Reena Thomas

Advances in the management of glioblastoma: the role of temozolomide and MGMT testing

Glioblastoma (GB) is one of the most lethal forms of cancer, with an invasive growth pattern that requires the use of adjuvant therapies, including chemotherapy and radiation, to prolong survival. Temozolomide (TMZ) is an oral chemotherapy with a limited side effect profile that has become the standard of care in GB treatment. While TMZ has made an impact on survival, tumor recurrence and TMZ resistance remain major challenges. Molecular markers, such as O6-methylguanine-DNA methyltransferase methylation status, can be helpful in predicting tumor response to TMZ, and therefore guides clinical decision making. This review will discuss the epidemiology and possible genetic underpinnings of GB, how TMZ became the standard of care for GB patients, the pharmacology of TMZ, the practical aspects of using TMZ in clinic, and how molecular diagnostics – particularly the use of O6-methylguanine-DNA methyltransferase status – affect clinical management.

Simultaneous perfusion and permeability measurements using combined spin- and gradient-echo MRI.

The purpose of this study was to estimate magnetic resonance imaging-based brain perfusion parameters from combined multiecho spin-echo and gradient-echo acquisitions, to correct them for T1-, T2-, and T∗2-related contrast agent (CA) extravasation effects, and to simultaneously determine vascular permeability. Perfusion data were acquired using a combined multiecho spin- and gradient-echo (SAGE) echo-planar imaging sequence, which was corrected for CA extravasation effects using pharmacokinetic modeling. The presented method was validated in simulations and brain tumor patients, and compared with uncorrected single-echo and multiecho data. In the presence of CA extravasation, uncorrected single-echo data resulted in underestimated CA concentrations, leading to underestimated single-echo cerebral blood volume (CBV) and mean transit time (MTT). In contrast, uncorrected multiecho data resulted in overestimations of CA concentrations, CBV, and MTT. The correction of CA extravasation effects resulted in CBV and MTT estimates that were more consistent with the underlying tissue characteristics. Spin-echo perfusion data showed reduced large-vessel blooming effects, facilitating better distinction between increased CBV due to active tumor progression and elevated CBV due to the presence of cortical vessels in tumor proximity. Furthermore, extracted permeability parameters were in good agreement with elevated T1-weighted postcontrast signal values.

Melanoma central nervous system metastases: current approaches, challenges, and opportunities

Melanoma central nervous system metastases are increasing, and the challenges presented by this patient population remain complex. In December 2015, the Melanoma Research Foundation and the Wistar Institute hosted the First Summit on Melanoma Central Nervous System (CNS) Metastases in Philadelphia, Pennsylvania. Here, we provide a review of the current status of the field of melanoma brain metastasis research; identify key challenges and opportunities for improving the outcomes in patients with melanoma brain metastases; and set a framework to optimize future research in this critical area.

A Phase I/II Trial of 5 Fraction Stereotactic Radiosurgery With 5-mm Margins With Concurrent and Adjuvant Temozolomide in Newly Diagnosed Supratentorial Glioblastoma Multiforme.

The spine cases included a fifth lumbar spine (case 1), fifth thoracic spine (case 2), and 10th thoracic spine metastases (case 3). Targets and organs at risk (OAR) were contoured by one experienced radiation oncologist according to International Spine Radiosurgery Consortium Consensus Guidelines and a 2 mm planning target volume (PTV) applied. The DICOM files were sent to each institute for planning. The treatment planning guidelines in the previous study included, prescribed dose of 24 Gy in two fractions with more than 70% prescribed dose to encompass D95, D0.035 <140% of the prescribed dose, and a maximum dose to the spinal cord planning organ at risk volume (PRV) or thecal sac <17 Gy. New guidelines added (D95 should be as high as possible (AHAP), D50 should be between 110% and 115% of prescribed dose and AHAP and D0.035 should be between 125% and 135% of the prescribed dose). The dose volume histograms (DVHs) were centrally reviewed. Results: In our previous study the PTV D95 ranged from 70.0% to 99.6% in case 1 (mean SD; 21.21 2.43 Gy), 70.4% to 98.8% in case 2 (20.32 2.22 Gy), and 70.0% to 94.2% in case 3 (19.78 1.97 Gy), respectively, and D50 for PTV ranged from 99.2% to 116.3% in case 1 (25.62 1.34 Gy), 91.7% to 119.6% in case 2 (25.97 2.18 Gy) and 84.2% to 114.2% in case 3 (25.57 2.14 Gy), respectively. In this study PTV D95 ranged from 80.4% to 100.0% in case 1 (21.96 1.67 Gy), 76.3% to 95.8% in case 2 (20.91 1.67 Gy), and 70.4% to 94.2% in case 3 (20.3 1.86 Gy), respectively and D50 for PTV ranged from 109.6% to 115.4% in case 1 (27.02 0.53 Gy), 110.0% to 117.5% in case 2 (27.06 0.63 Gy) and 107.5% to 115.0% in case 3 (26.89 0.67 Gy), respectively. Conclusion: We succeeded to minimize the inter-institutional variations. This study highlights dose constraints of D95, D50, and D0.035 should be used to minimize the variations. Author Disclosure: H. Tanaka: None. T. Furuya: None. Y. Kumazaki: None. M. Nakayama: None. H. Nishimura: None. M.E. Ruschin: None. D. Pinnaduwage: None. J. Phua: None. I. Thibault: None. J. StHilaire: None. L. Ma: None. A. Sahgal: None. N. Shikama: None. K. Karasawa: None.

Locoregional Radiogenomic Models Capture Gene Expression Heterogeneity in Glioblastoma

Radiogenomics mapping noninvasively determines important relationships between the molecular genotype and imaging phenotype of various tumors, allowing advances in both clinical care and cancer research. While early work has shown its technical feasibility, here we extend radiogenomic mapping to a locoregional level that can account for the molecular heterogeneity of tumors. To achieve this, our data processing pipeline relies on three main steps: 1) the use of multi-omics data fusion to generate a set of 100 interpretable gene modules, 2) the use of patch-based image analysis (specifically of contrast-enhanced T1-weighted weighted MR images) combined with Generalized Linear Models (GLM) to establish potential links between module expressions and local MR signal, and 3) the use of expression heatmaps based on GLMs decision values to explore visualization of tumor molecular heterogeneity. The performance of the proposed approach was evaluated using a leave-one-patient-out crossvalidation method as well as a separate validation data set. The top performing models were based on a small set of 20 features and yielded Area Under the receiver operating characteristic Curve (AUC) above 0.65 on the validation cohort for eight modules. Next, we demonstrate the clinical and biological interpretation of four modules using molecular expression heatmaps superimposed on clinical radiographic images, showing the potential for assessing tumor molecular heterogeneity and the utility of this method for precision treatment in clinical decision making and imaging surveillance.

Space exploration and toxicology : a new frontier

Results of the microbial and immunological studies discussed above clearly illustrate an in-flight or post-flight blunting of the cellular immune mechanism in humans and test animals, coincident with a relative increase in pathogenic microorganisms. This situation predicts an increased incidence of in-flight infectious disease events. To prevent this from occurring, most observers agree that a robust program of preflight and in-flight immunological and microbiological monitoring, combined with an effective countermeasures program, are required for optimally successful long-duration spaceflight.