Searched for: in-biosketch:true
person:dz4
Rheumatoid disease of the CNS with meningeal vasculitis presenting with a seizure [Case Report]
Neamtu L; Belmont M; Miller DC; Leroux P; Weinberg H; Zagzag D
PMID: 11274328
ISSN: 0028-3878
CID: 20807
Consistent and selective expression of the discoidin domain receptor-1 tyrosine kinase in human brain tumors
Weiner HL; Huang H; Zagzag D; Boyce H; Lichtenbaum R; Ziff EB
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
PMID: 11126911
ISSN: 0148-396x
CID: 17520
Primitive neuroectodermal tumors of the brainstem: investigation of seven cases
Zagzag D; Miller DC; Knopp E; Farmer JP; Lee M; Biria S; Pellicer A; Epstein FJ; Allen JC
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
PMID: 11061774
ISSN: 1098-4275
CID: 26837
Involvement of hypoxia-inducible factor 1 in tumor progression [Meeting Abstract]
Semenza, GL; Bedi, A; Bhujwalla, Z; Chiles, K; De Marzo, A; Feldser, D; Hilton, D; Laughner, E; Ravi, R; Simons, J; Zagzag, D; Zhong, H
ISI:000165409000051
ISSN: 1078-0432
CID: 54438
Neurolisteriosis presenting as recurrent transient ischemic attacks [Case Report]
Staudinger R; Levine D; Swaminathan B; Zagzag D
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
PMID: 11026451
ISSN: 0364-5134
CID: 20546
Vascular apoptosis and involution in glioma progression is associated with angiopoietin-2 expression [Meeting Abstract]
Zagzag, D; Amirnovin, R; Greco, A; Yee, H; Holash, J; Wiegand, S; Yancopoulos, G; Grumet, M
ISI:000088213000506
ISSN: 1015-6305
CID: 54520
Polyglucosan body myopathy [Meeting Abstract]
Carniciu, S; Kiprovski, K; Levine, DN; ZagZag, D; Bronfin, L; Kolodny, EH
ISI:000089024600118
ISSN: 0364-5134
CID: 74939
Mutations of the INI1 rhabdoid tumor suppressor gene in medulloblastomas and primitive neuroectodermal tumors of the central nervous system [In Process Citation]
Biegel JA; Fogelgren B; Zhou JY; James CD; Janss AJ; Allen JC; Zagzag D; Raffel C; Rorke LB
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
PMID: 10914721
ISSN: 1078-0432
CID: 9341
Molecular events implicated in brain tumor angiogenesis and invasion
Zagzag D; Friedlander DR; Margolis B; Grumet M; Semenza GL; Zhong H; Simons JW; Holash J; Wiegand SJ; Yancopoulos GD
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
PMID: 11025423
ISSN: 1016-2291
CID: 34745
Expression of hypoxia-inducible factor 1alpha in brain tumors: association with angiogenesis, invasion, and progression [In Process Citation]
Zagzag D; Zhong H; Scalzitti JM; Laughner E; Simons JW; Semenza GL
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.
PMID: 10861440
ISSN: 0008-543x
CID: 9343