Defining the landscape of ATP-competitive inhibitor resistance residues in protein kinases.

Kinases are involved in disease development and modulation of their activity can be therapeutically beneficial. Drug-resistant mutant kinases are valuable tools in drug discovery efforts, but the prediction of mutants across the kinome is challenging. Here, we generate deep mutational scanning data to identify mutant mammalian kinases that drive resistance to clinically relevant inhibitors. We aggregate these data with subsaturation mutagenesis data and use it to develop, test and validate a framework to prospectively identify residues that mediate kinase activity and drug resistance across the kinome. We validate predicted resistance mutations in CDK4, CDK6, ERK2, EGFR and HER2. Capitalizing on a highly predictable residue, we generate resistance mutations in TBK1, CSNK2A1 and BRAF. Unexpectedly, we uncover a potentially generalizable activation site that mediates drug resistance and confirm its impact in BRAF, EGFR, HER2 and MEK1. We anticipate that the identification of these residues will enable the broad interrogation of the kinome and its inhibitors.

Spiritual, religious, and existential concerns of cancer survivors in a secular country with focus on age, gender, and emotional challenges.

PURPOSE: The purpose of this study was to examine the associations between self-reported spiritual/religious concerns and age, gender, and emotional challenges among cancer survivors who have completed a 5-day rehabilitation course at a rehabilitation center in Denmark (the former RehabiliteringsCenter Dallund (RC Dallund)). METHODS: The data stem from the so-called Dallund Scale which was adapted from the NCCN Distress Thermometer and comprised questions to identify problems and concerns of a physical, psychosocial, and spiritual/religious nature. Descriptive statistics were performed using means for continuous variables and frequencies for categorical variables. Odds ratios were calculated by logistic regression. RESULTS: In total, 6640 participants filled in the questionnaire. Among participants, 21% reported one or more spiritual/religious concerns, the most reported concerns related to existence and guilt. Having one or more spiritual/religious concerns was significantly associated with age (OR 0.88), female gender (OR 1.38), and by those reporting emotional problems such as being without hope (OR 2.51), depressed (OR 1.49), and/or anxious (OR 1.95). Among participants, 8% stated they needed help concerning spiritual/religious concerns. CONCLUSIONS: Cancer patients, living in a highly secular country, report a significant frequency of spiritual/religious and existential concerns. Such concerns are mostly reported by the young, female survivors and by those reporting emotional challenges. Spiritual/religious and existential concerns are often times tabooed in secular societies, despite being present in patients. Our results call for an increased systemic attention among health professionals to these concerns, and a particular focus on identifying and meeting the spiritual/religious and existential concerns of women, the young and those challenged by hopelessness, depression, and anxiety.

Outcome of Adult Brain Tumor Consortium (ABTC) prospective dose-finding trials of I-125 balloon brachytherapy in high-grade gliomas: challenges in clinical trial design and technology development when MRI treatment effect and recurrence appear similar.

OBJECTIVES: The aim of this study is to define the maximal safe radiation dose to guide further study of the GliaSite balloon brachytherapy (GSBT) system in untreated newly diagnosed glioblastoma (NEW-GBM) and recurrent high-grade glioma (REC-HGG). GBST is a balloon placed in the resection cavity and later filled through a subcutaneous port with liquid I-125 Iotrex, providing radiation doses that diminish uniformly with distance from the balloon surface. METHODS: The Adult Brain Tumor Consortium initiated prospective dose-finding studies to determine maximum tolerated dose in NEW-GBM treated before standard RT or after surgery for REC-HGG. Patients were inevaluable if there was progression before the 90-day posttreatment toxicity evaluation point. RESULTS: Ten NEW-GBM patients had the balloon placed, and 2/10 reached the 90 day timepoint. Five REC-HGG enrolled and two were assessable at the 90-day evaluation endpoint. Imaging progression occurred before 90-day evaluation in 7/12 treated patients. The trials were closed as too few patients were assessable to allow dose escalation, although no dose-limiting toxicities (DLTs) were observed. Median survival from treatment was 15.3 months (95 % CI 7.1-23.6) for NEW-GBM and 12.8 months (95 % CI 4.2-20.9) for REC-HGG. CONCLUSION: These trials failed to determine a maximum tolerated dose (MTD) for further testing as early imaging changes, presumed to be progression, were common and interfered with the assessment of treatment-related toxicity. The survival outcomes in these and other related studies, although based on small populations, suggest that GSBT may be worthy of further study using clinical and survival endpoints, rather than standard imaging results. The implications for local therapy development are discussed.

Leaf surface wax is a source of plant methane formation under UV radiation and in the presence of oxygen.

The terrestrial vegetation is a source of UV radiation-induced aerobic methane (CH4 ) release to the atmosphere. Hitherto pectin, a plant structural component, has been considered as the most likely precursor for this CH4 release. However, most of the leaf pectin is situated below the surface wax layer, and UV transmittance of the cuticle differs among plant species. In some species, the cuticle effectively absorbs and/or reflects UV radiation. Thus, pectin may not necessarily contribute substantially to the UV radiation-induced CH4 emission measured at surface level in all species. Here, we investigated the potential of the leaf surface wax itself as a source of UV radiation-induced leaf aerobic CH4 formation. Isolated leaf surface wax emitted CH4 at substantial rates in response to UV radiation. This discovery has implications for how the phenomenon should be scaled to global levels. In relation to this, we demonstrated that the UV radiation-induced CH4 emission is independent of leaf area index above unity. Further, we observed that the presence of O2 in the atmosphere was necessary for achieving the highest rates of CH4 emission. Methane formation from leaf surface wax is supposedly a two-step process initiated by a photolytic rearrangement reaction of the major component followed by an α-cleavage of the generated ketone.

OATP1B1 polymorphism as a determinant of erythromycin disposition.

Previous studies have demonstrated that the pharmacokinetic profile of erythromycin, a probe for CYP3A4 activity, is affected by inhibitors or inducers of hepatic solute carriers. We hypothesized that these interactions are mediated by OATP1B1 (gene symbol, SLCO1B1), a polypeptide expressed on the basolateral surface of hepatocytes. Using stably transfected Flp-In T-Rex293 cells, erythromycin was found to be a substrate for OATP1B1*1A (wild type) with a Michaelis-Menten constant of ~13 µmol/l, and that its transport was reduced by ~50% in cells expressing OATP1B1*5 (V174A). Deficiency of the ortholog transporter Oatp1b2 in mice was associated with a 52% decrease in the metabolic rate of erythromycin (P = 0.000043). In line with these observations, in humans the c.521T>C variant in SLCO1B1 (rs4149056), encoding OATP1B1*5, was associated with a decline in erythromycin metabolism (P = 0.0072). These results suggest that impairment of OATP1B1 function can alter erythromycin metabolism, independent of changes in CYP3A4 activity.

Correlation of perfusion parameters with genes related to angiogenesis regulation in glioblastoma: a feasibility study.

BACKGROUND AND PURPOSE: Integration of imaging and genomic data is critical for a better understanding of gliomas, particularly considering the increasing focus on the use of imaging biomarkers for patient survival and treatment response. The purpose of this study was to correlate CBV and PS measured by using PCT with the genes regulating angiogenesis in GBM. MATERIALS AND METHODS: Eighteen patients with WHO grade IV gliomas underwent pretreatment PCT and measurement of CBV and PS values from enhancing tumor. Tumor specimens were analyzed by TCGA by using Human Gene Expression Microarrays and were interrogated for correlation between CBV and PS estimates across the genome. We used the GO biologic process pathways for angiogenesis regulation to select genes of interest. RESULTS: We observed expression levels for 92 angiogenesis-associated genes (332 probes), 19 of which had significant correlation with PS and 9 of which had significant correlation with CBV (P < .05). Proangiogenic genes such as TNFRSF1A (PS = 0.53, P = .024), HIF1A (PS = 0.62, P = .0065), KDR (CBV = 0.60, P = .0084; PS = 0.59, P = .0097), TIE1 (CBV = 0.54, P = .022; PS = 0.49, P = .039), and TIE2/TEK (CBV = 0.58, P = .012) showed a significant positive correlation; whereas antiangiogenic genes such as VASH2 (PS = -0.72, P = .00011) showed a significant inverse correlation. CONCLUSIONS: Our findings are provocative, with some of the proangiogenic genes showing a positive correlation and some of the antiangiogenic genes showing an inverse correlation with tumor perfusion parameters, suggesting a molecular basis for these imaging biomarkers; however, this should be confirmed in a larger patient population.

Permeability estimates in histopathology-proved treatment-induced necrosis using perfusion CT: can these add to other perfusion parameters in differentiating from recurrent/progressive tumors?

BACKGROUND AND PURPOSE: Differentiating treatment effects from RPT is a common yet challenging task in a busy neuro-oncologic practice. PS probably represents a different aspect of angiogenesis and vasculature and can provide additional physiologic information about recurrent/progressive enhancing lesions. The purpose of the study was to use PS measured by using PCT to differentiate TIN from RPT in patients with previously irradiated brain tumor who presented with a recurrent/progressive enhancing lesion. MATERIALS AND METHODS: Seventy-two patients underwent PCT for assessment of a recurrent/progressive enhancing lesion from January 2006 to November 2009. Thirty-eight patients who underwent surgery and histopathologic diagnosis were included in this analysis. Perfusion parameters such as PS, CBV, CBF, and MTT were obtained from the enhancing lesion as well as from the NAWM. RESULTS: Of 38 patients, 11 were diagnosed with pure TIN and 27 had RPT. Patients with TIN showed significantly lower mean PS values than those with RPT (1.8 ± 0.8 versus 3.6 ± 1.6 mL/100 g/min; P value=.001). The TIN group also showed lower rCBV (1.2 ± 0.3 versus 2.1 ± 0.7; P value<.001), lower rCBF (1.2 ± 0.5 versus 2.6 ± 1.7; P value=.004), and higher rMTT (1.4 ± 0.4 versus 1.0 ± 0.4; P value=.018) compared with the RPT group. CONCLUSIONS: PCT and particularly PS can be used in patients with previously treated brain tumors to differentiate TIN from RPT. PS estimates can help increase the accuracy of PCT in differentiating these 2 entities.

In vivo correlation of tumor blood volume and permeability with histologic and molecular angiogenic markers in gliomas.

BACKGROUND AND PURPOSE: Tumor angiogenesis is very heterogeneous and in vivo correlation of perfusion imaging parameters with angiogenic markers can help in better understanding the role of perfusion imaging as an imaging biomarker. The purpose of this study was to correlate PCT parameters such as CBV and PS with histologic and molecular angiogenic markers in gliomas. MATERIALS AND METHODS: Thirty-six image-guided biopsy specimens in 23 patients with treatment-naive gliomas underwent PCT examinations. We correlated MVD, MVCP, VEGFR-2 expression, tumor cellularity, and WHO grade of the image-guided biopsy specimens with the PCT parameters. Histologic sections were stained with hematoxylin-eosin, CD34, and VEGFR-2 and examined under a light microscope. These histologic and molecular angiogenic markers were correlated with perfusion parameters of the region of interest corresponding to the biopsy specimen. Pearson correlation coefficients and multiple regression analyses by using clustering methods were performed to assess these correlations. RESULTS: CBV showed a significant positive correlation with MVD (r = 0.596, P < .001), whereas PS showed a significant positive correlation with MVCP (r = 0.546, P = .001). Both CBV (r = 0.373, P = .031) and PS (r = 0.452, P = .039) also showed a significant correlation with WHO grade. VEGFR-2 positive specimens showed higher PS and CBV; however, neither was statistically significant at the .05 level. CONCLUSIONS: CBV showed a significant positive correlation with MVD, whereas PS showed a significant positive correlation with MVCP, suggesting that these 2 perfusion parameters represent different aspects of tumor vessels; hence, in vivo evaluation of these could be important in a better understanding of tumor angiogenesis.

Effects of temperature, ultraviolet radiation and pectin methyl esterase on aerobic methane release from plant material.

This study examines the effects of different irradiance types on aerobic methane (CH(4)) efflux rates from terrestrial plant material. Furthermore, the role of the enzyme pectin methyl esterase (PME) on CH(4) efflux potential was also examined. Different types of plant tissue and purified pectin were incubated in glass vials with different combinations of irradiation and/or temperature. Purified dry pectin was incubated in solution, and with or without PME. Before and after incubation, the concentration of CH(4) was measured with a gas chromatograph. Rates of CH(4) emission were found to depend exponentially on temperature and linearly on UV-B irradiance. UV-B had a greater stimulating effect than UV-A, while visible light had no effect on emission rates. PME was found to substantially reduce the potential for aerobic CH(4) emissions upon demethylation of pectin.

Contribution of organic cation transporter 2 (OCT2) to cisplatin-induced nephrotoxicity.

Cisplatin is one of the most widely used anticancer agents for the treatment of solid tumors. The clinical use of cisplatin is associated with dose-limiting nephrotoxicity, which occurs in one-third of patients despite intensive prophylactic measures. Organic cation transporter 2 (OCT2) has been implicated in the cellular uptake of cisplatin, but its role in cisplatin-induced nephrotoxicity remains unknown. In mice, deletion of Oct1 and Oct2 resulted in significantly impaired urinary excretion of cisplatin without an apparent influence on plasma levels. Furthermore, the Oct1/Oct2-deficient mice were protected from severe cisplatin-induced renal tubular damage. Subsequently, we found that a nonsynonymous single-nucleotide polymorphism (SNP) in the OCT2 gene SLC22A2 (rs316019) was associated with reduced cisplatin-induced nephrotoxicity in patients. Collectively, these results indicate the critical importance of OCT2 in the renal handling and related renal toxicity of cisplatin and provide a rationale for the development of new targeted approaches to mitigate this debilitating side effect.

Intake of vitamin C and E in pregnancy and risk of pre-eclampsia: prospective study among 57 346 women.

OBJECTIVE: It has been suggested that vitamin C, alone or in combination with vitamin E, may protect against pre-eclampsia, whereas the safety of high-dose vitamin E supplements has been questioned. We investigated dietary intakes of vitamins C and E to see if they correlated with the incidence of pre-eclampsia. DESIGN: Prospective cohort study. SETTING: The Danish National Birth Cohort; a population-based pregnancy cohort; analyses were based on 57 346 pregnancies. METHODS: Vitamin intake was estimated from a food frequency questionnaire completed in gestational week 25, recording intake from diet and supplements during the previous four weeks. Pre-eclampsia diagnoses were obtained from the Danish National Patient Registry; we worked with two entities, 'pre-eclampsia (all types)' and 'severe pre-eclampsia/eclampsia/HELLP'. We adjusted for confounding factors by logistic regression. MAIN OUTCOME MEASURES: A small increase in the incidence of severe disease was also seen in the group of women (64, n = 49 373) with a high intake of vitamin E from supplements and dietary sources. RESULTS: The incidence of 'pre-eclampsia (all types)' did not correlate with dietary vitamin C and E intake. There was a decreasing trend (P = 0.01) in the incidence of 'severe pre-eclampsia/eclampsia/HELLP' with increasing dietary vitamin C intake; with an intake of 130-170 mg/day as reference, odds ratios ranged from 1.21 (95% confidence interval 0.83 to 1.75) for an intake below 70 mg/day to 0.70 (0.40 to 1.23) for an intake exceeding 275 mg/day (total n = 57 346). For vitamin E intake aggregated from diet and supplements (n = 49 373), with an intake of 10.5-13.5 mg/day as reference, the 'severe pre-eclampsia/eclampsia/HELLP' odds ratio was 1.46 (1.02 to 2.09) for an intake exceeding 18 mg/day. CONCLUSIONS: Low dietary intake of vitamin C was associated with a trend towards an increased incidence of either severe pre-eclampsia, eclampsia or HELLP. A small increase in the incidence of severe disease was also seen in the group of women with a high intake of vitamin E from supplements and dietary sources.

Requirements for estimation of doses from contaminants dispersed by a 'dirty bomb' explosion in an urban area.

The ARGOS decision support system is currently being extended to enable estimation of the consequences of terror attacks involving chemical, biological, nuclear and radiological substances. This paper presents elements of the framework that will be applied in ARGOS to calculate the dose contributions from contaminants dispersed in the atmosphere after a 'dirty bomb' explosion. Conceptual methodologies are presented which describe the various dose components on the basis of knowledge of time-integrated contaminant air concentrations. Also the aerosolisation and atmospheric dispersion in a city of different types of conceivable contaminants from a 'dirty bomb' are discussed.

Efficacy, safety and patterns of response and recurrence in patients with recurrent high-grade gliomas treated with bevacizumab plus irinotecan.

Our objective is to assess treatment efficacy, safety and pattern of response and recurrence in patients with recurrent high-grade glioma treated with bevacizumab and irinotecan. We reviewed retrospectively 51 patients with recurrent high-grade glioma treated with this combination at the Henry Ford Hermelin Brain Tumor Center from 11/15/2005 to 04/01/2008. The 6-month progression-free survival (PFS) for anaplastic gliomas (AGs) was 78.6 and 63.7% for glioblastoma. The median PFS was 13.4 months for AG and 7.6 months for those with glioblastoma. The overall survival rate (OS) at 6 months was 85.7% for AG and 78.0% for glioblastoma. The 12-month OS was 77.9% for AG and 42.6% for glioblastoma. The median OS time for AGs was not reached and was 11.5 months for those with glioblastoma. Thirty-six out of 51 (70.59%) patients demonstrated partial (32/51) or complete (4/51) radiographic response to treatment and 8/51 (15.69%) remained stable. Of the 38 who demonstrated progression on post-gadolinium studies, 23 showed distant progression with or without local recurrence. Seven patients showed progression on FLAIR without concordant findings on post-Gd sequences. Six patients (11.76%) discontinued treatment due to a treatment-emergent adverse event, including one with end-stage renal failure and another with gastric perforation. No symptomatic intracranial hemorrhages were reported. Patients with recurrent high-grade glioma treated with bevacizumab plus irinotecan demonstrate an excellent radiographic response rate and improved clinical outcome when compared to historical data. The high rate of distant tumor progression suggests that tumors may adapt to inhibition of angiogenesis by increased infiltration and vascular co-option.

Temozolomide single-agent chemotherapy for newly diagnosed anaplastic oligodendroglioma.

The treatment of patients with anaplastic oligodendroglioma (AO) has been significantly impacted by the molecular detection of loss of sequences on chromosomes 1p and 19q. We performed a clinical trial to prospectively evaluate the safety of treating patients with AO with temozolomide (TMZ) alone in patients with chromosome 1p/19q loss and with chemo-radiation in patients not harboring this loss. Forty-eight patients were enrolled, 36/48 (75%) with evidence of chromosome 1p/19q loss treated with TMZ alone and 12/18 (25%) without such losses, treated with pre-radiation TMZ followed by chemo-radiation. Despite more aggressive treatment, patients without 1p/19q loss had a shorter progression-free survival (PFS) of 13.5 months. With a median follow-up time of 32 months, patients with 1p/19q LOH had a median TTP of 28.7 months. Patients with AO with 1p/19q LOH can be safely treated with single-agent TMZ and do not appear to experience earlier or more frequent tumor progression. This treatment regimen should be studied as part of a formal randomized clinical trial.

Estimation of health hazards resulting from a radiological terrorist attack in a city.

In recent years, the concern for protection of urban populations against terror attacks involving radiological, biological or chemical substances has attracted increasing attention. It sets new demands to decision support and consequence assessment tools, where the focus has traditionally been on accidental exposure. The aim of the present study was to illustrate issues that need to be considered in evaluating the radiological consequences of a 'dirty bomb' explosion. This is done through a worked example of simplified calculations of relative dose contributions for a specific 'dirty bomb' scenario leading to atmospheric dispersion of 90Sr contamination over a city area. Also, the requirements of atmospheric dispersion models for such scenarios are discussed.

Quantitative estimation of permeability surface-area product in astroglial brain tumors using perfusion CT and correlation with histopathologic grade.

BACKGROUND AND PURPOSE: Glioma angiogenesis and its different hemodynamic features, which can be evaluated by using perfusion CT (PCT) imaging of the brain, have been correlated with the grade and the aggressiveness of gliomas. Our hypothesis was that quantitative estimation of permeability surface area product (PS), cerebral blood volume (CBV), cerebral blood flow (CBF), and mean transit time (MTT) in astroglial brain tumors by using PCT will correlate with glioma grade. High-grade gliomas will show higher PS and CBV as compared with low-grade gliomas. MATERIALS AND METHODS: PCT was performed in 32 patients with previously untreated astroglial tumors (24 high-grade gliomas and 8 low-grade gliomas) by using a total acquisition time of 170 seconds. World Health Organization (WHO) glioma grades were compared with PCT parameter absolute values by using Student or nonparametric Wilcoxon 2-sample tests. Receiver operating characteristic (ROC) analyses were also done for each of the parameters. RESULTS: The differences in PS, CBV, and CBF between the low- and high-grade tumor groups were statistically significant, with the low-grade group showing lower mean values than the high-grade group. ROC analyses showed that both CBV (C-statistic 0.930) and PS (C-statistic 0.927) were very similar to each other in differentiating low- and high-grade gliomas and had higher predictability compared with CBF and MTT. Within the high-grade group, differentiation of WHO grade III and IV gliomas was also possible by using PCT parameters, and PS showed the highest C-statistic value (0.926) for the ROC analyses in this regard. CONCLUSIONS: Both PS and CBV showed strong association with glioma grading, high-grade gliomas showing higher PS and CBV as compared with low-grade gliomas. Perfusion parameters, especially PS, can also be used to differentiate WHO grade III from grade IV in the high-grade tumor group.

Major dietary patterns in pregnancy and fetal growth.

OBJECTIVES: To investigate possible associations between maternal diet during pregnancy and fetal growth. METHOD: Factor analysis was used to explore dietary patterns among pregnant women. The association between maternal dietary patterns and fetal growth (in terms of small for gestational age, SGA) was investigated by logistic regression. Prospective cohort study, including information on 44 612 women in Denmark. RESULTS: Two major dietary patterns were defined: the first pattern was characterized by red and processed meat, high-fat dairy, and the second pattern was characterized by intake of vegetables, fruits, poultry and fish. Women were classified into three classes according to their diet: the first class had high intake of foods of the first dietary pattern, and was classified as 'the Western diet', the second class preferred foods of the second pattern and was classified as the 'Health Conscious'; and the third one had eaten foods of both patterns, and was classified as the 'Intermediate'. The odds ratio of having a small for gestational-age infant (with a birth weight below the 2.5th percentile for gestational age and gender) was 0.74 (95% CI 0.64-0.86) for women in the Health Conscious class compared with women in the Western Diet class. The analyses were adjusted for parity, maternal smoking, age, height, pre-pregnancy weight and father's height. CONCLUSIONS: Our results indicated that a diet in pregnancy, based on red and processed meat and high-fat diary, was associated with increased risk for SGA. Further studies are warranted to identify specific macro-, or micronutrients that may be underlying these associations.

Role of perfusion CT in glioma grading and comparison with conventional MR imaging features.

BACKGROUND AND PURPOSE: Perfusion imaging using CT can provide additional information about tumor vascularity and angiogenesis for characterizing gliomas. The purpose of our study was to demonstrate the usefulness of various perfusion CT (PCT) parameters in assessing the grade of treatment-naïve gliomas and also to compare it with conventional MR imaging features. MATERIALS AND METHODS: PCT was performed in 19 patients with glioma (14 high-grade gliomas and 5 low-grade gliomas). Normalized ratios of the PCT parameters (normalized cerebral blood volume [nCBV], normalized cerebral blood flow [nCBF], normalized mean transit time [nMTT]) were used for final analysis. Conventional MR imaging features of these tumors were assessed separately and compared with PCT parameters. Low- and high-grade gliomas were compared by using the nonparametric Wilcoxon 2-sample tests. RESULTS: Mean nCBV in the high- and low-grade gliomas was 3.06 +/- 1.35 and 1.44 +/- 0.42, respectively, with a statistically significant difference between the 2 groups (P = .005). Mean nCBF for the high- and low-grade gliomas was 3.03 +/- 2.16 and 1.16 +/- 0.36, respectively, with a statistically significant difference between the 2 groups (P = .045). Cut points of >1.92 for nCBV (85.7% sensitivity and 100% specificity), >1.48 for nCBF (71.4% sensitivity and 100% specificity), and <1.94 for nMTT (92.9% sensitivity and 40% specificity) were found to identify the high-grade gliomas. nCBV was the single best parameter; however, using either nCBV of >1.92 or nCBF of >1.48 improved the sensitivity and specificity to 92.9% and 100%, respectively. The sensitivity and specificity for diagnosing a high-grade glioma with conventional MR imaging were 85.7% and 60%, respectively. CONCLUSIONS: PCT can be used for preoperative grading of gliomas and can provide valuable complementary information about tumor hemodynamics, not available with conventional imaging techniques. nCBV was the single best parameter correlating with glioma grades, though using nCBF when nCBV was <1.92 improved the sensitivity. An nCBV threshold of >1.92 was found to identify the high-grade gliomas.