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Shah N.,Swedish Neuroscience Institute | Lin B.,Swedish Neuroscience Institute | Sibenaller Z.,University of Iowa | Ryken T.,Iowa Spine and Brain Institute | And 4 more authors.
PLoS ONE | Year: 2011

O6-methylguanine DNA-methyltransferase (MGMT) promoter methylation has been identified as a potential prognostic marker for glioblastoma patients. The relationship between the exact site of promoter methylation and its effect on gene silencing, and the patient's subsequent response to therapy, is still being defined. The aim of this study was to comprehensively characterize cytosine-guanine (CpG) dinucleotide methylation across the entire MGMT promoter and to correlate individual CpG site methylation patterns to mRNA expression, protein expression, and progression-free survival. To best identify the specific MGMT promoter region most predictive of gene silencing and response to therapy, we determined the methylation status of all 97 CpG sites in the MGMT promoter in tumor samples from 70 GBM patients using quantitative bisulfite sequencing. We next identified the CpG site specific and regional methylation patterns most predictive of gene silencing and improved progression-free survival. Using this data, we propose a new classification scheme utilizing methylation data from across the entire promoter and show that an analysis based on this approach, which we call 3R classification, is predictive of progression-free survival (HR = 5.23, 95% CI [2.089-13.097], p>0.0001). To adapt this approach to the clinical setting, we used a methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) test based on the 3R classification and show that this test is both feasible in the clinical setting and predictive of progression free survival (HR = 3.076, 95% CI [1.301-7.27], p = 0.007). We discuss the potential advantages of a test based on this promoterwide analysis and compare it to the commonly used methylation-specific PCR test. Further prospective validation of these two methods in a large independent patient cohort will be needed to confirm the added value of promoter wide analysis of MGMT methylation in the clinical setting. © 2011 Shah et al.


Ryken T.C.,Iowa Spine and Brain Institute | Ryken T.C.,University of Iowa | Aygun N.,Johns Hopkins University | Morris J.,Mayo Medical School | And 5 more authors.
Journal of Neuro-Oncology | Year: 2014

Question: Which imaging techniques most accurately differentiate true tumor progression from pseudo-progression or treatment related changes in patients with previously diagnosed glioblastoma? Target population: These recommendations apply to adults with previously diagnosed glioblastoma who are suspected of experiencing progression of the neoplastic process. Recommendations Level II: Magnetic resonance imaging with and without gadolinium enhancement is recommended as the imaging surveillance method to detect the progression of previously diagnosed glioblastoma. Level II: Magnetic resonance spectroscopy is recommended as a diagnostic method to differentiate true tumor progression from treatment-related imaging changes or pseudo-progression in patients with suspected progressive glioblastoma. Level III: The routine use of positron emission tomography to identify progression of glioblastoma is not recommended. Level III: Single-photon emission computed tomography imaging is recommended as a diagnostic method to differentiate true tumor progression from treatment-related imaging changes or pseudo-progression in patients with suspected progressive glioblastoma. © 2014 Springer Science+Business Media.


Olson J.J.,Emory University | Nayak L.,Dana-Farber Cancer Institute | Nayak L.,Brigham and Womens Cancer Center | Ormond D.R.,Emory University | And 4 more authors.
Journal of Neuro-Oncology | Year: 2014

Question: What is the influence of targeted medical therapies on disease control and survival in the adult patient with progressive glioblastoma? Targeted population: This recommendation applies to adult patients with progressive glioblastoma Recommendations Level III: Treatment with bevacizumab is recommended as it provides improved disease control compared to historical controls as measured by best imaging response and progression free survival at 6 months. Given that there are a large number of therapies are available for progressive glioblastoma that may be applied under selected circumstances dependent on patient characteristics and treating physician judgment, it is strongly recommended that patients with progressive glioblastoma be enrolled in properly designed clinical investigations to provide convincing evidence of therapeutic value. © 2014 Springer Science+Business Media.


Brat D.J.,Emory University | Ryken T.C.,Iowa Spine and Brain Institute | Ryken T.C.,University of Iowa | Kalkanis S.N.,Ford Motor Company | Olson J.J.,Emory University
Journal of Neuro-Oncology | Year: 2014

Question: 1. What are the most important diagnostic considerations in reporting progressive glioblastoma? Target population: These recommendations apply to adults with progressive glioblastoma Recommendations Level III: For patients who undergo biopsy or neurosurgical resection at the time of radiologic or clinical progression, it is recommended that the pathologist report the presence and extent of progressive neoplasm as well as the presence and extent of necrosis within the pathologic material examined. Furthermore, to ensure the proper interpretation of progressive glioblastoma, it is recommended that the pathologist take into account the patient's previous diagnosis and treatment, as well as the current clinical and neuroimaging features that have led to a second biopsy or resection. Question: 2. What techniques and ancillary studies are most useful in separating malignant progression from treatment effect? Target population: These recommendations apply to adults with progressive glioblastoma Recommendations Level III: In the setting of prior radiation and chemotherapy, it is recommended to adhere to strict histologic criteria for microvascular proliferation and necrosis in order to establish a diagnosis of a glioblastoma. Immunohistochemistry and genetic studies are selectively recommended for distinguishing neoplastic cells from atypical reactive cells in progressive glioblastoma. © 2014 Springer Science+Business Media.


Ryken T.C.,Iowa Spine and Brain Institute | Ryken T.C.,University of Iowa | Kalkanis S.N.,Ford Motor Company | Buatti J.M.,University of Iowa | Olson J.J.,Emory University
Journal of Neuro-Oncology | Year: 2014

Question: Should patients with previously diagnosed malignant glioma who are suspected of experiencing progression of the neoplasm process undergo repeat open surgical resection? Target population: These recommendations apply to adults with previously diagnosed malignant glioma who are suspected of experiencing progression of the neoplastic process and are amenable to surgical resection. Recommendations Level II: Repeat cytoreductive surgery is recommended in symptomatic patients with locally recurrent or progressive malignant glioma. The median survival in these patient diagnosed with glioblastoma is expected to range from 6 to 17 months following a second procedure. It is recommended that the following preoperative factors be considered when evaluating a patient for repeat operation: location of recurrence in eloquent/critical brain regions, Karnofsky Performance Status and tumor volume. © 2014 Springer Science+Business Media.


Agarwal S.,University of Iowa | Al-Keilani M.S.,University of Iowa | Alqudah M.A.Y.,University of Iowa | Sibenaller Z.A.,University of Iowa | And 3 more authors.
PLoS ONE | Year: 2013

Poor prognosis and resistance to therapy in malignant gliomas is mainly due to the highly dispersive nature of glioma cells. This dispersive characteristic results from genetic alterations in key regulators of cell migration and diffusion. A better understanding of these regulatory signals holds promise to improve overall survival and response to therapy. Using mapping arrays to screen for genomic alterations in gliomas, we recently identified alterations of the protein tyrosine phosphatase receptor type kappa gene (PTPRK) that correlate to patient outcomes. These PTPRK alterations are very relevant to glioma biology as PTPRK can directly sense cell-cell contact and is a dephosphorylation regulator of tyrosine phosphorylation signaling, which is a major driving force behind tumor development and progression. Subsequent sequencing of the full length PTPRK transcripts revealed novel PTPRK gene deletion and missense mutations in numerous glioma biopsies. PTPRK mutations were cloned and expressed in PTPRK-null malignant glioma cells. The effect of these mutations on PTPRK anti-oncogenic function and their association with response to anti-glioma therapeutics, such as temozolomide and tyrosine kinase inhibitors, was subsequently analyzed using in vitro cell-based assays. These genetic variations altered PTPRK activity and its post-translational processing. Reconstitution of wild-type PTPRK in malignant glioma cell lines suppressed cell growth and migration by inhibiting EGFR and β-catenin signaling and improved the effect of conventional therapies for glioma. However, PTPRK mutations abrogated tumor suppressive effects of wild-type PTPRK and altered sensitivity of glioma cells to chemotherapy. © 2013 Agarwal et al.


Alqudah M.A.Y.,University of Iowa | Agarwal S.,University of Iowa | Al-Keilani M.S.,University of Iowa | Sibenaller Z.A.,University of Iowa | And 3 more authors.
PLoS ONE | Year: 2013

Using a GWA analysis of a comprehensive glioma specimen population, we identified whole gain of chromosome 19 as one of the major chromosomal aberrations that correlates to patients' outcomes. Our analysis of significant loci revealed for the first time NOTCH3 as one of the most significant amplification. NOTCH3 amplification is associated with worse outcome compared to tumors with non-amplified locus. NOTCH receptors (NOTCH1-4) are key positive regulators of cell-cell interactions, angiogenesis, cell adhesion and stem cell niche development which have been shown to play critical roles in several human cancers. Our objective is to determine the molecular roles of NOTCH3 in glioma pathogenesis and aggressiveness. Here we show for the first time that NOTCH3 plays a major role in glioma cell proliferation, cell migration, invasion and apoptosis. Therefore, our study uncovers the prognostic value and the oncogenic function of NOTCH3 in gliomagenesis and supports NOTCH3 as a promising target of therapy in high grade glioma. Our studies allowed the identification of a subset of population that may benefit from GSI- or anti-NOTCH3- based therapies. This may lead to the design of novel strategies to improve therapeutic outcome of patients with glioma by establishing medical and scientific basis for personalized chemotherapies. © 2013 Alqudah et al.


Arora S.,Translational Genomics Research Institute | Ranade A.R.,Translational Genomics Research Institute | Tran N.L.,Translational Genomics Research Institute | Nasser S.,Translational Genomics Research Institute | And 12 more authors.
International Journal of Cancer | Year: 2011

Brain metastasis (BM) can affect ∼ 25% of nonsmall cell lung cancer (NSCLC) patients during their lifetime. Efforts to characterize patients that will develop BM have been disappointing. microRNAs (miRNAs) regulate the expression of target mRNAs. miRNAs play a role in regulating a variety of targets and, consequently, multiple pathways, which make them a powerful tool for early detection of disease, risk assessment, and prognosis. We investigated miRNAs that may serve as biomarkers to differentiate between NSCLC patients with and without BM. miRNA microarray profiling was performed on samples from clinically matched NSCLC from seven patients with BM (BM+) and six without BM (BM-). Using t-test and further qRT-PCR validation, eight miRNAs were confirmed to be significantly differentially expressed. Of these, expression of miR-328 and miR-330-3p were able to correctly classify BM+ vs. BM- patients. This classifier was used on a validation cohort (n = 15), and it correctly classified 12/15 patients. Gene expression analysis comparing A549 parental and A549 cells stably transfected to over-express miR-328 (A549-328) identified several significantly differentially expressed genes. PRKCA was one of the genes over-expressed in A549-328 cells. Additionally, A549-328 cells had significantly increased cell migration compared to A549 cells, which was significantly reduced upon PRKCA knockdown. In summary, miR-328 has a role in conferring migratory potential to NSCLC cells working in part through PRKCA and with further corroboration in additional independent cohorts, these miRNAs may be incorporated into clinical treatment decision making to stratify NSCLC patients at higher risk for developing BM. Copyright © 2011 UICC.


Chowdhary S.A.,Florida Hospital Cancer Institute | Ryken T.,Iowa Spine and Brain Institute | Newton H.B.,Ohio State University
Journal of Neuro-Oncology | Year: 2015

Carmustine wafers (CW; Gliadel® wafers) are approved to treat newly-diagnosed high-grade glioma (HGG) and recurrent glioblastoma. Widespread use has been limited for several reasons, including concern that their use may preclude enrollment in subsequent clinical trials due to uncertainty about confounding of results and potential toxicities. This meta-analysis estimated survival following treatment with CW for HGG. A literature search identified relevant studies. Overall survival (OS), median survival, and adverse events (AEs) were summarized. Analysis of variance evaluated effects of treatment (CW vs non-CW) and diagnosis (new vs recurrent) on median survival. The analysis included 62 publications, which reported data for 60 studies (CW: n = 3,162; non-CW: n = 1,736). For newly-diagnosed HGG, 1-year OS was 67 % with CW and 48 % without; 2-year OS was 26 and 15 %, respectively; median survival was 16.4 ± 21.6 months and 13.1 ± 29.9 months, respectively. For recurrent HGG, 1-year OS was 37 % with CW and 34 % without; 2-year OS was 15 and 12 %, respectively; median survival was 9.7 ± 20.9 months and 8.6 ± 22.6 months, respectively. Effects of treatment (longer median survival with CW than without; P = 0.043) and diagnosis (longer median survival for newly-diagnosed HGG than recurrent; P < 0.001) on median survival were significant, with no significant treatment-by-diagnosis interaction (P = 0.620). The most common AE associated with wafer removal was surgical site infection (SSI); the most common AEs for repeat surgery were mass effect, SSI, hydrocephalus, cysts in resection cavity, acute hematoma, wound healing complications, and brain necrosis. These data may be useful in the context of utilizing CW in HGG management, and in designing future clinical trials to allow CW-treated patients to participate in experimental protocols. © 2015, The Author(s).


Owonikoko T.K.,Emory University | Arbiser J.,Emory University | Zelnak A.,Emory University | Shu H.-K.G.,Emory University | And 10 more authors.
Nature Reviews Clinical Oncology | Year: 2014

Metastatic tumours involving the brain overshadow primary brain neoplasms in frequency and are an important complication in the overall management of many cancers. Importantly, advances are being made in understanding the molecular biology underlying the initial development and eventual proliferation of brain metastases. Surgery and radiation remain the cornerstones of the therapy for symptomatic lesions; however, image-based guidance is improving surgical technique to maximize the preservation of normal tissue, while more sophisticated approaches to radiation therapy are being used to minimize the long-standing concerns over the toxicity of whole-brain radiation protocols used in the past. Furthermore, the burgeoning knowledge of tumour biology has facilitated the entry of systemically administered therapies into the clinic. Responses to these targeted interventions have ranged from substantial toxicity with no control of disease to periods of useful tumour control with no decrement in performance status of the treated individual. This experience enables recognition of the limits of targeted therapy, but has also informed methods to optimize this approach. This Review focuses on the clinically relevant molecular biology of brain metastases, and summarizes the current applications of these data to imaging, surgery, radiation therapy, cytotoxic chemotherapy and targeted therapy. © 2014 Macmillan Publishers Limited All rights reserved.

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