Brain metastases.
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Antineoplastic Agents↗
Biomedical subjects
Michael A Vogelbaum
Publications and source records attributed to Michael A Vogelbaum.
Update of stereotactic radiosurgery for brain tumors.
PURPOSE OF REVIEW: This paper will review the recent publications of stereotactic radiosurgery for brain tumors. RECENT ADVANCES: Despite its controversial beginning, stereotactic radiosurgery has rapidly gained acceptance among neurosurgeons, radiation oncologists, and neuro-oncologists as a valuable treatment option for patients with certain benign and malignant brain tumors. Over the past year, a number of publications have confirmed the efficacy and safety of this treatment modality as the sole treatment modality or as part of the multimodality management of brain tumor patients. These publications ranged from the first multi-institutional phase III trial of radiosurgery for patients with brain metastases to numerous retrospective papers about treatment outcomes. Also, a number of these publications have explored the use of newer imaging modalities to improve treatment outcomes while others reported on the rare complication of radiation-associated second tumors. SUMMARY: Recent publications of stereotactic radiosurgery have increased our understanding of the use of this technology. Future studies are needed to further improve outcomes, minimize toxicities and increase our understanding of this treatment modality.
Brain↗
Epidermal growth factor receptor antagonists: novel therapy for the treatment of high-grade gliomas.
Overactivation of epidermal growth factor receptor (EGFR) signaling has been recognized as an important step in the pathogenesis and progression of multiple forms of cancer of epithelial origin. This knowledge has led to a surge of interest in novel anticancer therapies targeting key constituents of the EGFR signal transduction pathway. Several molecular strategies have been developed recently to modulate either EGFR or the downstream signal beyond the cell surface receptor. The important role of aberrant EGFR signaling in the progression of malignant gliomas makes EGFR-targeted therapies of particular interest in this form of cancer. The use of anti-EGFR therapies against malignant brain tumors, although in its infancy, promises to yield exciting results as these new drugs probably will enhance the usefulness of existing therapies.
Brain Neoplasms↗
Cyclooxygenase-2 in oligodendroglial neoplasms.
BACKGROUND: Although increased expression of cyclooxygenase-2 (COX-2) has been described in association with a variety of neoplasms, including tumors of astrocytic derivation, limited data are available on COX-2 expression in oligodendrogliomas. METHODS: The current study retrospectively reviewed 53 oligodendrogliomas and 7 oligodendroglioma-predominant oligoastrocytomas (mixed gliomas) for COX-2 expression and MIB-1 proliferative index (by immunohistochemistry) and for chromosome 1p status (by fluorescence in situ hybridization). RESULTS: Patients included 35 males and 25 females, with a mean age of 41 years (range, 12-73 years) at the time of surgery. Forty-four tumor specimens were classified as World Health Organization (WHO) Grade II neoplasms and 16 as WHO Grade III tumors. MIB-1 labeling indices (marker of cell proliferation) ranged from 0 to 22.3 (mean 4.5). Twenty-eight tumor specimens demonstrated allelic loss on chromosome 1p. Positive staining was observed in 17 tumor specimens with COX-2 antibody. COX-2-positive tumor specimens were also evaluated with CD68 (macrophage/microglial cell marker) by coimmunolabeling to confirm that the observed COX-2 immunostaining was not due to immunoreactive macrophages or microglial cells. COX-2 expression, lack of allelic loss at chromosome 1p, and high proliferation indices were associated with decreased survival (P = 0.002, P = 0.009, and P = 0.015, respectively). No correlation with outcome was found with patient gender, age at diagnosis, or histologic grade. CONCLUSIONS: Chromosome 1p, COX-2 immunoreactivity, and MIB-1 labeling indices correlated with outcome and were associated with decreased survival. There was not a one-to-one correspondence between COX-2 immunoreactivity and lack of allelic loss at chromosome 1p. Tumors with expression of COX-2 by immunohistochemistry may, in theory, benefit from treatment with therapeutic agents that inhibit COX-2.
Adolescent↗
Serum S100beta: a noninvasive marker of blood-brain barrier function and brain lesions.
BACKGROUND: S100beta protein is expressed constitutively by brain astrocytes. Elevated S100beta levels in cerebrospinal fluid and serum reported after head trauma, subarachnoid hemorrhage, and stroke were correlated with the extent of brain damage. Because elevated serum S100beta also was shown to indicate blood-brain barrier (BBB) dysfunction in the absence of apparent brain injury, it remains unclear whether elevation of serum levels of S100beta reflect BBB dysfunction, parenchymal damage, or both. METHODS: The authors conducted a prospective study of serum S100beta levels in six patients who underwent hyperosmotic BBB disruption (BBBD) with intraarterial chemotherapy for primary central nervous system lymphoma. In addition, 53 serum S100beta samples were measured in 51 patients who had a variety of primary or metastatic brain lesions at the time of neuroimaging. RESULTS: S100beta was correlated directly with the degree of clinical and radiologic signs of BBBD in patients who were enrolled in the hyperosmotic study. In patients with neoplastic brain lesions, gadolinium enhancement on a magnetic resonance image was correlated with elevated S100beta levels (n = 45 patients; 0.16 +/- 0.1 microg/L; mean +/- standard error of the mean) versus nonenhancing scans (n = 8 patients; 0.069 +/- 0.04 microg/L). Primary brain tumors (n = 8 patients; 0.12 +/- 0.08) or central nervous system metastases also presented with elevated serum S100beta levels (n = 27 patients; 0.14 +/- 0.34). Tumor volume was correlated with serum S100beta levels only in patients with vestibular schwannoma (n = 6 patients; 0.13 +/- 0.10 microg/L) but not in patients with other brain lesions. CONCLUSIONS: S100beta was correlated directly with the extent and temporal sequence of hyperosmotic BBBD, further suggesting that S100beta is a marker of BBB function. Elevated S100beta levels may indicate the presence of radiologically detectable BBB leakage. Larger prospective studies may better determine the true specificity of S100beta as a marker for BBB function and as an early detection or follow-up marker of brain tumors.
Adult↗
Posterior fossa metastases: aggressive treatment improves survival.
BACKGROUND: Brain metastases are a leading cause of mortality and morbidity in patients with malignancies. Infratentorial location has been considered a negative prognostic factor. METHODS: This retrospective study evaluated patients with cerebellar metastasis. Statistical analysis assessed age, extracranial disease, performance status and treatment. Patients were categorized by Radiation Therapy Oncology Group recursive partitioning analysis (RPA). Treatment included surgery, stereotactic radiosurgery (SRS) and whole brain radiotherapy (WBRT) alone or in combination. RESULTS: Of 93 patients, the median survival was 12.9 months for RPA class I, 11 months for class II and 8 months for class III. On multivariate analysis, RPA class was an important predictor for overall survival. However, SRS with WBRT or surgery with WBRT or a combination of SRS, surgery and WBRT, was more favorable than surgery or SRS alone within RPA class II patients. CONCLUSIONS: Survival of patients with cerebellar brain metastasis is comparable to that of patients with supratentorial brain metastasis using RPA classification. Aggressive multimodality therapy has a favorable impact on survival.
Aged↗
Inhibition of constitutively active Stat3 suppresses proliferation and induces apoptosis in glioblastoma multiforme cells.
Glioblastoma multiforme (GBM), the most common and malignant central nervous system tumor in humans, is highly proliferative and resistant to apoptosis. Stat3, a latent transcription factor being activated by aberrant cytokine or growth factor signaling, acts as a suppressor of apoptosis in a number of cancer cells. Here we report that GBM tumors and cell lines contain high levels of constitutively activated Stat3 when compared with normal human astrocytes, white matter, and normal tissue adjacent to tumor. The persistent activation of Stat3 is in part, attributable to an autocrine action of interleukin-6 in the GBM cell line U251. Janus kinase inhibitor AG490 inhibits Stat3 activation with a concomitant reduction in steady-state levels of Bcl-X(L), Bcl-2 and Mcl-1 proteins and induces apoptosis in U251 cells as revealed by Poly (ADP-ribose) polymerase cleavage and Annexin-V staining. Expression of a dominant negative mutant Stat3 protein or treatment with AG490 markedly reduces the proliferation of U251 cells by inhibiting the constitutive activation of Stat3. These results provide evidence that constitutive activation of Stat3 contributes to the pathogenesis of glioblastoma by promoting both proliferation and survival of GBM cells. Therefore, targeting Stat3 signaling may provide a potential therapeutic intervention for GBM.
Acute-Phase Proteins↗
IL-13R(alpha)2, a decoy receptor for IL-13 acts as an inhibitor of IL-4-dependent signal transduction in glioblastoma cells.
Interleukin (IL)-4 and IL-13 share the type II IL-4 receptor for cell signaling. We show that despite expressing the necessary signaling components, glioblastoma cells failed to respond to either IL-4 or IL-13. This was in part because of the expression of a high-affinity IL-13-binding transmembrane protein IL-13R(alpha)2 that inhibited IL-13-mediated Stat6 activation by acting as a decoy receptor. In contrast, normal human astrocytes that did not express the IL-13R(alpha)2 gene efficiently induced Stat6 activation in response to both IL-4 and IL-13. Transient expression of the IL-13R(alpha)2 transgene in nonexpressing heterologous cells inhibited not only IL-13- but also IL-4-mediated signal transduction and Stat6-responsive gene expression. The inhibition was likely mediated through the physical interaction between the short intracellular domain of the IL-13R(alpha)2 protein and the cytoplasmic domain of the IL-4R(alpha) chain that harbors the Stat6 docking sites. Thus, IL-13R(alpha)2 acts as an inhibitor of IL-4-dependent signal transduction pathways via a novel mechanism that is independent of ligand binding.
3T3 Cells↗
Cyclooxygenase-2 (COX-2) expression by immunohistochemistry in glioblastoma multiforme.
Cyclooxygenase-2 (COX-2) (an enzyme responsible for the conversion of arachidonic acid to prostaglandin) upregulation has been described in association with a variety of tumors including gliomas. This study reviews the immunohistochemical profile of 47 glioblastoma multiforme using COX-2 antibody and correlates the results with MIB-1 (marker of cell proliferation) immunostaining. Positive staining with COX-2 was observed in 35 tumors (74.5%); more than 10% tumor cell positivity was seen in 10 tumors (21.3%). Immunostaining results were as follows: no staining, N = 12 (25.5%); 0% to 5% of tumor cells, N = 20 (42.6%); 5% to 10%, N = 5 (10.6%); 10% to 20%, N = 4 (8.5%); 20% to 50%, N = 4 (8.5%); and greater than 50%, N = 2 (4.3%). The mean MIB-1 labeling index for all tumors ranged from 3.0 to 76.4 (mean, 19.6). Mean MIB-1 labeling indices were higher in tumors with greater than 5% COX-2 immunostaining (mean MIB-1 labeling index, 23.5) versus tumors with 0% to 5% COX-2 immunostaining (mean MIB-1 labeling index, 17.7). There is evidence of COX-2 expression by immunohistochemistry in the majority of glioblastoma multiforme. As a group, tumors with a higher rate of cell proliferation tended to have increased expression of COX-2. These findings are significant in that therapeutic agents, which inhibit COX-2, are currently available and may play a role in the management of glioblastoma multiforme.
Adolescent↗
Caspase-9 transduction overrides the resistance mechanism against p53-mediated apoptosis in U87MG glioma cells.
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Apoptosis↗
Intracranial navigation by using low-field intraoperative magnetic resonance imaging: preliminary experience.
OBJECT: Intracranial navigation by using intraoperative magnetic resonance (iMR) imaging allows the surgeon to reassess anatomical relationships in near-real time during brain tumor surgery. The authors report their initial experience with a novel neuronavigation system coupled to a low-field iMR imaging system. METHODS: Between October 2000 and December 2001, 70 neurosurgical procedures were performed using the mobile 0.12-tesla PoleStar N-10 iMR imaging system. The cases included 38 craniotomies, 15 brain biopsies, nine transsphenoidal approaches, and one drainage of a subdural hematoma. Tumor resection was performed using the awake method in seven of 38 cases. Of the craniotomies, image-confirmed complete or radical tumor resection was achieved in 28 cases, subtotal resection in eight cases, and open biopsies in two cases. Tumor resection was controlled with the use of image guidance until the final intraoperative images demonstrated that there was no residual tumor or that no critical brain tissue was at risk of compromise. In each stereotactic biopsy the location of the biopsy needle could be verified by intraoperative imaging and diagnostic tissue was obtained. Complications included a case of aseptic meningitis after a biopsy and one case of temporary intraoperative failure of the anesthesia machine. Awake craniotomies were performed successfully with no permanent neurological complications. CONCLUSIONS: Intraoperative MR image-based neuronavigation is feasible when using the Odin PoleStar N-10 system for tumor resections that require multiple other surgical adjuncts including awake procedures, cortical mapping, monitoring of somatosensory evoked potentials, or electrocorticography. Use of the system for brain biopsies offers the opportunity of immediate verification of the needle tip location. Standard neurosurgical drills, microscopes, and other equipment can be used safely in conjunction with this iMR imaging system.
Adult↗
Posterior fossa metastases: risk of leptomeningeal disease when treated with stereotactic radiosurgery compared to surgery.
INTRODUCTION: Leptomeningeal disease (LMD) represents a diffuse form of central nervous system metastatic disease that is often associated with poor quality of life and prognosis. Our objective was to compare the incidence of LMD in patients with posterior fossa metastases (PFM) following stereotactic radiosurgery (SRS) versus surgical resection. METHODS: The medical records of 93 patients aged 57.9 +/- 10.8 years (mean +/- SD) with PFM treated at the Cleveland Clinic from 1995 to 2001 were analyzed retrospectively. Treatments consisted of surgery with whole brain radiation therapy (WBRT) or SRS with or without WBRT. The impact of age, Karnofsky performance status (KPS) at presentation, Radiation Therapy Oncology Group, recursive partitioning analysis (RPA) class, status of extracranial disease, number, size, volume, pathology of brain metastases and steroid use were studied using univariate and multivariate analyses. RESULTS: There were 80 evaluable patients (10 lost to follow-up and three excluded for supratentorial surgery with subsequent LMD). LMD occurred after the surgical removal of the PFM in 9 of 18 patients (50%), whereas LMD occurred after SRS in 4 of 62 patients (6.5%) (p = 0.0028). Multivariate analysis also showed that patients who had surgery were more likely to develop LMD compared to patients treated with SRS (p = 0.0024). Patients had a median KPS decline of 30 points after LMD was diagnosed. There was no statistically significant difference in survival of patients with LMD and the rest of the patients (13.5 vs. 11.7 months, p = 0.7659). Patients treated surgically had significantly larger lesions (3.43 +/- 0.74 vs. 1.96 +/- 0.95 cm maximum diameter, p < 0.0001). All surgical patients belonged to RPA class II at diagnosis. Their survival was not different from the RPA class II patients in the SRS group. Surgery and SRS had comparable complication rates (8.1% vs. 5.6%, p = 0.99), although the surgical complications were more serious (e.g. hemorrhage, CSF leak). The duration of steroid use was longer after SRS compared to surgery (2.1 +/- 3.6 vs. 1.3 +/- 2.4 months); however, the difference was not statistically significant. Myopathy and psychosis in one patient after SRS, were the only steroid-related complications. There was no statistically significant association between the primary tumor type and the presence of LMD. CONCLUSIONS: In this retrospective analysis of patients with PFM, SRS was associated with a lower incidence of LMD than was surgery. Although LMD was associated with rapid and considerable decline in the quality of life, it did not influence the overall survival. SRS was associated with less serious complications than surgery. Surgery in this study was performed on patients with larger lesion sizes and a trend toward poorer initial performance status, which could bias these results. A prospective study directly comparing surgery and SRS and further evaluating the significance of LMD in PFM is warranted.
Cranial Irradiation↗