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2018 World Health Organization (WHO) guidelines for the treatment of isoniazid (H)-resistant (Hr) tuberculosis recommend a four-drug regimen: rifampicin (R), ethambutol (E), pyrazinamide (Z) and levofloxacin (Lfx), with or without H ([H]RZE-Lfx). This is used once Hr is known, such that patients complete 6 months of Lfx (≥6[H]RZE-6Lfx). This cohort study assessed the impact of fluoroquinolones (Fq) on treatment effectiveness, accounting for Hr mutations and degree of phenotypic resistance. This was a retrospective cohort study of 626 Hr tuberculosis patients notified in London, 2009-2013. Regimens were described and logistic regression undertaken of the association between regimen and negative regimen-specific outcomes (broadly, death due to tuberculosis, treatment failure or disease recurrence). Of 594 individuals with regimen information, 330 (55.6%) were treated with (H)RfZE (Rf=rifamycins) and 211 (35.5%) with (H)RfZE-Fq. The median overall treatment period was 11.9 months and median Z duration 2.1 months. In a univariable logistic regression model comparing (H)RfZE with and without Fqs, there was no difference in the odds of a negative regimen-specific outcome (baseline (H)RfZE, cluster-specific odds ratio 1.05 (95% CI 0.60-1.82), p=0.87; cluster NHS trust). Results varied minimally in a multivariable model. This odds ratio dropped (0.57, 95% CI 0.14-2.28) when Hr genotype was included, but this analysis lacked power (p=0.42). In a high-income setting, we found a 12-month (H)RfZE regimen with a short Z duration to be similarly effective for Hr tuberculosis with or without a Fq. This regimen may result in fewer adverse events than the WHO recommendations.

PurposeTo introduce a new pH-sensitive and oxygen-sensitive MRI technique using amine proton CEST echo spin-and-gradient echo (SAGE) EPI (CEST-SAGE-EPI).MethodspH-weighting was obtained using CEST estimations of magnetization transfer ratio asymmetry (MTRasym ) at 3 ppm, and oxygen-weighting was obtained using R2' measurements. Glutamine concentration, pH, and relaxation rates were varied in phantoms to validate simulations and estimate relaxation rates. The values of MTRasym and R2' in normal-appearing white matter, T2 hyperintensity, contrast enhancement, and macroscopic necrosis were measured in 47 gliomas.ResultsSimulation and phantom results confirmed an increase in MTRasym with decreasing pH. The CEST-SAGE-EPI estimates of R2 , R2*, and R2' varied linearly with gadolinium diethylenetriamine penta-acetic acid concentration (R2  = 6.2 mM-1 ·sec-1 and R2* = 6.9 mM-1 ·sec-1 ). The CEST-SAGE-EPI and Carr-Purcell-Meiboom-Gill estimates of R2 (R2  = 0.9943) and multi-echo gradient-echo estimates of R2* (R2  = 0.9727) were highly correlated. T2 lesions had lower R2' and higher MTRasym compared with normal-appearing white matter, suggesting lower hypoxia and high acidity, whereas contrast-enhancement tumor regions had elevated R2' and MTRasym , indicating high hypoxia and acidity.ConclusionThe CEST-SAGE-EPI technique provides simultaneous pH-sensitive and oxygen-sensitive image contrasts for evaluation of the brain tumor microenvironment. Advantages include fast whole-brain acquisition, in-line B0 correction, and simultaneous estimation of CEST effects, R2 , R2*, and R2' at 3 T.

PURPOSE:To introduce a new pH-sensitive and oxygen-sensitive MRI technique using amine proton CEST echo spin-and-gradient echo (SAGE) EPI (CEST-SAGE-EPI). METHODS:pH-weighting was obtained using CEST estimations of magnetization transfer ratio asymmetry (MTRasym ) at 3 ppm, and oxygen-weighting was obtained using R2' measurements. Glutamine concentration, pH, and relaxation rates were varied in phantoms to validate simulations and estimate relaxation rates. The values of MTRasym and R2' in normal-appearing white matter, T2 hyperintensity, contrast enhancement, and macroscopic necrosis were measured in 47 gliomas. RESULTS:Simulation and phantom results confirmed an increase in MTRasym with decreasing pH. The CEST-SAGE-EPI estimates of R2 , R2*, and R2' varied linearly with gadolinium diethylenetriamine penta-acetic acid concentration (R2  = 6.2 mM-1 ·sec-1 and R2* = 6.9 mM-1 ·sec-1 ). The CEST-SAGE-EPI and Carr-Purcell-Meiboom-Gill estimates of R2 (R2  = 0.9943) and multi-echo gradient-echo estimates of R2* (R2  = 0.9727) were highly correlated. T2 lesions had lower R2' and higher MTRasym compared with normal-appearing white matter, suggesting lower hypoxia and high acidity, whereas contrast-enhancement tumor regions had elevated R2' and MTRasym , indicating high hypoxia and acidity. CONCLUSION:The CEST-SAGE-EPI technique provides simultaneous pH-sensitive and oxygen-sensitive image contrasts for evaluation of the brain tumor microenvironment. Advantages include fast whole-brain acquisition, in-line B0 correction, and simultaneous estimation of CEST effects, R2 , R2*, and R2' at 3 T.

BackgroundIn the current study we used contrast-enhanced T1 subtraction maps to test whether early changes in enhancing tumor volume are prognostic for overall survival (OS) in newly diagnosed glioblastoma (GBM) patients treated with chemoradiation with or without bevacizumab (BV).MethodsSeven hundred ninety-eight patients (404 BV and 394 placebo) with newly diagnosed GBM in the AVAglio trial (NCT00943826) had baseline MRI scans available, while 337 BV-treated and 269 placebo-treated patients had >4 MRI scans for response evaluation. The volume of contrast-enhancing tumor was quantified and used for subsequent analyses.ResultsA decrease in tumor volume during chemoradiation was associated with a longer OS in the placebo group (hazard ratio [HR] = 1.578, P < 0.0001) but not BV-treated group (HR = 1.135, P = 0.4889). Results showed a higher OS in patients on the placebo arm with a sustained decrease in tumor volume using a post-chemoradiation baseline (HR = 1.692, P = 0.0005), and a trend toward longer OS was seen in BV-treated patients (HR = 1.264, P = 0.0724). Multivariable Cox regression confirmed that sustained response or stable disease was prognostic for OS (HR = 0.7509, P = 0.0127) when accounting for age (P = 0.0002), KPS (P = 0.1516), postsurgical tumor volume (P < 0.0001), O6-methylguanine-DNA methyltransferase status (P < 0.0001), and treatment type (P = 0.7637) using the post-chemoradiation baseline.ConclusionsThe post-chemoradiation timepoint is a better baseline for evaluating efficacy in newly diagnosed GBM. Early progression during the maintenance phase is consequential in predicting OS, supporting the use of progression-free survival rates as a meaningful surrogate for GBM.

Background:In the current study we used contrast-enhanced T1 subtraction maps to test whether early changes in enhancing tumor volume are prognostic for overall survival (OS) in newly diagnosed glioblastoma (GBM) patients treated with chemoradiation with or without bevacizumab (BV). Methods:Seven hundred ninety-eight patients (404 BV and 394 placebo) with newly diagnosed GBM in the AVAglio trial (NCT00943826) had baseline MRI scans available, while 337 BV-treated and 269 placebo-treated patients had >4 MRI scans for response evaluation. The volume of contrast-enhancing tumor was quantified and used for subsequent analyses. Results:A decrease in tumor volume during chemoradiation was associated with a longer OS in the placebo group (hazard ratio [HR] = 1.578, P < 0.0001) but not BV-treated group (HR = 1.135, P = 0.4889). Results showed a higher OS in patients on the placebo arm with a sustained decrease in tumor volume using a post-chemoradiation baseline (HR = 1.692, P = 0.0005), and a trend toward longer OS was seen in BV-treated patients (HR = 1.264, P = 0.0724). Multivariable Cox regression confirmed that sustained response or stable disease was prognostic for OS (HR = 0.7509, P = 0.0127) when accounting for age (P = 0.0002), KPS (P = 0.1516), postsurgical tumor volume (P < 0.0001), O6-methylguanine-DNA methyltransferase status (P < 0.0001), and treatment type (P = 0.7637) using the post-chemoradiation baseline. Conclusions:The post-chemoradiation timepoint is a better baseline for evaluating efficacy in newly diagnosed GBM. Early progression during the maintenance phase is consequential in predicting OS, supporting the use of progression-free survival rates as a meaningful surrogate for GBM.

BackgroundTo overcome challenges with traditional response assessment in anti-angiogenic agents, the current study uses T1 subtraction maps to quantify volumetric radiographic response in monotherapy with cabozantinib, an orally bioavailable tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 (VEGFR2), hepatocyte growth factor receptor (MET), and AXL, in an open-label, phase II trial in patients with recurrent glioblastoma (GBM) (NCT00704288).MethodsA total of 108 patients with adequate imaging data and confirmed recurrent GBM were included in this retrospective study from a phase II multicenter trial of cabozantinib monotherapy (XL184-201) at either 100 mg (N = 87) or 140 mg (N = 21) per day. Contrast enhanced T1-weighted digital subtraction maps were used to define volume of contrast-enhancing tumor at baseline and subsequent follow-up time points. Volumetric radiographic response (>65% reduction in contrast-enhancing tumor volume from pretreatment baseline tumor volume sustained for more than 4 wk) was tested as an independent predictor of overall survival (OS).ResultsVolumetric response rate for all therapeutic doses was 38.9% (41.4% and 28.6% for 100 mg and 140 mg doses, respectively). A log-linear association between baseline tumor volume and OS (P = 0.0006) and a linear correlation between initial change in tumor volume and OS (P = 0.0256) were observed. A significant difference in OS was observed between responders (median OS = 20.6 mo) and nonresponders (median OS = 8.0 mo) (hazard ratio [HR] = 0.3050, P < 0.0001). Multivariable analyses showed that continuous measures of baseline tumor volume (HR = 1.0233, P < 0.0001) and volumetric response (HR = 0.2240, P < 0.0001) were independent predictors of OS.ConclusionsT1 subtraction maps provide value in determining response in recurrent GBM treated with cabozantinib and correlated with survival benefit.

PurposeTo quantify changes and prognostic value of diffusion MRI measurements obtained using mono-exponential, diffusion kurtosis imaging (DKI) and stretched exponential (SE) models prior and after chemoradiation in newly diagnosed glioblastoma (GBM).MethodsDiffusion-weighted images (DWIs) were acquired in twenty-three patients following surgery, prior chemoradiation and within 7 days following completion of treatment, using b-values ranging from 0 to 5000s/mm2. Mono-exponential diffusion (apparent diffusion coefficient: ADC), isotropic (non-directional) DKI model with apparent diffusivity (Dapp) and kurtosis (Kapp) estimates as well as SE model with distributed-diffusion coefficient (DDC) and mean intra-voxel heterogeneity (α) were computed for all patients prior and after chemoradiation. Median values were calculated for normal appearing white matter (NAWM) and contrast-enhancing tumor (CET). The magnitudes of diffusion change prior and after chemoradiation were used to predict overall survival (OS).ResultsDiffusivity in NAWM was consistent for all diffusion measures during chemoradiation, while diffusivity measurements (ADC, Dapp and DDC) within CET changed significantly. A strong positive correlation existed between ADC, Dapp, and DDC measurements prior to chemoradiation; however, this association was weak following chemoradiation, suggesting a more complex microstructural environment after cytotoxic therapy. When combined with baseline tumor volume and MGMT status, age and ADC changes added significant prognostic values, whereas more complex diffusion models did not show significant value in predicting OS.ConclusionsDespite increased tissue complexity following chemoradiation, advanced diffusion models have longer acquisition times, provide largely comparable measures of diffusivity, and do not appear to provide additional prognostic value compared to mono-exponential ADC maps.

Background:To overcome challenges with traditional response assessment in anti-angiogenic agents, the current study uses T1 subtraction maps to quantify volumetric radiographic response in monotherapy with cabozantinib, an orally bioavailable tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 (VEGFR2), hepatocyte growth factor receptor (MET), and AXL, in an open-label, phase II trial in patients with recurrent glioblastoma (GBM) (NCT00704288). Methods:A total of 108 patients with adequate imaging data and confirmed recurrent GBM were included in this retrospective study from a phase II multicenter trial of cabozantinib monotherapy (XL184-201) at either 100 mg (N = 87) or 140 mg (N = 21) per day. Contrast enhanced T1-weighted digital subtraction maps were used to define volume of contrast-enhancing tumor at baseline and subsequent follow-up time points. Volumetric radiographic response (>65% reduction in contrast-enhancing tumor volume from pretreatment baseline tumor volume sustained for more than 4 wk) was tested as an independent predictor of overall survival (OS). Results:Volumetric response rate for all therapeutic doses was 38.9% (41.4% and 28.6% for 100 mg and 140 mg doses, respectively). A log-linear association between baseline tumor volume and OS (P = 0.0006) and a linear correlation between initial change in tumor volume and OS (P = 0.0256) were observed. A significant difference in OS was observed between responders (median OS = 20.6 mo) and nonresponders (median OS = 8.0 mo) (hazard ratio [HR] = 0.3050, P < 0.0001). Multivariable analyses showed that continuous measures of baseline tumor volume (HR = 1.0233, P < 0.0001) and volumetric response (HR = 0.2240, P < 0.0001) were independent predictors of OS. Conclusions:T1 subtraction maps provide value in determining response in recurrent GBM treated with cabozantinib and correlated with survival benefit.

Purpose: Anti-VEGF therapies remain controversial in the treatment of recurrent glioblastoma (GBM). In the current study, we demonstrate that recurrent GBM patients with a specific diffusion MR imaging signature have an overall survival (OS) advantage when treated with cediranib, bevacizumab, cabozantinib, or aflibercept monotherapy at first or second recurrence. These findings were validated using a separate trial comparing bevacizumab with lomustine.Experimental Design: Patients with recurrent GBM and diffusion MRI from the monotherapy arms of 5 separate phase II clinical trials were included: (i) cediranib (NCT00035656); (ii) bevacizumab (BRAIN Trial, AVF3708g; NCT00345163); (iii) cabozantinib (XL184-201; NCT00704288); (iv) aflibercept (VEGF Trap; NCT00369590); and (v) bevacizumab or lomustine (BELOB; NTR1929). Apparent diffusion coefficient (ADC) histogram analysis was performed prior to therapy to estimate "ADCL," the mean of the lower ADC distribution. Pretreatment ADCL, enhancing volume, and clinical variables were tested as independent prognostic factors for OS.Results: The coefficient of variance (COV) in double baseline ADCL measurements was 2.5% and did not significantly differ (P = 0.4537). An ADCL threshold of 1.24 μm2/ms produced the largest OS differences between patients (HR ∼ 0.5), and patients with an ADCL > 1.24 μm2/ms had close to double the OS in all anti-VEGF therapeutic scenarios tested. Training and validation data confirmed that baseline ADCL was an independent predictive biomarker for OS in anti-VEGF therapies, but not in lomustine, after accounting for age and baseline enhancing tumor volume.Conclusions: Pretreatment diffusion MRI is a predictive imaging biomarker for OS in patients with recurrent GBM treated with anti-VEGF monotherapy at first or second relapse. Clin Cancer Res; 23(19); 5745-56. ©2017 AACR.

BackgroundThe prognostic significance of baseline contrast enhancing tumor prior to second- or third-line therapy in recurrent glioblastoma (GBM) for overall survival (OS) remains controversial, particularly in the context of repeated surgical resection and/or use of anti-angiogenic therapy. In the current study, we examined recurrent GBM patients from both single and multicenter clinical trials to test whether baseline enhancing tumor volume, including central necrosis, is a significant prognostic factor for OS in recurrent GBM.MethodsIncluded were 497 patients with recurrent GBM from 4 data sources: 2 single-center sites (University of Toronto, University of California Los Angeles) and 2 phase II multicenter trials (AVF3708G, Bevacizumab ± Irinotecan, NCT00345163; XL184-201, Cabozantinib, NCT00704288). T1 subtraction maps were used to define volume of contrast enhancing tumor, including central necrosis. Cox multivariable and univariate analyses were used to evaluate the relationship between tumor volume prior to second- or third-line therapy and OS.ResultsBoth continuous measures of baseline tumor volume and tumors dichotomized into large (≥15cc) and small (

BackgroundThe prognostic significance of baseline contrast enhancing tumor prior to second- or third-line therapy in recurrent glioblastoma (GBM) for overall survival (OS) remains controversial, particularly in the context of repeated surgical resection and/or use of anti-angiogenic therapy. In the current study, we examined recurrent GBM patients from both single and multicenter clinical trials to test whether baseline enhancing tumor volume, including central necrosis, is a significant prognostic factor for OS in recurrent GBM.MethodsIncluded were 497 patients with recurrent GBM from 4 data sources: 2 single-center sites (University of Toronto, University of California Los Angeles) and 2 phase II multicenter trials (AVF3708G, Bevacizumab ± Irinotecan, NCT00345163; XL184-201, Cabozantinib, NCT00704288). T1 subtraction maps were used to define volume of contrast enhancing tumor, including central necrosis. Cox multivariable and univariate analyses were used to evaluate the relationship between tumor volume prior to second- or third-line therapy and OS.ResultsBoth continuous measures of baseline tumor volume and tumors dichotomized into large (≥15cc) and small (

PurposeFit-for-purpose pharmacodynamic biomarkers could expedite development of combination antiangiogenic regimens. Plasma sVEGFR2 concentrations ([sVEGFR2]) mark sunitinib effects on the systemic vasculature. We hypothesized that cilengitide would impair microvasculature recovery during sunitinib withdrawal and could be detected through changes in [sVEGFR2].Experimental designAdvanced solid tumor patients received 50 mg sunitinib daily for 14 days. For the next 14 days, patients were randomized to arm A (cilengitide 2,000 mg administered intravenously twice weekly) or arm B (no treatment). The primary endpoint was change in [sVEGFR2] between days 14 and 28. A candidate pharmacodynamic biomarker of cilengitide inhibition of integrin αvβ3, serum c-telopeptide collagen crosslinks (CTx), was also measured.ResultsOf 21 patients, 14 (7 per arm) received all treatments without interruption and had all blood samples available for analysis. The mean change and SD of [sVEGFR2] for all sunitinib-treated patients was consistent with previous data. There was no significant difference in the mean change in [sVEGFR2] from days 14 to 28 between the arms [arm A: 2.8 ng/mL; 95% confidence interval (CI), 2.1-3.6 vs. arm B: 2.0 ng/mL; 95% CI, 0.72-3.4; P = 0.22, 2-sample t test]. Additional analyses suggested (i) prior bevacizumab therapy to be associated with unusually low baseline [sVEGFR2] and (ii) sunitinib causes measurable changes in CTx.ConclusionsCilengitide had no measurable effects on any circulating biomarkers. Sunitinib caused measurable declines in serum CTx. The properties of [sVEGFR2] and CTx observed in this study inform the design of future combination antiangiogenic therapy trials.

BackgroundInterstitial tissue acidosis resulting from abnormal perfusion and metabolism is a hallmark of cancer. The current study demonstrates that chemical exchange saturation transfer (CEST) MRI can be used as a noninvasive pH-weighted molecular imaging technique by targeting the chemical exchange between amine protons and protons in extracellular bulk water.MethodsFirst, the sensitivity of amine CEST was validated in phantoms under a variety of conditions, including different magnetic field strengths, amino acid concentrations, and pH values. Amine CEST was compared with histology in both a preclinical GL261 intracranial glioma model at 7T and human patients at 3T. The association between physiologic and pH-weighted MRI was explored, along with the ability to predict time to progression to radiochemotherapy in 20 glioblastoma patients.Resultsz-Spectral asymmetry increased at 3 ppm (amine range) on CEST MRI with decreasing pH within the range observed in tumors for both 3T and 7T scanners. Lesions with acidic signatures showed active tumor and pseudopalisading tumor on histology and showed elevated FDOPA PET uptake, lactate on MR spectroscopy, and perfusion abnormalities. Patients with acidic lesions after surgery or stable/growing acidic lesions had a shorter time to progression following radiochemotherapy compared with patients with lesions demonstrating relatively low acidity (P < .001).ConclusionResults suggest pH-weighted MRI may provide new insight into brain tumor physiology beyond traditional imaging technologies.

Biopsies and ANCA testing for limited forms of granulomatosis with polyangiitis (GPA) are frequently non-diagnostic. We characterized gene expression in GPA and other causes of orbital inflammation. We tested the hypothesis that a sub-set of patients with non-specific orbital inflammation (NSOI, also known as pseudotumor) mimics a limited form of GPA. Formalin-fixed, paraffin-embedded orbital biopsies were obtained from controls (n=20) and patients with GPA (n=6), NSOI (n=25), sarcoidosis (n=7), or thyroid eye disease (TED) (n=20) and were divided into discovery and validation sets. Transcripts in the tissues were quantified using Affymetrix U133 Plus 2.0 microarrays. Distinct gene expression profiles for controls and subjects with GPA, TED, or sarcoidosis were evident by principal coordinate analyses. Compared with healthy controls, 285 probe sets had elevated signals in subjects with GPA and 1472 were decreased (>1.5-fold difference, false discovery rate adjusted p

PurposeDiffusion magnetic resonance imaging (MRI) and 6-[(18)F]fluoro-L-dopa ([(18)F]FDOPA) positron emission tomography (PET) are used to interrogate malignant tumor microenvironment. It remains unclear whether there is a relationship between [(18)F]FDOPA uptake, diffusion MRI estimates of apparent diffusion coefficient (ADC), and mitotic activity in the context of recurrent malignant gliomas, where the tumor may be confounded by the effects of therapy. The purpose of the current study is to determine whether there is a correlation between these imaging techniques and mitotic activity in malignant gliomas.ProceduresWe retrospectively examined 29 patients with recurrent malignant gliomas who underwent structural MRI, diffusion MRI, and [(18)F]FDOPA PET prior to surgical resection. Qualitative associations were noted, and quantitative voxel-wise and median measurement correlations between [(18)F]FDOPA PET, ADC, and mitotic index were performed.ResultsAreas of high [(18)F]FDOPA uptake exhibited low ADC and areas of hyperintensity T2/fluid-attenuated inversion recovery (FLAIR) with low [(18)F]FDOPA uptake exhibited high ADC. There was a significant inverse voxel-wise correlation between [(18)F]FDOPA and ADC for all patients. Median [(18)F]FDOPA uptake and median ADC also showed a significant inverse correlation. Median [(18)F]FDOPA uptake was positively correlated, and median ADC was inversely correlated with mitotic index from resected tumor tissue.ConclusionsA significant association may exist between [(18)F]FDOPA uptake, diffusion MRI, and mitotic activity in recurrent malignant gliomas.

PurposeDiffusion magnetic resonance imaging (MRI) and 6-[(18)F]fluoro-L-dopa ([(18)F]FDOPA) positron emission tomography (PET) are used to interrogate malignant tumor microenvironment. It remains unclear whether there is a relationship between [(18)F]FDOPA uptake, diffusion MRI estimates of apparent diffusion coefficient (ADC), and mitotic activity in the context of recurrent malignant gliomas, where the tumor may be confounded by the effects of therapy. The purpose of the current study is to determine whether there is a correlation between these imaging techniques and mitotic activity in malignant gliomas.ProceduresWe retrospectively examined 29 patients with recurrent malignant gliomas who underwent structural MRI, diffusion MRI, and [(18)F]FDOPA PET prior to surgical resection. Qualitative associations were noted, and quantitative voxel-wise and median measurement correlations between [(18)F]FDOPA PET, ADC, and mitotic index were performed.ResultsAreas of high [(18)F]FDOPA uptake exhibited low ADC and areas of hyperintensity T2/fluid-attenuated inversion recovery (FLAIR) with low [(18)F]FDOPA uptake exhibited high ADC. There was a significant inverse voxel-wise correlation between [(18)F]FDOPA and ADC for all patients. Median [(18)F]FDOPA uptake and median ADC also showed a significant inverse correlation. Median [(18)F]FDOPA uptake was positively correlated, and median ADC was inversely correlated with mitotic index from resected tumor tissue.ConclusionsA significant association may exist between [(18)F]FDOPA uptake, diffusion MRI, and mitotic activity in recurrent malignant gliomas.

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.

BackgroundManagement of language difficulties is an important aspect of clinical care for glioma patients, and accurately identifying the possible language deficits in patients based on lesion location would be beneficial to clinicians. To that end, we examined the relationship between lesion presence and language performance on tests of receptive language and expressive language using a highly specific voxel-based lesion-symptom mapping (VLSM) approach in glioma patients.Methods98 adults with primary glioma, who were pre-surgical candidates, were administered seven neurocognitive tests within the domains of receptive language and expressive language. The association between language performance and lesion presence was examined using VLSM. Statistical parametric maps were created for each test, and composite maps for both receptive language and expressive language were created to display the significant voxels common to all tests within these language domains.ResultsWe identified clusters of voxels with a significant relationship between lesion presence and language performance. All tasks were associated with several white matter pathways. The receptive language tasks were additionally all associated with regions primarily within the lateral temporal lobe and medial temporal lobe. In contrast, the expressive language tasks shared little overlap, despite each task being independently associated with large anatomic areas.ConclusionsOur findings identify the key anatomic structures involved in language functioning in adult glioma patients using an innovative lesion analysis technique and suggest that expressive language abilities may be more task-dependent and distributed than receptive language abilities.

BackgroundManagement of language difficulties is an important aspect of clinical care for glioma patients, and accurately identifying the possible language deficits in patients based on lesion location would be beneficial to clinicians. To that end, we examined the relationship between lesion presence and language performance on tests of receptive language and expressive language using a highly specific voxel-based lesion-symptom mapping (VLSM) approach in glioma patients.Methods98 adults with primary glioma, who were pre-surgical candidates, were administered seven neurocognitive tests within the domains of receptive language and expressive language. The association between language performance and lesion presence was examined using VLSM. Statistical parametric maps were created for each test, and composite maps for both receptive language and expressive language were created to display the significant voxels common to all tests within these language domains.ResultsWe identified clusters of voxels with a significant relationship between lesion presence and language performance. All tasks were associated with several white matter pathways. The receptive language tasks were additionally all associated with regions primarily within the lateral temporal lobe and medial temporal lobe. In contrast, the expressive language tasks shared little overlap, despite each task being independently associated with large anatomic areas.ConclusionsOur findings identify the key anatomic structures involved in language functioning in adult glioma patients using an innovative lesion analysis technique and suggest that expressive language abilities may be more task-dependent and distributed than receptive language abilities.

IMPORTANCE Accurately characterizing nasal septal deviations is valuable for surgical planning, classifying nasal septal deviations, providing a means to accurately perform outcomes research, and understanding the causes of chronic conditions. OBJECTIVE To determine and quantify regions of septal deformity that can be used to develop a comprehensive classification system. DESIGN, SETTING, AND PARTICIPANTS A retrospective case series study was conducted at an academic tertiary care hospital. Sixty-four participants were selected based on a convenience sample of computed tomography (CT) scans of the paranasal sinuses and midface available between June 29, 2011, and August 16, 2012. Exclusion criteria consisted of incomplete or inadequate CT series. The most recent CT scans were chosen for analyses regardless of the indication for imaging. Digital Imaging and Communications in Medicine format bitmap file–formatted data were obtained and analyzed using MATLAB and OsiriX. The line to curve ratio, deviation area, and root mean square (RMS) values of the septal contour vs the ideal straight septum fit were calculated. Analysis was performed to detect significant differences (P < .05) using the 3 measures.MAIN OUTCOMES AND MEASURES Quantitative analysis of nasal septal deviation.RESULTS The population consisted of 50 male and 14 female patients aged 3 to 83 years(mean, 42 years). Mean line to curve ratios, areas, and RMS values were highest in contours that intersected the perpendicular plate–vomer junction, with a mean line to curve ratio of1.04 and mean deviated area of 627.16 arbitrary units (P = .02). Maximal deviation areas were also seen midway from the perpendicular plate–vomer junction to the nasal spine with a mean area of 577.31 arbitrary units (P = .01). The RMS values were significantly elevated along the crista galli and perpendicular plate–vomer junction (P < .05).CONCLUSIONS AND RELEVANCE Maximum septal deviation is seen at the perpendicular plate–vomer junction and in the regions near the crista galli and anterior nasal spine.Deviation area and RMS values are important measures to characterize septal deviations.Understanding septal deviations can aid in developing a functional classification system of nasal septal deviations for clinical use and a means to better record and compare surgical outcomes.

IMPORTANCE Accurately characterizing nasal septal deviations is valuable for surgical planning, classifying nasal septal deviations, providing a means to accurately perform outcomes research, and understanding the causes of chronic conditions. OBJECTIVE To determine and quantify regions of septal deformity that can be used to develop a comprehensive classification system. DESIGN, SETTING, AND PARTICIPANTS A retrospective case series study was conducted at an academic tertiary care hospital. Sixty-four participants were selected based on a convenience sample of computed tomography (CT) scans of the paranasal sinuses and midface available between June 29, 2011, and August 16, 2012. Exclusion criteria consisted of incomplete or inadequate CT series. The most recent CT scans were chosen for analyses regardless of the indication for imaging. Digital Imaging and Communications in Medicine format bitmap file–formatted data were obtained and analyzed using MATLAB and OsiriX. The line to curve ratio, deviation area, and root mean square (RMS) values of the septal contour vs the ideal straight septum fit were calculated. Analysis was performed to detect significant differences (P < .05) using the 3 measures.MAIN OUTCOMES AND MEASURES Quantitative analysis of nasal septal deviation.RESULTS The population consisted of 50 male and 14 female patients aged 3 to 83 years(mean, 42 years). Mean line to curve ratios, areas, and RMS values were highest in contours that intersected the perpendicular plate–vomer junction, with a mean line to curve ratio of1.04 and mean deviated area of 627.16 arbitrary units (P = .02). Maximal deviation areas were also seen midway from the perpendicular plate–vomer junction to the nasal spine with a mean area of 577.31 arbitrary units (P = .01). The RMS values were significantly elevated along the crista galli and perpendicular plate–vomer junction (P < .05).CONCLUSIONS AND RELEVANCE Maximum septal deviation is seen at the perpendicular plate–vomer junction and in the regions near the crista galli and anterior nasal spine.Deviation area and RMS values are important measures to characterize septal deviations.Understanding septal deviations can aid in developing a functional classification system of nasal septal deviations for clinical use and a means to better record and compare surgical outcomes.

PurposeTo compare the capability to aid prediction of clinical outcome measures, including progression-free survival (PFS) and overall survival (OS), between volumetric estimates from contrast material-enhanced (CE) T1-weighted subtraction maps and traditional segmentation in a randomized multicenter clinical trial of recurrent glioblastoma (GBM) patients treated with bevacizumab.Materials and methodsAll patients participating in this study signed institutional review board-approved informed consent at their respective institutions prior to enrolling in the multicenter clinical trial. One-hundred sixty patients with recurrent GBM enrolled as part of a HIPAA-compliant, multicenter clinical trial (AVF3708 g, BRAIN trial). Contrast-enhancing tumor volumes and change in volumes as a response to therapy were quantified by using either conventional segmentation or CE T1-weighted subtraction maps created by voxel-by-voxel subtraction of intensity-normalized nonenhanced T1-weighted images from CE T1-weighted images. These volumes were then tested as predictors of PFS and OS by using log-rank univariate analysis, the multivariate Cox proportional hazards regression model, and receiver operating characteristic analysis.ResultsUse of CE T1-weighted subtraction maps qualitatively improved visualization and improved quantification of tumor volume after bevacizumab treatment. Significant trends between the volume of tumor and change in tumor volume after therapy on CE T1-weighted subtraction maps were found for both PFS and OS (pretreatment volume < 15 cm(3), P < .003; posttreatment volume < 7.5 cm(3), P < .05; percentage change in volume > 25%, P = .004 for PFS and P = .053 for OS). CE T1-weighted subtraction maps were significantly better at aiding prediction of 6-month PFS and 12-month OS compared with conventional segmentation by using receiver operating characteristic analysis (P < .05).ConclusionUse 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.

PurposeTo compare the capability to aid prediction of clinical outcome measures, including progression-free survival (PFS) and overall survival (OS), between volumetric estimates from contrast material-enhanced (CE) T1-weighted subtraction maps and traditional segmentation in a randomized multicenter clinical trial of recurrent glioblastoma (GBM) patients treated with bevacizumab.Materials and methodsAll patients participating in this study signed institutional review board-approved informed consent at their respective institutions prior to enrolling in the multicenter clinical trial. One-hundred sixty patients with recurrent GBM enrolled as part of a HIPAA-compliant, multicenter clinical trial (AVF3708 g, BRAIN trial). Contrast-enhancing tumor volumes and change in volumes as a response to therapy were quantified by using either conventional segmentation or CE T1-weighted subtraction maps created by voxel-by-voxel subtraction of intensity-normalized nonenhanced T1-weighted images from CE T1-weighted images. These volumes were then tested as predictors of PFS and OS by using log-rank univariate analysis, the multivariate Cox proportional hazards regression model, and receiver operating characteristic analysis.ResultsUse of CE T1-weighted subtraction maps qualitatively improved visualization and improved quantification of tumor volume after bevacizumab treatment. Significant trends between the volume of tumor and change in tumor volume after therapy on CE T1-weighted subtraction maps were found for both PFS and OS (pretreatment volume < 15 cm(3), P < .003; posttreatment volume < 7.5 cm(3), P < .05; percentage change in volume > 25%, P = .004 for PFS and P = .053 for OS). CE T1-weighted subtraction maps were significantly better at aiding prediction of 6-month PFS and 12-month OS compared with conventional segmentation by using receiver operating characteristic analysis (P < .05).ConclusionUse 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.

BackgroundIsocitrate dehydrogenase 1 (IDH1) mutations have been linked to favorable outcomes in patients with glioblastoma multiforme (GBM). Recent in vitro experiments suggest that IDH1 mutation sensitizes tumors to radiation damage. We hypothesized that radiographic treatment response would be significantly different between IDH1 mutant versus wild-type GBMs after radiotherapy (RT) and concurrent temozolomide (TMZ).MethodsA total of 39 newly diagnosed GBM patients with known IDH1 mutational status (10 IDH1 mutants), who followed standard therapy and had regular post-contrast T1W (T1+C) and T2W/ fluid-attenuated inversion recovery (FLAIR) images in the 6-month period after starting RT, were enrolled. The volume of contrast-enhancing and FLAIR hyperintensity were calculated from each scan. Linear and polynomial regression techniques were used to estimate the rate of change and temporal patterns in tumor volumes.ResultsIDH1 mutant GBMs demonstrated a favorable response to RT/TMZ in the study period, as demonstrated by 10 of 10 mutants showing radiographic response (decreasing V(T1+C)), compared with 13 of 29 wild-types (P < .001). During the study period, V(T1+C) and V(FLAIR) changed at -3.6% per week and +0.6% per week in IDH1 mutant tumors, respectively, as compared with +0.8% per week and +5.2% per week in IDH1 wild-type tumors (P = .0076 and P = .0118, respectively). Amongst the radiographic responders, IDH1 mutant GBMs still demonstrated significant progression-free and overall survival benefit. Aggregated tumor kinetics by group showed significant lower rate in IDH1 mutant GBMs in specific periods: >105 days for V(FLAIR) and 95-120 and >150 days for V(T1+C) from starting RT/TMZ.ConclusionsThe current study supports the hypothesis that IDH1 mutant GBMs are more sensitive to radiochemotherapy than IDH1 wild-type GBMs.

BackgroundIsocitrate dehydrogenase 1 (IDH1) mutations have been linked to favorable outcomes in patients with glioblastoma multiforme (GBM). Recent in vitro experiments suggest that IDH1 mutation sensitizes tumors to radiation damage. We hypothesized that radiographic treatment response would be significantly different between IDH1 mutant versus wild-type GBMs after radiotherapy (RT) and concurrent temozolomide (TMZ).MethodsA total of 39 newly diagnosed GBM patients with known IDH1 mutational status (10 IDH1 mutants), who followed standard therapy and had regular post-contrast T1W (T1+C) and T2W/ fluid-attenuated inversion recovery (FLAIR) images in the 6-month period after starting RT, were enrolled. The volume of contrast-enhancing and FLAIR hyperintensity were calculated from each scan. Linear and polynomial regression techniques were used to estimate the rate of change and temporal patterns in tumor volumes.ResultsIDH1 mutant GBMs demonstrated a favorable response to RT/TMZ in the study period, as demonstrated by 10 of 10 mutants showing radiographic response (decreasing V(T1+C)), compared with 13 of 29 wild-types (P < .001). During the study period, V(T1+C) and V(FLAIR) changed at -3.6% per week and +0.6% per week in IDH1 mutant tumors, respectively, as compared with +0.8% per week and +5.2% per week in IDH1 wild-type tumors (P = .0076 and P = .0118, respectively). Amongst the radiographic responders, IDH1 mutant GBMs still demonstrated significant progression-free and overall survival benefit. Aggregated tumor kinetics by group showed significant lower rate in IDH1 mutant GBMs in specific periods: >105 days for V(FLAIR) and 95-120 and >150 days for V(T1+C) from starting RT/TMZ.ConclusionsThe current study supports the hypothesis that IDH1 mutant GBMs are more sensitive to radiochemotherapy than IDH1 wild-type GBMs.

BackgroundIsocitrate dehydrogenase 1 (IDH1) mutations have been linked to favorable outcomes in patients with glioblastoma multiforme (GBM). Recent in vitro experiments suggest that IDH1 mutation sensitizes tumors to radiation damage. We hypothesized that radiographic treatment response would be significantly different between IDH1 mutant versus wild-type GBMs after radiotherapy (RT) and concurrent temozolomide (TMZ).MethodsA total of 39 newly diagnosed GBM patients with known IDH1 mutational status (10 IDH1 mutants), who followed standard therapy and had regular post-contrast T1W (T1+C) and T2W/ fluid-attenuated inversion recovery (FLAIR) images in the 6-month period after starting RT, were enrolled. The volume of contrast-enhancing and FLAIR hyperintensity were calculated from each scan. Linear and polynomial regression techniques were used to estimate the rate of change and temporal patterns in tumor volumes.ResultsIDH1 mutant GBMs demonstrated a favorable response to RT/TMZ in the study period, as demonstrated by 10 of 10 mutants showing radiographic response (decreasing V(T1+C)), compared with 13 of 29 wild-types (P < .001). During the study period, V(T1+C) and V(FLAIR) changed at -3.6% per week and +0.6% per week in IDH1 mutant tumors, respectively, as compared with +0.8% per week and +5.2% per week in IDH1 wild-type tumors (P = .0076 and P = .0118, respectively). Amongst the radiographic responders, IDH1 mutant GBMs still demonstrated significant progression-free and overall survival benefit. Aggregated tumor kinetics by group showed significant lower rate in IDH1 mutant GBMs in specific periods: >105 days for V(FLAIR) and 95-120 and >150 days for V(T1+C) from starting RT/TMZ.ConclusionsThe current study supports the hypothesis that IDH1 mutant GBMs are more sensitive to radiochemotherapy than IDH1 wild-type GBMs.

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.

Background and purposeTo determine the effect of intravenous tissue plasminogen activator (IV-tPA) on outcomes in patients with severe major anterior circulation ischemic stroke.MethodsProspectively, 649 patients with acute stroke had admission National Institutes of Health stroke scale (NIHSS) scores, noncontrast computed tomography (CT), CT angiography (CTA), and 6-month outcome assessed using modified Rankin scale. IV-tPA treatment decisions were made before CTA, at the time of noncontrast CT scanning, as per routine clinical protocol. Severe symptoms were defined as NIHSS>10. Poor outcome was defined as modified Rankin scale >2. Major occlusions were identified on CTA. Univariate and multivariate stepwise-forward logistic regression analyses of the full cohort were performed.ResultsOf 649 patients, 188 (29%) patients presented with NIHSS>10, and 64 out of 188 (34%) patients received IV-tPA. Admission NIHSS, large artery occlusion, and IV-tPA all independently predicted good outcomes; however, a significant interaction existed between IV-tPA and occlusion (P10 with anterior circulation occlusion, twice the percentage had good outcomes if they received IV-tPA (17 out of 49 patients, 35%) than if they did not (13 out of 77 patients, 17%; P=0.031). The number needed to treat was 7 (95% confidence interval, 3-60).ConclusionsIV-tPA treatment resulted in significantly better outcomes in patients with severely symptomatic stroke with major anterior circulation occlusions. The 35% good outcome rate was similar to rates found in endovascular therapy trials. Vascular imaging may help in patient selection and stratification for trials of IV-thrombolytic and endovascular therapies.

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by recurring abdominal pain associated with alterations in bowel habits. We hypothesized that patients with chronic visceral pain associated with IBS may have microstructural differences in the brain compared with healthy control subjects (HCs), indicative of long-term neural reorganization of chronic pain pathways and regions associated with sensory integration. In the current study we performed population-based voxel-wise diffusion tensor imaging (DTI) comparisons and probabilistic tractography in a large sample of phenotyped patients with IBS (n=33) and in HCs (n=93). Patients had lower fractional anisotropy (FA) in thalamic regions, the basal ganglia (BG) and sensory/motor association/integration regions as well as higher FA in frontal lobe regions and the corpus callosum. In addition, patients had reduced mean diffusivity (MD) within the globus pallidus (GP) and higher MD in the thalamus, internal capsule, and coronal radiata projecting to sensory/motor regions, suggestive of differential changes in axon/dendritic density in these regions. Sex differences in FA and MD were also observed in the patients but not in HCs. Probabilistic tractography in patients confirmed a higher degree of connectivity between the thalamus and prefrontal cortex, as well as between the medial dorsal thalamic nuclei and anterior cingulate cortex, and a lower degree of connectivity between the GP and thalamus. Together, these results support the hypothesis that patients with chronically recurring visceral pain from IBS have long-term microstructural changes within the brain, particularly in regions associated with integration of sensory information and corticothalamic modulation.

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by recurring abdominal pain associated with alterations in bowel habits. We hypothesized that patients with chronic visceral pain associated with IBS may have microstructural differences in the brain compared with healthy control subjects (HCs), indicative of long-term neural reorganization of chronic pain pathways and regions associated with sensory integration. In the current study we performed population-based voxel-wise diffusion tensor imaging (DTI) comparisons and probabilistic tractography in a large sample of phenotyped patients with IBS (n=33) and in HCs (n=93). Patients had lower fractional anisotropy (FA) in thalamic regions, the basal ganglia (BG) and sensory/motor association/integration regions as well as higher FA in frontal lobe regions and the corpus callosum. In addition, patients had reduced mean diffusivity (MD) within the globus pallidus (GP) and higher MD in the thalamus, internal capsule, and coronal radiata projecting to sensory/motor regions, suggestive of differential changes in axon/dendritic density in these regions. Sex differences in FA and MD were also observed in the patients but not in HCs. Probabilistic tractography in patients confirmed a higher degree of connectivity between the thalamus and prefrontal cortex, as well as between the medial dorsal thalamic nuclei and anterior cingulate cortex, and a lower degree of connectivity between the GP and thalamus. Together, these results support the hypothesis that patients with chronically recurring visceral pain from IBS have long-term microstructural changes within the brain, particularly in regions associated with integration of sensory information and corticothalamic modulation.

PurposeTo improve ischemic stroke outcome prediction using imaging information from a prospective cohort who received admission CT angiography (CTA).MethodsIn a prospectively designed study, 649 stroke patients diagnosed with acute ischemic stroke had admission NIH stroke scale scores, noncontrast CT (NCCT), CTA, and 6-month outcome assessed using the modified Rankin scale (mRS) scores. Poor outcome was defined as mRS>2. Strokes were classified as "major" by the (1) Alberta Stroke Program Early CT Score (ASPECTS+) if NCCT ASPECTS was ≤7; (2) Boston Acute Stroke Imaging Scale (BASIS+) if they were ASPECTS+ or CTA showed occlusion of the distal internal carotid, proximal middle cerebral, or basilar arteries; and (3) NIHSS for scores >10.ResultsOf 649 patients, 253 (39.0%) had poor outcomes. NIHSS, BASIS, and age, but not ASPECTS, were independent predictors of outcome. BASIS and NIHSS had similar sensitivities, both superior to ASPECTS (p10/BASIS+ had poor outcomes, versus 21.5% (77/358) with NIHSS≤10/BASIS- (p10/BASIS+ compared to patients who are NIHSS≤10/BASIS-; the odds ratio is 5.4 (95% CI: 3.5 to 8.5) when compared to patients who are only NIHSS>10 or BASIS+.ConclusionsBASIS and NIHSS are independent outcome predictors. Their combination is stronger than either instrument alone in predicting outcomes. The findings suggest that CTA is a significant clinical tool in routine acute stroke assessment.

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.

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.

PurposeTo improve ischemic stroke outcome prediction using imaging information from a prospective cohort who received admission CT angiography (CTA).MethodsIn a prospectively designed study, 649 stroke patients diagnosed with acute ischemic stroke had admission NIH stroke scale scores, noncontrast CT (NCCT), CTA, and 6-month outcome assessed using the modified Rankin scale (mRS) scores. Poor outcome was defined as mRS>2. Strokes were classified as "major" by the (1) Alberta Stroke Program Early CT Score (ASPECTS+) if NCCT ASPECTS was ≤7; (2) Boston Acute Stroke Imaging Scale (BASIS+) if they were ASPECTS+ or CTA showed occlusion of the distal internal carotid, proximal middle cerebral, or basilar arteries; and (3) NIHSS for scores >10.ResultsOf 649 patients, 253 (39.0%) had poor outcomes. NIHSS, BASIS, and age, but not ASPECTS, were independent predictors of outcome. BASIS and NIHSS had similar sensitivities, both superior to ASPECTS (p10/BASIS+ had poor outcomes, versus 21.5% (77/358) with NIHSS≤10/BASIS- (p10/BASIS+ compared to patients who are NIHSS≤10/BASIS-; the odds ratio is 5.4 (95% CI: 3.5 to 8.5) when compared to patients who are only NIHSS>10 or BASIS+.ConclusionsBASIS and NIHSS are independent outcome predictors. Their combination is stronger than either instrument alone in predicting outcomes. The findings suggest that CTA is a significant clinical tool in routine acute stroke assessment.