Quantification of perineural satellitosis in pretreatment glioblastoma with structural MRI and a diffusion tensor imaging template.

Background: Survival outcomes for glioblastoma (GBM) patients remain unfavorable, and tumor recurrence is often observed. Understanding the radiological growth patterns of GBM could aid in improving outcomes. This study aimed to examine the relationship between contrast-enhancing tumor growth direction and white matter, using an image registration and deformation strategy. Methods: In GBM patients 2 pretreatment scans (diagnostic and neuronavigation) were gathered retrospectively, and coregistered to a template and diffusion tensor imaging (DTI) atlas. The GBM lesions were segmented and coregistered to the same space. Growth vectors were derived and divided into vector populations parallel (Φ = 0-20°) and perpendicular (Φ = 70-90°) to white matter. To test for statistical significance between parallel and perpendicular groups, a paired samples Student's t-test was performed. O6-methylguanine-DNA methyltransferase (MGMT) methylation status and its correlation to growth rate were also tested using a one-way ANOVA test. Results: For 78 GBM patients (mean age 61 years ±â€…13 SD, 32 men), the included GBM lesions showed a predominant preference for perineural satellitosis (P < .001), with a mean percentile growth of 30.8% (95% CI: 29.6-32.0%) parallel (0°â€…< |Φ| < 20°) to white matter. Perpendicular tumor growth with respect to white matter microstructure (70°â€…< |Φ| < 90°) showed to be 22.7% (95% CI: 21.3-24.1%) of total tumor growth direction. Conclusions: The presented strategy showed that tumor growth direction in pretreatment GBM patients correlated with white matter architecture. Future studies with patient-specific DTI data are required to verify the accuracy of this method prospectively to identify its usefulness as a clinical metric in pre and posttreatment settings.

Explainable Artificial Intelligence for Human-Machine Interaction in Brain Tumor Localization.

Primary malignancies in adult brains are globally fatal. Computer vision, especially recent developments in artificial intelligence (AI), have created opportunities to automatically characterize and diagnose tumor lesions in the brain. AI approaches have provided scores of unprecedented accuracy in different image analysis tasks, including differentiating tumor-containing brains from healthy brains. AI models, however, perform as a black box, concealing the rational interpretations that are an essential step towards translating AI imaging tools into clinical routine. An explainable AI approach aims to visualize the high-level features of trained models or integrate into the training process. This study aims to evaluate the performance of selected deep-learning algorithms on localizing tumor lesions and distinguishing the lesion from healthy regions in magnetic resonance imaging contrasts. Despite a significant correlation between classification and lesion localization accuracy (R = 0.46, p = 0.005), the known AI algorithms, examined in this study, classify some tumor brains based on other non-relevant features. The results suggest that explainable AI approaches can develop an intuition for model interpretability and may play an important role in the performance evaluation of deep learning models. Developing explainable AI approaches will be an essential tool to improve human-machine interactions and assist in the selection of optimal training methods.

An integrated RF-receive/B0-shim array coil boosts performance of whole-brain MR spectroscopic imaging at 7 T.

Metabolic imaging of the human brain by in-vivo magnetic resonance spectroscopic imaging (MRSI) can non-invasively probe neurochemistry in healthy and disease conditions. MRSI at ultra-high field (≥ 7 T) provides increased sensitivity for fast high-resolution metabolic imaging, but comes with technical challenges due to non-uniform B0 field. Here, we show that an integrated RF-receive/B0-shim (AC/DC) array coil can be used to mitigate 7 T B0 inhomogeneity, which improves spectral quality and metabolite quantification over a whole-brain slab. Our results from simulations, phantoms, healthy and brain tumor human subjects indicate improvements of global B0 homogeneity by 55%, narrower spectral linewidth by 29%, higher signal-to-noise ratio by 31%, more precise metabolite quantification by 22%, and an increase by 21% of the brain volume that can be reliably analyzed. AC/DC shimming provide the highest correlation (R2 = 0.98, P = 0.001) with ground-truth values for metabolite concentration. Clinical translation of AC/DC and MRSI is demonstrated in a patient with mutant-IDH1 glioma where it enables imaging of D-2-hydroxyglutarate oncometabolite with a 2.8-fold increase in contrast-to-noise ratio at higher resolution and more brain coverage compared to previous 7 T studies. Hence, AC/DC technology may help ultra-high field MRSI become more feasible to take advantage of higher signal/contrast-to-noise in clinical applications.

Effect of exercise training on cardiac metabolism in rats with heart failure.

Objectives. Heart failure (HF) impairs resting myocardial energetics, myocardial mitochondrial performance, and maximal oxygen uptake (VO2max). Exercise training is included in most rehabilitation programs and benefits HF patients. However, the effect of exercise intensity on cardiac mitochondrial respiration and concentrations of the key bioenergetic metabolites phosphocreatine (PCr), adenosine triphosphate (ATP), and inorganic phosphate (Pi) is unclear. This study aimed to investigate the effects of exercise training at different intensities in rats with HF. Methods. Rats underwent myocardial infarction or sham operations and were divided into three subgroups: sedentary, moderate intensity, or high intensity. The impact of HF and 6 weeks of exercise training on energy metabolism was evaluated by 31P magnetic resonance spectroscopy and mitochondrial respirometry. The concentrations of PCr, ATP, and Pi were quantified by magnetic resonance spectroscopy. VO2max was measured by treadmill respirometry. Results. Exercise training increased VO2max in sham and HF. PCr/ATP ratio was reduced in HF (p < .01) and remained unchanged by exercise training. PCr concentration was significantly lower in HF compared to sham (p < .01). Moderate and high-intensity exercise training increased ATP in HF and sham. HF impaired complex I (CI) and complex II (p = .034) respiration. High-intensity exercise training recovered CI respiration in HF rats compared to HF sedentary (p = .014). Conclusions. Exercise training improved cardiac performance, as indicated by increased VO2max and higher exercise capacity, without changing the myocardial PCr/ATP ratio. These observations suggest that the PCr/ATP biomarker is not suited to evaluate the beneficial effects of exercise training in the heart. The exact mechanisms require further investigations, as exercise training did increase ATP levels and CI respiration.

Simultaneous 18F-fluciclovine Positron Emission Tomography and Magnetic Resonance Spectroscopic Imaging of Prostate Cancer.

Purpose: To investigate the associations of metabolite levels derived from magnetic resonance spectroscopic imaging (MRSI) and 18F-fluciclovine positron emission tomography (PET) with prostate tissue characteristics. Methods: In a cohort of 19 high-risk prostate cancer patients that underwent simultaneous PET/MRI, we evaluated the diagnostic performance of MRSI and PET for discrimination of aggressive cancer lesions from healthy tissue and benign lesions. Data analysis comprised calculations of correlations of mean standardized uptake values (SUVmean), maximum SUV (SUVmax), and the MRSI-derived ratio of (total choline + spermine + creatine) to citrate (CSC/C). Whole-mount histopathology was used as gold standard. Results: The results showed a moderate significant correlation between both SUVmean and SUVmax with CSC/C ratio. Conclusions: We demonstrated that the simultaneous acquisition of 18F-fluciclovine PET and MRSI with an integrated PET/MRI system is feasible and a combination of these imaging modalities has potential to improve the diagnostic sensitivity and specificity of prostate cancer lesions.

The Direction of Tumour Growth in Glioblastoma Patients.

Generating MR-derived growth pattern models for glioblastoma multiforme (GBM) has been an attractive approach in neuro-oncology, suggesting a distinct pattern of lesion spread with a tendency in growing along the white matter (WM) fibre direction for the invasive component. However, the direction of growth is not much studied in vivo. In this study, we sought to study the dominant directions of tumour expansion/shrinkage pre-treatment. We examined fifty-six GBMs at two time-points: at radiological diagnosis and as part of the pre-operative planning, both with contrast-enhanced T1-weighted MRIs. The tumour volumes were semi-automatically segmented. A non-linear registration resulting in a deformation field characterizing the changes between the two time points was used together with the segmented tumours to determine the dominant directions of tumour change. To compute the degree of alignment between tumour growth vectors and WM fibres, an angle map was calculated. Our results demonstrate that tumours tend to grow predominantly along the WM, as evidenced by the dominant vector population with the maximum alignments. Our findings represent a step forward in investigating the hypothesis that tumour cells tend to migrate preferentially along the WM.

In vivo MR spectroscopy predicts high tumor grade in endometrial cancer.

Background In vivo magnetic resonance spectroscopy (MRS) enables non-invasive measurements of tumor metabolites. Choline-containing metabolites play a key role in tumor metabolism. Purpose To explore whether preoperative MRS-derived tumor choline levels are associated with clinical and histological features in endometrial carcinomas. Material and Methods Preoperative pelvic magnetic resonance imaging (MRI) (1.5T), including structural and diffusion-weighted imaging and localized multivoxel proton MR (1H-MR) spectroscopy, was performed in 77 prospectively included patients with histologically confirmed endometrial carcinomas. Relative levels of total choline-containing metabolites (tCho) in tumor and myometrium were measured using the ratios: tCho/Creatine; tCho/Water; and tCho/Noise. MRS parameters were analyzed in relation to histological subtype and grade, surgicopathological staging parameters, MRI-measured tumor volume, and tumor apparent diffusion coefficient (ADC) value and clinical outcome. Results Tumor tissue had significantly higher ratios for tCho/Creatine, tCho/Water, and tCho/Noise than normal myometrial tissue ( P < 0.001 for all). High tumor tCho/Water ratio was significantly associated with high tumor grade in endometrioid tumors ( P = 0.02). Tumor tCho/Creatine ratio was positively correlated to MRI-measured tumor volume (rs = 0.25; P = 0.03). Conclusion High choline levels in tumor are associated with high-risk features. In vivo MRS may potentially aid in the preoperative risk stratification in endometrial cancer.

Early changes in glioblastoma metabolism measured by MR spectroscopic imaging during combination of anti-angiogenic cediranib and chemoradiation therapy are associated with survival.

Precise assessment of treatment response in glioblastoma during combined anti-angiogenic and chemoradiation remains a challenge. In particular, early detection of treatment response by standard anatomical imaging is confounded by pseudo-response or pseudo-progression. Metabolic changes may be more specific for tumor physiology and less confounded by changes in blood-brain barrier permeability. We hypothesize that metabolic changes probed by magnetic resonance spectroscopic imaging can stratify patient response early during combination therapy. We performed a prospective longitudinal imaging study in newly diagnosed glioblastoma patients enrolled in a phase II clinical trial of the pan-vascular endothelial growth factor receptor inhibitor cediranib in combination with standard fractionated radiation and temozolomide (chemoradiation). Forty patients were imaged weekly during therapy with an imaging protocol that included magnetic resonance spectroscopic imaging, perfusion magnetic resonance imaging, and anatomical magnetic resonance imaging. Data were analyzed using receiver operator characteristics, Cox proportional hazards model, and Kaplan-Meier survival plots. We observed that the ratio of total choline to healthy creatine after 1 month of treatment was significantly associated with overall survival, and provided as single parameter: (1) the largest area under curve (0.859) in receiver operator characteristics, (2) the highest hazard ratio (HR = 85.85, P = 0.006) in Cox proportional hazards model, (3) the largest separation (P = 0.004) in Kaplan-Meier survival plots. An inverse correlation was observed between total choline/healthy creatine and cerebral blood flow, but no significant relation to tumor volumetrics was identified. Our results suggest that in vivo metabolic biomarkers obtained by magnetic resonance spectroscopic imaging may be an early indicator of response to anti-angiogenic therapy combined with standard chemoradiation in newly diagnosed glioblastoma.

Multimodal 18F-Fluciclovine PET/MRI and Ultrasound-Guided Neurosurgery of an Anaplastic Oligodendroglioma.

BACKGROUND: Structural magnetic resonance imaging (MRI) and histopathologic tissue sampling are routinely performed as part of the diagnostic workup for patients with glioma. Because of the heterogeneous nature of gliomas, there is a risk of undergrading caused by histopathologic sampling errors. MRI has limitations in identifying tumor grade and type, detecting diffuse invasive growth, and separating recurrences from treatment induced changes. Positron emission tomography (PET) can provide quantitative information of cellular activity and metabolism, and may therefore complement MRI. In this report, we present the first patient with brain glioma examined with simultaneous PET/MRI using the amino acid tracer 18F-fluciclovine (18F-FACBC) for intraoperative image-guided surgery. CASE DESCRIPTION: A previously healthy 60-year old woman was admitted to the emergency care with speech difficulties and a mild left-sided hemiparesis. MRI revealed a tumor that was suggestive of glioma. Before surgery, the patient underwent a simultaneous PET/MRI examination. Fused PET/MRI, T1, FLAIR, and intraoperative three-dimensional ultrasound images were used to guide histopathologic tissue sampling and surgical resection. Navigated, image-guided histopathologic samples were compared with PET/MRI image data to assess the additional value of the PET acquisition. Histopathologic analysis showed anaplastic oligodendroglioma in the most malignant parts of the tumor, while several regions were World Health Organization (WHO) grade II. CONCLUSIONS: 18F-Fluciclovine uptake was found in parts of the tumor where regional WHO grade, cell proliferation, and cell densities were highest. This finding suggests that PET/MRI with this tracer could be used to improve accuracy in histopathologic tissue sampling and grading, and possibly for guiding treatments targeting the most malignant part of extensive and eloquent gliomas.

In vivo ³¹P magnetic resonance spectroscopic imaging (MRSI) for metabolic profiling of human breast cancer xenografts.

PURPOSE: To study cancer associated with abnormal metabolism of phospholipids, of which several have been proposed as biomarkers for malignancy or to monitor response to anticancer therapy. We explored 3D (31) P magnetic resonance spectroscopic imaging (MRSI) at high magnetic field for in vivo assessment of individual phospholipids in two patient-derived breast cancer xenografts representing good and poor prognosis (luminal- and basal-like tumors). MATERIALS AND METHODS: Metabolic profiles from luminal-like and basal-like xenograft tumors were obtained in vivo using 3D (31) P MRSI at 11.7T and from tissue extracts in vitro at 14.1T. Gene expression analysis was performed in order to support metabolic differences between the two xenografts. RESULTS: In vivo (31) P MR spectra were obtained in which the prominent resonances from phospholipid metabolites were detected at a high signal-to-noise ratio (SNR >7.5). Metabolic profiles obtained in vivo were in agreement with those obtained in vitro and could be used to discriminate between the two xenograft models, based on the levels of phosphocholine, phosphoethanolamine, glycerophosphocholine, and glycerophosphoethanolamine. The differences in phospholipid metabolite concentration could partly be explained by gene expression profiles. CONCLUSION: Noninvasive metabolic profiling by 3D (31) P MRSI can discriminate between subtypes of breast cancer based on different concentrations of choline- and ethanolamine-containing phospholipids.

IDH1 R132H mutation generates a distinct phospholipid metabolite profile in glioma.

Many patients with glioma harbor specific mutations in the isocitrate dehydrogenase gene IDH1 that associate with a relatively better prognosis. IDH1-mutated tumors produce the oncometabolite 2-hydroxyglutarate. Because IDH1 also regulates several pathways leading to lipid synthesis, we hypothesized that IDH1-mutant tumors have an altered phospholipid metabolite profile that would impinge on tumor pathobiology. To investigate this hypothesis, we performed (31)P-MRS imaging in mouse xenograft models of four human gliomas, one of which harbored the IDH1-R132H mutation. (31)P-MR spectra from the IDH1-mutant tumor displayed a pattern distinct from that of the three IDH1 wild-type tumors, characterized by decreased levels of phosphoethanolamine and increased levels of glycerophosphocholine. This spectral profile was confirmed by ex vivo analysis of tumor extracts, and it was also observed in human surgical biopsies of IDH1-mutated tumors by (31)P high-resolution magic angle spinning spectroscopy. The specificity of this profile for the IDH1-R132H mutation was established by in vitro (31)P-NMR of extracts of cells overexpressing IDH1 or IDH1-R132H. Overall, our results provide evidence that the IDH1-R132H mutation alters phospholipid metabolism in gliomas involving phosphoethanolamine and glycerophosphocholine. These new noninvasive biomarkers can assist in the identification of the mutation and in research toward novel treatments that target aberrant metabolism in IDH1-mutant glioma.

Impacts of MR spectroscopic imaging on glioma patient management.

Magnetic resonance (MR) modalities are routine imaging tools in the diagnosis and management of gliomas. MR spectroscopic imaging (MRSI), which relies on the metabolic characteristics of tissues, has been developed to accelerate the understanding of gliomas and to aid in effective clinical decision making and development of targeted therapies. In this review, the potentials and practical challenges to frequently use this technique in clinical management of gliomas are discussed. The applications of new biomarkers detectable by MRSI in differential glioma diagnosis, pre- and post-treatment evaluations, and neurosurgery are also addressed.

Quantitative (31)P HR-MAS MR spectroscopy for detection of response to PI3K/mTOR inhibition in breast cancer xenografts.

PURPOSE: Phospholipid metabolites are of importance in cancer studies, and have been suggested as candidate metabolic biomarkers for response to targeted anticancer drugs. The purpose of this study was to develop a phosphorus ((31) P) high resolution magic angle spinning magnetic resonance spectroscopy protocol for quantification of phosphorylated metabolites in intact cancer tissue. METHODS: (31) P spectra were acquired on a 14.1 T spectrometer with a triplet (1) H/(13) C/(31) P MAS probe. Quantification of metabolites was performed using the PULCON principle. Basal-like and luminal-like breast cancer xenografts were treated with the dual PI3K/mTOR inhibitor BEZ235, and the impact of treatment on the concentration of phosphocholine, glycerophosphocholine, phosphoethanolamine and glycerophosphoethanolamine was evaluated. RESULTS: In basal-like xenografts, BEZ235 treatment induced a significant decrease in phosphoethanolamine (-25.6%, P = 0.01) whilst phosphocholine (16.5%, P = 0.02) and glycerophosphocholine (37.3%, P < 0.001) were significantly increased. The metabolic changes could partially be explained by increased levels of phospholipase A2 group 4A (PLA2G4A). CONCLUSION: (31) P high resolution magic angle spinning magnetic resonance spectroscopy is a useful method for quantitative assessment of metabolic responses to PI3K inhibition. Using the PULCON principle for quantification, the levels of phosphocholine, glycerophosphocholine, phosphoethanolamine, and glycerophosphoethanolamine could be evaluated with high precision and accuracy.

2-hydroxyglutarate as a magnetic resonance biomarker for glioma subtyping.

Mutations in the isocitrate dehydrogenase (IDH) genes are frequently found in gliomas and in a fraction of acute myeloid leukemia patients. This results in the production of an oncometabolite, 2-hydroxyglutarate (2-HG). Glioma patients harboring IDH mutations have a longer survival than their wild-type counterparts. 2-HG has been detected noninvasively in gliomas with IDH mutations using magnetic resonance spectroscopy (MRS), suggesting its potential clinical relevance for identifying glioma subtypes with better prognosis. In this paper, the recent developments in the MRS detection of the 2-HG in gliomas are reviewed, including the therapeutic potentials and translational values.