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Biomedical subjects

D Zagzag

Publications and source records attributed to D Zagzag.

At least 19 recordsLinked to original sources
PubMed2006

Comparing perfusion metrics obtained from a single compartment versus pharmacokinetic modeling methods using dynamic susceptibility contrast-enhanced perfusion MR imaging with glioma grade.

BACKGROUND AND PURPOSE: Numerous different parameters measured by perfusion MR imaging can be used for characterizing gliomas. Parameters derived from 3 different analyses were correlated with histopathologically confirmed grade in gliomas to determine which parameters best predict tumor grade. METHODS: Seventy-four patients with gliomas underwent dynamic susceptibility contrast-enhanced MR imaging (DSC MR imaging). Data were analyzed by 3 different algorithms. Analysis 1 estimated relative cerebral blood volume (rCBV) by using a single compartment model. Analysis 2 estimated fractional plasma volume (V(p)) and vascular transfer constant (K(trans)) by using a 2-compartment pharmacokinetic model. Analysis 3 estimated absolute cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) by using a single compartment model and an automated arterial input function. The Mann-Whitney U test was used make pairwise comparisons. Binary logistic regression was used to assess whether rCBV, V(p), K(trans), CBV, CBF, and MTT can discriminate high- from low-grade tumors. RESULTS: rCBV was the best discriminator of tumor grade ype, followed by CBF, CBV, and K(trans). Spearman rank correlation factors were the following: rCBV = 0.812 (P < .0001), CBF = 0.677 (P < .0001), CBV = 0.604 (P < .0001), K(trans) = 0.457 (P < .0001), V(p) = 0.301 (P =.009), and MTT = 0.089 (P = .448). rCBV was the best single predictor, and K(trans) with rCBV was the best set of predictors of high-grade glioma. CONCLUSION: rCBV, CBF, CBV K(trans), and V(p) measurements correlated well with histopathologic grade. rCBV was the best predictor of glioma grade, and the combination of rCBV with K(trans) was the best set of metrics to predict glioma grade.

Adolescent↗
PubMed2002

Enhanced expression of a novel protein in human cancer cells: a potential aid to cancer diagnosis.

Cap43 is a protein whose RNA is induced under conditions of severe hypoxia or prolonged elevations of intracellular calcium. Cap43 protein is expressed at low levels in normal tissues; however, in a variety of cancers, including lung, brain, melanoma, liver, prostate, breast, and renal cancers, Cap43 protein is overexpressed in cancer cells. The low level of expression of Cap43 in some normal tissues compared to their cancerous counterparts combined with the high stability of Cap43 protein and mRNA makes the Cap43 gene a new, important cancer marker. We hypothesize that the mechanism of Cap43 overexpression in cancer cells involves a state of hypoxia characteristic of cancer cells where the Cap43 protein becomes a signature for this hypoxic state.

Blotting, Western↗
PubMed2002

Angiogenesis in the central nervous system: a role for vascular endothelial growth factor/vascular permeability factor and tenascin-C. Common molecular effectors in cerebral neoplastic and non-neoplastic "angiogenic diseases".

Human pathological conditions of the central nervous system (CNS) associated with angiogenesis (i.e. neovascularization) include neoplastic, as well as infectious, ischemic, and traumatic processes. Upregulation of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) and tenascin-C (TN-C) is spatially and temporally related to neovascularization. Spatially, VEGF/VPF and TN-C are both found at the site of neovascularization, but they are not detected in areas of normal brain or in areas without neovascularization. Temporally, VEGF/VPF and TN-C are found at the peak of angiogenesis and are not detected when angiogenesis had ceased.

Adult↗
PubMed2002

Dynamic contrast-enhanced T2*-weighted MR imaging of gliomatosis cerebri.

BACKGROUND AND PURPOSE: MR imaging characteristics of gliomatosis cerebri reiterate the diffuse nature of this tumor but are nonspecific and thus may pose a diagnostic challenge. Because perfusion MR imaging can provide a physiologic map of the microcirculation, we compared the measured relative cerebral blood volume (rCBV) at perfusion imaging with histopathologic findings in gliomatosis cerebri. MR spectroscopic findings were also reviewed. METHODS: Retrospective analysis was performed of conventional and perfusion MR images from seven patients with proved gliomatosis cerebri. The conventional MR images were evaluated for the presence or absence of contrast enhancement, necrosis, and extent of T2-weighted signal intensity abnormality. Dynamic contrast-enhanced T2*-weighted gradient-echo echo-planar images were acquired during the first pass of a bolus injection of gadopentetate dimeglumine. The rCBV was calculated by using nondiffusible tracer kinetics and expressed relative to normal-appearing white matter. Pathologic findings were reviewed in all patients and compared with the MR perfusion data. Multivoxel 2D chemical shift imaging proton MR spectroscopic data were available for three patients and single-voxel data for one patient. RESULTS: Conventional MR images showed diffuse abnormality in all cases and absence of contrast enhancement in all but one case. Average rCBV range was 0.75-1.26 (mean, 1.02 +/- 0.42 [SD]). MR spectroscopic data revealed spectra consistent with presence of tumoral disease. Histopathologic review showed absence of vascular hyperplasia in all specimens. CONCLUSION: The low MR rCBV measurements of gliomatosis cerebri are in concordance with the lack of vascular hyperplasia found at histopathologic examination; thus, perfusion MR imaging provides useful adjunctive information that is not available from conventional MR imaging techniques.

Adolescent↗
PubMed2001

Reduced tumorigenicity of rat glioma cells in the brain when mediated by hygromycin phosphotransferase.

OBJECT: A variant of C6 glioma cells, C6R-G/H cells express hygromycin phosphotransferase (HPT) and appear to have reduced tumorigenicity in the embryonic brain. The goal of this study was to investigate their reduced capacity to generate tumors in the adult rat brain. METHODS: Cell lines were implanted into rat brains and tumorigenesis was evaluated. After 3 weeks, all rats with C6 cells showed signs of neurological disease, whereas rats with C6R-G/H cells did not and were either killed then or allowed to survive until later. Histological studies were performed to analyze tumor size, malignancy, angiogenesis, and cell proliferation. Cells isolated from rat brain tumors were analyzed for mutation to HPT by testing their sensitivity to hygromycin. CONCLUSIONS: The results indicate that HPT suppresses tumor formation. Three weeks after implantation, only 44% of animals implanted with C6R-G/H cells developed tumors, whereas all animals that received C6 glioma cells developed high-grade gliomas. The C6R-G/H cells filled a 20-fold smaller maximal cross-sectional area than the C6 cells, and exhibited less malignant characteristics, including reduced angiogenesis, mitosis, and cell proliferation. Similar results were obtained in the brain of nude rats, indicating that the immune system did not play a significant role in suppressing tumor growth. The combination of green fluorescent protein (GFP) and HPT was more effective in suppressing tumorigenesis than either plasmid by itself, indicating that the GFP may protect against inactivation of the HPT. Interestingly. hygromycin resistance was lost in tumor cells that were recovered from a group of animals in which C6R-G/H cells formed tumors, confirming the correlation of HPT with reduced tumorigenicity.

Animals↗
PubMed2000

Expression of hypoxia-inducible factor 1alpha in brain tumors: association with angiogenesis, invasion, and progression.

BACKGROUND: Hypoxia inducible factor-1 (HIF-1) plays a critical role in angiogenesis during vascular development. The authors tested the hypothesis that HIF-1 expression correlates with progression and angiogenesis in brain tumors. METHODS: The authors investigated the expression of the HIF-1alpha and HIF-1beta subunits in human glioma cell lines and brain tumor tissues using Western blot analysis and immunohistochemistry. RESULTS: In glioblastomas multiforme (GBMs), HIF-1alpha primarily was localized in pseudopalisading cells around areas of necrosis and in tumor cells infiltrating the brain at the tumor margin. In contrast, HIF-1alpha was expressed in stromal cells throughout hemangioblastomas (HBs). Like HIF-1alpha, HIF-1beta was most highly expressed in high grade tumors but was expressed more widely than HIF-1alpha, including cells away from necrotic zones. In the brains of mice injected with Glioma 261 cells, a pattern of HIF-1alpha expression identical to that observed in human GBMs was noted. CONCLUSIONS: In GBMs, the heterogeneous pattern of HIF-1alpha expression appears to be determined at least in part by tissue oxygenation, whereas in HBs the homogeneous expression of HIF-1alpha may be driven by an oncogenic rather than a physiologic stimulus.

Animals↗
PubMed2000

Vascular apoptosis and involution in gliomas precede neovascularization: a novel concept for glioma growth and angiogenesis.

Vascular changes in gliomas were analyzed by implanting fluorescent-labeled glioma 261 cells in the brains of 28 mice. Seven animals were killed each week for 4 weeks. We investigated the expression of angiopoietin-2 (Ang-2) by in situ hybridization and compared it with the distribution of apoptotic cells identified by DNA strand breaks (using the terminal deoxynucleotidyl transferase-mediated biotinylated deoxyuridine triphosphate nick end labeling [TUNEL] method) and transmission electron microscopy (TEM). As early as 1 week after implantation, tumor cells accumulated around vessels, which expressed Ang-2 and were TUNEL negative. TEM showed tumor cells adjacent to the vascular cells "lifting up" the normal astrocytic feet processes away from the endothelial cells and disrupting normal pericytic cuffing. After 2 weeks the number of perivascular glioma cells had increased. No increase in the number of blood vessels was detected at this time. Vascular cells remained positive for Ang-2 and rare ones were TUNEL positive. TEM showed closely packed proliferating perivascular tumor cells. After 3 weeks, there was vascular involution with scant zones of tumor necrosis. Ang-2 was still detected in vascular cells, but now numerous vascular cells were TUNEL positive. In addition, TEM showed apoptotic vascular cells. After 4 weeks, there were extensive areas of tumor necrosis with pseudopalisading and adjacent angiogenesis. Ang-2 was detected in vascular cells at the edge of the tumors in the invaded brain and in vessels surrounded by tumor cells. At both 3 and 4 weeks, most of the TUNEL-positive tumor cells lacked morphological features characteristic of apoptosis and displayed features consistent with necrotic cell death as determined by TEM. Only rare tumor cells appeared truly apoptotic. In contrast, the TUNEL-positive endothelial cells and pericytes were round and shrunken, with condensed nuclear chromatin by TEM, suggesting that vascular cells were undergoing an apoptotic cell death. These results suggest that vascular cell apoptosis and involution preceded tumor necrosis and that angiogenesis is a later event in tumor progression in experimental gliomas. Moreover, Ang-2 is detected prior to the onset of apoptosis in vascular cells and could be linked to vascular involution.

Angiopoietin-2↗
PubMed2000

Molecular events implicated in brain tumor angiogenesis and invasion.

We have conducted studies designed to help elucidate the molecular mechanisms involved in brain tumor invasion and angiogenesis, which are critical in the growth of malignant tumors of the central nervous system. A variety of molecular factors have been implicated in these processes. Here we focus on three that are of particular importance in the progression of brain tumors. Angiopoietins are involved in the regulation of vascular development. Hypoxia inducible factor-1 is a transcription factor that up-regulates genes, including genes encoding vascular endothelial growth factor under hypoxic conditions. Focal adhesion kinase is associated with infiltration of tumor cells and angiogenesis.

Brain Neoplasms↗
PubMed2000

Primitive neuroectodermal tumors of the brainstem: investigation of seven cases.

OBJECTIVE: We discuss the clinical aspects, pathology, and molecular genetics of 7 patients with primitive neuroectodermal tumors (PNETs) arising in the brainstem that were treated at our institution from 1986 through 1995. Most neuro-oncologists avoid performing biopsies in children with pontine tumors. This article raises the question as to whether biopsies should be performed, because treatment recommendations might differ if a PNET was diagnosed rather than a pontine glioma. PATIENTS AND METHODS: We reviewed the clinical neuro-oncology database and the files of the Division of Neuropathology at New York University Medical Center from 1986 through 1995 and identified 7 histologically confirmed PNETs arising in the brainstem among 146 pediatric brainstem tumors. The clinical, neuroradiological, and neuropathological data were reviewed. Postmortem examinations were performed in 2 cases. Formalin-fixed, paraffin-embedded tumor tissues were also available in 6 of 7 patients that were tested for p53 gene mutations using single-strand conformation polymorphism analysis. We also tested 9 cerebellar PNETs, 9 brainstem gliomas, and 3 normal brains for p53 gene mutations as controls. RESULTS: All 7 patients presented with focal cranial nerve deficits, and 2 were also hemiparetic. The median age at diagnosis was 2.7 (1-8 years). Magnetic resonance imaging (MRI) characteristics included a focal intrinsic exophytic nonenhancing brainstem lesion that had low T1-weighted and high T2-weighted signals. Hydrocephalus was present in 5 patients at diagnosis, 3 of whom had leptomeningeal dissemination. Meningeal dissemination occurred later in the course of the disease in 3 other patients. Five children required shunts at diagnosis and another 2 at recurrence. Despite therapy, all 7 PNET patients died within 17 months of diagnosis with a mean survival of 8 (4-17) months. No mutation in the p53 gene was detected. CONCLUSIONS: Brainstem PNETs tend to arise at a younger age than brainstem gliomas and medulloblastomas. The MRI pattern suggests a localized rather than a diffuse intrinsic nonenhancing brainstem tumor. Like other PNETs, brainstem PNETs have a high predilection to disseminate within the central nervous system. The absence of p53 mutations is similar to other PNETs. Despite their origin close to the cerebellum, brainstem PNETs exhibit a more aggressive behavior and result in worse clinical outcomes than do cerebellar PNETs.

Brain Neoplasms↗
PubMed2000

Dynamic contrast-enhanced T2-weighted MR imaging of recurrent malignant gliomas treated with thalidomide and carboplatin.

BACKGROUND AND PURPOSE: Dynamic, contrast-enhanced MR imaging has allowed quantitative assessment of cerebral blood volume (CBV) in brain tumors. The purpose of our study was to compare postcontrast T1-weighted imaging with dynamic, contrast-enhanced T2*-weighted echo-planar imaging in the evaluation of the response of recurrent malignant gliomas to thalidomide and carboplatin. METHODS: Serial MR imaging was performed in 18 consecutive patients with recurrent malignant gliomas receiving both thalidomide and carboplatin for 12-month periods. Six patients undergoing carboplatin therapy alone were chosen as control subjects. Conventional postcontrast T1-weighted images were compared with relative CBV (rCBV) maps calculated on a pixel-by-pixel basis from dynamic echo-planar imaging data. Tumor progression was evaluated clinically using established criteria for malignant gliomas. Studies were performed at 2- to 3-month intervals, and imaging and clinical findings were compared. RESULTS: Tumor response to treatment, based on clinical findings, did not correlate well with conventional imaging findings. The rCBV values decreased significantly in all patients between the start of therapy and the first follow-up in the study group, but not in the control group. The difference in rCBV values between the clinically stable and the progressive group at 12-month follow-up was statistically significant, with the progressive group having higher values. CONCLUSION: Dynamic, contrast-enhanced MR imaging is a valuable adjunct to conventional imaging in assessing tumor activity during antiangiogenic therapy, and correlates better than conventional studies with clinical status and response to therapy.

Adult↗
PubMed2000

Mutations of the INI1 rhabdoid tumor suppressor gene in medulloblastomas and primitive neuroectodermal tumors of the central nervous system.

Germ-line and somatic mutations of the hSNF5/INI1 gene have been reported in atypical teratoid/rhabdoid tumors (AT/RTs) of the brain, consistent with its role as a tumor suppressor gene. In the present study, we determined the frequency of deletions and mutations of INI1 in 52 children whose original diagnosis was medulloblastoma (MB) or primitive neuroectodermal tumor (PNET) of the central nervous system. Mutations were detected in DNA isolated from four tumors, all from children less than 3 years of age at diagnosis. Two of the four were reviewed and reclassified as atypical teratoid tumor, whereas there was insufficient material to establish this diagnosis in the two remaining cases. The relatively low frequency of mutations, even in a large series of infants, suggests that loss of sequences from chromosome 22 and/or mutations of INI1 do not account for the poor prognosis of children with MB or PNET who are less than 3 years of age at diagnosis. Nevertheless, chromosome 22 deletion and INI1-mutation analysis of infants with MB/PNET should be considered for all children who are less than 1 year of age. Detection of these mutations suggests that the child has an AT/RT, rather than a MB/PNET, a finding with important prognostic value.

Adolescent↗
PubMed2000

Neurolisteriosis presenting as recurrent transient ischemic attacks.

An elderly man experienced recurrent transient episodes of right arm weakness and expressive aphasia. He was initially treated with aspirin and then with coumadin. Thirteen days after initial presentation, he became febrile and had signs of meningitis. The illness progressed relentlessly to death 9 weeks after admission to the hospital. Necropsy showed prominent meningitis with vasculitis extending into the left frontal lobe. Polymerase chain reaction identified the organism as Listeria monocytogenes.

Aged↗
PubMed2000

Consistent and selective expression of the discoidin domain receptor-1 tyrosine kinase in human brain tumors.

OBJECTIVE: Few molecular targets are both consistently and selectively expressed in a majority of central nervous system (CNS) neoplasms. Receptor tyrosine kinases have been implicated in brain tumor oncogenesis. We previously isolated one such receptor, discoidin domain receptor-1 (DDR1), from high-grade pediatric brain tumors. Here, we analyze the cellular origin and distribution of DDR1 expression in human brain tumors and its expression in tumor cells relative to surrounding brain. METHODS: By use of a digoxigenin-labeled DDR1 riboprobe, we investigated the expression of DDR1 messenger ribonucleic acid in a prospective series of 30 resected human primary and metastatic brain neoplasms, nonneoplastic human brain, and mouse embryonic brain, as well as a mouse glioblastoma model, by in situ hybridization. RESULTS: All the high-grade primary brain and metastatic brain tumors showed unequivocal, intense DDR1 expression within the majority of tumor cells, whereas expression was not observed in hyperplastic tumor blood vessels, normal brain blood vessels, inflammatory cells, or in the normal brain tissue that surrounded the tumor. Receptor expression was limited to tumor cells located within solid tumor tissue. Overall, 27 of 29 resected CNS tumors exhibited tumor cell-specific DDR1 expression, whereas one specimen composed of isolated glioblastoma cells within invaded brain parenchyma showed no detectable staining for this receptor. DDR1 was also expressed preferentially in the ventricular zone (a region of highly proliferating precursor cells) of mice at embryonic Day 15.5. CONCLUSION: We found that DDR1 is consistently expressed in all high-grade brain neoplasms studied and is selective for tumor cells in the specimens analyzed. The expression of DDR1 by tumor cells of CNS neoplasms and by primitive cells of the embryonic ventricular zone suggests that DDR1 is a potentially useful marker of tumor cells within the CNS.

Adolescent↗
PubMed1999

Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases.

Neovascularization and increased glycolysis, two universal characteristics of solid tumors, represent adaptations to a hypoxic microenvironment that are correlated with tumor invasion, metastasis, and lethality. Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding glucose transporters, glycolytic enzymes, and vascular endothelial growth factor. HIF-1 transcriptional activity is determined by regulated expression of the HIF-1alpha subunit. In this study, HIF-1alpha expression was analyzed by immunohistochemistry in 179 tumor specimens. HIF-1alpha was overexpressed in 13 of 19 tumor types compared with the respective normal tissues, including colon, breast, gastric, lung, skin, ovarian, pancreatic, prostate, and renal carcinomas. HIF-1alpha expression was correlated with aberrant p53 accumulation and cell proliferation. Preneoplastic lesions in breast, colon, and prostate overexpressed HIF-1alpha, whereas benign tumors in breast and uterus did not. HIF-1alpha overexpression was detected in only 29% of primary breast cancers but in 69% of breast cancer metastases. In brain tumors, HIF-1alpha immunohistochemistry demarcated areas of angiogenesis. These results provide the first clinical data indicating that HIF-1alpha may play an important role in human cancer progression.

Animals↗
PubMed1999

Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts.

Id proteins may control cell differentiation by interfering with DNA binding of transcription factors. Here we show that targeted disruption of the dominant negative helix-loop-helix proteins Id1 and Id3 in mice results in premature withdrawal of neuroblasts from the cell cycle and expression of neural-specific differentiation markers. The Id1-Id3 double knockout mice also display vascular malformations in the forebrain and an absence of branching and sprouting of blood vessels into the neuroectoderm. As angiogenesis both in the brain and in tumours requires invasion of avascular tissue by endothelial cells, we examined the Id knockout mice for their ability to support the growth of tumour xenografts. Three different tumours failed to grow and/or metastasize in Id1+/- Id3-/- mice, and any tumour growth present showed poor vascularization and extensive necrosis. Thus, the Id genes are required to maintain the timing of neuronal differentiation in the embryo and invasiveness of the vasculature. Because the Id genes are expressed at very low levels in adults, they make attractive new targets for anti-angiogenic drug design.

Animals↗
PubMed1999

Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF.

In contrast with the prevailing view that most tumors and metastases begin as avascular masses, evidence is presented here that a subset of tumors instead initially grows by coopting existing host vessels. This coopted host vasculature does not immediately undergo angiogenesis to support the tumor but instead regresses, leading to a secondarily avascular tumor and massive tumor cell loss. Ultimately, however, the remaining tumor is rescued by robust angiogenesis at the tumor margin. The expression patterns of the angiogenic antagonist angiopoietin-2 and of pro-angiogenic vascular endothelial growth factor (VEGF) suggest that these proteins may be critical regulators of this balance between vascular regression and growth.

Adenocarcinoma↗