Efficient Green Spin Light-Emitting Diodes Enabled by Ultrafast Energy- and Spin-Funneling in Chiral Perovskites.

Introducing molecular chirality into perovskite crystal structures has enabled the control of carrier spin states, giving rise to circularly polarized luminescence (CPL) in thin films and circularly polarized electroluminescence (CPEL) in LEDs. Spin-LEDs can be fabricated either through a spin-filtering layer enabled by chiral-induced spin selectivity or a chiral emissive layer. The former requires a high degree of spin polarization and a compatible spinterface for efficient spin injection, which might not be easily integrated into LEDs. Alternatively, a chiral emissive layer can also generate circularly polarized electroluminescence, but the efficiency remains low and the fundamental mechanism is elusive. In this work, we report an efficient green LED based on quasi-two-dimensional (quasi-2D) chiral perovskites as the emitting layer (EML), where CPEL is directly produced without separate carrier spin injection. The optimized chiral perovskite thin films exhibited strong CPL at 535 nm with a photoluminescence quantum yield (PLQY) of 91% and a photoluminescence dissymmetry factor (glum) of 8.6 × 10-2. Efficient green spin-LEDs were successfully demonstrated, with a large EL dissymmetry factor (gEL) of 7.8 × 10-2 and a maximum external quantum efficiency (EQE) of 13.5% at room temperature. Ultrafast transient absorption (TA) spectroscopic study shows that the CPEL is generated from a rapid energy transfer accompanied by spin transfer from 2D to 3D perovskites. Our study not only demonstrates a reliable approach to achieve high performance spin-LEDs but also reveals the fundamental mechanism of CPEL with an emissive layer of chiral perovskites.

Quantification of the in vivo brain ultrashort-T2* component in healthy volunteers.

PURPOSE: Recent work has shown MRI is able to measure and quantify signals of phospholipid membrane-bound protons associated with myelin in the human brain. This work seeks to develop an improved technique for characterizing this brain ultrashort- T 2 ∗ $$ {\mathrm{T}}_2\ast $$ component in vivo accounting for T 1 $$ {\mathrm{T}}_1 $$ weighting. METHODS: Data from ultrashort echo time scans from 16 healthy volunteers with variable flip angles (VFA) were collected and fitted into an advanced regression model to quantify signal fraction, relaxation time, and frequency shift of the ultrashort- T 2 ∗ $$ {\mathrm{T}}_2\ast $$ component. RESULTS: The fitted components show intra-subject differences of different white matter structures and significantly elevated ultrashort- T 2 ∗ $$ {\mathrm{T}}_2\ast $$ signal fraction in the corticospinal tracts measured at 0.09 versus 0.06 in other white matter structures and significantly elevated ultrashort- T 2 ∗ $$ {\mathrm{T}}_2\ast $$ frequency shift in the body of the corpus callosum at - $$ - $$ 1.5 versus - $$ - $$ 2.0 ppm in other white matter structures. CONCLUSION: The significantly different measured components and measured T 1 $$ {\mathrm{T}}_1 $$ relaxation time of the ultrashort- T 2 ∗ $$ {\mathrm{T}}_2\ast $$ component suggest that this method is picking up novel signals from phospholipid membrane-bound protons.

Altered Iron and Microstructure in Huntington's Disease Subcortical Nuclei: Insight From 7T MRI.

BACKGROUND: Pathophysiological changes of Huntington's disease (HD) can precede symptom onset by decades. Robust imaging biomarkers are needed to monitor HD progression, especially before the clinical onset. PURPOSE: To investigate iron dysregulation and microstructure alterations in subcortical regions as HD imaging biomarkers, and to associate such alterations with motor and cognitive impairments. STUDY TYPE: Prospective. POPULATION: Fourteen individuals with premanifest HD (38.0 ± 11.0 years, 9 females; far-from-onset N = 6, near-onset N = 8), 21 manifest HD patients (49.1 ± 12.1 years, 11 females), and 33 age-matched healthy controls (43.9 ± 12.2 years, 17 females). FIELD STRENGTH/SEQUENCE: 7 T, T1 -weighted imaging, quantitative susceptibility mapping, and diffusion tensor imaging. ASSESSMENT: Volume, susceptibility, fractional anisotropy (FA), and mean diffusivity (MD) within subcortical brain structures were compared across groups, used to establish HD classification models, and correlated to clinical measures and cognitive assessments. STATISTICAL TESTS: Generalized linear model, multivariate logistic regression, receiver operating characteristics with the area under the curve (AUC), and likelihood ratio test comparing a volumetric model to one that also includes susceptibility and diffusion metrics, Wilcoxon paired signed-rank test, and Pearson's correlation. A P-value <0.05 after Benjamini-Hochberg correction was considered statistically significant. RESULTS: Significantly higher striatal susceptibility and FA were found in premanifest and manifest HD preceding atrophy, even in far-from-onset premanifest HD compared to controls (putamen susceptibility: 0.027 ± 0.022 vs. 0.018 ± 0.013 ppm; FA: 0.358 ± 0.048 vs. 0.313 ± 0.039). The model with additional susceptibility, FA, and MD features showed higher AUC compared to volume features alone when differentiating premanifest HD from HC (0.83 vs. 0.66), and manifest from premanifest HD (0.94 vs. 0.83). Higher striatal susceptibility significantly correlated with cognitive deterioration in HD (executive function: r = -0.600; socioemotional function: r = -0.486). DATA CONCLUSION: 7 T MRI revealed iron dysregulation and microstructure alterations with HD progression, which could precede volume loss, provide added value to HD differentiation, and might be associated with cognitive changes. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Comparison of quantitative susceptibility mapping methods for iron-sensitive susceptibility imaging at 7T: An evaluation in healthy subjects and patients with Huntington's disease.

Quantitative susceptibility mapping (QSM) is a promising tool for investigating iron dysregulation in neurodegenerative diseases, including Huntington's disease (HD). Many diverse methods have been proposed to generate accurate and robust QSM images. In this study, we evaluated the performance of different dipole inversion algorithms for iron-sensitive susceptibility imaging at 7T on healthy subjects of a large age range and patients with HD. We compared an iterative least-squares-based method (iLSQR), iterative methods that use regularization, single-step approaches, and deep learning-based techniques. Their performance was evaluated by comparing: (1) deviations from a multiple-orientation QSM reference; (2) visual appearance of QSM maps and the presence of artifacts; (3) susceptibility in subcortical brain regions with age; (4) regional brain susceptibility with published postmortem brain iron quantification; and (5) susceptibility in HD-affected basal ganglia regions between HD subjects and healthy controls. We found that single-step QSM methods with either total variation or total generalized variation constraints (SSTV/SSTGV) and the single-step deep learning method iQSM generally provided the best performance in terms of correlation with iron deposition and were better at differentiating between healthy controls and premanifest HD individuals, while deep learning QSM methods trained with multiple-orientation susceptibility data created QSM maps that were most similar to the multiple orientation reference and with the best visual scores.

Amine-weighted chemical exchange saturation transfer magnetic resonance imaging in brain tumors.

Amine-weighted chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) is particularly valuable as an amine- and pH-sensitive imaging technique in brain tumors, targeting the intrinsically high concentration of amino acids with exchangeable amine protons and reduced extracellular pH in brain tumors. Amine-weighted CEST MRI contrast is dependent on the glioma genotype, likely related to differences in degree of malignancy and metabolic behavior. Amine-weighted CEST MRI may provide complementary value to anatomic imaging in conventional and exploratory therapies in brain tumors, including chemoradiation, antiangiogenic therapies, and immunotherapies. Continual improvement and clinical testing of amine-weighted CEST MRI has the potential to greatly impact patients with brain tumors by understanding vulnerabilities in the tumor microenvironment that may be therapeutically exploited.

Activity of a first-in-class oral HIF2-alpha inhibitor, PT2385, in patients with first recurrence of glioblastoma.

INTRODUCTION: Hypoxia inducible factor 2-alpha (HIF2α) mediates cellular responses to hypoxia and is over-expressed in glioblastoma (GBM). PT2385 is an oral HIF2α inhibitor with in vivo activity against GBM. METHODS: A two-stage single-arm open-label phase II study of adults with GBM at first recurrence following chemoradiation with measurable disease was conducted through the Adult Brain Tumor Consortium. PT2385 was administered at the phase II dose (800 mg b.i.d.). The primary outcome was objective radiographic response (ORR = complete response + partial response, CR + PR); secondary outcomes were safety, overall survival (OS), and progression free survival (PFS). Exploratory objectives included pharmacokinetics (day 15 Cmin), pharmacodynamics (erythropoietin, vascular endothelial growth factor), and pH-weighted amine- chemical exchange saturation transfer (CEST) MRI to quantify tumor acidity at baseline and explore associations with drug response. Stage 1 enrolled 24 patients with early stoppage for ≤ 1 ORR. RESULTS: Of the 24 enrolled patients, median age was 62.1 (38.7-76.7) years, median KPS 80, MGMT promoter was methylated in 46% of tumors. PT2385 was well tolerated. Grade ≥ 3 drug-related adverse events were hypoxia (n = 2), hyponatremia (2), lymphopenia (1), anemia (1), and hyperglycemia (1). No objective radiographic responses were observed; median PFS was 1.8 months (95% CI 1.6-2.5) and OS was 7.7 months (95% CI 4.9-12.6). Drug exposure varied widely and did not differ by corticosteroid use (p = 0.12), antiepileptics (p = 0.09), or sex (p = 0.37). Patients with high systemic exposure had significantly longer PFS (6.7 vs 1.8 months, p = 0.009). Baseline acidity by pH-weighted CEST MRI correlated significantly with treatment duration (R2 = 0.49, p = 0.017). Non-enhancing infiltrative disease with high acidity gave rise to recurrence. CONCLUSIONS: PT2385 monotherapy had limited activity in first recurrent GBM. Drug exposure was variable. Signals of activity were observed in GBM patients with high systemic exposure and acidic lesions on CEST imaging. A second-generation HIF2α inhibitor is being studied.

Simultaneous quantification of perfusion, permeability, and leakage effects in brain gliomas using dynamic spin-and-gradient-echo echoplanar imaging MRI.

OBJECTIVE: To determine the feasibility and biologic correlations of dynamic susceptibility contrast (DSC), dynamic contrast enhanced (DCE), and quantitative maps derived from contrast leakage effects obtained simultaneously in gliomas using dynamic spin-and-gradient-echo echoplanar imaging (dynamic SAGE-EPI) during a single contrast injection. MATERIALS AND METHODS: Thirty-eight patients with enhancing brain gliomas were prospectively imaged with dynamic SAGE-EPI, which was processed to compute traditional DSC metrics (normalized relative cerebral blood flow [nrCBV], percentage of signal recovery [PSR]), DCE metrics (volume transfer constant [Ktrans], extravascular compartment [ve]), and leakage effect metrics: ΔR2,ss* (reflecting T2*-leakage effects), ΔR1,ss (reflecting T1-leakage effects), and the transverse relaxivity at tracer equilibrium (TRATE, reflecting the balance between ΔR2,ss* and ΔR1,ss). These metrics were compared between patient subgroups (treatment-naïve [TN] vs recurrent [R]) and biological features (IDH status, Ki67 expression). RESULTS: In IDH wild-type gliomas (IDHwt-i.e., glioblastomas), previous exposure to treatment determined lower TRATE (p = 0.002), as well as higher PSR (p = 0.006), Ktrans (p = 0.17), ΔR1,ss (p = 0.035), ve (p = 0.006), and ADC (p = 0.016). In IDH-mutant gliomas (IDHm), previous treatment determined higher Ktrans and ΔR1,ss (p = 0.026). In TN-gliomas, dynamic SAGE-EPI metrics tended to be influenced by IDH status (p ranging 0.09-0.14). TRATE values above 142 mM-1s-1 were exclusively seen in TN-IDHwt, and, in TN-gliomas, this cutoff had 89% sensitivity and 80% specificity as a predictor of Ki67 > 10%. CONCLUSIONS: Dynamic SAGE-EPI enables simultaneous quantification of brain tumor perfusion and permeability, as well as mapping of novel metrics related to cytoarchitecture (TRATE) and blood-brain barrier disruption (ΔR1,ss), with a single contrast injection. CLINICAL RELEVANCE STATEMENT: Simultaneous DSC and DCE analysis with dynamic SAGE-EPI reduces scanning time and contrast dose, respectively alleviating concerns about imaging protocol length and gadolinium adverse effects and accumulation, while providing novel leakage effect metrics reflecting blood-brain barrier disruption and tumor tissue cytoarchitecture. KEY POINTS: • Traditionally, perfusion and permeability imaging for brain tumors requires two separate contrast injections and acquisitions. • Dynamic spin-and-gradient-echo echoplanar imaging enables simultaneous perfusion and permeability imaging. • Dynamic spin-and-gradient-echo echoplanar imaging provides new image contrasts reflecting blood-brain barrier disruption and cytoarchitecture characteristics.

Influence of phosphate concentration on amine, amide, and hydroxyl CEST contrast.

PURPOSE: To evaluate the influence of phosphate on amine, amide, and hydroxyl CEST contrast using Bloch-McConnell simulations applied to physical phantom data. METHODS: Phantom solutions of 4 representative metabolites with exchangeable protons-glycine (α-amine protons), Cr (η-amine protons), egg white protein (amide protons), and glucose (hydroxyl protons)-were prepared at different pH levels (5.6 to 8.9) and phosphate concentrations (5 to 80 mM). CEST images of the phantom were collected with CEST-EPI sequence at 3 tesla. The CEST data were then fitted to full Bloch-McConnell equation simulations to estimate the exchange rate constants. With the fitted parameters, simulations were performed to evaluate the intracellular and extracellular contributions of CEST signals in normal brain tissue and brain tumors, as well as in dynamic glucose-enhanced experiments. RESULTS: The exchange rates of α-amine and hydroxyl protons were found to be highly dependent on both pH and phosphate concentrations, whereas the exchange rates of η-amine and amide protons were pH-dependent, albeit not catalyzed by phosphate. With phosphate being predominantly intracellular, CEST contrast of α-amine exhibited a higher sensitivity to changes in the extracellular microenvironment. Simulations of dynamic glucose-enhanced signals demonstrated that the contrast between normal and tumor tissue was mostly due to the extracellular CEST effect. CONCLUSION: The proton exchange rates in some metabolites can be greatly catalyzed by the presence of phosphate at physiological concentrations, which substantially alters the CEST contrast. Catalytic agents should be considered as confounding factors in future CEST-MRI research. This new dimension may also benefit the development of novel phosphate-sensitive imaging methods.

Role of melatonin in UV-B signaling pathway and UV-B stress resistance in Arabidopsis thaliana.

Melatonin (N-acetyl-5-methoxytryptamine) plays important roles in plant defences against a variety of biotic and abiotic stresses, including UV-B stress. Molecular mechanisms underlying functions of melatonin in plant UV-B responses are poorly understood. Here, we show that melatonin effect on molecular signalling pathways, physiological changes and UV-B stress resistance in Arabidopsis. Both exogenous and endogenous melatonin affected expression of UV-B signal transduction pathway genes. Experiments using UV-B signalling component mutants cop1-4 and hy5-215 revealed that melatonin not only acts as an antioxidant to promote UV-B stress resistance, but also regulates expression of several key components of UV-B signalling pathway, including ubiquitin-degrading enzyme (COP1), transcription factors (HY5, HYH) and RUP1/2. Our findings indicate that melatonin delays and subsequently enhances expression of COP1, HY5, HYH and RUP1/2, which act as central effectors in UV-B signalling pathway, thus regulating their effects on antioxidant systems to protect the plant from UV-B stress.

Minimizing echo and repetition times in magnetic resonance imaging using a double half-echo k-space acquisition and low-rank reconstruction.

Sampling k-space asymmetrically (ie, partial Fourier sampling) in the readout direction is a common way to reduce the echo time (TE) during magnetic resonance image acquisitions. This technique requires overlap around the center of k-space to provide a calibration region for reconstruction, which limits the minimum fractional echo to ~60% before artifacts are observed. The present study describes a method for reconstructing images from exact half echoes using two separate acquisitions with reversed readout polarity, effectively providing a full line of k-space without additional data around central k-space. This approach can benefit sequences or applications that prioritize short TE, short inter-echo spacing or short repetition time. An example of the latter is demonstrated to reduce banding artifacts in balanced steady-state free precession.

Preferential tumor localization in relation to 18F-FDOPA uptake for lower-grade gliomas.

PURPOSE: Although tumor localization and 3,4-dihydroxy-6-18F-fluoro-L-phenylalanine (FDOPA) uptake may have an association, preferential tumor localization in relation to FDOPA uptake is yet to be investigated in lower-grade gliomas (LGGs). This study aimed to identify differences in the frequency of tumor localization between FDOPA hypometabolic and hypermetabolic LGGs using a probabilistic radiographic atlas. METHODS: Fifty-one patients with newly diagnosed LGG (WHO grade II, 29; III, 22; isocitrate dehydrogenase wild-type, 21; mutant 1p19q non-codeleted,16; mutant codeleted, 14) who underwent FDOPA positron emission tomography (PET) were retrospectively selected. Semiautomated tumor segmentation on FLAIR was performed. Patients with LGGs were separated into two groups (FDOPA hypometabolic and hypermetabolic LGGs) according to the normalized maximum standardized uptake value of FDOPA PET (a threshold of the uptake in the striatum) within the segmented regions. Spatial normalization procedures to build a 3D MRI-based atlas using each segmented region were validated by an analysis of differential involvement statistical mapping. RESULTS: Superimposition of regions of interest showed a high number of hypometabolic LGGs localized in the frontal lobe, while a high number of hypermetabolic LGGs was localized in the insula, putamen, and temporal lobe. The statistical mapping revealed that hypometabolic LGGs occurred more frequently in the superior frontal gyrus (close to the supplementary motor area), while hypermetabolic LGGs occurred more frequently in the insula. CONCLUSION: Radiographic atlases revealed preferential frontal lobe localization for FDOPA hypometabolic LGGs, which may be associated with relatively early detection.

A cross-sectional study of the epidemic situation on COVID-19 in Gansu Province, China - a big data analysis of the national health information platform.

BACKGROUND: In December 2019, a pneumonia caused by SARS-CoV-2 emerged in Wuhan, China and has rapidly spread around the world since then. This study is to explore the patient characteristics and transmission chains of COVID-19 in the population of Gansu province, and support decision-making. METHODS: We collected data from Gansu Province National Health Information Platform. A cross-sectional study was conducted, including patients with COVID-19 confirmed between January 23 and February 6, 2020, and analyzed the gender and age of the patients. We also described the incubation period, consultation time and sources of infection in the cases, and calculated the secondary cases that occurred within Gansu for each imported case. RESULTS: We found thirty-six (53.7%) of the patients were women and thirty-one (46.3%) men, and the median ages were 40 (IQR 31-53) years. Twenty-eight (41.8%) of the 67 cases had a history of direct exposure in Wuhan. Twenty-five (52.2%) cases came from ten families, and we found no clear reports of modes of transmission other than family clusters. The largest number of secondary cases linked to a single source was nine. CONCLUSION: More women than men were diagnosed with COVID-19 in Gansu Province. Although the age range of confirmed cases of COVID-19 in Gansu Province covered almost all age groups, most patients with confirmed COVID-19 tend to be middle aged persons. The most common suspected mode of transmission was through family cluster. Gansu and other settings worldwide should continue to strengthen the utilization of big data in epidemic control.

Relative oxygen extraction fraction (rOEF) MR imaging reveals higher hypoxia in human epidermal growth factor receptor (EGFR) amplified compared with non-amplified gliomas.

PURPOSE: Epidermal growth factor receptor (EGFR) amplification promotes gliomagenesis and is linked to lack of oxygen within the tumor microenvironment. Using hypoxia-sensitive spin-and-gradient echo echo-planar imaging and perfusion MRI, we investigated the influence of EGFR amplification on tissue oxygen availability and utilization in human gliomas. METHODS: This study included 72 histologically confirmed EGFR-amplified and non-amplified glioma patients. Reversible transverse relaxation rate (R2'), relative cerebral blood volume (rCBV), and relative oxygen extraction fraction (rOEF) were calculated for the contrast-enhancing and non-enhancing tumor regions. Using Student t test or Wilcoxon rank-sum test, median R2', rCBV, and rOEF were compared between EGFR-amplified and non-amplified gliomas. ROC analysis was performed to assess the ability of imaging characteristics to discriminate EGFR amplification status. Overall survival (OS) was determined using univariate and multivariate cox models. Kaplan-Meier survival curves were plotted and compared using the log-rank test. RESULTS: EGFR amplified gliomas exhibited significantly higher median R2' and rOEF than non-amplified gliomas. ROC analysis suggested that R2' (AUC = 0.7190; P = 0.0048) and rOEF (AUC = 0.6959; P = 0.0156) could separate EGFR status. Patients with EGFR-amplified gliomas had a significantly shorter OS than non-amplified patients. Univariate cox regression analysis determined both R2' and rOEF significantly influence OS. No significant difference was observed in rCBV between patient cohorts nor was rCBV found to be an effective differentiator of EGFR status. CONCLUSION: Imaging of tumor oxygen characteristics revealed EGFR-amplified gliomas to be more hypoxic and contribute to shorter patient survival than EGFR non-amplified gliomas.

A physical phantom for amine chemical exchange saturation transfer (CEST) MRI.

OBJECTIVE: To develop a robust amine chemical exchange saturation transfer (CEST) physical phantom, validate the temporal stability, and create a supporting software for automatic image processing and quality assurance. MATERIALS AND METHODS: The phantom was designed as an assembled laser-cut acrylic rack and 18 vials of phantom solutions, prepared with different pHs, glycine concentrations, and gadolinium concentrations. We evaluated glycine concentrations using ultraviolet absorbance for 70 days and measured the pH, relaxation rates, and CEST contrast for 94 days after preparation. We used Spearman's correlation to determine if glycine degraded over time. Linear regression and Bland-Altman analysis were performed between baseline and follow-up measurements of pH and MRI properties. RESULTS: No degradation of glycine was observed (p > 0.05). The pH and MRI measurements stayed stable for 3 months and showed high consistency across time points (R2 = 1.00 for pH, R1, R2, and CEST contrast), which was further validated by the Bland-Altman plots. Examples of automatically generated reports are provided. DISCUSSION: We designed a physical phantom for amine CEST-MRI, which is easy to assemble and transfer, holds 18 different solutions, and has excellent short-term chemical and MRI stability. We believe this robust phantom will facilitate the development of novel sequences and cross-scanners validations.

Rate of change in maximum 18F-FDOPA PET uptake and non-enhancing tumor volume predict malignant transformation and overall survival in low-grade gliomas.

PURPOSE: To examine whether the rate of change in maximum 18F-FDOPA PET uptake and the rate of change in non-enhancing tumor volume could predict malignant transformation and residual overall survival (OS) in low grade glioma (LGG) patients who received serial 18F-FDOPA PET and MRI scans. METHODS: 27 LGG patients with ≥ 2 18F-FDOPA PET and MRI scans between 2003 and 2016 were included. The rate of change in FLAIR volume (uL/day) and maximum normalized 18F-FDOPA specific uptake value (nSUVmax/month), were compared between histological and molecular subtypes. General linear models (GLMs) were used to integrate clinical information with MR-PET measurements to predict malignant transformation. Cox univariate and multivariable regression analyses were performed to identify imaging and clinical risk factors related to OS. RESULTS: A GLM using patient age, treatment, the rate of change in FLAIR and 18F-FDOPA nSUVmax could predict malignant transformation with > 67% sensitivity and specificity (AUC = 0.7556, P = 0.0248). A significant association was observed between OS and continuous rates of change in PET uptake (HR = 1.0212, P = 0.0034). Cox multivariable analysis confirmed that continuous measures of the rate of change in PET uptake was an independent predictor of OS (HR = 1.0242, P = 0.0033); however, stratification of patients based on increasing or decreasing rate of change in FLAIR (HR = 2.220, P = 0.025), PET uptake (HR = 2.148, P = 0.0311), or both FLAIR and PET (HR = 2.354, P = 0.0135) predicted OS. CONCLUSIONS: The change in maximum normalized 18F-FDOPA PET uptake, with or without clinical information and rate of change in tumor volume, may be useful for predicting the risk of malignant transformation and estimating residual survival in patients with LGG.

Multiparametric MR-PET measurements in hypermetabolic regions reflect differences in molecular status and tumor grade in treatment-naïve diffuse gliomas.

PURPOSE: To assess whether hypermetabolically-defined regions of interest (ROIs) on 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (FDOPA) positron emission tomography (PET) could be used to evaluate physiological features and whether there are measurable differences between molecular subtypes and tumor grades. METHODS: Sixty-eight treatment-naïve glioma patients who underwent FDOPA PET and magnetic resonance imaging (MRI) were retrospectively included. Fluid-attenuated inversion recovery hyperintense regions (FLAIRROI) were segmented. FDOPA hypermetabolic regions (FDOPAROI, tumor-to-striatum ratios > 1) within FLAIRROI were extracted. Normalized maximum standardized uptake value (nSUVmax), volume of each ROI, and median relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) within FLAIRROI or FDOPAROI were calculated. Imaging metrics were compared using Students t or Mann-Whitney U tests. Area under the curve (AUC) of receiver-operating characteristic curves were used to determine whether imaging metrics within FLAIRROI or FDOPAROI can discriminate different molecular statuses or grades. RESULTS: Using either FLAIRROI or FDOPAROI, the nSUVmax and rCBV were significantly higher and the ADC was lower in isocitrate dehydrogenase (IDH) wild-type than mutant gliomas, and in higher-grade gliomas (HGGs) than lower-grade gliomas (LGGs). The FDOPAROI volume was significantly higher in 1p19q codeleted than non-codeleted gliomas, and in HGGs than LGGs. Although not significant, imaging metrics extracted by FDOPAROI discriminated molecular status and tumor grade more accurately than those extracted by FLAIRROI (AUC of IDH status, 0.87 vs. 0.82; 1p19q status, 0.78 vs. 0.73; grade, 0.87 vs. 0.76). CONCLUSION: FDOPA hypermetabolic ROI may extract useful imaging features of gliomas, which can illuminate biological differences between different molecular status or tumor grades.

pH-weighted amine chemical exchange saturation transfer echoplanar imaging (CEST-EPI) as a potential early biomarker for bevacizumab failure in recurrent glioblastoma.

PURPOSE: The objective of the current study was to explore the efficacy of using pH-weighted amine CEST-EPI as a potential non-invasive imaging biomarker for treatment response and/or failure in recurrent GBM patients treated with bevacizumab. METHOD: A total of 11 patients with recurrent GBM treated with bevacizumab were included in this prospective study. CEST-EPI, perfusion MRI, and standardized anatomic MRI were obtained in patients before and after bevacizumab administration. CEST-EPI measures of magnetization transfer ratio asymmetry (MTRasym) at 3 ppm were used for pH-weighted imaging contrast. Multiple measures were examined for their association with progression-free survival (PFS). RESULT: Tumor acidity, measured with MTRasym at 3 ppm, was significantly reduced in both contrast enhancing and non-enhancing tumor after bevacizumab (p = 0.0002 and p < 0.00001, respectively). The reduction in tumor acidity in both contrast enhancing and non-enhancing tumor was linearly correlated with PFS (p = 0.044 and p = 0.00026, respectively). In 9 of the 11 patients, areas of residual acidity were localized to areas of tumor recurrence, typically around 2 months prior to radiographic progression. Univariate (p = 0.006) and multivariate Cox regression controlling for age (p = 0.009) both indicated that change in tumor acidity (ΔMTRasym at 3 ppm) was a significant predictor of PFS. CONCLUSIONS: This pilot study suggests pH-weighted amine CEST MRI may have value as a non-invasive, early imaging biomarker for bevacizumab treatment response and failure. Early decreases MTRasym at 3.0 ppm in recurrent GBM after bevacizumab may be associated with better PFS. Residual or emerging regions of acidity may colocalize to the site of tumor recurrence.

Simultaneous pH-sensitive and oxygen-sensitive MRI of human gliomas at 3 T using multi-echo amine proton chemical exchange saturation transfer spin-and-gradient echo echo-planar imaging (CEST-SAGE-EPI).

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.

18F-FDOPA PET and MRI characteristics correlate with degree of malignancy and predict survival in treatment-naïve gliomas: a cross-sectional study.

INTRODUCTION: To report the potential value of pre-operative 18F-FDOPA PET and anatomic MRI in diagnosis and prognosis of glioma patients. METHODS: Forty-five patients with a pathological diagnosis of glioma with pre-operative 18F-FDOPA PET and anatomic MRI were retrospectively examined. The volume of contrast enhancement and T2 hyperintensity on MRI images along with the ratio of maximum 18F-FDOPA SUV in tumor to normal tissue (T/N SUVmax) were measured and used to predict tumor grade, molecular status, and overall survival (OS). RESULTS: A significant correlation was observed between WHO grade and: the volume of contrast enhancement (r = 0.67), volume of T2 hyperintensity (r = 0.42), and 18F-FDOPA uptake (r = 0.60) (P < 0.01 for each correlation). The volume of contrast enhancement and 18F-FDOPA T/N SUVmax were significantly higher in glioblastoma (WHO IV) compared with lower grade gliomas (WHO I-III), as well as for high-grade gliomas (WHO III-IV) compared with low-grade gliomas (WHO I-II). Receiver-operator characteristic (ROC) analyses confirmed the volume of contrast enhancement and 18F-FDOPA T/N SUVmax could each differentiate patient groups. No significant differences in 18F-FDOPA uptake were observed by IDH or MGMT status. Multivariable Cox regression suggested age (HR 1.16, P = 0.0001) and continuous measures of 18F-FDOPA PET T/N SUVmax (HR 4.43, P = 0.016) were significant prognostic factors for OS in WHO I-IV gliomas. CONCLUSIONS: Current findings suggest a potential role for the use of pre-operative 18F-FDOPA PET in suspected glioma. Increased 18F-FDOPA uptake may not only predict higher glioma grade, but also worse OS.