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Home > Translational Research > Leia Nghiemphu M.D.   

Leia Nghiemphu M.D.

The Ronald Reagan Hospital at
UCLA Medical Center
710 Westwood Plaza
Reed Bldg RM 1-230
Los Angeles CA 90095


• Associate Professor 
• Director, Neuro-Oncology Fellowship Program 
• Director, Neuro-Oncology Clinical Service & NF2 Multidisciplinary Clinic
 


Attending:
Neurology, UCLA School of Medicine, 2003 - Present

Clinical Fellowship:
Neuro-Oncology Program, Department of Neurology
David Geffen School of Medicine at UCLA, 2003 - 2006

Translational Investigation Fellowship:
Track II of UCLA K30 Graduate Training Program in Translational Investigation
David Geffen School of Medicine at UCLA, 2004 - 2006

Research Fellowship:
Lab of Ingo Mellinghoff, M.D., Department of Molecular & Medical Pharmacology
David Geffen School of Medicine at UCLA, 2004 - 2006

Medical Board Certification:
Neurology, American Board of Psychiatry and Neurology, 2004 - Present

Residency:
Neurology, Stanford University Medical Center, 2000 - 2003

Internship:
Internal Medicine, Beth Israel Medical Center, 1999 - 2000

Medical Degree:
Albert Einstein College of Medicine, Bronx, NY, 1995 - 1999






















 
Incidence, survival, pathology, and genetics of adult Latino Americans with glioblastoma.
Source:Journal of neuro-oncology
Published:2/4/2017
Authors:Shabihkhani M; Telesca D; Movassaghi M; Naeini YB; Naeini KM; Hojat SA; Gupta D; Lucey GM; Ontiveros M; Wang MW; Hanna LS; Sanchez DE; Mareninov S; Khanlou N; Vinters HV; Bergsneider M; Nghiemphu PL; Lai A; Liau LM; Cloughesy TF; Yong WH;
Abstract:Latinos have a lower incidence of GBM and present slightly younger than non-Latino Whites. Cubans present at an older age than other Latino sub-populations. Latinos have a higher incidence of giant cell glioblastoma than non-Latino Whites while the incidence of gliosarcoma is similar. Despite lower rates of radiation therapy and greater rates of sub-total resection than non-Latino Whites, Latinos have better 1 and 5 year survival rates. SEER does not record chemotherapy data. Survivals of Latino sub-populations are similar with each other. Age, extent of resection, and the use of radiation therapy are associated with improved survival but none of these variables are sufficient in a multivariate analysis to explain the improved survival of Latinos relative to non-Latino Whites. As molecular data is not available in SEER records, we studied the MGMT and IDH status of 571 patients from a UCLA database. MGMT methylation and IDH1 mutation rates are not statistically significantly different between non-Latino Whites and Latinos. For UCLA patients with available information, chemotherapy and radiation rates are similar for non-Latino White and Latino patients, but the latter have lower rates of gross total resection and present at a younger age.
Baseline pretreatment contrast enhancing tumor volume including central necrosis is a prognostic factor in recurrent glioblastoma: evidence from single and multicenter trials.
Source:Neuro-oncology
Published:1/1/2017
Authors:Ellingson BM; Harris RJ; Woodworth DC; Leu K; Zaw O; Mason WP; Sahebjam S; Abrey LE; Aftab DT; Schwab GM; Hessel C; Lai A; Nghiemphu PL; Pope WB; Wen PY; Cloughesy TF;
Abstract:Baseline tumor volume is a significant prognostic factor in recurrent GBM. Clinical trial treatment arms must have a balanced distribution of tumor size, and tumor size should be considered when interpreting therapeutic efficacy.
Simulation, phantom validation, and clinical evaluation of fast pH-weighted molecular imaging using amine chemical exchange saturation transfer echo planar imaging (CEST-EPI) in glioma at 3?T.
Source:NMR in biomedicine
Published:11/1/2016
Authors:Harris RJ; Cloughesy TF; Liau LM; Nghiemphu PL; Lai A; Pope WB; Ellingson BM;
Abstract:Acidity within the extracellular milieu is a hallmark of cancer. There is a current need for fast, high spatial resolution pH imaging techniques for clinical evaluation of cancers, including gliomas. Chemical exchange saturation transfer (CEST) MRI targeting fast-exchanging amine protons can be used to obtain high-resolution pH-weighted images, but conventional CEST acquisition strategies are slow. There is also a need for more accurate MR simulations to better understand the effects of amine CEST pulse sequence parameters on pH-weighted image contrast. In the current study we present a simulation of amine CEST contrast specific for a newly developed CEST echoplanar imaging (EPI) pulse sequence. The accuracy of the simulations was validated by comparing the exchange rates and Z-spectrum under a variety of conditions using physical phantoms of glutamine with different pH values. The effects of saturation pulse shapes, pulse durations, pulse train lengths, repetition times, and relaxation rates of bulk water and exchangeable amine protons on the CEST signal were explored for normal-appearing white matter (NAWM), glioma, and cerebrospinal fluid. Last, 18 patients with WHO II-IV gliomas were evaluated. Results showed that the Z-spectrum was highly dependent on saturation pulse shape, repetition time, saturation amplitude, magnetic field strength, and T2 within bulk water; however, the Z-spectrum was only minimally influenced by saturation pulse duration and the specific relaxation rates of amine protons. Results suggest that a Gaussian saturation pulse train consisting of 3 × 100 ms pulses using the minimum allowable repetition time is optimal for achieving over 90% available contrast across all tissues. Results also demonstrate that high saturation pulse amplitude and scanner field strength (>3?T) are necessary for adequate endogenous pH-weighted amine CEST contrast. pH-weighted amine CEST contrast increased with increasing tumor grade, with glioblastoma showing significantly higher contrast compared with WHO II or III gliomas.
Bidirectional Contrast agent leakage correction of dynamic susceptibility contrast (DSC)-MRI improves cerebral blood volume estimation and survival prediction in recurrent glioblastoma treated with bevacizumab.
Source:Journal of magnetic resonance imaging : JMRI
Published:11/1/2016
Authors:Leu K; Boxerman JL; Lai A; Nghiemphu PL; Pope WB; Cloughesy TF; Ellingson BM;
Abstract:Accounting for T1 and T2* leakage contamination in DSC-MRI using a two-compartment, bidirectional rather than unidirectional exchange model might improve post-bevacizumab survival stratification in patients with recurrent GBM. J. Magn. Reson. Imaging 2016;44:1229-1237.
Human TERT promoter mutation enables survival advantage from MGMT promoter methylation in IDH1 wild-type primary glioblastoma treated by standard chemoradiotherapy.
Source:Neuro-oncology
Published:8/29/2016
Authors:Nguyen HN; Lie A; Li T; Chowdhury R; Liu F; Ozer B; Wei B; Green RM; Ellingson BM; Wang HJ; Elashoff R; Liau LM; Yong WH; Nghiemphu PL; Cloughesy T; Lai A;
Abstract:The prognostic influence of MGMT promoter methylation depends on hTERT promoter mutation. This interaction warrants further mechanistic investigation.
Improved Leakage Correction for Single-Echo Dynamic Susceptibility Contrast Perfusion MRI Estimates of Relative Cerebral Blood Volume in High-Grade Gliomas by Accounting for Bidirectional Contrast Agent Exchange.
Source:AJNR. American journal of neuroradiology
Published:8/1/2016
Authors:Leu K; Boxerman JL; Cloughesy TF; Lai A; Nghiemphu PL; Liau LM; Pope WB; Ellingson BM;
Abstract:Inclusion of the bidirectional exchange in leakage-correction models for single-echo DSC MR imaging improves the model fit to leakage-contaminated DSC MR imaging data and significantly improves the estimation of relative CBV in high-grade gliomas.
Phase 1 trial of vocimagene amiretrorepvec and 5-fluorocytosine for recurrent high-grade glioma.
Source:Science translational medicine
Published:6/1/2016
Authors:Cloughesy TF; Landolfi J; Hogan DJ; Bloomfield S; Carter B; Chen CC; Elder JB; Kalkanis SN; Kesari S; Lai A; Lee IY; Liau LM; Mikkelsen T; Nghiemphu PL; Piccioni D; Walbert T; Chu A; Das A; Diago OR; Gammon D; Gruber HE; Hanna M; Jolly DJ; Kasahara N; McCarthy D; Mitchell L; Ostertag D; Robbins JM; Rodriguez-Aguirre M; Vogelbaum MA;
Abstract:Toca 511 (vocimagene amiretrorepvec) is an investigational nonlytic, retroviral replicating vector (RRV) that delivers a yeast cytosine deaminase, which converts subsequently administered courses of the investigational prodrug Toca FC (extended-release 5-fluorocytosine) into the antimetabolite 5-fluorouracil. Forty-five subjects with recurrent or progressive high-grade glioma were treated. The end points of this phase 1, open-label, ascending dose, multicenter trial included safety, efficacy, and molecular profiling; survival was compared to a matching subgroup from an external control. Overall survival for recurrent high-grade glioma was 13.6 months (95% confidence interval, 10.8 to 20.0) and was statistically improved relative to an external control (hazard ratio, 0.45; P = 0.003). Tumor samples from subjects surviving more than 52 weeks after Toca 511 delivery disproportionately displayed a survival-related mRNA expression signature, identifying a potential molecular signature that may correlate with treatment-related survival rather than being prognostic. Toca 511 and Toca FC show excellent tolerability, with RRV persisting in the tumor and RRV control systemically. The favorable assessment of Toca 511 and Toca FC supports confirmation in a randomized phase 2/3 trial (NCT02414165).
Clinical aggressiveness of malignant gliomas is linked to augmented metabolism of amino acids.
Source:Journal of neuro-oncology
Published:5/1/2016
Authors:Panosyan EH; Lasky JL; Lin HJ; Lai A; Hai Y; Guo X; Quinn M; Nelson SF; Cloughesy TF; Nghiemphu PL;
Abstract:Glutamine, glutamate, asparagine, and aspartate are involved in an enzyme-network that controls nitrogen metabolism. Branched-chain-amino-acid aminotransferase-1 (BCAT1) promotes proliferation of gliomas with wild-type IDH1 and is closely connected to the network. We hypothesized that metabolism of asparagine, glutamine, and branched-chain-amino-acids is associated with progression of malignant gliomas. Gene expression for asparagine synthetase (ASNS), glutaminase (GLS), and BCAT1 were analyzed in 164 gliomas from 156 patients [33-anaplastic gliomas (AG) and 131-glioblastomas (GBM), 64 of which were recurrent GBMs]. ASNS and GLS were twofold higher in GBMs versus AGs. BCAT1 was also higher in GBMs. ASNS expression was twofold higher in recurrent versus new GBMs. Five patients had serial samples: 4-showed higher ASNS and 3-higher GLS at recurrence. We analyzed grade and treatment in 4 groups: (1) low ASNS, GLS, and BCAT1 (n = 96); (2) low ASNS and GLS, but high BCAT1 (n = 26); (3) high ASNS or GLS, but low BCAT1 (n = 25); and (4) high ASNS or GLS and high BCAT1 (n = 17). Ninety-one  % of patients (29/32) with grade-III lesions were in group 1. In contrast, 95 % of patients (62/65) in groups 2-4 had GBMs. Treatment was similar in 4 groups (radiotherapy-80 %; temozolomide-30 %; other chemotherapy-50 %). High expression of ASNS, GLS, and BCAT1 were each associated with poor survival in the entire group. The combination of lower ASNS, GLS, and BCAT1 levels correlated with better survival for newly diagnosed GBMs (66 patients; P = 0.0039). Only tumors with lower enzymes showed improved outcome with temozolomide. IDH1(WT) gliomas had higher expression of these genes. Manipulation of amino acid metabolism in malignant gliomas may be further studied for therapeutics development.
pH-weighted molecular imaging of gliomas using amine chemical exchange saturation transfer MRI.
Source:Neuro-oncology
Published:11/1/2015
Authors:Harris RJ; Cloughesy TF; Liau LM; Prins RM; Antonios JP; Li D; Yong WH; Pope WB; Lai A; Nghiemphu PL; Ellingson BM;
Abstract:Results suggest pH-weighted MRI may provide new insight into brain tumor physiology beyond traditional imaging technologies.
Quantification of Nonenhancing Tumor Burden in Gliomas Using Effective T2 Maps Derived from Dual-Echo Turbo Spin-Echo MRI.
Source:Clinical cancer research : an official journal of the American Association for Cancer Research
Published:10/1/2015
Authors:Ellingson BM; Lai A; Nguyen HN; Nghiemphu PL; Pope WB; Cloughesy TF;
Abstract:T2 maps using dual-echo data are feasible, stable, and can be used to objectively define NET burden for use in brain tumor characterization, prognosis, and response assessment. The use of effective T2 maps for defining NET burden should be validated in a randomized, clinical trial.
Diffusion MR Characteristics Following Concurrent Radiochemotherapy Predicts Progression-Free and Overall Survival in Newly Diagnosed Glioblastoma.
Source:Tomography : a journal for imaging research
Published:9/1/2015
Authors:Chang W; Pope WB; Harris RJ; Hardy AJ; Leu K; Mody RR; Nghiemphu PL; Lai A; Cloughesy TF; Ellingson BM;
Abstract:The standard of care for newly diagnosed glioblastoma (GBM) is surgery, then radiotherapy (RT) with concurrent temozolomide (TMZ), followed by adjuvant TMZ. We hypothesized patients with low diffusivity measured using apparent diffusion coefficient (ADC) histogram analysis evaluated after RT+TMZ, prior to adjuvant TMZ, would have a significantly shorter progression-free (PFS) and overall survival (OS). To test this hypothesis we evaluated 120 patients with newly diagnosed GBM receiving RT+TMZ followed by adjuvant TMZ. MRI was performed after completion of RT+TMZ, prior to initiation of adjuvant TMZ. A double Gaussian mixed model was used to describe the ADC histograms within the enhancing tumor, where ADCL and ADCH were defined as the mean ADC value of the lower and higher Gaussian distribution, respectively. An ADCL value of 1.0 um(2)/ms and ADCH value of 1.6 um(2)/ms were used to stratify patients into high and low risk categories. Results suggest patients with low ADCL had significantly shorter PFS (Cox Hazard Ratio = 0.12, P = 0.0006). OS was significantly shorter with low ADCL tumors, showing a median OS of 407 vs. 644 days (Cox Hazard Ratio = 0.31, P = 0.047). ADCH was not predictive of PFS or OS when accounting for age and ADCL. In summary, newly diagnosed glioblastoma patients with low ADCL after completion of RT+TMZ are likely to progress and die earlier than patients with higher ADCL. Results suggest ADC histogram analysis may be useful for patient risk stratification following completion of RT+TMZ.
Relationship Between [18F]FDOPA PET Uptake, Apparent Diffusion Coefficient (ADC), and Proliferation Rate in Recurrent Malignant Gliomas.
Source:Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging
Published:6/1/2015
Authors:Karavaeva E; Harris RJ; Leu K; Shabihkhani M; Yong WH; Pope WB; Lai A; Nghiemphu PL; Liau LM; Chen W; Czernin J; Cloughesy TF; Ellingson BM;
Abstract:A significant association may exist between [(18)F]FDOPA uptake, diffusion MRI, and mitotic activity in recurrent malignant gliomas.
MRI perfusion measurements calculated using advanced deconvolution techniques predict survival in recurrent glioblastoma treated with bevacizumab.
Source:Journal of neuro-oncology
Published:5/1/2015
Authors:Harris RJ; Cloughesy TF; Hardy AJ; Liau LM; Pope WB; Nghiemphu PL; Lai A; Ellingson BM;
Abstract:Bevacizumab is a therapeutic drug used in treatment of recurrent glioblastoma to inhibit angiogenesis. Treatment response is often monitored through the use of perfusion MRI measures of cerebral blood volume, flow, and other pharmacokinetic parameters; however, most methods for deriving these perfusion parameters can produce errors depending on bolus kinetics. Recently, a number of new methods have been developed to overcome these challenges. In the current study we examine cerebral blood volume and blood flow characteristics in 45 recurrent glioblastoma patients before and after treatment with bevacizumab. Perfusion MRI data was processed using a standard single value decomposition (SVD) technique, two block-circulant SVD techniques, and a Bayesian estimation technique. A proportional hazards model showed that patients with a large decrease in relative blood volume (RBV) after treatment had extended overall survival (P = 0.0048). Patients with large pre-treatment relative blood flow (RBF) showed extended progression-free survival (P = 0.0216) and overall survival (P = 0.0112), and patients with a large decrease in RBF following treatment showed extended overall survival (P = 0.0049). These results provide evidence that blood volume and blood flow measurements can be used as biomarkers in patients treated with bevacizumab.
Arterial spin-labeling perfusion MRI stratifies progression-free survival and correlates with epidermal growth factor receptor status in glioblastoma.
Source:AJNR. American journal of neuroradiology
Published:4/1/2015
Authors:Qiao XJ; Ellingson BM; Kim HJ; Wang DJ; Salamon N; Linetsky M; Sepahdari AR; Jiang B; Tian JJ; Esswein SR; Cloughesy TF; Lai A; Nghiemphu L; Pope WB;
Abstract:Qualitative evaluation of arterial spin-labeling CBF maps can be used to stratify survival and predict epidermal growth factor receptor variant III expression in patients with glioblastoma.
Tumor-suppressive miR148a is silenced by CpG island hypermethylation in IDH1-mutant gliomas.
Source:Clinical cancer research : an official journal of the American Association for Cancer Research
Published:11/15/2014
Authors:Li S; Chowdhury R; Liu F; Chou AP; Li T; Mody RR; Lou JJ; Chen W; Reiss J; Soto H; Prins R; Liau LM; Mischel PS; Nghiemphu PL; Yong WH; Cloughesy TF; Lai A;
Abstract:We identify miR148a as a novel G-CIMP-associated miRNA, and provide results suggesting that miR148a restoration may have therapeutic implications.
Hypervascular tumor volume estimated by comparison to a large-scale cerebral blood volume radiographic atlas predicts survival in recurrent glioblastoma treated with bevacizumab.
Source:Cancer imaging : the official publication of the International Cancer Imaging Society
Published:11/14/2014
Authors:Leu K; Enzmann DR; Woodworth DC; Harris RJ; Tran AN; Lai A; Nghiemphu PL; Pope WB; Cloughesy TF; Ellingson BM;
Abstract:This study highlights the advantages of large-scale population maps to identify abnormal biological tissues.
Deferred use of bevacizumab for recurrent glioblastoma is not associated with diminished efficacy.
Source:Neuro-oncology
Published:6/1/2014
Authors:Piccioni DE; Selfridge J; Mody RR; Chowdhury R; Li S; Lalezari S; Wawrzynski J; Quan J; Zurayk M; Chou AP; Sanchez DE; Liau LM; Ellingson BM; Pope WB; Nghiemphu PL; Green RM; Wang HJ; Yong WH; Elashoff R; Cloughesy TF; Lai A;
Abstract: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.
Recurrent glioblastoma treated with bevacizumab: contrast-enhanced T1-weighted subtraction maps improve tumor delineation and aid prediction of survival in a multicenter clinical trial.
Source:Radiology
Published:4/1/2014
Authors:Ellingson BM; Kim HJ; Woodworth DC; Pope WB; Cloughesy JN; Harris RJ; Lai A; Nghiemphu PL; Cloughesy TF;
Abstract:Use of CE T1-weighted subtraction maps improved visualization and aided better prediction of patient survival in recurrent GBM treated with bevacizumab compared with conventional segmentation of CE T1-weighted images. Clinical trial registration no. NCT00345163. Online supplemental material is available for this article.
Pretreatment ADC histogram analysis is a predictive imaging biomarker for bevacizumab treatment but not chemotherapy in recurrent glioblastoma.
Source:AJNR. American journal of neuroradiology
Published:4/1/2014
Authors:Ellingson BM; Sahebjam S; Kim HJ; Pope WB; Harris RJ; Woodworth DC; Lai A; Nghiemphu PL; Mason WP; Cloughesy TF;
Abstract:The mean lower Gaussian curve from ADC histogram analysis is a predictive imaging biomarker for bevacizumab-treated, not chemotherapy-treated, recurrent glioblastoma multiforme. Patients with recurrent glioblastoma multiforme with a mean lower Gaussian curve > 1.2 µm(2)/ms have a survival advantage when treated with bevacizumab.
Increased sensitivity to radiochemotherapy in IDH1 mutant glioblastoma as demonstrated by serial quantitative MR volumetry.
Source:Neuro-oncology
Published:3/1/2014
Authors:Tran AN; Lai A; Li S; Pope WB; Teixeira S; Harris RJ; Woodworth DC; Nghiemphu PL; Cloughesy TF; Ellingson BM;
Abstract:The current study supports the hypothesis that IDH1 mutant GBMs are more sensitive to radiochemotherapy than IDH1 wild-type GBMs.
C-terminally truncated form of aB-crystallin is associated with IDH1 R132H mutation in anaplastic astrocytoma.
Source:Journal of neuro-oncology
Published:3/1/2014
Authors:Avliyakulov NK; Rajavel KS; Le KM; Guo L; Mirsadraei L; Yong WH; Liau LM; Li S; Lai A; Nghiemphu PL; Cloughesy TF; Linetsky M; Haykinson MJ; Pope WB;
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 aB-crystallin, a small heat-shock and anti-apoptotic protein. aB-crystallin proteins are elevated up to 22-fold in IDH1(R132H) mutant tumors, and aB-crystallin expression appears to be controlled at the post-translational level. We identified the most abundant form of aB-crystallin as a low molecular weight species that is C-terminally truncated. We also found that overexpression of aB-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 aB-crystallin protein with the IDH1(R132H) mutation is a novel finding that could impact apoptosis and stress response in IDH1 mutant glioma.
Short-interval estimation of proliferation rate using serial diffusion MRI predicts progression-free survival in newly diagnosed glioblastoma treated with radiochemotherapy.
Source:Journal of neuro-oncology
Published:2/1/2014
Authors:Zaw TM; Pope WB; Cloughesy TF; Lai A; Nghiemphu PL; Ellingson BM;
Abstract:Cell invasion, motility, and proliferation level estimate (CIMPLE) mapping is a new imaging technique that provides parametric maps of microscopic invasion and proliferation rate estimates using serial diffusion MRI data. However, a few practical constraints have limited the use of CIMPLE maps as a tool for estimating these dynamic parameters, particularly during short-interval follow-up times. The purpose of the current study was to develop an approximation for the CIMPLE map solution for short-interval scanning involving the assumption that net intervoxel tumor invasion does not occur within sufficiently short time frames. Proliferation rate maps created using the "no invasion" approximation were found to be increasingly similar to maps created from full solution during increasingly longer follow-up intervals (3D cross correlation, R (2) = 0.5298, P = 0.0001). Results also indicate proliferation rate maps from the "no invasion" approximation had significantly higher sensitivity (82 vs. 64%) and specificity (90 vs. 80%) for predicting 6 month progression free survival and was a better predictor of time to progression during standard radiochemotherapy compared to the full CIMPLE solution (log-rank; no invasion estimation, P = 0.0134; full solution, P = 0.0555). Together, results suggest the "no invasion" approximation allows for quick estimation of proliferation rate using diffusion MRI data obtained from multiple scans obtained daily or biweekly for use in quantifying early treatment response.
Nonlinear distortion correction of diffusion MR images improves quantitative DTI measurements in glioblastoma.
Source:Journal of neuro-oncology
Published:2/1/2014
Authors:Woodworth DC; Pope WB; Liau LM; Kim HJ; Lai A; Nghiemphu PL; Cloughesy TF; Ellingson BM;
Abstract:The purpose of this study was to use a retrospective nonlinear distortion correction technique and evaluate the changes in DTI metrics in areas of interest in and around GBM tumors. A total of 24 histologically confirmed GBM patients with pre-operative 20-direction DTI scans were examined. Variability in apparent diffusion coefficient (ADC) and fractional anisotropy (FA) in normal tissue before and after distortion correction were examined. Changes in mean, median and variance of ADC and FA in contrast enhancing and T2/FLAIR ROIs were also examined with and without distortion correction. Results suggest the intra-subject SDs of ADC and FA decreased in normal tissue after the application of distortion correction (P < 0.0001). FA mean and median values decreased after distortion correction in both T1+C and T2 ROIs (P < 0.017), while ADC mean and median values did not significantly change except for the median ADC in T1+C ROIs (P = 0.0054). The intra-subject SD of ADC and FA values in tumor ROIs changed significantly with distortion correction, and Bland-Altman analysis indicated that the bias and the SD of the bias of these intra-subject SDs were larger than those of the mean and median terms. Additionally, the means of the two curves of a double Gaussian fit to the histogram of ADC values from T1+C ROIs, ADCL (mean of lower Gaussian) as well as ADCH (mean of the higher Gaussian) were found to change significantly with distortion correction (P = 0.0045 for ADCL and P = 0.0370 for ADCH). Nonlinear distortion correction better aligns neuro-anatomical structures between DTI and anatomical scans, and significantly alters the measurement of values within tumor ROIs for GBM patients.
Altered functional connectivity of the default mode network in diffuse gliomas measured with pseudo-resting state fMRI.
Source:Journal of neuro-oncology
Published:1/1/2014
Authors:Harris RJ; Bookheimer SY; Cloughesy TF; Kim HJ; Pope WB; Lai A; Nghiemphu PL; Liau LM; Ellingson BM;
Abstract:The purpose of the current study was to explore whether brain tumors disrupt the integrity of the default mode network (DMN), a well-characterized resting-state fMRI network. We evaluated whether tumor grade, volume, post-surgical/clinical status, or location decreased the functional connectivity within the DMN in patients with gliomas. Task-based fMRI data was obtained from 68 diffuse glioma patients and 12 healthy volunteers. Pseudo-resting state fMRI data was calculated from task-based fMRI data using standard techniques. Data was preprocessed and DMN integrity was compared across WHO grade, tumor volume surgical status (new vs. recurrent tumors), age, and KPS using univariate and multivariate linear models. WHO grade was the most significant predictor of DMN integrity (P = 0.004), whereas T2 hyperintense lesion volume was not a predictor (P = 0.154). DMN integrity was lower in high-grade (WHO III–IV) compared with low-grade (WHO II) patients (P = 0.020). Tumors in the left parietal lobe showed a more impaired DMN compared with tumors in the frontal lobe, while tumors within and outside the network nodes did not differ significantly. Results suggest higher tumor grade along with prior surgery and/or treatment cause the largest reduction in DMN functional connectivity in patients with primary gliomas, and that tumor location has an impact on connectivity.
Evaluation of high ipsilateral subventricular zone radiation therapy dose in glioblastoma: a pooled analysis.
Source:International journal of radiation oncology, biology, physics
Published:7/15/2013
Authors:Lee P; Eppinga W; Lagerwaard F; Cloughesy T; Slotman B; Nghiemphu PL; Wang PC; Kupelian P; Agazaryan N; Demarco J; Selch MT; Steinberg M; Kang JJ;
Abstract:High radiation therapy doses to ipsilateral CSC niches are associated with improved PFS in glioblastoma.
Identifying the mesenchymal molecular subtype of glioblastoma using quantitative volumetric analysis of anatomic magnetic resonance images.
Source:Neuro-oncology
Published:5/1/2013
Authors:Naeini KM; Pope WB; Cloughesy TF; Harris RJ; Lai A; Eskin A; Chowdhury R; Phillips HS; Nghiemphu PL; Behbahanian Y; Ellingson BM;
Abstract:Results suggest that volume ratio may be a simple, cost-effective, and noninvasive biomarker for quickly identifying MES GBM.
Pre- and post-contrast three-dimensional double inversion-recovery MRI in human glioblastoma.
Source:Journal of neuro-oncology
Published:4/1/2013
Authors:Harris RJ; Cloughesy TF; Pope WB; Godinez S; Natsuaki Y; Nghiemphu PL; Meyer H; Paul D; Behbahanian Y; Lai A; Ellingson BM;
Abstract:Fluid attenuated inversion recovery (FLAIR) MRI sequences have become an indispensible tool for defining the malignant boundary in patients with brain tumors by nulling the signal contribution from cerebrospinal fluid allowing both regions of edema and regions of non-enhancing, infiltrating tumor to become hyperintense on resulting images. In the current study we examined the utility of a three-dimensional double inversion recovery (DIR) sequence that additionally nulls the MR signal associated with white matter, implemented either pre-contrast or post-contrast, in order to determine whether this sequence allows for better differentiation between tumor and normal brain tissue. T1- and T2-weighted, FLAIR, dynamic susceptibility contrast (DSC)-MRI estimates of cerebral blood volume (rCBV), contrast-enhanced T1-weighted images (T1+C), and DIR data (pre- or post-contrast) were acquired in 22 patients with glioblastoma. Contrast-to-noise (CNR) and tumor volumes were compared between DIR and FLAIR sequences. Line profiles across regions of tumor were generated to evaluate similarities between image contrasts. Additionally, voxel-wise associations between DIR and other sequences were examined. Results suggested post-contrast DIR images were hyperintense (bright) in regions spatially similar those having FLAIR hyperintensity and hypointense (dark) in regions with contrast-enhancement or elevated rCBV due to the high sensitivity of 3D turbo spin echo sequences to susceptibility differences between different tissues. DIR tumor volumes were statistically smaller than tumor volumes as defined by FLAIR (Paired t test, P = 0.0084), averaging a difference of approximately 14 mL or 24 %. DIR images had approximately 1.5× higher lesion CNR compared with FLAIR images (Paired t test, P = 0.0048). Line profiles across tumor regions and scatter plots of voxel-wise coherence between different contrasts confirmed a positive correlation between DIR and FLAIR signal intensity and a negative correlation between DIR and both post-contrast T1-weighted image signal intensity and rCBV. Additional discrepancies between FLAIR and DIR abnormal regions were also observed, together suggesting DIR may provide additional information beyond that of FLAIR.
PET Parametric Response Mapping for Clinical Monitoring and Treatment Response Evaluation in Brain Tumors.
Source:PET clinics
Published:4/1/2013
Authors:Ellingson BM; Chen W; Harris RJ; Pope WB; Lai A; Nghiemphu PL; Czernin J; Phelps ME; Cloughesy TF;
Abstract:PET parametric response maps (PRMs) are a provocative new molecular imaging technique for quantifying brain tumor response to therapy in individual patients. By aligning sequential PET scans over time using anatomic MR imaging information, the voxel-wise change in radiotracer uptake can be quantified and visualized. PET PRMs can be performed before and after a particular therapy to test whether the tumor is responding favorably, or performed relative to a distant time point to monitor changes through the course of a treatment. This article focuses on many of the technical details involved in generating, visualizing, and quantifying PET PRMs, and practical applications and example case studies.
Combined analysis of O6-methylguanine-DNA methyltransferase protein expression and promoter methylation provides optimized prognostication of glioblastoma outcome.
Source:Neuro-oncology
Published:3/1/2013
Authors:Lalezari S; Chou AP; Tran A; Solis OE; Khanlou N; Chen W; Li S; Carrillo JA; Chowdhury R; Selfridge J; Sanchez DE; Wilson RW; Zurayk M; Lalezari J; Lou JJ; Ormiston L; Ancheta K; Hanna R; Miller P; Piccioni D; Ellingson BM; Buchanan C; Mischel PS; Nghiemphu PL; Green R; Wang HJ; Pope WB; Liau LM; Elashoff RM; Cloughesy TF; Yong WH; Lai A;
Abstract:Optimal assessment of MGMT status as a prognostic biomarker for patients with newly diagnosed GBM treated with chemoradiation requires determination of both promoter methylation and IHC protein expression.
Quantitative probabilistic functional diffusion mapping in newly diagnosed glioblastoma treated with radiochemotherapy.
Source:Neuro-oncology
Published:3/1/2013
Authors:Ellingson BM; Cloughesy TF; Lai A; Nghiemphu PL; Liau LM; Pope WB;
Abstract:Results suggest that probabilistic fDMs are a more predictive biomarker in terms of 12-month PFS and 24-month OS in newly diagnosed glioblastoma, compared with traditional fDM analysis.
Probabilistic radiographic atlas of glioblastoma phenotypes.
Source:AJNR. American journal of neuroradiology
Published:3/1/2013
Authors:Ellingson BM; Lai A; Harris RJ; Selfridge JM; Yong WH; Das K; Pope WB; Nghiemphu PL; Vinters HV; Liau LM; Mischel PS; Cloughesy TF;
Abstract:Radiographic atlases for specific phenotypes provide insight into overlap between prognostic variables and may help to identify niche locations for cancer cells of origin.
Imaging biomarkers for antiangiogenic therapy in malignant gliomas.
Source:CNS oncology
Published:1/1/2013
Authors:Leu K; Pope WB; Cloughesy TF; Lai A; Nghiemphu PL; Chen W; Liau LM; Ellingson BM;
Abstract:The discovery that malignant gliomas produce an excessive amount of VEGF, a key mediator of angiogenesis, has heightened interest in developing drugs that block angiogenic pathways. These antiangiogenic drugs tend to decrease vascular permeability, thereby diminishing tumor contrast enhancement independent of anti-tumor effects. This has made the determination of tumor response difficult, since contrast enhancement on post-contrast T1-weighted images is standard for assessing therapy effectiveness. In light of these unique challenges in assessing antiangiogenic therapy, new biomarkers have been proposed, based on advanced magnetic resonance techniques and PET. This article outlines the challenges associated with the evaluation of antiangiogenic therapy in malignant gliomas and describes how new imaging biomarkers can be used to better predict response.
A dose escalation trial for the combination of erlotinib and sirolimus for recurrent malignant gliomas.
Source:Journal of neuro-oncology
Published:11/1/2012
Authors:Nghiemphu PL; Lai A; Green RM; Reardon DA; Cloughesy T;
Abstract:In order to achieve higher dosages than previously used in clinical trials, we conducted a phase I trial to determine the maximum tolerated dose (MTD) for the combination of erlotinib and sirolimus for the treatments of recurrent malignant gliomas. Patients with pathologically proven World Health Organization (WHO) grade III glioma and grade IV glioblastoma and radiographically proven tumor recurrence were eligible for this study. Treatments included once daily erlotinib, which was given alone for the first 7 days of treatments, then in combination with once daily sirolimus. Sirolimus was given with a loading dose on day 8 followed by a maintenance dose starting on day 9. Dose-limiting toxicity (DLT) was determined over the first 28 days of treatments, and the MTD was determined in a 3 + 3 classic study design. 19 patients were enrolled, and 13 patients were eligible for MTD determination. The MTD was determined to be 150 mg daily for erlotinib and 5 mg daily (after a 15 mg loading dose) for sirolimus. The DLTs included rash and mucositis (despite maximal medical managements), hypophosphatemia, altered mental status, and neutropenia. The combination of erlotinib and sirolimus is difficult to tolerate at dosages higher than previously reported in phase II trials.
Identification of retinol binding protein 1 promoter hypermethylation in isocitrate dehydrogenase 1 and 2 mutant gliomas.
Source:Journal of the National Cancer Institute
Published:10/3/2012
Authors:Chou AP; Chowdhury R; Li S; Chen W; Kim AJ; Piccioni DE; Selfridge JM; Mody RR; Chang S; Lalezari S; Lin J; Sanchez DE; Wilson RW; Garrett MC; Harry B; Mottahedeh J; Nghiemphu PL; Kornblum HI; Mischel PS; Prins RM; Yong WH; Cloughesy T; Nelson SF; Liau LM; Lai A;
Abstract:RBP1 promoter hypermethylation is found in nearly all IDH1 and IDH2 mutant gliomas and is associated with improved patient survival. Because RBP1 is involved in retinoic acid synthesis, our results suggest that dysregulation of retinoic acid metabolism may contribute to glioma formation along the IDH1/IDH2-mutant pathway.
Persistent diffusion-restricted lesions in bevacizumab-treated malignant gliomas are associated with improved survival compared with matched controls.
Source:AJNR. American journal of neuroradiology
Published:10/1/2012
Authors:Mong S; Ellingson BM; Nghiemphu PL; Kim HJ; Mirsadraei L; Lai A; Yong W; Zaw TM; Cloughesy TF; Pope WB;
Abstract:Restricted-diffusion lesions in malignant gliomas treated with bevacizumab are generally stable with time and are associated with improved outcomes. These results combined with physiologic imaging and histopathologic data suggest that these lesions are not consistent with aggressive tumor.
Glioblastoma therapy in the elderly: one age does not fit all.
Source:The Lancet. Oncology
Published:9/1/2012
Authors:Nghiemphu PL; Cloughesy T;
Abstract:
18F-FDOPA and 18F-FLT positron emission tomography parametric response maps predict response in recurrent malignant gliomas treated with bevacizumab.
Source:Neuro-oncology
Published:8/1/2012
Authors:Harris RJ; Cloughesy TF; Pope WB; Nghiemphu PL; Lai A; Zaw T; Czernin J; Phelps ME; Chen W; Ellingson BM;
Abstract:The current study examined the use of voxel-wise changes in (18)F-FDOPA and (18)F-FLT PET uptake, referred to as parametric response maps (PRMs), to determine whether they were predictive of response to bevacizumab in patients with recurrent malignant gliomas. Twenty-four patients with recurrent malignant gliomas who underwent bevacizumab treatment were analyzed. Patients had MR and PET images acquired before and at 2 time points after bevacizumab treatment. PRMs were created by examining the percentage change in tracer uptake between time points in each image voxel. Voxel-wise increase in PET uptake in areas of pretreatment contrast enhancement defined by MRI stratified 3-month progression-free survival (PFS) and 6-month overall survival (OS) according to receiver-operating characteristic curve analysis. A decrease in PET tracer uptake was associated with longer PFS and OS, whereas an increase in PET uptake was associated with short PFS and OS. The volume fraction of increased (18)F-FDOPA PET uptake between the 2 posttreatment time points also stratified long- and short-term PFS and OS (log-rank, P < .05); however, (18)F-FLT uptake did not stratify OS. This study suggests that an increase in FDOPA or FLT PET uptake on PRMs after bevacizumab treatment may be a useful biomarker for predicting PFS and that FDOPA PET PRMs are also predictive of OS in recurrent gliomas treated with bevacizumab.
Bevacizumab as first-line therapy for glioblastoma.
Source:Future oncology (London, England)
Published:8/1/2012
Authors:Piccioni D; Lai A; Nghiemphu P; Cloughesy T;
Abstract:Bevacizumab is a monoclonal antibody that binds and neutralizes VEGF. Bevacizumab is currently indicated as monotherapy for recurrent glioblastoma. Recent data from Phase II trials of bevacizumab as first-line therapy for glioblastoma have been promising, and have led to two Phase III trials evaluating the use of bevacizumab as first-line therapy when combined with radiation and temozolomide. Potential complications relating to interpretation of the results of these Phase III studies include the crossover use of bevacizumab upon recurrence in the placebo arm. Recently published single-arm evaluations of adding bevacizumab to standard first-line therapy in glioblastoma multiforme have shown an improvement in progression-free survival and overall survival when compared with historical controls obtained prior to widespread use of bevacizumab in recurrent glioblastoma multiforme. When these data are compared with more contemporary studies from the bevacizumab era, the improvement in progression-free survival seems to be maintained but the impact on overall survival with first-line bevacizumab therapy seems less clear. Bevacizumab therapy alters the imaging characteristics of glioblastoma, and new criteria have been established to assess treatment response and progression in the setting of widespread bevacizumab use.
Relationship between tumor enhancement, edema, IDH1 mutational status, MGMT promoter methylation, and survival in glioblastoma.
Source:AJNR. American journal of neuroradiology
Published:8/1/2012
Authors:Carrillo JA; Lai A; Nghiemphu PL; Kim HJ; Phillips HS; Kharbanda S; Moftakhar P; Lalaezari S; Yong W; Ellingson BM; Cloughesy TF; Pope WB;
Abstract:Imaging features are potentially predictive of IDH1 mutational status but were poorly correlated with MGMT promoter methylation. Edema stratifies survival in MGMT promoter methylated but not in unmethylated tumors; patients with methylated tumors with little or no edema have particularly long survival.
Apparent diffusion coefficient histogram analysis stratifies progression-free and overall survival in patients with recurrent GBM treated with bevacizumab: a multi-center study.
Source:Journal of neuro-oncology
Published:7/1/2012
Authors:Pope WB; Qiao XJ; Kim HJ; Lai A; Nghiemphu P; Xue X; Ellingson BM; Schiff D; Aregawi D; Cha S; Puduvalli VK; Wu J; Yung WK; Young GS; Vredenburgh J; Barboriak D; Abrey LE; Mikkelsen T; Jain R; Paleologos NA; Rn PL; Prados M; Goldin J; Wen PY; Cloughesy T;
Abstract:We have tested the predictive value of apparent diffusion coefficient (ADC) histogram analysis in stratifying progression-free survival (PFS) and overall survival (OS) in bevacizumab-treated patients with recurrent glioblastoma multiforme (GBM) from the multi-center BRAIN study. Available MRI's from patients enrolled in the BRAIN study (n = 97) were examined by generating ADC histograms from areas of enhancing tumor on T1 weighted post-contrast images fitted to a two normal distribution mixture curve. ADC classifiers including the mean ADC from the lower curve (ADC-L) and the mean lower curve proportion (LCP) were tested for their ability to stratify PFS and OS by using Cox proportional hazard ratios and the Kaplan-Meier method with log-rank test. Mean ADC-L was 1,209 × 10(-6)mm(2)/s ± 224 (SD), and mean LCP was 0.71 ± 0.23 (SD). Low ADC-L was associated with worse outcome. The hazard ratios for 6-month PFS, overall PFS, and OS in patients with less versus greater than mean ADC-L were 3.1 (95 % confidence interval: 1.6, 6.1; P = 0.001), 2.3 (95 % CI: 1.3, 4.0; P = 0.002), and 2.4 (95 % CI: 1.4, 4.2; P = 0.002), respectively. In patients with ADC-L <1,209 and LCP >0.71 versus ADC-L >1,209 and LCP <0.71, there was a 2.28-fold reduction in the median time to progression, and a 1.42-fold decrease in the median OS. The predictive value of ADC histogram analysis, in which low ADC-L was associated with poor outcome, was confirmed in bevacizumab-treated patients with recurrent GBM in a post hoc analysis from the multi-center (BRAIN) study.
Comparison between intensity normalization techniques for dynamic susceptibility contrast (DSC)-MRI estimates of cerebral blood volume (CBV) in human gliomas.
Source:Journal of magnetic resonance imaging : JMRI
Published:6/1/2012
Authors:Ellingson BM; Zaw T; Cloughesy TF; Naeini KM; Lalezari S; Mong S; Lai A; Nghiemphu PL; Pope WB;
Abstract:The results suggest Gaussian normalization of leakage-corrected CBV maps may be the best choice for image intensity correction for use in large-scale, multicenter clinical trials where MR scanners and protocols vary widely due to ease of implementation, lowest variability, and highest tumor to normal tissue contrast.
Differential gene expression in glioblastoma defined by ADC histogram analysis: relationship to extracellular matrix molecules and survival.
Source:AJNR. American journal of neuroradiology
Published:6/1/2012
Authors:Pope WB; Mirsadraei L; Lai A; Eskin A; Qiao J; Kim HJ; Ellingson B; Nghiemphu PL; Kharbanda S; Soriano RH; Nelson SF; Yong W; Phillips HS; Cloughesy TF;
Abstract:High-ADC GBMs show greater levels of ECM protein gene expression compared with low-ADC GBMs. It is unclear whether this translates to the accumulation of higher levels of the encoded proteins. However, because ECM molecules could contribute to a proinvasive phenotype, this relationship merits further investigation.
Differential sensitivity of glioma- versus lung cancer-specific EGFR mutations to EGFR kinase inhibitors.
Source:Cancer discovery
Published:5/1/2012
Authors:Vivanco I; Robins HI; Rohle D; Campos C; Grommes C; Nghiemphu PL; Kubek S; Oldrini B; Chheda MG; Yannuzzi N; Tao H; Zhu S; Iwanami A; Kuga D; Dang J; Pedraza A; Brennan CW; Heguy A; Liau LM; Lieberman F; Yung WK; Gilbert MR; Reardon DA; Drappatz J; Wen PY; Lamborn KR; Chang SM; Prados MD; Fine HA; Horvath S; Wu N; Lassman AB; DeAngelis LM; Yong WH; Kuhn JG; Mischel PS; Mehta MP; Cloughesy TF; Mellinghoff IK;
Abstract:Approximately 40% of human glioblastomas harbor oncogenic EGFR alterations, but attempts to therapeutically target EGFR with first-generation EGFR kinase inhibitors have failed. Here, we demonstrate selective sensitivity of glioma-specific EGFR mutants to ATP-site competitive EGFR kinase inhibitors that target the inactive conformation of the catalytic domain.
Functional diffusion maps (fDMs) evaluated before and after radiochemotherapy predict progression-free and overall survival in newly diagnosed glioblastoma.
Source:Neuro-oncology
Published:3/1/2012
Authors:Ellingson BM; Cloughesy TF; Zaw T; Lai A; Nghiemphu PL; Harris R; Lalezari S; Wagle N; Naeini KM; Carrillo J; Liau LM; Pope WB;
Abstract:Functional diffusion mapping (fDM) has shown promise as a sensitive imaging biomarker for predicting survival in initial studies consisting of a small number of patients, mixed tumor grades, and before routine use of anti-angiogenic therapy. The current study tested whether fDM performed before and after radiochemotherapy could predict progression-free and overall survival in 143 patients with newly diagnosed glioblastoma from 2007 through 2010, many treated with anti-angiogenic therapy after recurrence. Diffusion and conventional MRI scans were obtained before and 4 weeks after completion of radiotherapy and concurrent temozolomide treatment. FDM was created by coregistering pre- and posttreatment apparent diffusion coefficient (ADC) maps and then performing voxel-wise subtraction. FDMs were categorized according to the degree of change in ADC in pre- and posttreatment fluid-attenuated inversion recovery (FLAIR) and contrast-enhancing regions. The volume fraction of fDM-classified increasing ADC(+), decreasing ADC(-), and change in ADC(+/-) were tested to determine whether they were predictive of survival. Both Bonferroni-corrected univariate log-rank analysis and Cox proportional hazards modeling demonstrated that patients with decreasing ADC in a large volume fraction of pretreatment FLAIR or contrast-enhancing regions were statistically more likely to progress earlier and expire sooner than in patients with a lower volume fraction. The current study supports the hypothesis that fDM is a sensitive imaging biomarker for predicting survival in glioblastoma.
Impact of 3,4-dihydroxy-6-18F-fluoro-L-phenylalanine PET/CT on managing patients with brain tumors: the referring physician's perspective.
Source:Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Published:3/1/2012
Authors:Walter F; Cloughesy T; Walter MA; Lai A; Nghiemphu P; Wagle N; Fueger B; Satyamurthy N; Phelps ME; Czernin J;
Abstract:(18)F-DOPA PET/CT changed the intended management of 41% of patients with brain tumors, and intended management changes were implemented in 75% of these. These changes suggest a potentially important clinical role of imaging amino acid transport in the management of brain tumor patients.
Anatomic localization of O6-methylguanine DNA methyltransferase (MGMT) promoter methylated and unmethylated tumors: a radiographic study in 358 de novo human glioblastomas.
Source:NeuroImage
Published:1/16/2012
Authors:Ellingson BM; Cloughesy TF; Pope WB; Zaw TM; Phillips H; Lalezari S; Nghiemphu PL; Ibrahim H; Naeini KM; Harris RJ; Lai A;
Abstract:Promoter methylation of O6-methylguanine DNA methyltransferase (MGMT) is associated with a favorable prognosis in glioblastoma multiforme (GBM) and has been hypothesized to occur early in tumor transformation of glial cells. Thus, a possible link exists between the site of malignant transformation and MGMT promoter methylation status. Using the Analysis of Differential Involvement (ADIFFI) statistical mapping technique in a total of 358 patients with GBM, we demonstrate that human de novo GBMs occur in a high frequency contiguous with the posterior subventricular zone (SVZ); MGMT promoter methylated GBMs are lateralized to the left hemisphere, while MGMT unmethylated GBMs are lateralized to the right hemisphere; and tumors near the left temporal lobe have a significantly longer overall survival compared with tumors occurring elsewhere, independent of treatment or MGMT methylation status.
Quantification of edema reduction using differential quantitative T2 (DQT2) relaxometry mapping in recurrent glioblastoma treated with bevacizumab.
Source:Journal of neuro-oncology
Published:1/1/2012
Authors:Ellingson BM; Cloughesy TF; Lai A; Nghiemphu PL; Lalezari S; Zaw T; Motevalibashinaeini K; Mischel PS; Pope WB;
Abstract:The purpose of the current study was to quantify the reduction in T2 signal abnormality accompanying administration of the anti-angiogenic drug bevacizumab in recurrent glioblastoma (GBM) patients using a voxel-wise differential quantitative T2 (DQT2) mapping technique. Twenty-six patients with recurrent GBM treated with bevacizumab were scanned before and 4-6 weeks after treatment on a 1.5T clinical MR scanner. Quantitative T2 maps were created from proton density and T2-weighted images acquired using a standard multi-echo fast-spin echo sequence. T2 maps after treatment were co-registered with T2 maps prior to treatment in the same patient, and then voxel-wise subtraction was performed to create DQT2 maps for each patient. Results suggest DQT2 maps allow visualization and quantification of voxel-wise T2 changes resulting from anti-VEGF therapy. Results demonstrated a significant decrease in T2 within pre-treatment T2 abnormal regions (mean reduction = 49.4 ms at 1.5T) following anti-VEGF treatment (Wilcoxon signed rank test, P < 0.0001). An elevated residual, post-treatment, median T2 was predictive of both progression-free (Log-rank, P = 0.0074) and overall survival (Log-rank, P = 0.0393).
Nonlinear registration of diffusion-weighted images improves clinical sensitivity of functional diffusion maps in recurrent glioblastoma treated with bevacizumab.
Source:Magnetic resonance in medicine
Published:1/1/2012
Authors:Ellingson BM; Cloughesy TF; Lai A; Nghiemphu PL; Pope WB;
Abstract:Diffusion-weighted imaging estimates of apparent diffusion coefficient (ADC) have shown sensitivity to brain tumor cellularity as well as response to therapy. Functional diffusion maps (fDMs) exploit these principles by examining voxelwise changes in ADC within the same patient over time. Currently, the fDM technique involves linear image registration of ADC maps from subsequent follow-up times to pretreatment ADC maps; however, misregistration of ADC maps due to geometric distortions as well as mass effect from growing tumor can confound fDM measurements. In this study, we compare the use of a nonlinear registration scheme to the current linear fDM technique in 70 patients with recurrent glioblastoma multiforme treated with bevacizumab. Results suggest that nonlinear registration of pretreatment ADC maps to post-treatment ADC maps improves the clinical predictability, sensitivity, and specificity of fDMs for both progression-free and overall survival.
Evidence for sequenced molecular evolution of IDH1 mutant glioblastoma from a distinct cell of origin.
Source:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Published:12/1/2011
Authors:Lai A; Kharbanda S; Pope WB; Tran A; Solis OE; Peale F; Forrest WF; Pujara K; Carrillo JA; Pandita A; Ellingson BM; Bowers CW; Soriano RH; Schmidt NO; Mohan S; Yong WH; Seshagiri S; Modrusan Z; Jiang Z; Aldape KD; Mischel PS; Liau LM; Escovedo CJ; Chen W; Nghiemphu PL; James CD; Prados MD; Westphal M; Lamszus K; Cloughesy T; Phillips HS;
Abstract:Although histologically similar, GBMs arising with and without IDH1(R132MUT) appear to represent distinct disease entities that arise from separate cell types of origin as the result of largely nonoverlapping sets of molecular events. Optimal clinical management should account for the distinction between these GBM disease subtypes.
A phase I trial of tipifarnib with radiation therapy, with and without temozolomide, for patients with newly diagnosed glioblastoma.
Source:International journal of radiation oncology, biology, physics
Published:12/1/2011
Authors:Nghiemphu PL; Wen PY; Lamborn KR; Drappatz J; Robins HI; Fink K; Malkin MG; Lieberman FS; DeAngelis LM; Torres-Trejo A; Chang SM; Abrey L; Fine HA; Demopoulos A; Lassman AB; Kesari S; Mehta MP; Prados MD; Cloughesy TF;
Abstract:Tipifarnib is well tolerated at 300 mg bid given discontinuously (21/28 days) in 4-week cycles, concurrently with standard chemo/radiotherapy. A Phase II study should evaluate the efficacy of tipifarnib with radiation and TMZ in patients with newly diagnosed glioblastoma and not receiving EIAED.
Graded functional diffusion map-defined characteristics of apparent diffusion coefficients predict overall survival in recurrent glioblastoma treated with bevacizumab.
Source:Neuro-oncology
Published:10/1/2011
Authors:Ellingson BM; Cloughesy TF; Lai A; Mischel PS; Nghiemphu PL; Lalezari S; Schmainda KM; Pope WB;
Abstract:Diffusion imaging has shown promise as a predictive and prognostic biomarker in glioma. We assessed the ability of graded functional diffusion maps (fDMs) and apparent diffusion coefficient (ADC) characteristics to predict overall survival (OS) in recurrent glioblastoma multiforme (GBM) patients treated with bevacizumab. Seventy-seven patients with recurrent GBMs were retrospectively examined. MRI scans were obtained before and approximately 6 weeks after treatment with bevacizumab. Graded fDMs were created by registering datasets to each patient's pretreatment scan and then performing voxel-wise subtraction between post- and pretreatment ADC maps. Voxels were categorized according to the degree of change in ADC within pretreatment fluid-attenuated inversion recovery (FLAIR) and contrast-enhancing regions of interest (ROIs). We found that the volume of tissue showing decreased ADC within both FLAIR and contrast-enhancing regions stratified OS (log-rank, P < .05). fDMs applied to contrast-enhancing ROIs more accurately predicted OS compared with fDMs applied to FLAIR ROIs. Graded fDMs (showing voxels with decreased ADC between 0.25 and 0.4 µm(2)/ms) were more predictive of OS than traditional (single threshold) fDMs, and the predictive ability of graded fDMs could be enhanced even further by adding the ADC characteristics from the fDM-classified voxels to the analysis (log-rank, P < .001). These results demonstrate that spatially resolved diffusion-based tumor metrics are a powerful imaging biomarker of survival in patients with recurrent GBM treated with bevacizumab.
Cell invasion, motility, and proliferation level estimate (CIMPLE) maps derived from serial diffusion MR images in recurrent glioblastoma treated with bevacizumab.
Source:Journal of neuro-oncology
Published:10/1/2011
Authors:Ellingson BM; Cloughesy TF; Lai A; Nghiemphu PL; Pope WB;
Abstract:Microscopic invasion of tumor cells and undetected tumor proliferation is the primary reason for a dismal prognosis in glioblastoma patients. Identification and quantification of spatially localized brain regions undergoing high rates of cell migration and proliferation is critical for improving patient survival; however, there are currently no non-invasive imaging biomarkers for estimating proliferation and migration rates of human gliomas in vivo. To accomplish this, we developed CIMPLE (cell invasion, motility, and proliferation level estimates) image maps using serial diffusion MRI scans and a solution to a glioma growth model equation. CIMPLE represent a novel method of quantifying the level of aggressive malignant behavior. In the current pilot study, we demonstrate the utility of CIMPLE maps to predict progression free survival (PFS) and overall survival (OS) in 26 recurrent glioblastoma patients treated with bevacizumab from our Neuro-Oncology database. Voxel-wise estimates of cell proliferation rate predicted spatial regions of contrast enhancement in 35% of patients. A linear correlation was found between the mean proliferation rate and progression-free survival (PFS; P < 0.0001) as well as overall survival (OS; P = 0.0093). Similarly, the mean proliferation rate was able to stratify patients with early and late PFS as well as OS.
High order diffusion tensor imaging in human glioblastoma.
Source:Academic radiology
Published:8/1/2011
Authors:Ellingson BM; Cloughesy TF; Lai A; Nghiemphu PL; Liau LM; Pope WB;
Abstract:These results suggest that the fourth-order diffusion tensor has the ability to add value to second-order (traditional) diffusion tensor imaging in the evaluation of glioblastoma.
Apparent diffusion coefficient histogram analysis stratifies progression-free survival in newly diagnosed bevacizumab-treated glioblastoma.
Source:AJNR. American journal of neuroradiology
Published:5/1/2011
Authors:Pope WB; Lai A; Mehta R; Kim HJ; Qiao J; Young JR; Xue X; Goldin J; Brown MS; Nghiemphu PL; Tran A; Cloughesy TF;
Abstract:Pretreatment ADC histogram analysis can stratify progression-free survival in bevacizumab-treated patients with newly diagnosed GBM. Lower ADC is associated with tumor MGMT promoter methylation, which may, in part, account for the favorable outcome associated with low ADC(L) tumors.
Quantitative volumetric analysis of conventional MRI response in recurrent glioblastoma treated with bevacizumab.
Source:Neuro-oncology
Published:4/1/2011
Authors:Ellingson BM; Cloughesy TF; Lai A; Nghiemphu PL; Mischel PS; Pope WB;
Abstract:Although the effects of bevacizumab on magnetic resonance images (MRIs) of recurrent glioblastoma multiforme (GBM) are well documented, to our knowledge, no studies have explicitly quantified the volumetric changes resulting from initial treatment, nor have there been studies examining the ability for volumetric changes in conventional MRI to predict progression-free survival (PFS) and overall survival (OS). In the current study, we retrospectively examined volumetric changes on conventional MRI scans in 84 patients with recurrent GBM. MRIs were obtained before (mean, 11 days) and after (mean, 42 days) treatment with bevacizumab. The volume of abnormal fluid-attenuated inversion recovery (FLAIR) signal intensity, the volume of contrast enhancement, and the ratio of the 2 were quantified for each patient before and after initial treatment. Results demonstrated that initial treatment with bevacizumab resulted in a significant decrease in both the volume of abnormal FLAIR signal and the volume of contrast enhancement. Initial, residual, and change in FLAIR volume were not predictive of PFS or OS. Initial contrast-enhancing volume was predictive of PFS but not OS. The pretreatment relative nonenhancing tumor ratio, defined as the ratio of FLAIR to contrast-enhancing volume, was found to be predictive of both PFS and OS.
Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme.
Source:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Published:1/10/2011
Authors:Lai A; Tran A; Nghiemphu PL; Pope WB; Solis OE; Selch M; Filka E; Yong WH; Mischel PS; Liau LM; Phuphanich S; Black K; Peak S; Green RM; Spier CE; Kolevska T; Polikoff J; Fehrenbacher L; Elashoff R; Cloughesy T;
Abstract:Patients treated with BV and TMZ during and after RT showed improved PFS without improved OS compared to the University of California, Los Angeles/KPLA control group. Additional studies are warranted to determine if BV administered first-line improves survival compared to BV at recurrence.
Correlation of 6-18F-fluoro-L-dopa PET uptake with proliferation and tumor grade in newly diagnosed and recurrent gliomas.
Source:Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Published:10/1/2010
Authors:Fueger BJ; Czernin J; Cloughesy T; Silverman DH; Geist CL; Walter MA; Schiepers C; Nghiemphu P; Lai A; Phelps ME; Chen W;
Abstract:(18)F-FDOPA uptake is significantly higher in high-grade than in low-grade tumors in newly diagnosed but not recurrent tumors that had been treated previously. A significant correlation between (18)F-FDOPA uptake and tumor proliferation in newly diagnosed tumors was observed, whereas this correlation was not identified for recurrent tumors. Thus, (18)F-FDOPA PET might serve as a noninvasive marker of tumor grading and might provide a useful surrogate of tumor proliferative activity in newly diagnosed gliomas.
Safety and efficacy of erlotinib in first-relapse glioblastoma: a phase II open-label study.
Source:Neuro-oncology
Published:10/1/2010
Authors:Yung WK; Vredenburgh JJ; Cloughesy TF; Nghiemphu P; Klencke B; Gilbert MR; Reardon DA; Prados MD;
Abstract:Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is active in glioblastoma. We evaluated erlotinib efficacy in patients with first-relapse glioblastoma and assessed whether response was related to EGFR amplification and/or concomitant use of enzyme-inducing antiepileptic drugs (EIAEDs) in a phase II open-label study of glioblastoma patients in first relapse. Patients took erlotinib daily until progression. Starting dose was 150 mg for patients not taking EIAEDs and 300 mg for patients taking EIAEDs. Tumors were radiographically assessed every 8 weeks. Response was evaluated by investigators and confirmed by an independent radiology facility (IRF). The primary efficacy outcome was the objective response (OR) rate, according to the modified WHO criteria. Enrollment (n = 48) was terminated after a planned interim analysis due to an insufficient number of responses. The IRF confirmed 1 complete and 2 partial responses (PRs), for an OR rate of 6.3% (95% confidence interval [CI]: 1.7-17.0). Investigators determined 1 complete response and 3 PRs, median response duration of 7.0 months, 6-month progression-free survival (PFS) of 20% (95% CI: 10.0-32.4), and median survival of 9.7 months (95% CI: 5.9-11.6). Outcomes were not related to EGFR amplification or EIAED status. Diarrhea and rash were the most common adverse events (AEs); 23% of patients experienced grade 3-4 drug-related AEs. Despite the limited number of responses, 6-month PFS and median survival reached or exceeded the previously reported values for patients undergoing chemotherapy for recurrent glioblastoma. EGFR amplification was not associated with erlotinib activity. Given the large CIs and nonrandomized nature of the study, results should be interpreted cautiously.
Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis.
Source:Cancer cell
Published:7/7/2009
Authors:McGillicuddy LT; Fromm JA; Hollstein PE; Kubek S; Beroukhim R; De Raedt T; Johnson BW; Williams SM; Nghiemphu P; Liau LM; Cloughesy TF; Mischel PS; Parret A; Seiler J; Moldenhauer G; Scheffzek K; Stemmer-Rachamimov AO; Sawyers CL; Brennan C; Messiaen L; Mellinghoff IK; Cichowski K;
Abstract:Loss-of-function mutations in the NF1 tumor suppressor result in deregulated Ras signaling and drive tumorigenesis in the familial cancer syndrome neurofibromatosis type I. However, the extent to which NF1 inactivation promotes sporadic tumorigenesis is unknown. Here we report that NF1 is inactivated in sporadic gliomas via two mechanisms: excessive proteasomal degradation and genetic loss. NF1 protein destabilization is triggered by the hyperactivation of protein kinase C (PKC) and confers sensitivity to PKC inhibitors. However, complete genetic loss, which only occurs when p53 is inactivated, mediates sensitivity to mTOR inhibitors. These studies reveal an expanding role for NF1 inactivation in sporadic gliomagenesis and illustrate how different mechanisms of inactivation are utilized in genetically distinct tumors, which consequently impacts therapeutic sensitivity.
Recurrent glioblastoma multiforme: ADC histogram analysis predicts response to bevacizumab treatment.
Source:Radiology
Published:7/1/2009
Authors:Pope WB; Kim HJ; Huo J; Alger J; Brown MS; Gjertson D; Sai V; Young JR; Tekchandani L; Cloughesy T; Mischel PS; Lai A; Nghiemphu P; Rahmanuddin S; Goldin J;
Abstract:Pretreatment ADC histogram analysis can stratify progression-free survival in bevacizumab-treated patients with recurrent GBM.
Bevacizumab and chemotherapy for recurrent glioblastoma: a single-institution experience.
Source:Neurology
Published:4/7/2009
Authors:Nghiemphu PL; Liu W; Lee Y; Than T; Graham C; Lai A; Green RM; Pope WB; Liau LM; Mischel PS; Nelson SF; Elashoff R; Cloughesy TF;
Abstract:Bevacizumab in combination with chemotherapy may be a more effective treatment for recurrent glioblastoma and warrants further randomized prospective studies to determine its effect on survival. Bevacizumab also has more effect in those with older age and might reflect biologic differences in glioblastoma in different age groups as seen with the expression of vascular endothelial growth factor.
The L84F polymorphic variant of human O6-methylguanine-DNA methyltransferase alters stability in U87MG glioma cells but not temozolomide sensitivity.
Source:Neuro-oncology
Published:2/1/2009
Authors:Remington M; Chtchetinin J; Ancheta K; Nghiemphu PL; Cloughesy T; Lai A;
Abstract:First-line therapy for patients with glioblastoma multiforme includes treatment with radiation and temozolomide (TMZ), an oral DNA alkylating chemotherapy. Sensitivity of glioma cells to TMZ is dependent on the level of cellular O(6)-methylguanine-DNA methyltransferase (MGMT) repair activity. Several common coding-region polymorphisms in the MGMT gene (L84F and the linked pair I143V/K178R) modify functional characteristics of MGMT and cancer risk. To determine whether these polymorphic changes influence the ability of MGMT to protect glioma cells from TMZ, we stably overexpressed enhanced green fluorescent protein (eGFP)-tagged MGMT constructs in U87MG glioma cells. We confirmed that the wild-type (WT) eGFP-MGMT protein is properly localized within the nucleus and found that L84F, I143V/K178R, and L84F/I143V/K178R eGFP-MGMT variants exhibited nuclear localization patterns indistinguishable from WT. Using MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide] proliferation and clonogenic survival assays, we confirmed that WT cells expressing eGFP-MGMT are resistant to TMZ treatment compared with control U87MG cells, and that each of the polymorphic eGFP-MGMT variants confers similar resistance to TMZ. However, upon exposure to O(6)-benzylguanine (O(6)-BG), a synthetic MGMT inhibitor, the L84F and L84F/I143V/K178R variants were degraded more rapidly than WT or I143V/K178R in a proteasome-dependent manner. Despite the increased O(6)-BG- stimulated protein turnover caused by the L84F alteration, cells expressing L84F eGFP-MGMT did not exhibit altered sensitivity to the combination of O(6)-BG and TMZ compared with WT cells. In conclusion, we demonstrated that the L84F polymorphic variant has altered protein turnover without modifying sensitivity of U87MG cells to TMZ or combined TMZ and O(6)-BG. These findings may provide a clue to determining the clinical significance of MGMT coding-region polymorphisms.
Relationship between gene expression and enhancement in glioblastoma multiforme: exploratory DNA microarray analysis.
Source:Radiology
Published:10/1/2008
Authors:Pope WB; Chen JH; Dong J; Carlson MR; Perlina A; Cloughesy TF; Liau LM; Mischel PS; Nghiemphu P; Lai A; Nelson SF;
Abstract:The enhancement pattern divides GBM in two groups with differing prognoses. By comparing gene expression between IE and CE GBMs, it was possible to identify genes that may affect magnetic resonance imaging features of edema and enhancement, and genes whose expression levels are predictive of both improved and shortened survival.
Phase II pilot study of bevacizumab in combination with temozolomide and regional radiation therapy for up-front treatment of patients with newly diagnosed glioblastoma multiforme: interim analysis of safety and tolerability.
Source:International journal of radiation oncology, biology, physics
Published:8/1/2008
Authors:Lai A; Filka E; McGibbon B; Nghiemphu PL; Graham C; Yong WH; Mischel P; Liau LM; Bergsneider M; Pope W; Selch M; Cloughesy T;
Abstract:The observed toxicities were acceptable to continue enrollment toward the overall target group of 70 patients. Preliminary efficacy analysis shows encouraging mean progression-free survival. At this time data are not sufficient to encourage routine off-label use of BV combined with TMZ/RT in the setting of newly diagnosed glioblastoma without longer follow-up, enrollment of additional patients, and thorough efficacy assessment.
Time course of imaging changes of GBM during extended bevacizumab treatment.
Source:Journal of neuro-oncology
Published:7/1/2008
Authors:Ananthnarayan S; Bahng J; Roring J; Nghiemphu P; Lai A; Cloughesy T; Pope WB;
Abstract:Glioblastoma multiforme (GBM) are morphologically heterogeneous tumors, with varying amounts of necrosis, and edema. Previous studies have shown that treatments incorporating the VEGF antibody bevacizumab can reduce edema and tumor burden in GBM. Additionally it has been suggested that bevacizumab regimen treatment reduces the percent of tumoral necrosis. Therefore we sought to (1) determine the time course of change in necrosis, tumor, and edema volume in patients who respond to bevacizumab regimen treatment and (2) determine if GBM that progress following a response to bevacizumab regimen treatment are morphologically different from their appearance at prior tumor progression. Therefore, we retrospectively assessed tumor, necrosis, and edema volumes on MRI scans from 15 patients with recurrent GBM who responded to bevacizumab regimen treatment, and had extended (>7 month) follow-up. We found that the median time to best tumor response was 158 days (range, 16-261, SD = 63). The median best response was 72.1% reduction in tumor volume and 72.8% reduction in peritumoral edema. Most tumors (77.8%) showed resolution of necrotic areas. The relative reduction of edema and necrosis was sustained, even in patients (n = 7) who developed tumor progression. Thus the mean ratio of edema-to-tumor volume at progression on bevacizumab regimen treatment was 38.4% lower than that for the same tumors seen on progression scans following prior chemotherapy. The percentage of necrotic tumor also was diminished following progression on bevacizumab regimen treatment. These findings illustrate the time course of changes in edema and tumor volume with prolonged bevacizumab regimen treatment, and support the conclusion that the morphology of recurrent GBM following bevacizumab regimen therapy is distinct from that on other chemotherapy.
Safety of anticoagulation use and bevacizumab in patients with glioma.
Source:Neuro-oncology
Published:6/1/2008
Authors:Nghiemphu PL; Green RM; Pope WB; Lai A; Cloughesy TF;
Abstract:Bevacizumab in combination with chemotherapy is now being studied for the treatment of malignant gliomas. However, the risk of intracranial hemorrhage has limited its use in patients requiring full anticoagulation for venous thrombosis. To assess the safety of using anticoagulation with bevacizumab, we conducted a retrospective review of our patients who were treated with bevacizumab while receiving anticoagulation. We reviewed their medical records and imaging for signs of hemorrhage. In total, we had 21 patients who received anticoagulation and bevacizumab concurrently for a median time of 72 days. Eighteen patients had adequate anticoagulation for venous thrombosis. There were no frank lobar hemorrhages in any patient. Three patients had small, intraparenchymal hemorrhages on MRI, but only one patient actually developed symptoms due to the hemorrhage. None of these patients had residual neurological deficits from the hemorrhages. Two more patients had evidence of a minor increase in signal on noncontrast T1-weighted sequence, presumed to be petechial hemorrhages, without any clinical sequelae or progression. In contrast, seven patients who had symptomatic hemorrhages from bevacizumab were not on any anticoagulation. In this retrospective review, anticoagulation did not lead to any major hemorrhages and does not appear to be a contraindication for starting bevacizumab therapy.
Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma.
Source:PLoS medicine
Published:1/22/2008
Authors:Cloughesy TF; Yoshimoto K; Nghiemphu P; Brown K; Dang J; Zhu S; Hsueh T; Chen Y; Wang W; Youngkin D; Liau L; Martin N; Becker D; Bergsneider M; Lai A; Green R; Oglesby T; Koleto M; Trent J; Horvath S; Mischel PS; Mellinghoff IK; Sawyers CL;
Abstract:http://www.ClinicalTrials.gov (#NCT00047073).
Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma.
Source:Proceedings of the National Academy of Sciences of the United States of America
Published:12/11/2007
Authors:Beroukhim R; Getz G; Nghiemphu L; Barretina J; Hsueh T; Linhart D; Vivanco I; Lee JC; Huang JH; Alexander S; Du J; Kau T; Thomas RK; Shah K; Soto H; Perner S; Prensner J; Debiasi RM; Demichelis F; Hatton C; Rubin MA; Garraway LA; Nelson SF; Liau L; Mischel PS; Cloughesy TF; Meyerson M; Golub TA; Lander ES; Mellinghoff IK; Sellers WR;
Abstract:Comprehensive knowledge of the genomic alterations that underlie cancer is a critical foundation for diagnostics, prognostics, and targeted therapeutics. Systematic efforts to analyze cancer genomes are underway, but the analysis is hampered by the lack of a statistical framework to distinguish meaningful events from random background aberrations. Here we describe a systematic method, called Genomic Identification of Significant Targets in Cancer (GISTIC), designed for analyzing chromosomal aberrations in cancer. We use it to study chromosomal aberrations in 141 gliomas and compare the results with two prior studies. Traditional methods highlight hundreds of altered regions with little concordance between studies. The new approach reveals a highly concordant picture involving approximately 35 significant events, including 16-18 broad events near chromosome-arm size and 16-21 focal events. Approximately half of these events correspond to known cancer-related genes, only some of which have been previously tied to glioma. We also show that superimposed broad and focal events may have different biological consequences. Specifically, gliomas with broad amplification of chromosome 7 have properties different from those with overlapping focalEGFR amplification: the broad events act in part through effects on MET and its ligand HGF and correlate with MET dependence in vitro. Our results support the feasibility and utility of systematic characterization of the cancer genome.
Relationship between survival and edema in malignant gliomas: role of vascular endothelial growth factor and neuronal pentraxin 2.
Source:Clinical cancer research : an official journal of the American Association for Cancer Research
Published:5/1/2007
Authors:Carlson MR; Pope WB; Horvath S; Braunstein JG; Nghiemphu P; Tso CL; Mellinghoff I; Lai A; Liau LM; Mischel PS; Dong J; Nelson SF; Cloughesy TF;
Abstract:VEGF expression was predictive of survival in tumors with little or no edema [Cox proportional hazard model, 6.88; 95% confidence interval (95% CI), 2.61-18.1; P<0.0001], but not in tumors with extensive edema. The expression of several proangiogenic genes, including adrenomedullin (correlation coefficient, 0.80), hypoxia-inducible factor-1A (0.51), and angiopoietin-2 (0.44), was correlated with VEGF expression (all with P<0.0001), whereas that of several antiangiogenic genes was inversely correlated. The expression of six genes was increased greater than 3-fold in edematous versus nonedematous tumors in the absence of increased VEGF expression. The most increased, neuronal pentraxin 2 (NPTX2, 7-fold change), was predictive of survival in tumors with the highest levels of edema, in contrast to VEGF (hazard ratio, 2.73; 95% CI, 1.49-5.02; P=0.049). NPTX2 was tightly correlated with expression of the water channel aquaporin-3 (0.74, P<0.0001). These results suggest that there are both VEGF-dependent and VEGF-independent pathways of edema production in gliomas and may explain why edema is not reduced in some patients following anti-VEGF treatment.
Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain.
Source:PLoS medicine
Published:12/1/2006
Authors:Lee JC; Vivanco I; Beroukhim R; Huang JH; Feng WL; DeBiasi RM; Yoshimoto K; King JC; Nghiemphu P; Yuza Y; Xu Q; Greulich H; Thomas RK; Paez JG; Peck TC; Linhart DJ; Glatt KA; Getz G; Onofrio R; Ziaugra L; Levine RL; Gabriel S; Kawaguchi T; O'Neill K; Khan H; Liau LM; Nelson SF; Rao PN; Mischel P; Pieper RO; Cloughesy T; Leahy DJ; Sellers WR; Sawyers CL; Meyerson M; Mellinghoff IK;
Abstract:Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma.
MRI in patients with high-grade gliomas treated with bevacizumab and chemotherapy.
Source:Neurology
Published:4/25/2006
Authors:Pope WB; Lai A; Nghiemphu P; Mischel P; Cloughesy TF;
Abstract:Patients with recurrent gliomas (n = 14) were treated with bevacizumab and carboplatin, cpt-11, or etoposide. Follow-up MRI scans were obtained 2 to 6 weeks after initiation of treatment. Contrast-enhancing tumor shrank in 7 patients, with reductions evident in as little as 2 weeks after initiation of therapy. Treatment seemed more effective for heterogeneously enhancing tumor compared with solidly enhancing tumor.

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