Role of Histogram Features on Arterial Spin Labeling Perfusion Magnetic Resonance Imaging in Identifying Isocitrate Dehydrogenase Genotypes and Glioma Malignancies.

AIM: To explore the use of histogram features on noninvasive arterial spin labeling (ASL) perfusion magnetic resonance imaging (MRI) in differentiating isocitrate dehydrogenase mutant-type (IDH-mut) from isocitrate dehydrogenase wild-type (IDH-wt) gliomas, and lower-grade gliomas (LGGs) from glioblastomas. MATERIAL AND METHODS: This retrospective study included 131 patients who underwent ASL MRI and anatomic MRI. Cerebral blood flow (CBF) maps were calculated, from which 10 histogram features describing the CBF distribution were extracted within the tumor region. Correlation analysis was performed to determine the correlations between histogram features as well as tumor grades and IDH genotypes. The independent t-test and Fisher's exact test were used to determine differences in the extracted histogram features, age at diagnosis, and sex in different glioma subtypes. Multivariate binary logistic regression analysis was performed, and diagnostic performances were evaluated with the receiver operating characteristic curves. RESULTS: CBF histogram features were significantly correlated with tumor grades and IDH genotypes. These features can effectively differentiate LGGs from glioblastomas, and IDH-mut from IDH-wt gliomas. The area under the receiving operating characteristic curve of the model calculated using combined CBF 30th percentile and age at diagnosis in differentiating LGGs from glioblastomas was 0.73. Integrating age at diagnosis and CBF 10th percentile could be more effective in differentiating IDH-mut from IDH-wt gliomas. Furthermore, the combined model had a better area under the receiving operating characteristic curve at 0.856 (sensitivity: 84.4%, specificity: 82.9%). CONCLUSION: The histogram features on ASL were significantly correlated with tumor grade and IDH genotypes. Moreover, the use of these features could effectively differentiate glioma subtypes. The combined application of age at diagnosis and perfusion histogram features resulted in a more comprehensive identification of tumor subtypes. Therefore, ASL can be a noninvasive tool for the pre-surgical evaluation of gliomas.

The characterization of metabolic changes in adipose tissues and muscles due to different exercise intensities by Dixon in healthy young men.

PURPOSE: To delineate the alterations in adipose and muscle tissue composition and functionality among healthy young men across varying exercise intensities, which help to elucidate the impact of exercise intensity on weight management and inform fitness planning. METHOD: 3D Dixon MRI scans were performed on the neck and supraclavicular area in 10 high-intensity exercises (HIE) athletes, 20 moderate intensity exercises (MIE) athletes and 19 low-intensity exercises non-athlete male controls (NCM). Twelve imaging parameters, including the total volume of muscle, white adipose tissue (WAT), brown adipose tissue (BAT), and the mean fat-water fraction (FWF) within these tissues. Additionally, ratios of BAT or WAT to total fat (BATr or WATr) and the proportions of muscle, BAT, or WAT to total tissue volume (Musp, BATp, and WATp) were calculated. Parameters were compared across groups and correlated with Body Mass Index (BMI), waistline, and hipline. RESULTS: The HIE group exhibited the highest total muscle (totalMUS) and brown adipose tissue (totalBAT) volumes among the three groups. Conversely, the NCM group had significantly higher fwfFAT and fwfBAT values. The MUSp was higher in the HIE and MIE groups compared to NCM, while the BATp and WATp were lower. Furthermore, the BATr in HIE and MIE groups were higher than NCM group while the WATr were lower. Significant linear relationships were observed between totalBAT, totalWAT, MUSp, BATr, fwfFAT, and BMI, waistline (P < 0.05) across all groups. CONCLUSIONS: MIE is sufficient for the purpose of weight control, While HIE helps to further increase the muscle mass. All three physical indexes were significantly associated with the image parameters, with waistline emerging as the most effective indicator for detecting metabolic changes across all groups.

Induced saturation transfer recovery steady states (iSTRESS) for proton exchange rate mapping with CEST MRI, a preliminary study.

Proton exchange underpins essential mechanisms in diverse MR imaging contrasts. Omega plots have proven effective in mapping proton exchange rates (kex) in live human brains, enabling the differentiation of MS lesion activities and characterization of ischemic stroke. However, Omega plots require extended saturation durations (typically 5 to 10 s), resulting in high specific absorption rates (SAR) that can hinder clinical feasibility. In this study, we introduce a novel kex mapping approach, named induced Saturation Transfer Recovery Steady-States (iSTRESS). iSTRESS integrates an excitation flip angle pulse prior to chemical exchange saturation transfer (CEST) saturation, effectively aligning the magnetization with its steady-state value. This innovation reduces saturation times and mitigates SAR concerns. The formula for iSTRESS-based kex quantification was derived theoretically, involving two measurements with distinct excitation flip angles and saturation B1 values. Bloch-McConnell simulations confirmed that iSTRESS-based kex values closely matched input values (R2 > 0.99). An iSTRESS MRI sequence was implemented on a 9.4 T preclinical MRI, imaging protein phantoms with pH values ranging from 6.2 to 7.4 (n = 4). Z-spectra were acquired using excitation flip angles of 30° and 60°, followed by CEST saturation at powers of 30 and 120 Hz respectively, with a total saturation time of <1 s, resulting in two iSTRESS states for kex mapping. kex maps derived from the phantom study exhibited a linear correlation (R2 > 0.99) with Omega plot results. The developed iSTRESS method allows for kex quantification with significantly reduced saturation times, effectively minimizing SAR concerns.

Analytical solution of the Bloch-McConnell equations for steady-state CEST Z-spectra.

PURPOSE: To derive an analytic expression for the steady-state Chemical Exchange Saturation Transfer (CEST) Z-spectra of a two-pool proton-exchanging system, facilitating simulations and expedited fitting of steady-state Z-spectra. METHOD: The analytical expression is derived by directly solving the set of Bloch-McConnell differential equations in matrix form for a two-pool exchanging system, determining water magnetization under steady-state saturation across the entire Z-spectrum. The analytic solution is compared and validated against the numerical solution of Bloch-McConnell equations under prolonged saturation. The study also explores the line shape of a CEST peak, interpolating under-sampled Z-spectra, and Z-spectral fitting in the presence of noise. RESULTS: The derived analytic solution accurately reproduces spectra obtained through numerical solutions. Direct fitting of simulated CEST spectra with the analytical solution yields the physical parameters of the exchanging system. The study shows that the analytical solution enables the reproduction of fully sampled spectra from sparsely sampled Z-spectra. Additionally, it confirms the approximation of the CEST spectrum of a single exchanging proton species with a Lorentzian function. Monte Carlo simulations reveal that the accuracy and precision of Z-spectral fittings for physical parameters are significantly influenced by data noise. The study also derives and discusses the analytical solution for three-pool Z-spectra. CONCLUSION: The derived analytic solution for steady state Z-spectra can be utilized for simulations and Z-spectrum fitting, significantly reducing fitting times compared to numerical methods employed for fitting CEST Z-spectra.

Intravoxel incoherent motion diffusion-weighted imaging of pancreas: Probing evidence of ß-cell dysfunction in asymptomatic adults with hyperglycemia in vivo.

PURPOSE: Early evaluation of ß-cell dysfunction of hyperglycemic patients in asymptomatic adults would be valuable for timely prevention of the diabetes. This study aimed to evaluate functional changes in the pancreas using intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) and determine whether it could be used as a non-invasive method of assessing ß-cell dysfunction. METHODS: This prospective cohort study was conducted from August 2022 to November 2022 in Jinan University Affiliated Guangdong Second General Hospital. Three groups were enrolled and underwent IVIM-DWI: confirmed patients with type 2 diabetes (T2DM); hyperglycemic patients in asymptomatic adults; and the volunteers with normal glucose tolerance (NGT). Imaging parameters were obtained: apparent diffusion coefficient (ADC), the true diffusion coefficient (Dt), the pseudo-diffusion coefficient (Dp), and the perfusion fraction (f). The ß-cell function indexes were calculated from blood examinations: composite insulin sensitivity index (ISI), 60-min insulinogenic index (IGI60), and the disposition index (DI). We compared imaging parameters among three groups, calculated the diagnostic performance of them for differentiating different groups, and the reproducibility of them was evaluated using intraclass correlation coefficient (ICC). RESULTS: The imaging parameters except f gradually decreased among the groups with significant differences for ADC (p < 0.0001), Dt (p < 0.0001), and Dp (p = 0.013). Dt demonstrated the best diagnostic performance for differentiating asymptomatic patients from NGT (Area Under Curve [AUC] = 0.815, p < 0.0001). IVIM-DWI parameters correlated with composite ISI and DI, of which, Dt has the highest correlation with DI (Pearson correlation coefficient [r] = 0.546, p < 0.0001). The ICC of IVIM-DWI parameters was very good, Dt was highest (Interobserver ICC = 0.938, 95% Confidence Interval [CI], 0.899-0.963; Intraobserver ICC = 0.941, 95% CI, 0.904-0.965). CONCLUSION: IVIM-DWI is a non-invasive quantitative method that can identify ß-cell dysfunction in the pancreas.

Noninvasive Characterization of Metabolic Changes in Ischemic Stroke Using Z-spectrum-fitted Multiparametric Chemical Exchange Saturation Transfer-weighted Magnetic Resonance Imaging.

OBJECTIVE: This study aimed to noninvasively characterize the metabolic alterations in ischemic brain tissues using Z-spectrum-fitted multiparametric chemical exchange saturation transfer-weighted magnetic resonance imaging (CEST-MRI). METHODS: Three sets of Z-spectrum data with saturation power (B1) values of 1.5, 2.5, and 3.5 µT, respectively, were acquired from 17 patients with ischemic stroke. Multiple contrasts contributing to the Z-spectrum, including fitted amide proton transfer (APTfitted), +2 ppm peak (CEST@2ppm), concomitantly fitted APTfitted and CEST@2ppm (APT&CEST@2ppm), semisolid magnetization transfer contrast (MT), aliphatic nuclear Overhauser effect (NOE), and direct saturation of water (DSW), were fitted with 4 and 5 Lorentzian functions, respectively. The CEST metrics were compared between ischemic lesions and contralateral normal white matter (CNWM), and the correlation between the CEST metrics and the apparent diffusion coefficient (ADC) was assessed. The differences in the Z-spectrum metrics under varied B1 values were also investigated. RESULTS: Ischemic lesions showed increased APTfitted, CEST@2ppm, APT&CEST@2ppm, NOE, and DSW as well as decreased MT. APT&CEST@2ppm, MT, and DSW showed a significant correlation with ADC [APT&CEST@2ppm at the 3 B1 values: R=0.584/0.467/0.551; MT at the 3 B1 values: R=-0.717/-0.695/-0.762 (4-parameter fitting), R=-0.734/-0.711/-0.785 (5-parameter fitting); DSW of 4-/5-parameter fitting: R=0.794/0.811 (2.5 µT), R=0.800/0.790 (3.5 µT)]. However, the asymmetric analysis of amide proton transfer (APTasym) could not differentiate the lesions from CNWM and showed no correlation with ADC. Furthermore, the Z-spectrum contrasts varied with B1. CONCLUSION: The Z-spectrum-fitted multiparametric CEST-MRI can comprehensively detect metabolic alterations in ischemic brain tissues.

Endothelial Cell APOE3 Regulates Neurovascular, Neuronal, and Behavioral Function.

BACKGROUND: Specialized brain endothelial cells and human APOE3 are independently important for neurovascular function, yet whether APOE3 expression by endothelial cells contributes to brain function is currently unknown. In the present study, we determined whether the loss of endothelial cell APOE3 impacts brain vascular and neural function. METHODS: We developed APOE3fl/fl/Cdh5(PAC)-CreERT2+/- (APOE3Cre+/-) and APOE3fl/fl/Cdh5(PAC)-CreERT2-/- (APOE3Cre-/-, control) mice and induced endothelial cell APOE3 knockdown with tamoxifen at ≈4 to 5 weeks of age. Neurovascular and neuronal function were evaluated by biochemistry, immunohistochemistry, behavioral testing, and electrophysiology at 9 months of age. RESULTS: We found that the loss of endothelial APOE3 expression was sufficient to cause neurovascular dysfunction including higher permeability and lower vessel coverage in tandem with deficits in spatial memory and fear memory extinction and a disruption of cortical excitatory/inhibitory balance. CONCLUSIONS: Our data collectively support the novel concept that endothelial APOE3 plays a critical role in the regulation of the neurovasculature, neural circuit function, and behavior.

A cell-penetrating PHLPP peptide improves cardiac arrest survival in murine and swine models.

Out-of-hospital cardiac arrest is a leading cause of death in the US, with a mortality rate over 90%. Preclinical studies demonstrate that cooling during cardiopulmonary resuscitation (CPR) is highly beneficial, but can be challenging to implement clinically. No medications exist for improving long-term cardiac arrest survival. We have developed a 20-amino acid peptide, TAT-PHLPP9c, that mimics cooling protection by enhancing AKT activation via PH domain leucine-rich repeat phosphatase 1 (PHLPP1) inhibition. Complementary studies were conducted in mouse and swine. C57BL/6 mice were randomized into blinded saline control and peptide-treatment groups. Following a 12-minute asystolic arrest, TAT-PHLPP9c was administered intravenously during CPR and significantly improved the return of spontaneous circulation, mean arterial blood pressure and cerebral blood flow, cardiac and neurological function, and survival (4 hour and 5 day). It inhibited PHLPP-NHERF1 binding, enhanced AKT but not PKC phosphorylation, decreased pyruvate dehydrogenase phosphorylation and sorbitol production, and increased ATP generation in heart and brain. TAT-PHLPP9c treatment also reduced plasma taurine and glutamate concentrations after resuscitation. The protective benefit of TAT-PHLPP9c was validated in a swine cardiac arrest model of ventricular fibrillation. In conclusion, TAT-PHLPP9c may improve neurologically intact cardiac arrest survival without the need for physical cooling.

Applications of chemical exchange saturation transfer magnetic resonance imaging in identifying genetic markers in gliomas.

Chemical exchange saturation transfer (CEST) imaging is an important molecular magnetic resonance imaging technique that can image numerous low-concentration biomolecules with water-exchangeable protons (such as cellular proteins) and tissue pH. CEST, or more specially amide proton transfer-weighted imaging, has been widely used for the detection, diagnosis, and response assessment of brain tumors, and its feasibility in identifying molecular markers in gliomas has also been explored in recent years. In this paper, after briefing on the basic principles and quantification methods of CEST imaging, we review its early applications in identifying isocitrate dehydrogenase mutation status, MGMT methylation status, 1p/19q deletion status, and H3K27M mutation status in gliomas. Finally, we discuss the limitations or weaknesses in these studies.

Proton exchange rate of chemical exchange saturation transfer MRI constructed from direct saturation-removed omega plots to improve the assessment of patients with ischemic stroke.

Background: Proton exchange rate (k ex) magnetic resonance imaging (MRI) has recently been developed, with preliminary results demonstrating its potential for evaluating reactive oxygen species. This prospective cohort study investigated the k ex in different stroke stages and its correlation with stroke severity and prognosis. Methods: In all, 96 ischemic stroke patients were included in the study. Patients were divided into 3 groups based on stroke phase (acute, subacute, and chronic). A spin echo-echo planar imaging sequence with presaturation powers of 1.5, 2.5, and 3.5 µT was implemented to obtain Z-spectra, and k ex maps were constructed from direct saturation-removed omega plots. Relative k ex (rk ex) and the relative apparent diffusion coefficient (rADC) were calculated as the ratio of k ex or ADC in the infarcts to values in contralateral tissue, respectively. Correlations between both k ex and rk ex and National Institute of Health Stroke Scale (NIHSS) scores were evaluated. Receiver operating characteristic (ROC) analysis was used to evaluate the performance of k ex, rk ex, rADC, and lesion volume for predicting acute stroke outcome. Results: The k ex was significantly higher in ischemic lesions than in contralateral tissue at all stages. In addition, the k ex of acute lesions was higher than that of subacute and chronic lesions [mean (± SD) 935.1±81.5 vs. 881.4±55.7 and 866.9±76.7 s-1, respectively; P<0.05 and P<0.01, respectively]. The difference in k ex between subacute and chronic lesions was not significant. In acute stroke, there was a limited correlation between a lesion's k ex and NIHSS score (R2=0.16; P=0.01) and between rk ex and NIHSS score (R2=0.28; P=0.001). Acute stroke patients with poor prognosis had significantly higher lesion k ex and rk ex than did those with good prognosis (k ex: 991.1±78.2 vs. 893.1±55.1 s-1, P<0.001; rk ex: 1.28±0.09 vs. 1.15±0.06, P<0.001). In ROC analyses, k ex and rk ex showed favorable predictive performance for acute stroke outcome, with areas under the curve (AUC) of 0.837 and 0.880, respectively, which were slightly but not significantly higher than the AUCs for lesion volume (0.730) and rADC (0.673). Conclusions: This study indicates that k ex MRI is promising for the diagnosis and management of ischemic stroke because it can reflect the oxidative stress of lesions and predict prognosis.

Toward In Vivo MRI of the Tissue Proton Exchange Rate in Humans.

Quantification of proton exchange rate (kex) is a challenge in MR studies. Current techniques either have low resolutions or are dependent on the estimation of parameters that are not measurable. The Omega plot method, on the other hand, provides a direct way for determining kex independent of the agent concentration. However, it cannot be used for in vivo studies without some modification due to the contributions from the water signal. In vivo tissue proton exchange rate (kex) MRI, based on the direct saturation (DS) removed Omega plot, quantifies the weighted average of kex of the endogenous tissue metabolites. This technique has been successfully employed for imaging the variation in the kex of ex vivo phantoms, as well as in vivo human brains in healthy subjects, and stroke or multiple sclerosis (MS) patients. In this paper, we present a brief review of the methods used for kex imaging with a focus on the development of in vivo kex MRI technique based on the DS-removed Omega plot. We then review the recent clinical studies utilizing this technique for better characterizing brain lesions. We also outline technical challenges for the presented technique and discuss its prospects for detecting tissue microenvironmental changes under oxidative stress.

Review and consensus recommendations on clinical APT-weighted imaging approaches at 3T: Application to brain tumors.

Amide proton transfer-weighted (APTw) MR imaging shows promise as a biomarker of brain tumor status. Currently used APTw MRI pulse sequences and protocols vary substantially among different institutes, and there are no agreed-on standards in the imaging community. Therefore, the results acquired from different research centers are difficult to compare, which hampers uniform clinical application and interpretation. This paper reviews current clinical APTw imaging approaches and provides a rationale for optimized APTw brain tumor imaging at 3 T, including specific recommendations for pulse sequences, acquisition protocols, and data processing methods. We expect that these consensus recommendations will become the first broadly accepted guidelines for APTw imaging of brain tumors on 3 T MRI systems from different vendors. This will allow more medical centers to use the same or comparable APTw MRI techniques for the detection, characterization, and monitoring of brain tumors, enabling multi-center trials in larger patient cohorts and, ultimately, routine clinical use.

Early detection of increased marrow adiposity with age in rats using Z-spectral MRI at ultra-high field (7 T).

BACKGROUND: Nowadays, the drive towards high-field MRI is fueled by the pursuit of higher signal-to-noise ratio, spatial resolution, and imaging speed. However, high field strength is associated with field inhomogeneity, acceleration of T2 * decay, and increased chemical shift, which may pose challenges to conventional MRI for fat quantification in complex tissues such as bone marrow. With proton MRI spectroscopy (1 H-MRS), on the other hand, it is difficult to produce high resolution. As a novel alternative fat quantification method, high-resolution Z-spectral MRI (ZS-MRI) can achieve fat quantification by acquiring direct saturated images of both fat and water under the same TE , which may be less affected by T2 * decay and field inhomogeneity. PURPOSE: To demonstrate ZS-MRI for marrow adipose tissue (MAT) quantification in rat's lumbar spine and the early detection of MAT changes with age. METHODS: The accuracy of ZS-MRI for fat quantification at ultra-high-field MRI (7 T) was verified with MRS and conventional Dixon MRI in water-oil mixed phantoms with varying fat fraction (FF). Dixon MRI data were processed with iterative decomposition of water and fat with echo asymmetry and least-squares estimation. ZS-MRI was then used to longitudinally monitor the adiposity in the lumbar spine of young healthy rats at 13, 17, and 21 weeks to detect the early changes of FF with age in MAT. Hematoxylin-eosin staining of lumbar spines from separated rat groups was performed for verification. RESULTS: In ex vivo phantom experiments, both Dixon MRI and ZS-MRI were well correlated with 1 H-MRS for the quantification of FF at 7 T (R > 0.99). Compared with Dixon MRI, ZS-MRI showed reduced image artifacts due to field inhomogeneity and presented better agreement with 1 H-MRS for the early detection of increased MAT due to age at 7 T (ZS-MRI R = 0.78 versus Dixon MRI R = 0.34). The increased MAT FF due to age was confirmed by histology. CONCLUSION: ZS-MRI proves itself as an alternative fat quantification method for bone marrow in rats at 7 T.

Multi-parametric Z-spectral MRI may have a good performance for glioma stratification in clinical patients.

OBJECTIVES: To comprehensively and noninvasively risk-stratify glioma grade, isocitrate dehydrogenase (IDH) genotype, and 1p/19q codeletion status using multi-contrast Z-spectral magnetic resonance imaging (MRI). METHODS: One hundred and thirteen patients with glioma were retrospectively included. Multiple contrasts contributing to Z-spectra, including direct saturation of water (DSW), semi-solid magnetization transfer contrast (MTC), amide proton transfer (APT) effect, aliphatic nuclear Overhauser effect, and the 2-ppm chemical exchange saturation transfer peak (CEST@2ppm), were fitted with five individual Lorentzian functions. Z-spectral contrasts were compared according to the three most important risk stratifications: tumor grade, IDH genotype, and 1p/19q codeletion status. We further investigated the differentiation of 1p/19q codeletion status within IDH mutant gliomas. The stratification performance of individual Z-spectral contrasts and their combination was quantified using receiver operating characteristic (ROC) analyses. RESULTS: DSW was significantly different within grade, IDH genotypes, and 1p/19q codeletion status. APT was significantly different with grade and IDH mutation, but not with 1p/19q subtypes. CEST@2ppm was only significantly different with 1p/19q codeletion subtypes. DSW and CEST@2ppm were the two Z-spectral contrasts able to differentiate 1p/19q codeletion subtypes within IDH mutant gliomas. For differentiating glioma grades using ROC analyses, DSW achieved the largest AUC. For differentiating IDH genotypes, DSW and APT achieved comparable AUCs. DSW was the best metric for differentiating 1p/19q codeletion status within all patients and within the IDH mutant patients. Combining all Z-spectral contrasts improved sensitivity and specificity for all risk stratifications. CONCLUSIONS: Multi-parametric Z-spectral MRI serves as a useful, comprehensive, and noninvasive imaging technique for glioma stratification in clinical patients. KEY POINTS: • Multiple contrasts contributing to Z-spectra were separately fitted with Lorentzian functions. • Z-spectral contrasts were compared within the three most important and common tumor risk stratifications for gliomas: tumor grade, IDH genotype, and 1p/19q codeletion status. • The stratification performance of individual Z-spectral contrasts and their combination was quantified using receiver operating characteristic analyses, which found Z-spectral MRI to be a useful and comprehensive imaging biomarker for glioma stratification.

Phase-independent thermometry by Z-spectrum MR imaging.

PURPOSE: Z-spectrum imaging, defined as the consecutive collection of images after saturating over a range of frequency offsets, has been recently proposed as a method to measure the fat-water fraction by the simultaneous detection of fat and water resonances. By incorporating a binomial pulse irradiated at each offset before the readout, the spectral selectivity of the sequence can be further amplified, making it possible to monitor the subtle proton resonance frequency shift that follows a change in temperature. METHODS: We tested the hypothesis in aqueous and cream phantoms and in healthy mice, all under thermal challenge. The binomial module consisted of 2 sinc-shaped pulses of opposite phase separated by a delay. Such a delay served to spread out off-resonance spins, with the resulting excitation profile being a periodic function of the delay and the chemical shift. RESULTS: During heating experiments, the water resonance shifted downfield, and by fitting the curve to a sine function it was possible to quantify the change in temperature. Results from Z-spectrum imaging correlated linearly with data from conventional MRI techniques like T1 mapping and phase differences from spoiled GRE. CONCLUSION: Because the measurement is performed solely on magnitude images, the technique is independent of phase artifacts and is therefore applicable in mixed tissues (e.g., fat). We showed that Z-spectrum imaging can deliver reliable temperature change measurement in both muscular and fatty tissues.

Combining in vivo proton exchange rate (k ex) MRI with quantitative susceptibility mapping to further stratify the gadolinium-negative multiple sclerosis lesions.

Background: Conventional gadolinium (Gd)-enhanced MRI is currently used for stratifying the lesion activity of multiple sclerosis (MS) despite limited correlation with disability and disease activity. The stratification of MS lesion activity needs further improvement to better support clinics. Purpose: To investigate if the novel proton exchange rate (k ex ) MRI combined with quantitative susceptibility mapping (QSM) may help to further stratify non-enhanced (Gd-negative) MS lesions. Materials and methods: From December 2017 to December 2020, clinically diagnosed relapsing-remitting MS patients who underwent MRI were consecutively enrolled in this IRB-approved retrospective study. The customized MRI protocol covered conventional T2-weighted, T2-fluid-attenuated-inversion-recovery, pre- and post-contrast T1-weighted imaging, and quantitative sequences, including k ex MRI based on direct-saturation removed omega plots and QSM. Each MS lesion was evaluated based on its Gd-enhancement as well as its susceptibility and k ex elevation compared to the normal appearing white matter. The difference and correlation concerning lesion characteristics and imaging contrasts were analyzed using the Mann-Whitney U test or Kruskal-Wallis test, and Spearman rank analysis with p < 0.05 considered significant. Results: A total of 322 MS lesions from 30 patients were identified with 153 Gd-enhanced and 169 non-enhanced lesions. We found that the k ex elevation of all lesions significantly correlated with their susceptibility elevation (r = 0.30, p < 0.001). Within the 153 MS lesions with Gd-enhancement, ring-enhanced lesions showed higher k ex elevation than the nodular-enhanced ones' (p < 0.001). Similarly, lesions with ring-hyperintensity in QSM also had higher k ex elevation than the lesions with nodular-QSM-hyperintensity (p < 0.001). Of the 169 Gd-negative lesions, three radiological patterns were recognized according to lesion manifestations on the k ex map and QSM images: Pattern I (k ex + and QSM+, n = 114, 67.5%), Pattern II (only k ex + or QSM+, n = 47, 27.8%) and Pattern III (k ex - and QSM-, n = 8, 4.7%). Compared to Pattern II and III, Pattern I had higher k ex (p < 0.001) and susceptibility (p < 0.05) elevation. The percentage of Pattern I of each subject was negatively correlated with the disease duration (r = -0.45, p = 0.015). Conclusion: As a potential imaging biomarker for inflammation due to oxidative stress, in vivo k ex MRI combined with QSM is promising in extending the clinical classification of MS lesions beyond conventional Gd-enhanced MRI.

Combination of natural killer cell-based immunotherapy and irreversible electroporation for the treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is among the most lethal cancer types despite great advancement in overall survival of the patients over the last decades. Surgical resection or partial hepatectomy has been approved as the curative treatment for early-stage HCC patients however only up to 30% of them are eligible for the procedures. Natural killer (NK) cells are cytotoxic lymphocytes recognized for killing virally infected cells and improving immune functions for defending the body against malignant cells. Although autologous NK cells failed to demonstrate significant clinical benefit, transfer of allogeneic adoptive NK cells arises as a promising approach for the treatment of solid tumors. The immunosuppressive tumor microenvironment and inadequate homing efficiency of NK cells to tumors can inhibit adoptive transfer immunotherapy (ATI) efficacy. However, potential of the NK cells is challenged by the transfection efficiency. The local ablation techniques that employ thermal or chemical energy have been investigated for the destruction of solid tumors for three decades and demonstrated promising benefits for individuals not eligible for surgical resection or partial hepatectomy. Irreversible electroporation (IRE) is one of the most recent minimally invasive ablation methods that destruct the cell within the targeted region through non-thermal energy. IRE destroys the tumor cell membrane by delivering high-frequency electrical energy in short pulses and overcomes tumor immunosuppression. The previous studies demonstrated that IRE can induce immune changes which can facilitate activation of specific immune responses and improve transfection efficiency. In this review paper, we have discussed the mechanism of NK cell immunotherapy and IRE ablation methods for the treatment of HCC patients and the combinatorial benefits of NK cell immunotherapy and IRE ablation.

Predicting cancer malignancy and proliferation in glioma patients: intra-subject inter-metabolite correlation analyses using MRI and MRSI contrast scans.

BACKGROUND: The non-invasive characterization of glioma metabolites would greatly assist the management of glioma patients in the clinical setting. This study investigated the applicability of intra-subject inter-metabolite correlation analyses for differentiating glioma malignancy and proliferation. METHODS: A total of 17 negative controls (NCs), 39 low-grade gliomas (LGGs) patients, and 25 high-grade gliomas (HGGs) subjects were included in this retrospective study. Amide proton transfer (APT) and magnetization transfer contrast (MTC) imaging contrasts, as well as total choline/total creatine (tCho/tCr) and total N-acetylaspartate/total creatine (tNAA/tCr) ratios quantified from magnetic resonance spectroscopic imaging (MRSI) were co-registered voxel-wise and used to produce three intra-subject inter-metabolite correlation coefficients (IMCCs), namely, RAPT vs . MTC, RAPT vs . tCho/tCr, and RMTC vs . tNAA/tCr. The correlation between the IMCCs and tumor grade and Ki-67 labeling index (LI) for tumor proliferation were explored. The differences in the IMCCs between the three groups were compared with one-way analysis of variance (ANOVA). Finally, regression analysis was used to build a combined model with multiple IMCCs to improve the diagnostic performance for tumor grades based on receiver operator characteristic curves. RESULTS: Compared with the NCs, gliomas showed stronger inter-metabolic correlations. RAPT vs . MTC was significantly different among the three groups (NC vs. LGGs vs. HGGs: -0.18±0.38 vs. -0.40±0.34 vs. -0.70±0.29, P<0.0001). No significant differences were detected in RMTC vs . tNAA/tCr among the three groups. RAPT vs . MTC and RAPT vs . tCho/tCr correlated significantly with tumor grade (R=-0.41, P=0.001 and R=0.448, P<0.001, respectively). However, only RAPT vs . MTC was mildly correlated with Ki-67 (R=-0.33, P=0.02). RAPT vs . MTC and RAPT vs . tCho/tCr achieved areas under the curve (AUCs) of 0.754 and 0.71, respectively, for differentiating NCs from gliomas; and 0.77 and 0.78, respectively, for differentiating LGGs from HGGs. The combined multi-IMCCs model improved the correlation with the Ki-67 LI (R=0.46, P=0.0008) and the tumor-grade stratification with AUC increased to 0.85 (sensitivity: 80.0%, specificity: 79.5%). CONCLUSIONS: This study demonstrated that glioma patients showed stronger inter-metabolite correlations than control subjects, and the IMCCs were significantly correlated with glioma grade and proliferation. The multi-IMCCs combined model further improved the performance of clinical diagnosis.

Neurite Orientation Dispersion and Density Imaging of Rat Brain Microstructural Changes due to Middle Cerebral Artery Occlusion at a 3T MRI.

The purpose of this work was to demonstrate the feasibility of neurite orientation dispersion and density imaging (NODDI) in characterizing the brain tissue microstructural changes of middle cerebral artery occlusion (MCAO) in rats at 3T MRI, and to validate NODDI metrics with histology. A multi-shell diffusion MRI protocol was performed on 11 MCAO rats and 10 control rats at different post-operation time points of 0.5, 2, 6, 12, 24 and 72 h. NODDI orientation dispersion index (ODI) and intracellular volume fraction (Vic) metrics were compared between MCAO group and control group. The evolution of NODDI metrics was characterized and validated by histology. Infarction was consistent with significantly increased ODI and Vic in comparison to control tissues at all time points (P<0.001). Lesion ODI increased gradually from 0.5 to 72 h, while its Vic showed a more complicated and fluctuated evolution. ODI and Vic were significantly different between hyperacute and acute stroke periods (P<0.001). The NODDI metrics were found to be consistent with the histological findings. In conclusion, NODDI can reflect microstructural changes of brain tissues in MCAO rats at 3T MRI and the metrics are consistent with histology. This study helps to prepare NODDI for the diagnosis and management of ischemic stroke in translational research and clinical practice.

Combination of NK-based immunotherapy and sorafenib against hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most frequent malignancy of the liver, which is considered the fourth leading cause of cancer-related death in the United States. Liver transplant and surgical resection are curative treatments for HCC, but only 10-15% of HCC patients are eligible candidates. The FDA-approved sorafenib is a multi-kinase inhibitor systemic therapy for advanced HCC that extends the overall survival by over 3 months when compared with placebo. Adoptive transfer of Natural Killer (NK) cells holds great promise for clinical cancer treatment. However, only limited clinical benefit has been achieved in cancer patients. Therefore, there is currently considerable interest in development of the combination of sorafenib and NK cells for the treatment of HCC patients. However, the mechanism of how sorafenib affects the function of NK cells remains to be comprehensively clarified. In this paper, we will discuss NK cell-based immunotherapies that are currently under preclinical and clinical investigation and its potential combination with sorafenib for improving the survival of HCC patients.