William H Yong

Harbor-UCLA Medical Center, Torrance, California, United States

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Publications (109)641.27 Total impact

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    ABSTRACT: Background: Immunotherapy is an ideal treatment modality to specifically target the diffusely infiltrative tumor cells of malignant gliomas while sparing the normal brain parenchyma. However, progress in the development of these therapies for glioblastoma has been slow due to the lack of immunogenic antigen targets that are expressed uniformly and selectively by gliomas. Methods: We utilized human glioblastoma cell cultures to induce expression of New York-esophageal squamous cell carcinoma (NY-ESO-1) following in vitro treatment with the demethylating agent decitabine. We then investigated the phenotype of lymphocytes specific for NY-ESO-1 using flow cytometry analysis and cytotoxicity against cells treated with decitabine using the xCelligence real-time cytotoxicity assay. Finally, we examined the in vivo application of this immune therapy using an intracranially implanted xenograft model for in situ T cell trafficking, survival, and tissue studies. Results: Our studies showed that treatment of intracranial glioma-bearing mice with decitabine reliably and consistently induced the expression of an immunogenic tumor-rejection antigen, NY-ESO-1, specifically in glioma cells and not in normal brain tissue. The upregulation of NY-ESO-1 by intracranial gliomas was associated with the migration of adoptively transferred NY-ESO-1-specific lymphocytes along white matter tracts to these tumors in the brain. Similarly, NY-ESO-1-specific adoptive T cell therapy demonstrated antitumor activity after decitabine treatment and conferred a highly significant survival benefit to mice bearing established intracranial human glioma xenografts. Transfer of NY-ESO-1-specific T cells systemically was superior to intracranial administration and resulted in significantly extended and long-term survival of animals. Conclusion: These results reveal an innovative, clinically feasible strategy for the treatment of glioblastoma.
    Neuro-Oncology 09/2015; DOI:10.1093/neuonc/nov153 · 5.56 Impact Factor
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    ABSTRACT: Lymphocytic hypophysitis (LH) is a poorly understood autoimmune disorder of the pituitary gland. Symptoms include headache, pituitary dysfunction, visual disturbances and neurological deficits. The diagnosis can be made based on clinical and biochemical findings but for atypical presentations, no circulatory diagnostic biomarkers exist and pituitary biopsy is necessary for diagnosis. We used high-resolution human leukocyte antigen (HLA) screening assays to investigate for a relationship between specific HLA markers and lymphocytic hypophysitis. This was a retrospective analysis Setting: The study was conducted at a tertiary referral center. Fifteen patients with sporadic LH and 4 melanoma patients who developed hypophysitis following administration of CTLA4 antibodies and one patient with sarcoid-associated hypophysitis were evaluated. Clinical data including endocrine function, were assessed and HLA typing performed in all 20 patients with hypophysitis, 50 control patients with other sellar abnormalities and 4 CTLA4 antibody-treated patients without hypophysitis. Two major histocompatibility class II HLA markers, DQ8 and DR53, were found in 13/15 (87%) and 12/15 (80.0%) patients with sporadic lymphocytic hypophysitis respectively. In contrast, none of 4 patients who developed hypophysitis after administration of the CTLA4 antibodies exhibited the HLA-DQ8 marker and only 1/ 4(25%) exhibited the HLA-DR53 marker. In a parallel group of 50 control subjects with sellar masses and 4 CTLA4-Ab treated patients who did not develop evidence of pituitary failure, the candidate HLA subtypes were found in ∼20% for DQ8 and ∼48% for DR53 respectively. & Relevance: The HLA markers, DQ8 and DR53, were found to be commonly present in patients with LH. The odds ratio of a patient with LH expressing the HLA-DQ8 marker is 23.1-fold higher compared to a patient with another sellar mass. HLA-DQ8 testing may assist in diagnosis and avoid unnecessary biopsy in atypical LH cases.
    The Journal of Clinical Endocrinology and Metabolism 08/2015; DOI:10.1210/jc.2015-2702 · 6.21 Impact Factor
  • Journal of Neurological Surgery, Part B: Skull Base 08/2015; DOI:10.1055/s-0035-1554907 · 0.72 Impact Factor
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    ABSTRACT: Management of intracranial chordomas remains challenging, despite improvements in microsurgical techniques and radiotherapy. Here, we analyzed the prognostic factors associated with improved rates of tumor control in patients with intracranial chordomas, who received either gross (GTR) or subtotal resections (STR). A retrospective review was performed to identify all patients who were undergoing resection of their intracranial chordomas at the Ronald Reagan University of California Los Angeles Medical Center from 1990 to 2011. In total, 57 patients undergoing 81 resections were included. There were 24 females and 33 males with a mean age of 44.6years, and the mean tumor diameter was 3.36cm. The extent of resection was not associated with recurrence. For all 81 operations, the 1 and 5year progression free survival (PFS) was 87.5 and 40.4%, and 88.0 and 33.6% for STR and GTR, respectively (p=0.90). Adjuvant radiotherapy was associated with improved rates of PFS (hazard ratio [HR] 0.20; p=0.009). Additionally, age >45years (HR 5.88; p=0.01) and the presence of visual deficits (HR 7.59; p=0.03) were associated with worse rates of tumor control. Tumor size, sex, tumor histology, and recurrent tumors were not predictors of recurrence. Younger age, lack of visual symptoms on presentation and adjuvant radiotherapy were associated with improved rates of tumor control following surgery. However, GTR and STR produced comparable rates of tumor control. The surgical management of intracranial chordomas should take a conservative approach, with the aim of maximal but safe cytoreductive resection with adjuvant radiation therapy, and a major focus on quality of life. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Journal of Clinical Neuroscience 07/2015; DOI:10.1016/j.jocn.2015.05.024 · 1.38 Impact Factor
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    ABSTRACT: Cancer cells adapt their signaling in response to nutrient availability. To uncover the mechanisms regulating this process and its functional consequences, we interrogated cell lines, mouse tumor models, and clinical samples of glioblastoma (GBM), the highly lethal brain cancer. We discovered that glucose or acetate is required for epidermal growth factor receptor vIII (EGFRvIII), the most common growth factor receptor mutation in GBM, to activate mechanistic target of rapamycin complex 2 (mTORC2) and promote tumor growth. Glucose or acetate promoted growth factor receptor signaling through acetyl-CoA-dependent acetylation of Rictor, a core component of the mTORC2 signaling complex. Remarkably, in the presence of elevated glucose levels, Rictor acetylation is maintained to form an autoactivation loop of mTORC2 even when the upstream components of the growth factor receptor signaling pathway are no longer active, thus rendering GBMs resistant to EGFR-, PI3K (phosphoinositide 3-kinase)-, or AKT (v-akt murine thymoma viral oncogene homolog)-targeted therapies. These results demonstrate that elevated nutrient levels can drive resistance to targeted cancer treatments and nominate mTORC2 as a central node for integrating growth factor signaling with nutrient availability in GBM.
    Proceedings of the National Academy of Sciences 07/2015; 112(30):201511759. DOI:10.1073/pnas.1511759112 · 9.67 Impact Factor
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    ABSTRACT: Interstitial tissue acidosis resulting from abnormal perfusion and metabolism is a hallmark of cancer. The current study demonstrates that chemical exchange saturation transfer (CEST) MRI can be used as a noninvasive pH-weighted molecular imaging technique by targeting the chemical exchange between amine protons and protons in extracellular bulk water. First, the sensitivity of amine CEST was validated in phantoms under a variety of conditions, including different magnetic field strengths, amino acid concentrations, and pH values. Amine CEST was compared with histology in both a preclinical GL261 intracranial glioma model at 7T and human patients at 3T. The association between physiologic and pH-weighted MRI was explored, along with the ability to predict time to progression to radiochemotherapy in 20 glioblastoma patients. z-Spectral asymmetry increased at 3 ppm (amine range) on CEST MRI with decreasing pH within the range observed in tumors for both 3T and 7T scanners. Lesions with acidic signatures showed active tumor and pseudopalisading tumor on histology and showed elevated FDOPA PET uptake, lactate on MR spectroscopy, and perfusion abnormalities. Patients with acidic lesions after surgery or stable/growing acidic lesions had a shorter time to progression following radiochemotherapy compared with patients with lesions demonstrating relatively low acidity (P < .001). Results suggest pH-weighted MRI may provide new insight into brain tumor physiology beyond traditional imaging technologies. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
    Neuro-Oncology 06/2015; DOI:10.1093/neuonc/nov106 · 5.56 Impact Factor
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    ABSTRACT: Brain biopsies have an uncertain role in the diagnosis of patients with dementia or neurologic decline of unknown etiology. They are often performed only after an exhaustive panel of less invasive tests and procedures have failed to provide a definitive diagnosis. The objective of this study was to evaluate the sensitivity of brain biopsies in this patient group through the retrospective analysis of 53 brain biopsies performed for neurologic disease of unknown etiology at a single tertiary care institution between December 2001 and December 2011. Patients with known nonlymphomatous neoplasms thought to be associated with the neurologic symptoms or with immunodeficiency were excluded from the study. Furthermore, the clinical presentation, imaging and laboratory tests were compared between diagnostic groups to identify factors more likely to yield a diagnosis. Sixty percent of the biopsies were diagnostic (32 of 53), with the most common histologic diagnosis of central nervous system lymphoma in 14 of 53 patients (26% of total) followed by infarct in four subjects (7.5%). A few patients were found to have rare and unsuspected diseases such as lymphomatosis cerebri, neurosarcoidosis and neuroaxonal leukodystrophy. Complications from biopsy were uncommon and included hemorrhage and infection with abscess formation at the biopsy site. These results suggest that brain biopsies may be useful in difficult cases in which less invasive measures have been unable to yield a definitive diagnosis. Copyright © 2015 Elsevier Inc. All rights reserved.
    Human pathology 12/2014; 46(4). DOI:10.1016/j.humpath.2014.12.003 · 2.77 Impact Factor
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    ABSTRACT: Purpose: Diffusion magnetic resonance imaging (MRI) and 6-[(18)F]fluoro-L-dopa ([(18)F]FDOPA) positron emission tomography (PET) are used to interrogate malignant tumor microenvironment. It remains unclear whether there is a relationship between [(18)F]FDOPA uptake, diffusion MRI estimates of apparent diffusion coefficient (ADC), and mitotic activity in the context of recurrent malignant gliomas, where the tumor may be confounded by the effects of therapy. The purpose of the current study is to determine whether there is a correlation between these imaging techniques and mitotic activity in malignant gliomas. Procedures: We retrospectively examined 29 patients with recurrent malignant gliomas who underwent structural MRI, diffusion MRI, and [(18)F]FDOPA PET prior to surgical resection. Qualitative associations were noted, and quantitative voxel-wise and median measurement correlations between [(18)F]FDOPA PET, ADC, and mitotic index were performed. Results: Areas of high [(18)F]FDOPA uptake exhibited low ADC and areas of hyperintensity T2/fluid-attenuated inversion recovery (FLAIR) with low [(18)F]FDOPA uptake exhibited high ADC. There was a significant inverse voxel-wise correlation between [(18)F]FDOPA and ADC for all patients. Median [(18)F]FDOPA uptake and median ADC also showed a significant inverse correlation. Median [(18)F]FDOPA uptake was positively correlated, and median ADC was inversely correlated with mitotic index from resected tumor tissue. Conclusions: A significant association may exist between [(18)F]FDOPA uptake, diffusion MRI, and mitotic activity in recurrent malignant gliomas.
    Molecular Imaging & Biology 12/2014; 17(3). DOI:10.1007/s11307-014-0807-3 · 2.77 Impact Factor
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    ABSTRACT: Background Ventriculoperitoneal shunt obstruction remains a major problem in pediatric neurosurgery. We analyzed the tissue reaction to ventriculoperitoneal shunts and compared the histology versus time elapsed to shunt failure. Methods 85 ventricular catheter tissues samples obtained from 71 patients were reviewed along with time elapsed to shunt revision. Pathology reports of all tissue samples were divided into three categories: inflammatory based on the presence of lymphocytes, macrophages, and microglial cells; reactive based on the presence of fibro-connective tissue, reactive astrocytes, and Rosenthal fibers; and normal brain tissue based on presence of choroid plexus. These categories were then grouped according to time elapsed to shunt revision. Group I had those shunts revised < 6 months, group II included shunts revised between 6 months to 3 years, while group III had shunts revised after more than 3 years. Results The incidence of inflammatory type of histology was 44% (16/36) in group I, 22% (6/27) in group II, and 18% (4/22) in group III. The reactive histology was 42% (15/36) in group I, 67% (18/27) in group II, and 77% (17/22) in group III. There was a clear noted difference of incidence between inflammatory versus reactive histology between early shunt failure compared to late shunt failure. Incidence of normal brain tissue remained high in group I with 8%, 11% in group II, and none in group III. Conclusion Early shunt obstruction arises from pathologies different from those causing late shunt obstructions.
    Clinical Neurology and Neurosurgery 12/2014; 127. DOI:10.1016/j.clineuro.2014.09.029 · 1.13 Impact Factor
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    ABSTRACT: Ornithine transcarbamylase deficiency (OTCD, OMIM 311250), the most common urea cycle disorder, results in impaired synthesis of citrulline from carbamoyl phosphate and ornithine. Individuals have been identified with OTCD due to a contiguous gene deletion at Xp11.4-p21.1 and unique clinical features, described as the "extended OTCD phenotype". We present a male with neonatal-lethal OTCD due to a 1.87Mb microdeletion at Xp11.4-p21.1 (37126841-38998991 hg18). Autopsy revealed a novel histological finding of hepatocyte globular and granular inclusions. Such inclusions have not been described in OTCD or other metabolic disorders and are not an associated finding in neonatal liver failure due to other causes. The deleted region includes the gene SYTL5, potentially involved in RAB27A-dependent membrane trafficking in the liver and placenta. We propose that the contiguous gene deletion could contribute to the severity of the clinical presentation here and hypothesize that deletion of SYTL5 could contribute to the liver findings. Copyright © 2014. Published by Elsevier B.V.
    Gene 11/2014; 556(2). DOI:10.1016/j.gene.2014.11.057 · 2.14 Impact Factor
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    ABSTRACT: Introduction: Persistent bacterial infection prolongs hospitalizations, leading to increased healthcare costs. Treatment of these infections costs several billion dollars annually. Biofilm production is one mechanism by which bacteria become resistant. With the help of biofilms, bacteria withstand the host immune response and are much less susceptible to antibiotics. Currently, there is interest in the use of laser-generated shockwaves (LGS) to delaminate biofilm from infected wound surfaces; however, the safety of such an approach has not yet been established. Of particular concern are the thermal and mechanical effects of the shockwave treatment on the epidermis and the underlying collagen structure of the dermis. The present study is a preliminary investigation of the effect of LGS on freshly harvested ex vivo porcine skin tissue samples. Materials and methods: Tissue samples for investigation were harvested immediately post-mortem and treated with LGS within 30 minutes. Previous studies have shown that laser fluences between 100 and 500 mJ/pulse are capable of delaminating biofilms off a variety of surfaces, thus our preliminary investigation focused on this range of laser energy. For each sample, LGS were produced via laser irradiation of a thin layer (0.5 µm) of titanium sandwiched between a 50 and 100 µm thick layer of water glass and a 0.1 mm thick sheet of Mylar. The rapid thermal expansion of the irradiated titanium film generates a transient compressive wave that is coupled through a liquid layer to the surface of the ex vivo pigskin sample. Shocked samples were immediately fixed in formalin and prepared for histological analysis. A blinded pathologist evaluated and scored each section on the basis of its overall appearance (O) and presence of linear/slit-like spaces roughly parallel to the surface of the skin (S). The scores were given on a scale of 0-3. Results: The present investigation revealed no visible difference between the tissue sections of the control sample and those that were subjected to laser-generated shockwaves. There was no relationship between the scores received by the samples and the energy with which they were shocked. Conclusion: Preliminary investigation into the safety of the LGS treatment for biofilm delamination appears promising. Additional investigation will continue on ex vivo porcine samples, followed by an in vivo animal trial to better understand the physiological response to LGS treatment.
    Lasers in Surgery and Medicine 10/2014; 46(8). DOI:10.1002/lsm.22278 · 2.62 Impact Factor
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    ABSTRACT: Purpose: IDH1/2-mutant gliomas harbor a distinct glioma-CpG island methylation phenotype (G-CIMP) that may promote the initiation and progression of secondary pathway gliomas by silencing tumor-suppressive genes. The potential role of tumor-suppressive microRNAs (miRNA; miR) in this process is not understood. Experimental design: To identify potential tumor-suppressive miRNA hypermethylated in glioma, the methylation profiles of IDH1/2(WT) gliomas (n = 11) and IDH1(MUT) glioma (n = 20) were compared by using massively parallel reduced representation bisulfite sequencing (RRBS). The methylation status of selected miRNA was validated by using targeted bisulfite sequencing (BiSEQ) in a large cohort of glioma tissue samples including 219 IDH1(WT) and 72 IDH1/2(MUT) samples. The expression of selected miRNAs was determined by using the TaqMan qPCR. Functional analyses of miR148a were conducted and target genes were identified. Results: We identify miR148a as a novel, G-CIMP-associated miRNA whose methylation is tightly correlated with IDH1 mutation and associated with improved survival in patients with malignant glioma. We confirm that downregulation of miR148a can occur via DNA methylation. We demonstrate that IDH1 mutation provides a mechanism of miR148a methylation and downregulation, and that restoration of miR148a reduced tumorigenic properties of glioma cells, possibly by targeting DNMT1. Conclusions: We identify miR148a as a novel G-CIMP-associated miRNA, and provide results suggesting that miR148a restoration may have therapeutic implications.
    Clinical Cancer Research 09/2014; 20(22). DOI:10.1158/1078-0432.CCR-14-0234 · 8.72 Impact Factor
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    ABSTRACT: Background: Nitroxoline is an FDA-approved antibiotic with potential antitumor activity. Here we evaluated whether nitroxoline has antiproliferative properties on glioma cell growth in vitro and in vivo using glioma cell lines and a genetically engineered PTEN/KRAS mouse glioma model. Methods: The effect of nitroxoline treatment on U87 and/or U251 glioma cell proliferation, cell-cycle arrest, invasion, and ability to induce an apoptotic cascade was determined in vitro. Magnetic resonance imaging was used to measure glioma volumes in genetically engineered PTEN/KRAS mice prior to and after nitroxoline therapy. Induction of apoptosis by nitroxoline was evaluated at the end of treatment using terminal deoxyribonucleotidyl transferase (TDT)-mediated dUTP-digoxigenin nick end labeling (TUNEL). Results: Nitroxoline inhibited the proliferation and invasion of glioblastoma cells in a time- and dose-dependent manner in vitro. Growth inhibition was associated with cell-cycle arrest in G1/G0 phase and induction of apoptosis via caspase 3 and cleaved poly(ADP-ribose) polymerase. In vivo, nitroxoline-treated mice had no increase in tumor volume after 14 days of treatment, whereas tumor volumes doubled in control mice. Histological examination revealed 15%-20% TUNEL-positive cells in nitroxoline-treated mice, compared with ∼5% in the control group. Conclusion: Nitroxoline induces apoptosis and inhibits glioma growth in vivo and in vitro. As an already FDA-approved treatment for urinary tract infections with a known safety profile, nitroxoline could move quickly into clinical trials pending confirmatory studies.
    Neuro-Oncology 07/2014; 17(1). DOI:10.1093/neuonc/nou139 · 5.56 Impact Factor
  • William H Yong · Sarah M Dry · Maryam Shabihkhani
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    ABSTRACT: Powerful technologies critical to personalized medicine and targeted therapeutics require the analysis of carefully validated, procured, stored, and managed biospecimens. Reflecting advancements in biospecimen science, the National Cancer Institute and the International Society for Biological and Environmental Repositories are periodically publishing best practices that can guide the biobanker. The modern biobank will operate more like a clinical laboratory with formal accreditation, standard operating procedures, and quality assurance protocols. This chapter highlights practical issues of consent, procurement, storage, quality assurance, disbursement, funding, and space. Common topics of concern are discussed including the differences between clinical and research biospecimens, stabilization of biospecimens during procurement, optimal storage temperatures, and technical validation of biospecimen content and quality. With quickly expanding biospecimen needs and limited healthcare budgets, biobanks may need to be selective as to what is stored. Furthermore, a shift to room-temperature storage modalities where possible can reduce long-term space and fiscal requirements.
    Methods in molecular biology (Clifton, N.J.) 07/2014; 1180:137-62. DOI:10.1007/978-1-4939-1050-2_8 · 1.29 Impact Factor
  • Brain Pathology 07/2014; 24(4):421-2. DOI:10.1111/bpa.12156 · 3.84 Impact Factor
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    ABSTRACT: Objectives To examine systemic and central nervous system (CNS) comorbidities of individuals with dementia evaluated during general autopsy.DesignRetrospective cohort study.SettingA large tertiary academic medical center in Los Angeles, California.ParticipantsIndividuals with clinically and neuropathologically diagnosed dementia who received complete autopsies (n = 86) and individuals with dementia who received partial (brain only) autopsies (n = 132).MeasurementsInformation on cause of death and systemic and CNS comorbidities was obtained from autopsy reports and clinical information as available from the medical records. Findings were tabulated with respect to type of dementia, semiquantitative assessment of the severity of cerebral amyloid angiopathy, semiquantitative assessment of the severity of cerebrovascular disease, and evidence of ischemic damage in the brain.ResultsOf 218 subjects with dementia, 175 (80.3%) had Alzheimer's disease alone or in combination with other lesions that might contribute to cognitive impairment, such as cerebrovascular disease and diffuse Lewy body disease (DLBD), 14 (6.4%) had frontotemporal dementia, and seven (3.2%) had isolated DLBD. The most common cause of death in participants with dementia was pneumonia (n = 57, 66.3%), followed by cardiovascular disease (n = 14, 16.3%). Eighteen subjects (20.9%) had lung disease, and 16 (18.6%) had evidence of an old or recent myocardial infarction. Clinically undiagnosed neoplasms included colonic adenocarcinoma, metastatic pulmonary neuroendocrine carcinoma, meningioma, and Schwannoma.Conclusion Significant comorbidities were discovered at autopsy in individuals with dementia. Understanding the causes of death and associated comorbidities in individuals with various subtypes of dementia is important in the assessment of end-of-life care in these individuals.
    Journal of the American Geriatrics Society 07/2014; 62(9). DOI:10.1111/jgs.12977 · 4.57 Impact Factor
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    ABSTRACT: The optimal timing to initiate bevacizumab (BV) therapy for recurrent glioblastoma (GBM) is currently unclear. To address this issue, we examined progression-free survival (PFS) and survival time (ST) in a large retrospective cohort of GBM patients treated with BV at different recurrences. We identified 468 primary GBM patients who underwent biopsy or surgery followed by radiation therapy and temozolomide (RT/TMZ), and then received BV. PFS and ST were compared between patients stratified by the recurrence that BV was initiated (upfront, first recurrence, second recurrence, or 3+ recurrences). We also examined the effect on PFS and ST of the addition of chemotherapy to BV. In a larger cohort of GBM patients, we determined overall treatment continuation rates at each recurrence and identified variables predictive of inability to continue treatment. BV PFS was similar for all 3 recurrence groups (median, 4.1 months). There were no differences in BV ST (median, 9.8 months). The addition of chemotherapy to BV improved PFS but not ST. Analysis of treatment continuation rates indicated that the number of patients unable to undergo further treatments is modest, and that patients unable to tolerate BV delay can be identified by age ≥60 years and low extent of resection. Deferred use of bevacizumab is not associated with diminished efficacy. Analysis of treatment continuation rates identified patients who may be unable to delay BV therapy. Our findings suggest that there is a fixed survival after BV initiation and that delayed BV treatment is preferable for most patients.
    Neuro-Oncology 03/2014; 16(6). DOI:10.1093/neuonc/nou028 · 5.56 Impact Factor
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    ABSTRACT: Most patients with large pituitary tumors do not exhibit hyperprolactinemia as a result of pituitary lactotroph disinhibition (stalk effect). Studies have demonstrated that increased intrasellar pressure is associated with both "stalk effect" hyperprolactinemia and pituitary insufficiency. Our primary hypothesis was that, despite continued disinhibition, lactotroph failure is responsible for normoprolactinemia in patients with large macroadenomas. As a corollary, we proposed that the hyperprolactinemia phase, which presumably would precede the insufficiency/normoprolactinemic state, would more likely be discovered in premenopausal females and go unnoticed in males. Prospective, consecutive surgical series of 98 patients of clinically nonfunctional pituitary adenomas. Lactotroph insufficiency was inferred by the coexistence of insufficiency in another pituitary axis. The existence of pre-operative lactotroph disinhibition was inferred based on comparison of pre- versus post-operative prolactin levels. 87 % of patients with tumor size >20 mm and normoprolactinemia had pituitary insufficiency. Pre-operative prolactin in patients with pituitary insufficiency were lower than those with intact pituitary function. Prolactin levels dropped in nearly all patients, including patients with normoprolactinemia pre-operatively. Premenopausal women had smaller tumors and higher pre-operative prolactin levels compared to males. No premenopausal female exhibited evidence of pituitary insufficiency. Our study provides suggestive evidence that the "stalk effect" pathophysiology is the norm rather than the exception, and that the finding of normoprolactinemia in a patient with a large macroadenoma is likely a consequence of lactotroph insufficiency. In males, the hyperprolactinemia window is more likely to be missed clinically due to an absence of prolactin-related symptoms.
    Journal of Neuro-Oncology 02/2014; 117(3). DOI:10.1007/s11060-014-1386-5 · 3.07 Impact Factor
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    ABSTRACT: Malignant gliomas are the most common human primary brain tumors. Point mutation of amino acid arginine 132 to histidine (R132H) in the IDH1 protein leads to an enzymatic gain-of-function and is thought to promote gliomagenesis. Little is known about the downstream effects of the IDH1 mutation on protein expression and how and whether changes in protein expression are involved in tumor formation or propagation. In the current study, we used 2D DIGE (difference gel electrophoresis) and mass spectrometry to analyze differences in protein expression between IDH1(R132H) mutant and wild type anaplastic (grade III) astrocytoma from human brain cancer tissues. We show that expression levels of many proteins are altered in IDH1(R132H) mutant anaplastic astrocytoma. Some of the most over-expressed proteins in the mutants include several forms of αB-crystallin, a small heat-shock and anti-apoptotic protein. αB-crystallin proteins are elevated up to 22-fold in IDH1(R132H) mutant tumors, and αB-crystallin expression appears to be controlled at the post-translational level. We identified the most abundant form of αB-crystallin as a low molecular weight species that is C-terminally truncated. We also found that overexpression of αB-crystallin can be induced by transfecting U251 human glioblastoma cell lines with the IDH1(R132H) mutation. In conclusion, the association of a C-terminally truncated form of αB-crystallin protein with the IDH1(R132H) mutation is a novel finding that could impact apoptosis and stress response in IDH1 mutant glioma.
    Journal of Neuro-Oncology 01/2014; 117(1). DOI:10.1007/s11060-014-1371-z · 3.07 Impact Factor
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    ABSTRACT: Well preserved frozen biospecimens are ideal for evaluating the genome, transcriptome, and proteome. While papers reviewing individual aspects of frozen biospecimens are available, we present a current overview of experimental data regarding procurement, storage, and quality assurance that can inform the handling of frozen biospecimens. Frozen biospecimen degradation can be influenced by factors independent of the collection methodology including tissue type, premortem agonal changes, and warm ischemia time during surgery. Rapid stabilization of tissues by snap freezing immediately can mitigate artifactually altered gene expression and, less appreciated, protein phosphorylation profiles. Collection protocols may be adjusted for specific tissue types as cellular ischemia tolerance varies widely. If data is not available for a particular tissue type, a practical goal is snap freezing within 20 minutes. Tolerance for freeze-thaw events is also tissue type dependent. Tissue storage at -80°C can preserve DNA and protein for years but RNA can show degradation at 5 years. For -80°C freezers, aliquots frozen in RNAlater or similar RNA stabilizing solutions is a consideration. It remains unresolved as to whether storage at -150°C provides significant advantages relative to -80°C. Histologic quality assurance of tissue biospecimens is typically performed at the time of surgery but should also be conducted on the aliquot to be distributed because of tissue heterogeneity. Biobanking protocols for blood and its components are highly dependent on intended use and multiple collection tube types may be needed. Additional quality assurance testing should be dictated by the anticipated downstream applications.
    Clinical biochemistry 01/2014; 47(4-5). DOI:10.1016/j.clinbiochem.2014.01.002 · 2.28 Impact Factor

Publication Stats

3k Citations
641.27 Total Impact Points


  • 2014
    • Harbor-UCLA Medical Center
      Torrance, California, United States
  • 2006–2014
    • University of California, Los Angeles
      • Department of Pathology and Laboratory Medicine
      Los Ángeles, California, United States
  • 2012
    • CSU Mentor
      Long Beach, California, United States
  • 2009
    • Laureate Institute for Brain Research
      Tulsa, Oklahoma, United States
  • 2008
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      • Department of Medicine
      Torrance, California, United States
  • 2005–2007
    • University of Southern California
      • Department of Biomedical Engineering
      Los Angeles, CA, United States
  • 2000–2004
    • Cedars-Sinai Medical Center
      • Cedars Sinai Medical Center
      Los Ángeles, California, United States
  • 2001
    • Los Angeles Neurosurgical Institute
      Los Angeles, California, United States