantation, or via injection into the internal carotid artery to simulate hematogenous metastatic spread. The effects of endostatin expression on tumor incidence, growth pattern, and vascularity were analyzed. RESULTS: In vitro secretion of endostatin by 2.5 x 10(5) cells within 24 hours was 0.12 +/- 0.03 ng, 4.35 +/- 0.4, and 1.18 +/- 0.7 ng/mL for wild type and two endostatin-transfected K1735 clones termed K1735-endo/2 and K1735-endo/8, respectively. Tumor inhibition in vivo correlated with endogenous endostatin production. Within 25 days, growth of s.c. K1735-endo/2 tumors was <20% compared with wild-type controls. Following intracerebral implantation the average survival time of mice was 27.8 +/- 2.6 versus 13.3 +/- 3.7 days in the K1735-endo/2 versus the wild-type group, respectively. Intracarotid injection of 1 x 10(5) wild-type cells killed the mice within 24 +/- 1.8 days. In contrast, endostatin expression prevented macroscopic metastatic tumor growth in 11 of 12 mice, although viable microscopic tumor pockets were detectable in all animals. CONCLUSION: Endostatin inhibits tumor progression of multiple cerebral metastases in vivo. Hematogenous micrometastases are more efficiently suppressed than tumors resulting from high focal cell numbers which may be due to a higher angiogenic signaling exerted by massive cell deposits. Endostatin may prevent solid tumor growth more effectively by inhibition of early angiogenesis.

Brain tumor tropism of transplanted human neural stem cells is induced by vascular endothelial growth factor.

The transplantation of neural stem cells (NSCs) offers a new potential therapeutic approach as a cell-based delivery system for gene therapy in brain tumors. This is based on the unique capacity of NSCs to migrate throughout the brain and to target invading tumor cells. However, the signals controlling the targeted migration of transplanted NSCs are poorly defined. We analyzed the in vitro and in vivo effects of angiogenic growth factors and protein extracts from surgical specimens of brain tumor patients on NSC migration. Here, we demonstrate that vascular endothelial growth factor (VEGF) is able to induce a long-range attraction of transplanted human NSCs from distant sites in the adult brain. Our results indicate that tumor-upregulated VEGF and angiogenic-activated microvasculature are relevant guidance signals for NSC tropism toward brain tumors.

Quantitatively determined survivin expression levels are of prognostic value in human gliomas.

PURPOSE: Survivin is a novel antiapoptotic gene that has been recently cloned and characterized. Its expression has been found to be of prognostic significance in several tumor types. This is the first study on the prognostic significance of survivin expression in human gliomas. MATERIALS AND METHODS: We used quantitative Western blot analysis with densitometry to determine survivin protein expression levels in 92 glioma cases for which frozen tissue was available for analysis. Survivin positivity and expression levels were correlated with histopathologic features of the tumors, apoptosis (as measured by cleaved, or activated, caspase 3 levels), and clinical outcome. RESULTS: Survivin expression has clear prognostic value in human gliomas. Patients with detectable survivin expression had significantly shorter overall survival times (P <.0001) compared with those without detectable expression when all glioma patients were considered. Although glioblastoma multiforme (GBM) patients had significantly higher rates of survivin positivity and higher levels of survivin expression (P <.0001) than their non-GBM counterparts, the prognostic value of survivin expression seemed to be independent of histology alone. Survivin-positive GBM patients had significantly shorter overall survival times compared with survivin-negative GBM patients (P <.0001). Likewise, survivin-positive non-GBM patients had shorter survival times compared with survivin-negative non-GBM patients (P =.029). Furthermore, increasing levels of survivin expression significantly correlated with reduced survival times when all glioma patients were considered, and markedly so for GBM patients (P <.0001). Increasing survivin levels significantly correlated with reduced expression of cleaved caspase 3, indicating its association with antiapoptotic activity. CONCLUSION: Survivin positivity and protein expression levels, as determined quantitatively, are of significant prognostic value in human gliomas and seem to be associated with reduced apoptotic capacity of these tumors.

Antiangiogenic therapy by local intracerebral microinfusion improves treatment efficiency and survival in an orthotopic human glioblastoma model.

Targeting active angiogenesis, which is a major hallmark of malignant gliomas, is a potential therapeutic approach. For effective inhibition of tumor-induced neovascularization, antiangiogenic compounds have to be delivered in sufficient quantities over a sustained period of time. The short biological half-life of many antiangiogenic inhibitors and the impaired intratumoral blood flow create logistical difficulties that make it necessary to optimize drug delivery for the treatment of malignant gliomas. In this study, we compared the effects of endostatin delivered by daily systemic administration or local intracerebral microinfusion on established intracranial U87 human glioblastoma xenografts in nude mice. Noninvasive magnetic resonance imaging methods were used to assess treatment effects and additional histopathological analysis of tumor volume, microvessel density, proliferation, and apoptosis rate were performed. Three weeks of local intracerebral microinfusion of endostatin (2 mg/kg/day) led to 74% (P < 0.05) reduction of tumor volumes with decreased microvessel densities (33.5%, P < 0.005) and a 3-fold increased tumor cell apoptosis (P < 0.002). Systemic administration of a 10-fold higher amount of endostatin (20 mg/kg/day) did not result in a reduction of tumor volume nor in an increase of tumor cell apoptosis despite a significant decrease of microvessel densities (26.9%, P < 0.005). Magnetic resonance imaging was used to successfully demonstrate treatment effects. The local microinfusion of human endostatin significantly increased survival when administered at 2 mg/kg/day and was prolonged further when the dose was increased to 12 mg/kg/day. Our results indicate that the local intracerebral microinfusion of antiangiogenic compounds is an effective way to overcome the logistical problems of inhibiting glioma-induced angiogenesis.

Low rate of venous thromboembolism after craniotomy for brain tumor using multimodality prophylaxis.

CONTEXT: Venous thromboembolism (VTE) is the most frequent complication following craniotomy for brain tumors. At Brigham and Women's Hospital, VTE after craniotomy for brain tumor is the leading cause of deep vein thrombosis (DVT) and pulmonary embolism (PE) among patients hospitalized for conditions other than VTE. OBJECTIVE: To minimize VTE among patients undergoing craniotomy for brain tumor. DESIGN: Randomized, prospective, double-blind clinical trial. SETTING: Brigham and Women's Hospital. PATIENTS: One hundred fifty patients undergoing craniotomy for brain tumor randomized to enoxaparin, 40 mg/d, vs heparin, 5,000 U bid, with all patients receiving graduated compression stockings and intermittent pneumatic compression. MAIN OUTCOME MEASURES: The rate of DVT detected by venous ultrasonography prior to hospital discharge. RESULTS: Symptomatic DVT or PE developed in none of the patients. The overall rate of asymptomatic VTE was 9.3%, with no significant difference in the rates between the two prophylaxis groups. Ten of the 14 patients identified with VTE had thrombus limited to the deep veins of the calf. CONCLUSIONS: Enoxaparin, 40 mg/d, or unfractionated heparin, 5,000 U bid, in combination with graduated compression stockings, intermittent pneumatic compression, and predischarge surveillance venous ultrasonography of the legs, resulted in 150 consecutive patients without symptomatic VTE. The low 9.3% frequency of asymptomatic VTE comprised mostly isolated calf DVT. Therefore, this comprehensive, multimodality approach to VTE prophylaxis achieved excellent efficacy and safety.

Perspectives of Cellular and Molecular Neurosurgery.

Therapeutic efforts for human glial tumors have over the past years been redirected towards a compartmental treatment concept. The diffusely infiltrative nature of the disease calls for therapeutic agents to reach single cells far beyond the focus of attention which present therapies like surgery and radiation are able to treat. Specific drug discovery approaches which seek to define targets which are specific for gliomas have generated therapeutic options which allow for a highly selective development of new reagents. Combined with new modalities for compartmental drug delivery, systemic complications might be reduced and advantage taken of a compartmental specificity of a target which otherwise in the context of systemic application would not be as specific or burdened with side effects. From the present status of therapeutic developments in neuro-oncology it can be expected that a sufficient number of drug targets emerge which can be exploited by means of interstitial or intracavitary delivery, which are not neurotoxic and which may even be imaged in their action with the new metabolic imaging modalities. Convection enhanced delivery, conditionally replicating oncolytic viruses and motile, genetically engineered neural stem cells all seem to fulfill the distribution requirements which an effective therapeutic for gliomas will need to overcome the very limited efficacy which surgery, conventional chemotherapy and radiation have to offer. Whereas the genomics based discovery approaches are not specific for neuro-oncology, the development of delivery strategies is highly specific for the central nervous system, thus creating a unique set of organ and disease specific therapies.

Neuroimaging in pediatric brain tumors: Gd-DTPA-enhanced, hemodynamic, and diffusion MR imaging compared with MR spectroscopic imaging.

BACKGROUND AND PURPOSE: Gadolinium-enhanced MR images assist in defining tumor borders; however, the relation between tumor cell extent and contrast-enhanced regions is unclear. Our aim was to improve conventional neuroimaging of pediatric brain tumors with hemodynamic, diffusion, and spectroscopic MR imaging. METHODS: We performed conventional MR and MR spectroscopic imaging in 31 children with neuroglial brain tumors. Hemodynamic MR imaging was performed in 16 patients with a first-pass intravenous bolus of gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA); apparent diffusion coefficients (ADCs) were measured in 12 patients. To account for multiple measurements in a patient, we used a nested analysis of variance. RESULTS: At MR spectroscopy, choline (Cho)-containing compounds (indicating tumor) and lipid levels (indicating necrosis) did not correlate with percent Gd-DTPA enhancement on MR images. Percent enhancement was positively correlated with relative cerebral blood volumes (rCBVs) (P =.05) and negatively correlated with ADCs (P <.001). Stepwise multiple linear regression revealed that rCBV (P =.008), ADC (P =.022), and lipid (P <.001) levels were significant independent predictors of percent enhancement. Tumor spectral patterns were detected in tumor regions and outside enhancing tumor beds in patients with clinical progression; these were confirmed at neuropathologic analysis. CONCLUSION: MR spectroscopic imaging improves the assessment of pediatric brain tumors by adding biochemical information regarding tumor involvement and by depicting residual or recurrent tumor outside the Gd-DTPA-enhanced tumor bed. rCBV and ADC mapping complemented MR spectroscopic imaging. We recommend the use of MR spectroscopic imaging in addition to conventional MR imaging in assessing pediatric brain tumors.

Metastasis and angiogenesis.

Angiogenesis and the development of metastases are intrinsically connected. Experimental data suggest that establishment and growth of metastases are influenced by soluble factors secreted from the originating solid tumor. Among these factors are so-called endogenous inhibitors of angiogenesis which keep metastasis in a non-proliferating quiescent state. For a number of tumors it has been shown that this dormant state is mediated through inhibition of angiogenesis. This dormant state is characterized by normal proliferation, increased apoptosis, and insufficient neovascularization. Removal of inhibiting antiangiogenic factors leads to growth of dormant metastases. Several endogenous inhibitors have been identified so far and some of them have already been successfully applied in experimental therapeutic trials. This might be of special interest for the treatment of cerebral metastases which are the most common type of malignant brain tumors. Similar to the spread of metastases, it is known that single glioma cells can be found in distant parts of the brain. While local recurrence is a common phenomenon in glioma, formation of clinical apparent distant metastasis occurs rarely. Several lines of evidence suggest that growth inhibition of remote glioma cells may be mediated by an endogenous inhibitory mechanism.

The neurosurgeon as local oncologist: cellular and molecular neurosurgery in malignant glioma therapy.

Malignant gliomas are among the most challenging of all cancers to treat successfully, being characterized not only by aggressive proliferation and expansion but also by inexorable tumor invasion into distant brain tissue. Although considerable progress has been made in the treatment of these tumors with combinations of surgery, radiotherapy, and chemotherapy, these efforts have not been curative. Neurosurgeons as oncologists have increasingly turned their attention to therapies on a molecular scale. Of particular interest to neurosurgeons is the ability to deliver therapy locally to the tumor site or to take advantage of existing immunological mediators, enhancing drug concentrations or therapeutic cell numbers while bypassing the blood-brain barrier to maximize efficacy and minimize systemic toxicity. Exciting local-therapy approaches have been proposed for these devastating tumors. In this review, we discuss the potential applications of bioreactors, neural stem cells, immunotherapies, biodegradable polymers, and convection-enhanced drug delivery in the treatment of malignant gliomas. These approaches are at different stages of readiness for application in clinical neurosurgery, and their eventual effects on the morbidity and mortality rates of gliomas among human patients are difficult to ascertain from successes in animal models. Nevertheless, we are entering an exciting era of "nanoneurosurgery," in which molecular therapies such as those discussed here may routinely complement existing surgical, radiological, and chemotherapeutic approaches to the treatment of neuro-oncological disease. The potential to deploy any of a number of eloquently devised molecular therapies may provide renewed hope for neurosurgeons treating malignant gliomas.

Sir Victor Horsley (1857-1916): pioneer of neurological surgery.

Immortalized in surgical history for the introduction of "antiseptic wax," Sir Victor Horsley played a pivotal role in shaping the face of standard neurosurgical practice. His contributions include the first laminectomy for spinal neoplasm, the first carotid ligation for cerebral aneurysm, the curved skin flap, the transcranial approach to the pituitary gland, intradural division of the trigeminal nerve root for trigeminal neuralgia, and surface marking of the cerebral cortex. A tireless scientist, he was a significant player in discovering the cure for myxedema, the eradication of rabies from England, and the invention of the Horsley-Clarke stereotactic frame. As a pathologist, Horsley performed research on bacteria and edema and founded the Journal of Pathology. Horsley's kindness, humility, and generous spirit endeared him to patients, colleagues, and students. Born to privilege, he was nonetheless dedicated to improving the lot of the common man and directed his efforts toward the suffrage of women, medical reform, and free health care for the working class. Knighted in 1902 for his many contributions to medicine, Sir Victor met an untimely death during World War I from heat stroke at the age of 59. An iconoclast of keen intellect, unlimited energy, and consummate skill, his life and work justify his epitaph as a "pioneer of neurological surgery."

Decreases in ventricular volume correlate with decreases in ventricular pressure in idiopathic normal pressure hydrocephalus patients who experienced clinical improvement after implantation with adjustable valve shunts.

OBJECTIVE: This retrospective study examined whether changes in ventricular volume correspond with changes in adjustable valve pressure settings in a cohort of patients who received shunts to treat idiopathic normal pressure hydrocephalus. We also examined whether these pressure-volume curves and other patient variables would co-occur with a positive clinical response to shunting. METHODS: We selected 51 patients diagnosed with idiopathic normal pressure hydrocephalus who had undergone implantation of a Codman Hakim programmable valve (Medos S.A., Le Locle, Switzerland). Clinical data were gathered from the patients' records and clinical notes by an investigator blinded to patients' ventricular volumes. Ventricular volume was measured using 3D Slicer, an image analysis and interactive visualization software package developed and maintained at the Surgical Planning Laboratory at Brigham and Women's Hospital. RESULTS: Eighty-six percent of patients with gait disturbance at presentation showed improvement of this symptom, 70% experienced improvement in incontinence, and 69% experienced improvement in dementia. For the group showing 100% clinical improvement, the correlation coefficient of average changes in valve pressure over time (delta P/delta T) and average changes in ventricular volume over time (delta V/delta T) were high at 0.843 (P < 0.05). For the group experiencing no or only partial improvement, the correlation coefficient was 0.257 (P = 0.32), indicating no correlation between average delta V/delta T and average delta P/delta T for each patient. CONCLUSION: This was a carefully analyzed modeling study of idiopathic normal pressure hydrocephalus treatment made possible only by adjustable valve technology. With careful volumetric analysis, we found that changes in ventricular volume correlated with adjustments in valve pressure settings for those patients who improved clinically after shunting. This suggests that positive clinical responders retained parenchymal elasticity, emphasizing the importance of dynamic changes in this cohort.

IS20I, a specific alphavbeta3 integrin inhibitor, reduces glioma growth in vivo.

OBJECTIVE: The biological features of malignant gliomas include high cell proliferation, extensive local infiltration of tumor cells into normal brain, and marked neovascularization. alphavbeta3 integrin is highly expressed in malignant gliomas and plays a role in glioma growth. This article investigates the in vitro and in vivo effects of a synthetic alphavbeta3 integrin inhibitor called IS20I on human malignant gliomas. METHODS: The in vitro effects of IS20I were studied by performing adhesion assays, competition studies, semi-in vivo angiogenic assays, and migration and proliferation assays. For the in vivo experiments, IS20I was administered systemically in nude mouse intracranial and subcutaneous malignant glioma models. RESULTS: IS20I reacted selectively to alphavbeta3 integrin in glioma cells and tissues. In vitro, IS20I strongly inhibited angiogenesis and simultaneously exhibited potent antimitotic and antimigratory effects on numerous tumor and endothelial cell lines. In addition, at high concentrations, IS20I induced endothelial and tumor cell apoptosis. In vivo, when IS20I was administered intraperitoneally in subcutaneous and intracranial nude mouse glioma models, it potently reduced malignant glioma growth. Inhibition levels of 76 and 82% were observed at concentrations of 1 and 5 mg/kg, respectively, in the U87 intracranial model. The suppression of tumor growth is associated with a decrease in tumor vascularity, an increase in apoptosis, and a decrease in tumor cell proliferation. CONCLUSION: This work expands the understanding of the effects of anti-alphavbeta3 integrin inhibitors on malignant gliomas. In addition to direct proapoptotic and antiangiogenic effects, IS20I inhibits tumor and endothelial cell proliferation and migration, resulting in a potent inhibition of glioma growth in vivo.

Meningiomas: updating basic science, management, and outcome.

BACKGROUND: Meningiomas are biologically complex and clinically and surgically challenging. These features, combined with the rewarding potential for cure, make them of great interest to neurologists, neurosurgeons, and neuroscientists alike. REVIEW SUMMARY: Initially, we review the clinical context of meningiomas, particularly recent changes in histopathological classification, diagnosis, and neuroimaging. Secondly, the underlying basic science as it has evolved over the last decades is summarized. The status of areas recently of intense interest, such as steroid hormone receptors and oncogenic viruses is described. Additionally, emerging areas of great promise, such as cytogenetics and molecular biology are presented. Lastly, we describe recent advances in management. In particular, skull-base surgery, image-guided surgery, and advances in radiotherapy are emphasized. The possible impact of basic research on management and outcome is also outlined. CONCLUSIONS: Although usually benign and amenable to cure, meningiomas still present significant diagnostic and treatment challenges. Advances in basic science, surgery, and adjuvant therapy are widening the potential for safe, effective, evidence-based management leading to even better outcomes

Biochemical characterization of pediatric brain tumors by using in vivo and ex vivo magnetic resonance spectroscopy.

OBJECT: Magnetic resonance (MR) spectroscopy provides biochemical information about tumors. The authors sought to determine the relationship between in vivo and ex vivo biochemical characterization of pediatric brain tumors by using MR spectroscopy. Their hypothesis was that ex vivo MR spectroscopy provides a link between in vivo MR spectroscopy and neuropathological analysis. METHODS: In vivo proton MR spectroscopy was performed before surgery in 11 patients with neuroepithelial tumors. During resection, a total of 40 tumor biopsy samples were obtained from within the volume of interest identified on in vivo MR spectroscopy and were frozen immediately in liquid nitrogen. High-Resolution Magic Angle Spinning (HRMAS) was used to perform ex vivo MR spectroscopy in these 40 tumor biopsy samples. Neuropathological analysis was performed using the same biopsy samples, and the tumors were classified as ependymoma, choroid plexus carcinoma, pineoblastoma (one each), and pilocytic astrocytoma, medullobastoma, low-grade glioma, and glioblastoma multiforme (two each). Ex vivo HRMAS MR spectroscopy improved line widths and line shapes in the spectra, compared with in vivo MR spectroscopy. Choline (Cho) detected in vivo corresponded to three different peaks ex vivo (glycerophosphocholine, phosphocholine [PCho], and Cho). Metabolite ratios from in vivo spectra correlated with ratios from ex vivo spectra (Pearson correlation coefficient range r = 0.72-0.91; p < or = 0.01). Metabolite ratios from ex vivo spectra, such as PCho/ total creatine (tCr) and lipid/tCr, correlated with the percentage of cancerous tissue and percentage of tumor necrosis, respectively (r = 0.84; p < 0.001). CONCLUSIONS: Agreement between in vivo and ex vivo MR spectroscopy indicates that ex vivo HRMAS MR spectroscopy can improve resolution of this modality and provide a link between in vivo MR spectroscopy and neuropathological analysis.

Frameless stereotaxy as an alternative to fluoroscopy for transsphenoidal surgery: use of the InstaTrak-3000 and a novel headset.

Our aim was to evaluate the applicability of an electromagnetic-based frameless stereotactic system for use in transsphenoidal surgery. The system utilizes a novel headset that acts as a replaceable fiducial frame as well as a fixation point for the system's transmitter. It can replace the fluoroscope as a guide to navigation in the sphenoid sinus and sella. The system was used in a consecutive series of 11 patients undergoing transsphenoidal surgery. It was used in conjunction with intraoperative fluoroscopy. We found the Instatrak-3000 to correlate well with lateral fluoroscopic images, and provide additional information in the axial and coronal planes. The InstaTrak-3000 frameless stereotactic system is accurate and obviates the need for intraoperative fluoroscopy during transsphenoidal surgery. Compared to other frameless systems, it avoids the use of fiducial skin markers and head fixation. In common with other frameless stereotactic systems, it provides additional information important for safely approaching the sella and avoids intraoperative radiation exposure for the patient and operating room staff.