Showing papers by "David Zagzag published in 2004"

Comparison of cerebral blood volume and vascular permeability from dynamic susceptibility contrast-enhanced perfusion MR imaging with glioma grade.

Abstract: BACKGROUND AND PURPOSE: Relative cerebral blood volume (rCBV) and vascular permeability (Ktrans) permit in vivo assessment of glioma microvasculature. We assessed the associations between rCBV and Ktrans derived from dynamic, susceptibility-weighted, contrast-enhanced (DSC) MR imaging and tumor grade and between rCBV and Ktrans. METHODS: Seventy-three patients with primary gliomas underwent conventional and DSC MR imaging. rCBVs were obtained from regions of maximal abnormality for each lesion on rCBV color maps. Ktrans was derived from a pharmacokinetic modeling algorithm. Histopathologic grade was compared with rCBV and Ktrans (Tukey honestly significant difference). Spearman and Pearson correlation factors were determined between rCBV, Ktrans, and tumor grade. The diagnostic utility of rCBV and Ktrans in discriminating grade II or III tumors from grade I tumors was assessed by logistic regression. RESULTS: rCBV was significantly different for all three grades (P ≤ .0005). Ktrans was significantly different between grade I and grade II or III (P = .027) but not between other grades or combinations of grades. Spearman rank and Pearson correlations, respectively, were as follows: rCBV and grade, r = 0.817 and r = 0.771; Ktrans and grade, r = 0.234 and r = 0.277; and rCBV and Ktrans, r = 0.266 and r = 0.163. Only rCBV was significantly predictive of high-grade gliomas (P CONCLUSION: rCBV with strongly correlated with tumor grade; the correlation between Ktrans and tumor grade was weaker. rCBV and Ktrans were positively but weakly correlated, suggesting that these parameters demonstrate different tumor characteristics. rCBV is a more significant predictor of high-grade glioma than Ktrans.

Diffusion-tensor MR imaging of intracranial neoplasia and associated peritumoral edema: introduction of the tumor infiltration index.

Abstract: PURPOSE: To determine whether diffusion-tensor magnetic resonance (MR) imaging metrics of peritumoral edema can be used to differentiate intra- from extraaxial lesions, metastatic lesions from gliomas, and high- from low-grade gliomas. MATERIALS AND METHODS: In this study, diffusion-tensor MR imaging was performed preoperatively in 40 patients with intracranial neoplasms, including meningiomas, metastatic lesions, glioblastomas multiforme, and low-grade gliomas. Histograms of mean diffusivity (MD) and fractional anisotropy (FA) were used to analyze both the tumor and the associated T2 signal intensity abnormality. An additional metric, the tumor infiltration index (TII), was evaluated. The TII is a measure of the change in FA presumably caused by tumor cells infiltrating the peritumoral edema. Student t test and least-squares linear regression analyses were performed. RESULTS: Peritumoral MD and FA values indicated no statistically significant difference between intra- and extraaxial lesions or between hi...

Invariant natural killer T cells are preserved in patients with glioma and exhibit antitumor lytic activity following dendritic cell-mediated expansion.

Abstract: Brain tumors carry a poor prognosis, and newer approaches to their therapy are urgently needed. Natural killer T (NKT) cells are distinct innate lymphocytes with antitumor potentials. Defects in NKT cell function have been observed in patients with other forms of cancer. Here we show that both the frequency and interferon-γ-producing function of NKT cells are well preserved in adult patients with glioma (n = 9) and comparable to findings in healthy controls (n = 9). These cells can be readily expanded in culture using autologous mature dendritic cells loaded with the NKT ligand, α-galactosyl ceramide. The expanded NKT cells from glioma patients are functional and, importantly, kill glioma cells in a ligand- and CD1d-dependent manner. Expression of CD1d is detected both on primary glioma cells as well as endothelial cells in infiltrating new blood vessels by immunohistochemistry of glioma tissue sections. These data suggest that targeting NKT cells may provide a novel strategy for immunotherapy of glioma. © 2004 Wiley-Liss, Inc.

Geldanamycin induces mitotic catastrophe and subsequent apoptosis in human glioma cells

Abstract: Geldanamycin (GA) binds to heat shock protein 90 (Hsp90) and interferes with its function which is to protect various cellular proteins involved in signaling, growth control, and survival from ubiquitination and subsequent degradation by the proteasome. Recently, we demonstrated that GA inhibited migration of glioma cells in vitro associated with downregulation of hypoxia-inducible factor (HIF-1 alpha) and phosphorylation of focal adhesion kinase (FAK) (Zagzag et al., 2003, J Cell Physiol 196:394-402). Here, we have investigated the mechanisms through which GA treatment of the T98G glioma cell line induces apoptosis. We found that GA treatment induced cell death in a caspase-dependent manner through activation of caspase-3 and PARP cleavage together with release of cytochrome c and apoptosis inducing factor (AIF) from the mitochondria. Use of synchronized T98G cells showed that GA treatment of glioma cells during S-phase enhanced cytotoxicity followed by M-phase arrest, resulting in mitotic catastrophe. In addition, apoptosis was associated with the downregulation of the survival protein, phosphorylated Akt (pAkt), an important signaling protein in the PI3K pathway, that is overexpressed in many cancers including gliomas. Given that many glioma tumors show deregulation of the PI3K signaling pathway, either through loss of the tumor suppressor protein PTEN or overexpression of the growth factor EGFR, the ability to identify different subsets of patients using simple immunohistochemistry for the presence of absence of pAkt could enable selection of the appropriate kinase inhibitor, such as GA, for drug therapy. Based on our data presented here, GA or its analogs may have potential in the treatment of glioma.

Differentiating surgical from non-surgical lesions using perfusion MR imaging and proton MR spectroscopic imaging

Abstract: Advanced MRI techniques, such as MR spectroscopy, diffusion and perfusion MR imaging can give important in vivo physiological and metabolic information, complementing morphologic findings from conventional MRI in the clinical setting. Combining perfusion MRI and MR spectroscopy can help in patients with brain masses in who the pre-operative differential diagnosis is unclear. This review demonstrates the use of dynamic, susceptibility weighted, contrast-enhanced MR imaging (DSC MRI) and magnetic resonance spectroscopic imaging (MRSI) to distinguish surgical from non-surgical lesions in the brain. There is overlap in the MRI appearance of many enhancing and ring-enhancing lesions such as gliomas, metastases, inflammatory lesions, demyelinating lesions, subacute ischemia, abscess and some AIDS related lesions. We review examples of histopathologically confirmed high-grade glioma, a middle cerebral artery territory infarct, a tumefactive demyelinating lesion and a metastasis for which conventional MR imaging (MRI) was non-specific and potentially misleading and demonstrate how DSC MRI and MRSI features were used to increase the specificity of neurodiagnosis. At several institutions, many patients routinely undergo MRI as well as MRSI and DSC MRI. Cerebral blood flow (CBF), mean transit time (MTT), and relative cerebral blood volume (rCBV) measurements are obtained from regions of maximal perfusion as determined from perfusion color overlay maps. Metabolite levels and ratios are determined for Choline (Cho), N-Acetyl Aspartate (NAA), Lactate and Lipids (LL). Metabolite levels are obtained by measuring the peak heights of each metabolite and the ratios are obtained from these measurements for Cho/Cr, Cho/NAA and NAA/Cr. Neurosurgical intervention carries substantial morbidity, mortality, financial and potential emotional cost to the patient and family. Making a pre-operative diagnosis allows the neurosurgeon to be confident in the choice of treatment plan for the patient and allays considerable patient anxiety. The utility of combining clinical findings with multi-parametric information from perfusion and spectroscopic MR imaging in differentiating surgical lesions from those which do not require surgical intervention is discussed.

Flavopiridol inhibits the Growth of GL261 Gliomas In Vivo: Implications for Malignant Glioma Therapy

Abstract: The mechanism of action of many chemotherapeutic agents targets the cell cycle. Recently, we demonstrated cytotoxic and other anti-tumor effects of flavopiridol, the first synthetic cyclin dependent kinase (CDK) inhibitor to enter clinical trials, on the murine GL261 glioma cell line in vitro (Newcomb et al., Cell Cycle 2003; 2:243). Given that flavopiridol has demonstrated anti-tumor activity in several human xenograft models, we wanted to evaluate it for anti-glioma activity in vivo in our established subcutaneous and intracranial GL261 experimental tumor models. In particular, the intracranial animal model recapitulates many of the histopathological and biological features of human high-grade glioma including both necrosis with pseudopalisading and invasion of the brain adjacent to tumor. Here we tested the activity of flavopiridol against tumors formed by GL261 cells, first as subcutaneous implants, and then in the intracranial model. We demonstrate efficacy of flavopiridol as a single modality treatment in delaying tumor growth in both animal models. We hypothesize that flavopiridol treatment induced tumor growth delay by two possible mechanisms involving growth arrest combined with recruitment of tumor cells to S-phase. Based on our findings, flavopiridol should be considered as a treatment approach for patients with high-grade glioma.

Dynamic Susceptibility Contrast-Enhanced Perfusion and Conventional MR Imaging Findings for Adult Patients with Cerebral Primitive Neuroectodermal Tumors

Abstract: BACKGROUND AND PURPOSE: Preoperative differentiation of primitive neuroectodermal tumors (PNETs) from other tumors is important for presurgical staging, intraoperative management, and postoperative treatment. Dynamic, susceptibility-weighted, contrast-enhanced MR imaging can provide in vivo assessment of the microvasculature in intracranial mass lesions. The purpose of this study was to determine the perfusion characteristics of adult cerebral PNETs and to compare those values with low and high grade gliomas. METHODS: Conventional MR images of 12 adult patients with pathologically proved cerebral PNETs were analyzed and provided a preoperative diagnosis. Relative cerebral blood volume (rCBV) measurements and estimates of the vascular permeability transfer constant, K trans , derived by a pharmacokinetic modeling algorithm, were also obtained. These results were compared with rCBV and K trans values obtained in a group of low grade gliomas (n 30) and a group of high grade gliomas (n 55) by using a Student t test. RESULTS: On conventional MR images, PNETs were generally well-defined contrast-enhancing masses with solid and cystic components, little or no surrounding edema, and occasional regions of susceptibility. The rCBV of cerebral PNETs was 4.76 1.99 SD, and the K trans was 0.0033 0.0035. A comparative group of patients with low grade gliomas (n 30) had significantly lower rCBV (P < .0005) and lower K trans (P < .05). Comparison with a group of high grade gliomas showed no statistical significance in the rCBV and K trans (P .53 and .19, respectively). CONCLUSION: Dynamic, susceptibility-weighted, contrast-enhanced MR imaging shows areas of increased cerebral blood volume and vascular permeability in PNETs. These results may be helpful in the diagnosis and preoperative differentiation between PNETs and other intracranial mass lesions (such as low grade gliomas), which have decreased perfusion but may sometimes have a similar conventional MR imaging appearance.

Cytological diagnosis of cystic brain tumors: a retrospective study of 88 cases.

Abstract: The stereotaxic aspiration of cystic brain tumors is performed to provide cyst decompression and/or to facilitate surgical resection. The purpose of our study was to determine the diagnostic value of brain cyst fluid cytology, especially in clinically suspected recurrent tumors with no histological follow-up (HF), when a diagnosis is most needed. We reviewed the cytological diagnoses of 88 aspirates from 70 patients with cystic brain tumors between 1995 and 2001, of which 31 had a prior known malignancy including 18 primary brain tumors (PBTs) and 13 adenocarcinomas (ACAs). Sixty-nine of 88 aspirates were obtained intraoperatively. Nineteen of 88 aspirates were obtained from 10 patients with recurrent or persistent cystic brain tumors (8 patients with PBT and 2 patients with ACA), with available clinicoradiological correlation (magnetic resonance imaging/computed tomography [MRI/CT] scans) in 13 of them. The 88 aspirates were classified in three categories: 28 positive (32%), 15 atypical (17%), and 45 negative (51%). Eight of 28 positive cases (5 case of PBT, 2 cases of ACA, and 1 case of melanoma) were given a nonspecific diagnosis of malignant neoplasm (9% of all cases). Fifteen of 28 positive cases (6 cases of PBT, 8 cases of ACA, and 1 case of melanoma) were diagnosed correctly and confirmed by HF (17% of all cases). Four of 28 cases were ACA diagnosed solely by cytology (<4% of all cases). One neurocytoma (1/28) case was mistaken for an oligodendroglioma despite cell blocks (CBs) and immunophenotyping (IPT) (<1% of all cases). Eleven of 15 atypical cases were 8 cases of PBT, 2 cases of ACA, and 1 case of postoperative change (PC). Four of 15 atypical cases (from three patients with suspected PBT recurrence) could not be further characterized by CB/IPT and had no HF. Twenty-seven of 45 negative cases were falsely negative (23 cases of PBT, 3 cases of ACA, and 1 case of malignant neoplasm); 11/45 cases were PC, and 7/45 (from five patients with clinically suspected tumor recurrence) cases had no HF. Cytological evaluation of brain cyst fluid is not a reliable means of diagnosing cystic brain neoplasms (including recurrences) due to a high false negative rate and a low sensitivity. Most of the negative or atypical cases (68% of all cases) were recurrent PBT of glial origin that may not be prone to exfoliate. These cytological specimens consisted of lysed blood, obscuring inflammatory cells, and degenerated diagnostic cells if any, yielding inconclusive results.

A morphologic study of the vasculature of malignant gliomas using thick celloidin sections and alkaline phosphatase stain.

Abstract: The combination of 100 microm thick celloidin sections and alkaline phosphatase (AP) enzyme histochemistry of the vascular endothelium offers a greatly enhanced, 3D morphologic perspective and reveals intricate details of the vasculature of brain. A study of tumor specimens obtained at craniotomy from 6 patients with glioblastomas, 1 with anaplastic oligodendroglioma and 1 with juvenile pilocytic astrocytoma was undertaken using this technique. Five of the 6 glioblastomas, the anaplastic oligodendroglioma and the low-grade astrocytoma specimen showed uniform staining of afferent tumor blood vessels. In the glioblastomas, newly formed vessels formed dense, festooned networks at the advancing edges of the tumor. Feeding arteries entered the tumor at the junction between the edge of the tumor and adjacent brain or meninges and proceeded to form striking, coiled vessels and smaller branches. The density of both small arteries and veins was greatly increased within the tumor although there was much variability. Disordered arborization, arteriole to venous and arteriole to arteriole shunts were observed, leading to a situation where arteries connected directly to veins. In necrotic areas, there were often no AP-stained vessels. In many places, arterioles and capillaries were lacking. Numerous AP-negative veins of various sizes drained the tumors. Glomeruloid proliferations were presumptively identified as focal stain smudges or clusters of capillaries arising from nearby vascular channels. Increased alkaline phosphatase staining and/or focal new vessels were seen outside necrotic areas. The pilocytic astrocytoma and the oligodendroglioma showed less dense vascularity and no formation of the focal festoons of vessels shown by the glioblastomas. This technique may be useful for the study of tumor angiogenesis and to evaluate vascularity in experimental and human brain tumors after various therapies.

Immunohistochemical detection of hypoxia-induced factor-alpha in endolymphatic sac tumors

Abstract: Problem: Endolymphatic sac tumor (ELST) is a rare vascular neoplasm associated with von Hippel-Landau disease, an autosomal dominant multitumor syndrome characterized by highly vascular tumors. The von Hippel-Landau (VHL) gene is located on chromosome 3p25 and encodes the VHL tumor suppressor protein, which plays a critical role in the degradation of HIF-1a. HIF-1a regulates vascular endothelial growth factor (VEGF)-mediated angiogenesis. The lack of degradation of HIF-1a due to a nonfunctioning VHL protein is thought to play a role in the proliferation of tumors associated with VHL syndrome. The goals of this study are to present clinical and radiological presentations of 3 patients with ELSTs and report on the HIF-1a overexpression in ELST cells. Methods: Our study consisted of chart and radiological review and immunohistochemical analysis. Specimens from 3 patients with pathologically confirmed ELST were analyzed for the presence of the HIF-1a protein using imunohistochemistry with a specific monoclonal antibody as previously described (Zagzag et al, Cancer 2000). Results: All patients presented with nonspecific findings seen with other temporal bone-related lesions of ipsilateral tinnitus and hearing loss. One patient was evaluated at a late stage who also presented with facial nerve weakness. Immunohistochemical analysis in all specimens confirmed overexpression of the HIF-1a protein in tumor cells. Conclusion: ELSTs are likely to be associated with HIF-1a mediated angiogenesis. These lesions are possibly associated with loss of VHL protein due to mutation of the VHL gene. Significance: Elucidation of the pathophysiology of endolymphatic sac tumors may lead to future novel approaches in the management of this unusual tumor associated with von Hippel-Lindau disease. Support: None reported.