Metabolic profiling of colorectal cancer organoids: A comparison between high-resolution magic angle spinning magnetic resonance spectroscopy and solution nuclear magnetic resonance spectroscopy of polar extracts

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Measurement of metabolite levels and treatment-induced changes in hepatic metastases of gastro-esophageal cancer using 7-T phosphorus magnetic resonance spectroscopic imaging

Methods for early treatment response evaluation to systemic therapy of liver metastases are lacking. Tumor tissue often exhibits an increased ratio of phosphomonoesters to phosphodiesters (PME/PDE), which can be noninvasively measured by phosphorus magnetic resonance spectroscopy ( 31P MRS), and may be a marker for early therapy response assessment in liver metastases. However, with commonly used 31P surface coils for liver 31P MRS, the liver is not fully covered, and metastases may be missed. The objective of this study was to demonstrate the feasibility of 31P MRS imaging ( 31P MRSI) with full liver coverage to assess 31P metabolite levels and chemotherapy-induced changes in liver metastases of gastro-esophageal cancer, using a 31P whole-body birdcage transmit coil in combination with a 31P body receive array at 7 T. 3D 31P MRSI data were acquired in two patients with hepatic metastases of esophageal cancer, before the start of chemotherapy and after 2 (and 9 in patient 2) weeks of chemotherapy. 3D 31P MRSI acquisitions were performed using an integrated 31P whole-body transmit coil in combination with a 16-channel body receive array at 7 T, with a field of view covering the full abdomen and a nominal voxel size of 20-mm isotropic. From the 31P MRSI data, 12 31P metabolite signals were quantified. Prior to chemotherapy initiation, both PMEs, that is, phosphocholine (PC) and phosphoethanolamine (PE), were significantly higher in all metastases compared with the levels previously determined in the liver of healthy volunteers. After 2 weeks of chemotherapy, PC and PE levels remained high or even increased further, resulting in increased PME/PDE ratios compared with healthy liver tissue, in correspondence with the clinical assessment of progressive disease after 2 months of chemotherapy. The suggested approach may present a viable tool for early therapy (non)response assessment of tumor metabolism in patients with liver metastases

Prospective of 31 P MR Spectroscopy in Hepatopancreatobiliary Cancer: A Systematic Review of the Literature.

BACKGROUND: The incidence of liver and pancreatic cancer is rising. Patients benefit from current treatments, but there are limitations in the evaluation of (early) response to treatment. Tumor metabolic alterations can be measured noninvasively with phosphorus ( 31 P) magnetic resonance spectroscopy (MRS). PURPOSE: To conduct a quantitative analysis of the available literature on 31 P MRS performed in hepatopancreatobiliary cancer and to provide insight into its current and potential for therapy (non-) response assessment. POPULATION: Patients with hepatopancreatobiliary cancer. FIELD STRENGTH/SEQUENCE: 31 P MRS. ASSESSMENT: The PubMed, EMBASE, and Cochrane library databases were systematically searched for studies published to 17 March 17, 2022. All 31 P MRS studies in hepatopancreatobiliary cancer reporting 31 P metabolite levels were included. STATISTICAL TESTS: Relative differences in 31 P metabolite levels/ratios between patients before therapy and healthy controls, and the relative changes in 31 P metabolite levels/ratios in patients before and after therapy were determined. RESULTS: The search yielded 10 studies, comprising 301 subjects, of whom 132 (44%) healthy volunteers and 169 (56%) patients with liver cancer of various etiology. To date, 31 P MRS has not been applied in pancreatic cancer. In liver cancer, alterations in levels of 31 P metabolites involved in cell proliferation (phosphomonoesters [PMEs] and phosphodiesters [PDEs]) and energy metabolism (ATP and inorganic phosphate [Pi]) were observed. In particular, liver tumors were associated with elevations of PME/PDE and PME/Pi compared to healthy liver tissue, although there was a broad variety among studies (elevations of 2%-267% and 21%-233%, respectively). Changes in PME/PDE in liver tumors upon therapy were substantial, yet very heterogeneous and both decreases and increases were observed, whereas PME/Pi was consistently decreased after therapy in all studies (-13% to -76%). DATA CONCLUSION: 31 P MRS has great potential for treatment monitoring in oncology. Future studies are needed to correlate the changes in 31 P metabolite levels in hepatopancreatobiliary tumors with treatment response. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2

Comparison of 2-Hydroxyglutarate Detection With sLASER and MEGA-sLASER at 7T

The onco-metabolite 2-hydroxyglutarate (2HG), a biomarker of IDH-mutant gliomas, can be detected with 1H MR spectroscopy (1H-MRS). Recent studies showed measurements of 2HG at 7T with substantial gain in signal to noise ratio (SNR) and spectral resolution, offering higher specificity and sensitivity for 2HG detection. In this study, we assessed the sensitivity of semi-localized by adiabatic selective refocusing (sLASER) and J-difference MEsher-GArwood-semi-LASER (MEGA-sLASER) for 2HG detection at 7T. We performed spectral editing at long TE using a TE-optimized sLASER sequence (110 ms) and J-difference spectroscopy using MEGA-sLASER (TE = 74ms) in phantoms with different 2HG concentrations to assess the sensitivity of 2HG detection. The robustness of the methods against B0 inhomogeneity was investigated. Moreover, the performance of these two techniques was evaluated in four patients with IDH1-mutated glioma. In contrary to MEGA-sLASER, sLASER was able to detect 2HG concentration as low as 0.5 mM. In case of a composite phantom containing 2HG with overlapping metabolites, MEGA-sLASER provided a clean 2HG signal with higher fitting reliability (lower %CRLB). The results demonstrate that sLASER is more robust against field inhomogeneities and experimental or motion-related artifacts which promotes to adopt sLASER in clinical implementations

Feasibility of P-31 spectroscopic imaging at 7 T in lung carcinoma patients

Currently, it is difficult to predict effective therapy response to molecular therapies for the treatment of lung cancer based solely on anatomical images. 31 P MR spectroscopic imaging could provide as a non-invasive method to monitor potential biomarkers for early therapy evaluation, a necessity to improve personalized care and reduce cost. However, surface coils limit the imaging volume in conventional 31 P MRSI. High-energetic adiabatic RF pulses are required to achieve flip angle homogeneity but lead to high SAR. Birdcage coils permit use of conventional amplitude modulated pulses, even over large FOV, potentially decreasing overall SAR massively. Here, we investigate the feasibility of 3D 31 P MRSI at 7 T in lung carcinoma patients using an integrated 31 P birdcage body coil in combination with either a dual-coil or a 16-channel receiver. Simulations showed a maximum decrease in SNR per unit of time of 8% for flip angle deviations in short TR low flip-angle excitation 3D CSI. The minimal SNR loss allowed for fast 3D CSI without time-consuming calibration steps (>10:00 min.). 31 P spectra from four lung carcinoma patients were acquired within 29:00 minutes and with high SNR using both receivers. The latter allowed discrimination of individual phosphodiesters, inorganic phosphate, phosphocreatine and ATP. The receiver array allowed for an increased FOV compared to the dual-coil receiver. 3D 31 P-CSI were acquired successfully in four lung carcinoma patients using the integrated 31 P body coil at ultra-high field. The increased spectral resolution at 7 T allowed differentiation of multiple 31 P metabolites related to phospholipid and energy metabolism. Simulations provide motivation to exclude 31 P B1 calibrations, potentially decreasing total scan duration. Employing large receiver arrays improves the field of view allowing for full organ coverage. 31 P MRSI is feasible in lung carcinoma patients and has potential as a non-invasive method for monitoring personalized therapy response in lung tumors

31P T2s of phosphomonoesters, phosphodiesters, and inorganic phosphate in the human brain at 7T

Purpose: To determine the phosphorus-31 T2s of phosphomonoesters, phosphodiesters, and inorganic phosphate in the healthy human brain at 7T. Methods: A 3D chemical shift imaging multi-echo sequence with composite block pulses for refocusing was used to measure one free induction decay (FID) and seven full echoes with an echo spacing of 45 ms on the brain of nine healthy volunteers (age range 22–45 years; average age 27 ± 8 years). Spectral fitting was used to determine the change in metabolic signal amplitude with echo time. Results: The average apparent T2s with their standard deviation were 202 ± 6 ms, 129 ± 6 ms, 86 ± 2 ms, 214 ± 10 ms, and 213 ± 11 ms for phosphoethanolamine, phosphocholine, inorganic phosphate, glycerophosphoethanolamine, and glycerophosphocholine, respectively. Conclusion: The determined apparent T2 for phosphoethanolamine, glycerophosphocholine, and glycerophosphoethanolamine is approximately 200 ms. The lower apparent T2 value for phosphocholine is attributed to the overlap of this resonance with the 3-phosphorous resonance of 2,3-diphosphoglycerate from blood, with an apparent shorter T2. Omitting the FID signal and the first echo of phosphocholine leads to a T2 of 182 ± 7 ms, whereas a biexponential analysis leads to 203 ± 4 ms. These values are more in line with phosphoethanolamine and the phosphodiesters. The short T2 of inorganic phosphate is subscribed to the fast reversible exchange with γ-adenosine triphosphate, which is mediated by glyceraldehyde-3-phosphate dehydrogenase and phosphoglycerate kinase within the glycolytic pathway. Magn Reson Med 80:29–35, 2018

Analysis of chemical exchange saturation transfer contributions from brain metabolites to the Z-spectra at various field strengths and pH

Chemical exchange saturation transfer (CEST) exploits the chemical exchange of labile protons of an endogenous or exogenous compound with water to image the former indirectly through the water signal. Z-spectra of the brain have traditionally been analyzed for two most common saturation phenomena: downfield amide proton transfer (APT) and upfield nuclear Overhauser enhancement (NOE). However, a great body of brain metabolites, many of interest in neurology and oncology, contributes to the downfield saturation in Z-spectra. The extraction of these “hidden” metabolites from Z-spectra requires careful design of CEST sequences and data processing models, which is only possible by first obtaining CEST signatures of the brain metabolites possessing labile protons. In this work, we measured exchange rates of all major-for-CEST brain metabolites in the physiological pH range at 37 °C. Analysis of their contributions to Z-spectra revealed that regardless of the main magnetic field strength and pH, five main contributors, i.e. myo-inositol, creatine, phosphocreatine, glutamate, and mobile (poly)peptides, account for ca. 90% of downfield CEST effect. The fundamental CEST parameters presented in this study can be exploited in the design of novel CEST sequences and Z-spectra processing models, which will enable simultaneous and quantitative CEST imaging of multiple metabolites: multicolor CEST

SNR optimized P-31 functional MRS to detect mitochondrial and extracellular pH change during visual stimulation

Summary: Energy metabolism of the human visual cortex was investigated by performing 31P functional MRS. Introduction: The human brain is known to be the main glucose demanding organ of the human body and neuronal activity can increase this energy demand. In this study we investigate whether alterations in pH during activation of the brain can be observed with MRS, focusing on the mitochondrial inorganic phosphate (Pi) pool as potential marker of energy demand. Methods: Six participants were scanned with 16 consecutive 31P-MRSI scans, which were divided in 4 blocks of 8:36 minutes of either rest or visual stimulation. Since the signals from the mitochondrial compartments of Pi are low, multiple approaches to achieve high SNR 31P measurements were combined. This included: a close fitting 31P RF coil, a 7 T-field strength, Ernst angle acquisitions and a stimulus with a large visual angle allowing large spectroscopy volumes containing activated tissue. Results: The targeted resonance downfield of the main Pi peak could be distinguished, indicating the high SNR of the 31P spectra. The peak downfield of the main Pi peak is believed to be connected to mitochondrial performance. In addition, a BOLD effect in the PCr signal was observed as a signal increase of 2–3% during visual stimulation as compared to rest. When averaging data over multiple volunteers, a small subtle shift of about 0.1 ppm of the downfield Pi peak towards the main Pi peak could be observed in the first 4 minutes of visual stimulation, but no longer in the 4 to 8 minute scan window. Indications of a subtle shift during visual stimulation were found, but this effect remains small and should be further validated. Conclusion: Overall, the downfield peak of Pi could be observed, revealing opportunities and considerations to measure specific acidity (pH) effects in the human visual cortex

2D AMESING multi-echo (31)P-MRSI of the liver at 7T allows transverse relaxation assessment and T2-weighted averaging for improved SNR

PURPOSE: Liver diseases are a major global health concern often requiring invasive assessment by needle biopsy. (31)P magnetic resonance spectroscopic imaging (MRSI) allows non-invasive probing of important liver metabolites. Recently, the adiabatic multi-echo spectroscopic imaging sequence with spherical k-space sampling (AMESING) was introduced at 7T, enabling acquisition of T2 information. T2-weighed averaging of the multiple echoes improves signal-to-noise ratio (SNR). The purpose of our study was to implement AMESING MRSI of the liver at 3T and 7T, derive localized T2 information and compare T2-weighted average spectra in terms of SNR. METHODS: Ten male volunteers underwent 2D AMESING MRSI at 3T and 7T after a minimum four-hour fast. SNR was calculated for PC, PE, Pi, GPE, GPC and α-ATP using maximum peak amplitudes and the SD of the noise. Metabolite peak ratios were calculated after fitting in jMRUI. SNR values and peak ratios were compared with the Wilcoxon signed-rank test. RESULTS: For the first time liver metabolites' T2 values at 7T were measured: PE (55.6±3.5 ms), PC (51.2±2.3 ms), Pi (46.4±1.1 ms), GPE (44.0±0.8 ms), GPC (50.4±0.8 ms) and α-ATP (18.2±0.4 ms). SNR gain using T2-weighted averaging at 7T resulted in a 1.2× SNR gain. In conjunction with higher field strength and improved coil set-up T2-weighted averaging at 7T allowed a total 3.2× SNR gain compared to 3T FID-only. CONCLUSION: AMESING 2D MRSI of the liver at 7T provides T2 values that allow T2-weighted averaging of data from multiple echoes resulting in improved SNR