Sriram Venneti

Memorial Sloan-Kettering Cancer Center, New York, New York, United States

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Publications (43)251.54 Total impact

  • Sriram Venneti, Jason T Huse
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    ABSTRACT: Low-grade gliomas (LGG) constitute grades I and II tumors of astrocytic and grade II tumors of oligodendroglial lineage. Although these tumors are typically slow growing, they may be associated with significant morbidity and mortality because of recurrence and malignant progression, even in the setting of optimal resection. LGG in pediatric and adult age groups are currently classified by morphologic criteria. Recent years have heralded a molecular revolution in understanding brain tumors, including LGG. Next-generation sequencing has definitively demonstrated that pediatric and adult LGG fundamentally differ in their underlying molecular characteristics, despite being histologically similar. Pediatric LGG show alterations in FGFR1 and BRAF in pilocytic astrocytomas and FGFR1 alterations in diffuse astrocytomas, each converging on the mitogen-activated protein kinase signaling pathway. Adult LGG are characterized by IDH1/2 mutations and ATRX mutations in astrocytic tumors and IDH1/2 mutations and 1p/19q codeletions in oligodendroglial tumors. TERT promoter mutations are also noted in LGG and are mainly associated with oligodendrogliomas. These findings have considerably refined approaches to classifying these tumors. Moreover, many of the molecular alterations identified in LGG directly impact on prognosis, tumor biology, and the development of novel therapies.
    Advances in Anatomic Pathology 03/2015; 22(2):94-101. DOI:10.1097/PAP.0000000000000049 · 3.10 Impact Factor
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    ABSTRACT: Glucose and glutamine are the two principal nutrients that cancer cells use to proliferate and survive. Many cancers show altered glucose metabolism, which constitutes the basis for in vivo positron emission tomography (PET) imaging with (18)F-fluorodeoxyglucose ((18)F-FDG). However, (18)F-FDG is ineffective in evaluating gliomas because of high background uptake in the brain. Glutamine metabolism is also altered in many cancers, and we demonstrate that PET imaging in vivo with the glutamine analog 4-(18)F-(2S,4R)-fluoroglutamine ((18)F-FGln) shows high uptake in gliomas but low background brain uptake, facilitating clear tumor delineation. Chemo/radiation therapy reduced (18)F-FGln tumor avidity, corresponding with decreased tumor burden. (18)F-FGln uptake was not observed in animals with a permeable blood-brain barrier or neuroinflammation. We translated these findings to human subjects, where (18)F-FGln showed high tumor/background ratios with minimal uptake in the surrounding brain in human glioma patients with progressive disease. These data suggest that (18)F-FGln is avidly taken up by gliomas, can be used to assess metabolic nutrient uptake in gliomas in vivo, and may serve as a valuable tool in the clinical management of gliomas. Copyright © 2015, American Association for the Advancement of Science.
    Science translational medicine 02/2015; 7(274):274ra17. DOI:10.1126/scitranslmed.aaa1009 · 14.41 Impact Factor
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    ABSTRACT: Many cancer cells consume large quantities of glutamine to maintain TCA cycle anaplerosis and support cell survival. It was therefore surprising when RNAi screening revealed that suppression of citrate synthase (CS), the first TCA cycle enzyme, prevented glutamine-withdrawal-induced apoptosis. CS suppression reduced TCA cycle activity and diverted oxaloacetate, the substrate of CS, into production of the nonessential amino acids aspartate and asparagine. We found that asparagine was necessary and sufficient to suppress glutamine-withdrawal-induced apoptosis without restoring the levels of other nonessential amino acids or TCA cycle intermediates. In complete medium, tumor cells exhibiting high rates of glutamine consumption underwent rapid apoptosis when glutamine-dependent asparagine synthesis was suppressed, and expression of asparagine synthetase was statistically correlated with poor prognosis in human tumors. Coupled with the success of L-asparaginase as a therapy for childhood leukemia, the data suggest that intracellular asparagine is a critical suppressor of apoptosis in many human tumors.
    Molecular Cell 09/2014; 56(2). DOI:10.1016/j.molcel.2014.08.018 · 14.46 Impact Factor
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    ABSTRACT: Pediatric glioblastomas (GBM) are highly aggressive and lethal tumors. Recent sequencing studies have shown that ~30 % of pediatric GBM and ~80 % of diffuse intrinsic pontine gliomas show K27M mutations in the H3F3A gene, a variant encoding histone H3.3. H3F3A K27M mutations lead to global reduction in H3K27me3. Our goal was to develop biomarkers for the histopathologic detection of these tumors. Therefore, we evaluated the utility of measuring H3K27me3 global reduction as a histopathologic and prognostic biomarker and tested an antibody directed specifically against the H3.3 K27M mutation in 290 samples. The study cohort included 203 pediatric (including 38 pediatric high-grade astrocytomas) and 38 adult brain tumors of various subtypes and grades and 49 non-neoplastic reactive brain tissues. Detection of H3.3 K27M by immunohistochemistry showed 100 % sensitivity and specificity and was superior to global reduction in H3K27me3 as a biomarker in diagnosing H3F3A K27M mutations. Moreover, cases that stained positive for H3.3 K27M showed a significantly poor prognosis compared to corresponding negative tumors. These results suggest that immunohistochemical detection of H3.3 K27M is a sensitive and specific surrogate for the H3F3A K27M mutation and defines a prognostically poor subset of pediatric GBM. Electronic supplementary material The online version of this article (doi:10.1007/s00401-014-1338-3) contains supplementary material, which is available to authorized users.
    Acta Neuropathologica 09/2014; 128(5). DOI:10.1007/s00401-014-1338-3 · 9.78 Impact Factor
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    ABSTRACT: The de novo synthesis of the non-essential amino acid serine is often upregulated in cancer. In this study we demonstrate that the serine catabolic enzyme, mitochondrial serine hydroxymethyltransferase (SHMT2) is induced when Myc-transformed cells are subjected to hypoxia. In mitochondria, SHMT2 can initiate the degradation of serine to CO2 and NH4+ resulting in net production of NADPH from NADP+. Knockdown of SHMT2 in Myc-dependent cells reduced cellular NADPH/NADP+ ratio, increased cellular reactive oxygen species (ROS) and triggered hypoxia-induced cell death. In vivo, SHMT2 suppression led to impaired tumor growth. In myc-amplified neuroblastoma patient samples, there was a significant correlation between SHMT2 and Hypoxia-inducible factor-1 α (HIF-1α) and SHMT2 expression correlated with unfavorable patient prognosis. Together these data demonstrate that mitochondrial serine catabolism supports tumor growth by maintaining mitochondrial redox balance and cell survival.
    Cancer Discovery 09/2014; 4(12). DOI:10.1158/2159-8290.CD-14-0250 · 15.93 Impact Factor
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    ABSTRACT: Histone acetylation plays important roles in gene regulation, DNA replication, and the response to DNA damage, and it is frequently deregulated in tumors. We postulated that tumor cell histone acetylation levels are determined in part by changes in acetyl coenzyme A (acetyl-CoA) availability mediated by oncogenic metabolic reprogramming. Here, we demonstrate that acetyl-CoA is dynamically regulated by glucose availability in cancer cells and that the ratio of acetyl-CoA:coenzyme A within the nucleus modulates global histone acetylation levels. In vivo, expression of oncogenic Kras or Akt stimulates histone acetylation changes that precede tumor development. Furthermore, we show that Akt's effects on histone acetylation are mediated through the metabolic enzyme ATP-citrate lyase and that pAkt(Ser473) levels correlate significantly with histone acetylation marks in human gliomas and prostate tumors. The data implicate acetyl-CoA metabolism as a key determinant of histone acetylation levels in cancer cells.
    Cell Metabolism 07/2014; 20(2). DOI:10.1016/j.cmet.2014.06.004 · 16.75 Impact Factor
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    ABSTRACT: Up to 30% of pediatric glioblastomas (GB) demonstrate mutations in H3F3A, a gene variant encoding histone H3.3. Global reduction in H3K27me3 is associated with H3F3A K27M mutation.
    Neuro-Oncology 07/2014; 16 Suppl 3:iii29-iii30. DOI:10.1093/neuonc/nou208.26 · 5.29 Impact Factor
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    ABSTRACT: Glioblastomas are aggressive adult brain tumors, characterized by inadequately organized vasculature and consequent nutrient and oxygen (O2)-depleted areas. Adaptation to low nutrients and hypoxia supports glioblastoma cell survival, progression and therapeutic resistance. However, specific mechanisms promoting cellular survival under nutrient and O2 deprivation remain incompletely understood. Here, we show that miR-124 expression is negatively correlated with a hypoxic gene signature in glioblastoma patient samples, suggesting that low miR-124 levels contribute to pro-survival adaptive pathways in this disease. As miR-124 expression is repressed in various cancer types (including glioblastoma), we quantified miR-124 abundance in normoxic and hypoxic regions in glioblastoma patient tissue, and investigated whether ectopic miR-124 expression compromises cell survival during tumor ischemia. Our results indicate that miR-124 levels are further diminished in hypoxic/ischemic regions within individual glioblastoma patient samples, compared with regions replete in O2 and nutrients. Importantly, we also show that increased miR-124 expression affects the ability of tumor cells to survive under O2 and/or nutrient deprivation. Moreover, miR-124 re-expression increases cell death in vivo and enhances the survival of mice bearing intracranial xenograft tumors. miR-124 exerts this phenotype in part by directly regulating TEAD1, MAPK14/p38α and SERP1, factors involved in cell proliferation and survival under stress. Simultaneous suppression of these miR-124 targets results in similar levels of cell death as caused by miR-124 restoration. Importantly, we further demonstrate that SERP1 reintroduction reverses the hypoxic cell death elicited by miR-124, indicating the importance of SERP1 in promoting tumor cell survival. In support of our experimental data, we observed a significant correlation between high SERP1 levels and poor patient outcome in glioblastoma patients. Collectively, among the many pro-tumorigeneic properties of miR-124 repression in glioblastoma, we delineated a novel role in promoting tumor cell survival under stressful microenvironments, thereby supporting tumor progression.Oncogene advance online publication, 23 June 2014; doi:10.1038/onc.2014.168.
    Oncogene 06/2014; 34(17). DOI:10.1038/onc.2014.168 · 8.56 Impact Factor
  • Cancer Research 05/2014; 73(13 Supplement):A01-A01. DOI:10.1158/1538-7445.CEC13-A01 · 9.28 Impact Factor
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    ABSTRACT: Glioblastoma multiforme (GBM) and the mesenchymal GBM subtype in particular are highly malignant tumors that frequently exhibit regions of severe hypoxia and necrosis. Because these features correlate with poor prognosis, we investigated microRNAs whose expression might regulate hypoxic GBM cell survival and growth. We determined that the expression of microRNA-218 (miR-218) is decreased significantly in highly necrotic mesenchymal GBM, and orthotopic tumor studies revealed that reduced miR-218 levels confer GBM resistance to chemotherapy. Importantly, miR-218 targets multiple components of receptor tyrosine kinase (RTK) signaling pathways, and miR-218 repression increases the abundance and activity of multiple RTK effectors. This elevated RTK signaling also promotes the activation of hypoxia-inducible factor (HIF), most notably HIF2α. We further show that RTK-mediated HIF2α regulation is JNK dependent, via jun proto-oncogene. Collectively, our results identify an miR-218-RTK-HIF2α signaling axis that promotes GBM cell survival and tumor angiogenesis, particularly in necrotic mesenchymal tumors.
    Proceedings of the National Academy of Sciences 12/2013; 111(1). DOI:10.1073/pnas.1314341111 · 9.81 Impact Factor
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    ABSTRACT: More than 50% of patients with chondrosarcomas exhibit gain-of-function mutations in either isocitrate dehydrogenase 1 (IDH1) or IDH2. In this study, we performed genome-wide CpG methylation sequencing of chondrosarcoma biopsies and found that IDH mutations were associated with DNA hypermethylation at CpG islands but not other genomic regions. Regions of CpG island hypermethylation were enriched for genes implicated in stem cell maintenance/differentiation and lineage specification. In murine 10T1/2 mesenchymal progenitor cells, expression of mutant IDH2 led to DNA hypermethylation and an impairment in differentiation that could be reversed by treatment with DNA-hypomethylating agents. Introduction of mutant IDH2 also induced loss of contact inhibition and generated undifferentiated sarcomas in vivo. The oncogenic potential of mutant IDH2 correlated with the ability to produce 2-hydroxyglutarate. Together, these data demonstrate that neomorphic IDH2 mutations can be oncogenic in mesenchymal cells.
    Genes & development 09/2013; 27(18):1986-98. DOI:10.1101/gad.226753.113 · 12.64 Impact Factor
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    ABSTRACT: Abstract Glypican-3 (GPC3) is a proteoglycan thought to play an important role during development. Germline GPC3 mutations are seen in the rare Simpson-Golabi-Behmel syndrome (SGBS), which predisposes patients to Wilms tumor, hepatoblastoma, and neuroblastoma. While numerous adult tumors have been evaluated by immunohistochemistry (IHC) for GPC3, no comprehensive assessment has been done in pediatric tumors. We investigated GPC3 expression in 143 pediatric central nervous system (CNS) tumors and 271 non-CNS tumors. Among non-CNS tumors, GPC3 expression was seen in 9/9 (100%) hepatoblastomas, 4/6 (67%) malignant rhabdoid tumors, 5/13 (38%) Wilms tumors, 11/37 (30%) alveolar rhabdomyosarcomas, and 8/45 (18%) embryonal rhabdomyosarcomas. All 136 neuroblastomas, 14 Ewing sarcoma/primitive neuroectodermal tumors and 11 synovial sarcomas were immunonegative for GPC3. Among CNS tumors, GPC3 had restricted expression with positivity in 6/6 (100%) AT/RTs and 1/4 (25%) craniopharyngiomas. The remaining 136 CNS tumors, including 23 medulloblastomas, 21 pilocytic astrocytomas, 13 gangliogliomas, 12 ependymomas, 12 glioblastomas, 11 choroid plexus neoplasms, 10 diffuse astrocytomas (grade II/III), 10 meningiomas, 8 dysembryoplastic neuroepithelial tumors, 8 oligodendrogliomas, 3 craniopharyngiomas, 3 germinomas, and 2 neurocytomas, were entirely negative for GPC3. These results showed GPC3 positivity in a number of non-CNS tumors with no consistent discrimination between tumors that are or are not associated with SGBS. Within the CNS, GPC3 positivity was limited to a small subset of CNS neoplasms and may serve as a useful positive diagnostic biomarker (P value <0.0001) in addition to negative INI1/BAF47/SMARCB1 staining to differentiate AT/RT from other high-grade pediatric brain tumors.
    Pediatric and Developmental Pathology 03/2013; 16(4). DOI:10.2350/12-06-1216-OA.1 · 0.86 Impact Factor
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    ABSTRACT: Trimethylation of histone 3 lysine 9 (H3K9me3) is a marker of repressed transcription. Cells transfected with mutant isocitrate dehydrogenase (IDH) show increased methylation of histone lysine residues, including H3K9me3, because of inhibition of histone demethylases by 2-hydroxyglutarate. Here, we evaluated H3K9me3 and its association with IDH mutations in 284 gliomas. Trimethylation of H3K9 was significantly associated with IDH mutations in oligodendrogliomas. Moreover, 72% of World Health Organization grade II and 65% of grade III oligodendrogliomas showed combined H3K9me3 positivity and 1p19q codeletion. In astrocytic tumors, H3K9me3 positivity was found in all grades of tumors; it showed a significant relationship with IDH mutational status in grade II astrocytomas but not in grade III astrocytomas or glioblastomas. Finally, H3K9me3-positive grade II oligodendrogliomas, but not other tumor subtypes, showed improved overall survival compared with H3K9me3-negative cases. These results suggest that repressive trimethylation of H3K9 in gliomas may occur in a context-dependent manner and is associated with IDH mutations in oligodendrogliomas but may be differently regulated in high-grade astrocytic tumors. Furthermore, H3K9me3 may define a subset of grade II oligodendrogliomas with better overall survival. Our results suggest variable roles for IDH mutations in the pathogenesis of oligodendrogliomas versus astrocytic tumors.
    03/2013; DOI:10.1097/NEN.0b013e3182898113
  • Sriram Venneti, Craig B Thompson
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    ABSTRACT: Cancer metabolism and epigenetics are two relatively new areas of cancer research. Recent years have seen an explosion of studies implicating either altered tumor metabolism or epigenetic mechanisms in the pathogenesis or maintenance of brain tumors. A new paradigm is emerging in cancer biology that represents a convergence of these themes, the metabolic regulation of epigenetics. We discuss this interrelationship in the context of two metabolic enzymes that can influence the pathogenesis of gliomas by altering the epigenetic state. The first of these enzymes is isocitrate dehydrogenase 1 (IDH1), which is mutated in secondary glioblastomas and ∼70% of grade II/III astrocytomas and oligodendrogliomas. Mutant IDH1 results in the production of a metabolite 2-hydroxyglutarate (2-HG) that can inhibit DNA and histone demethylating enzymes resulting in the glioma-CpG island phenotype (G-CIMP) and increased histone methylation marks. Pyruvate kinase M2 (PKM2), an enzyme that plays a critical role in the glycolytic pathway, is a second example of a metabolic enzyme that can affect histone modifications. In epidermal growth factor receptor (EGFR)-driven glioblastoma, PKM2 translocates to the nucleus and phosphorylates histone 3 at threonine 11 (H3-T11). This causes dissociation of HDAC3 from the CCND1 (Cyclin D1) and c-MYC promoters and subsequent histone acetylation, leading to transcription of Cyclin-D1 and c-MYC, and subsequent cell proliferation. Modification of the epigenetic state by alterations in metabolic enzymes is a novel phenomenon that contributes to the pathogenesis of gliomas and may help in the identification of new therapeutic targets.
    Brain Pathology 03/2013; 23(2):217-21. DOI:10.1111/bpa.12022 · 4.35 Impact Factor
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    ABSTRACT: High-grade astrocytomas (HGAs), corresponding to WHO grades III (AA) and IV (GBM), are biologically aggressive and their molecular classification is increasingly relevant to clinical management. PDGFRA amplification is common in HGAs, although its prognostic significance remains unclear. Using fluorescence in situ hybridization (FISH), the most sensitive technique for detecting PDGFRA copy number gains, we determined PDGFRA amplification status in 123 pediatric and 263 adult HGAs. A range of PDGFRA FISH patterns were identified and cases were scored as non-amplified (normal and polysomy) or amplified (low-level and high-level). PDGFRA amplification was frequent in pediatric (29.3%) and adult (20.9%) tumors. Amplification was not prognostic in pediatric HGAs. In adult tumors diagnosed initially as GBM, the presence of combined PDGFRA amplification and IDH1(R132H) mutation was a significant independent prognostic factor (p=0.01). In HGAs, PDGFRA amplification is common and can manifest as high-level and focal or low-level amplifications. Our data indicate that the latter is more prevalent than previously reported with copy number averaging techniques. To our knowledge, this is the largest survey of PDGFRA status in adult and pediatric HGAs and suggests PDGFRA amplification increases with grade and is associated with a less favorable prognosis in IDH1 mutant de novo GBMs.
    Brain Pathology 02/2013; 23(5). DOI:10.1111/bpa.12043 · 4.35 Impact Factor
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    ABSTRACT: H3F3A mutations are seen in ∼30% of pediatric glioblastoma (GBMs) and involve either the lysine residue at position 27 (K27M) or glycine at position 34 (G34R/V). Sixteen genes encode histone H3, each variant differing in only a few amino acids. Therefore, how mutations in a single H3 gene contribute to carcinogenesis is unknown. H3F3A K27M mutations are predicted to alter methylation of H3K27. H3K27me3 is a repressive mark critical to stem cell maintenance and is mediated by EZH2, a member of the polycomb-group (PcG) family. We evaluated H3K27me3 and EZH2 expression using immunohistochemistry in 76 pediatric brain tumors. H3K27me3 was lowered/absent in tumor cells but preserved in endothelial cells and infiltrating lymphocytes in six out of 20 GBMs. H3K27me3 showed strong immunoreactivity in all other tumor subtypes. Sequencing of GBMs showed H3F3A K27M mutations in all six cases with lowered/absent H3K27me3. EZH2 expression was high in GBMs, but absent/focal in other tumors. However, no significant differences in EZH2 expression were observed between H3F3A K27M mutant and wild type GBMs, suggesting that EZH2 mediated trimethylation of H3K27 is inhibited in GBM harboring K27M mutations. Our results indicate that H3F3A K27M mutant GBMs show decreased H3K27me3 that may be of both diagnostic and biological relevance.
    Brain Pathology 02/2013; 23(5). DOI:10.1111/bpa.12042 · 4.35 Impact Factor
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    ABSTRACT: Neuroinflammation perpetuates neuronal damage in many neurological disorders. Activation of resident microglia and infiltration of monocytes/macrophages contributes to neuronal injury and synaptic damage. Noninvasive imaging of these cells in vivo provides a means to monitor progression of disease as well as assess efficacies of potential therapeutics. This review provides an overview of positron emission tomography (PET) and magnetic resonance (MR) imaging of microglia/macrophages in the brain. We describe the rationale behind PET imaging of microglia/macrophages with ligands that bind to translocator protein-18 kDa (TSPO). We discuss the prototype TSPO radioligand [(11) C]PK11195, its limitations, and the development of newer TSPO ligands as PET imaging agents. PET imaging agents for targets other than TSPO are emerging, and we outline the potential of these agents for imaging brain microglia/macrophage activity in vivo. Finally, we briefly summarize advances in MR imaging of microglia/macrophages using iron oxide nanoparticles and ultra-small super paramagnetic particles that are phagocytosed. Despite many technical advances, more sensitive agents are required to be useful indicators of neuroinflammation in brain. © 2012 Wiley Periodicals, Inc.
    Glia 01/2013; 61(1). DOI:10.1002/glia.22357 · 5.47 Impact Factor
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    ABSTRACT: Background Meningiomas of the anterior skull base are attractive tumors for resection via an endoscopic endonasal route. The use of the vascularized Hadad-Bassagasteguy nasoseptal flap has dramatically reduced the cerebrospinal fluid (CSF) leak rate-the veritable Achilles heel of this surgical approach. Benign meningiomas, however, can erode through the nasal mucosa-the very same mucosa that is used to reconstruct the anterior cranial fossa floor. The goal of this study was to describe the presence of meningioma invasion into the mucosa in patients who underwent endoscopic endonasal resection of ventral skull base meningiomas. The implications of this finding are discussed with respect to resection, reconstruction, and recurrence.Patients, Materials, and Methods This is a retrospective review of three patients who underwent endoscopic endonasal complete resection of ventral skull base meningiomas. Surgically excised tissues were processed for routine histopathological analysis.Results A complete resection of the bone, dura, and tumor was performed in all three cases. Both patients with visual deficits improved. The first patient to undergo endoscopic surgical resection developed a CSF leak, but the later two patients with larger tumors did not. Histopathological analysis demonstrated mucosal invasion by World Health Organization (WHO) grade I meningioma in two of the three cases.Conclusion Ventral anterior skull base meningiomas can invade through bone into the mucosa. Because the endoscopic endonasal resection of these meningiomas often requires the use of a vascularized nasoseptal flap to minimize CSF leak complications, it is possible that the nasoseptal flap itself may be compromised by tumor tissue. The creation of the nasoseptal flap should take the findings of this study into consideration to minimize late recurrence.
    10/2012; 74(1). DOI:10.1055/s-0032-1322594
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    ABSTRACT: BACKGROUND:: In cases of progressive optic neuropathy, diagnostic uncertainty often persists despite extensive work-up. Optic nerve biopsy (ONB) can be considered, especially when visual decline of the affected or fellow eye ensues despite empiric therapy. We aimed to evaluate both diagnostic and therapeutic utilities of ONB based on the long-term experience at a tertiary care institution. METHODS:: This was a retrospective chart review of biopsies over 20 years at a single institution involving intrinsic or adherent optic nerve masses. Main outcome measures included the impact of tissue sampling on reaching a diagnosis and on guiding treatment. Secondary measures included vision in the eye of the ONB and the fellow eye. RESULTS:: Fifteen patients with a mean age of 51.7 ± 17.4 years underwent biopsies. At the time of biopsy, visual acuity was no light perception in 8 (53%) eyes, light perception to counting fingers in 5 (33%), and 20/400 or better in 2 (13%). The fellow eye of 7 patients (47%) experienced some degree of sequential vision loss before biopsy. Seven specimens included en bloc biopsy of the nerve, 7 contained the dural sheath (usually with a portion of the optic nerve), and 1 only of the compressive mass. Six patients (40%) had tumors. Six of 8 inflammatory lesions biopsied required further clinical data to arrive at specific diagnoses. In one case, a clinical diagnosis could not be made. No patients experienced further vision loss in the fellow eye at last follow-up (median, 8 months). CONCLUSIONS:: In diverse circumstances of progressive optic neuropathy, ONB can be beneficial in establishing the diagnosis. ONB can help direct specific local or systemic treatment, particularly when infectious or inflammatory etiologies are identified. ONB, if considered early in the disease course, can potentially halt or prevent vision loss when the fellow eye is threatened.
    Journal of neuro-ophthalmology: the official journal of the North American Neuro-Ophthalmology Society 06/2012; 32(4). DOI:10.1097/WNO.0b013e31825be81e · 1.81 Impact Factor
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    ABSTRACT: Central nervous system (CNS) tumors in von Hippel-Lindau syndrome (VHL) include hemangioblastomas and metastatic clear cell renal cell carcinomas (Met CCRCC). While these tumors often show similar histologic features, differentiating them is of significant importance as Met CCRCC are higher-grade tumors with worse prognosis. No single current immunohistochemical marker unequivocally differentiates between these two entities. MicroRNAs (miRNAs) are noncoding cellular small RNA molecules that play an important role in cancer. We hypothesized that hemangioblastomas and Met CCRCC display distinct miRNA signatures enabling their histologic differentiation. MiRNAs were profiled in 10 cases each of hemangioblastomas, Met CCRCC and primary CCRCC. Ten miRNAs had greater abundance (including miR-9 (∼10-fold) and miR-135a (∼7-fold)) and 39 miRNAs were lower [including miR-200a (∼22-fold) and miR-200b (∼12-fold)] in hemangioblastomas compared with Met CCRCC. Quantitative real-time RT-PCR in 20 hemangioblastomas and 13 Met CCRCC showed a 12-fold increase in miR-9 and a 15-fold decrease of miR-200a in hemangioblastomas compared with Met CCRCC. Finally, in situ hybridization for miR-9 in 15 hemangioblastomas and 10 Met CCRCC confirmed these results. Our data suggest that miR-9 and miR-200a can distinguish between hemangioblastomas and Met CCRCC. Further, these results may also provide insight in understanding the biology of hemangioblastomas.
    Brain Pathology 11/2011; 22(4):522-9. DOI:10.1111/j.1750-3639.2011.00551.x · 4.35 Impact Factor

Publication Stats

722 Citations
251.54 Total Impact Points

Institutions

  • 2013–2015
    • Memorial Sloan-Kettering Cancer Center
      • Division of Cancer Biology & Genetics
      New York, New York, United States
    • The Children's Hospital of Philadelphia
      Filadelfia, Pennsylvania, United States
  • 2014
    • Keck School of Medicine USC
      Los Angeles, California, United States
  • 2009–2014
    • University of Pennsylvania
      • • Department of Pathology and Laboratory Medicine
      • • Department of Radiation Oncology
      • • Department of Pathology
      • • Department of Medicine
      Philadelphia, Pennsylvania, United States
  • 2011
    • William Penn University
      Filadelfia, Pennsylvania, United States
  • 2010–2011
    • Hospital of the University of Pennsylvania
      • Department of Pathology and Laboratory Medicine
      Philadelphia, PA, United States
  • 2007–2008
    • University of Pittsburgh
      • Department of Pathology
      Pittsburgh, Pennsylvania, United States
    • National Institute of Radiological Sciences
      • Molecular Imagining Center
      Chiba-shi, Chiba-ken, Japan