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Background: Non‐invasive evaluation of phosphomonoesters (PMEs) and phosphodiesters (PDEs) by 31‐phosphorus MR spectroscopy (31P MRS) may have potential for early therapy (non‐)response assessment in cancer. However, 31P MRS has not yet been applied to investigate the human pancreas in vivo. Purpose: To assess the technical feasibility and repeatability of 31P MR spectroscopic imaging (MRSI) of the pancreas, compare 31P metabolite levels between pancreas and liver, and determine the feasibility of 31P MRSI in pancreatic cancer. Study Type: Prospective cohort study. Population: 10 healthy subjects (age 34 ± 12 years, four females) and one patient (73‐year‐old female) with pancreatic ductal adenocarcinoma. Field Strength/Sequence: 7‐T, 31P FID‐MRSI, 1H gradient‐echo MRI. Assessment: 31P FID‐MRSI of the abdomen (including the pancreas and liver) was performed with a nominal voxel size of 20 mm (isotropic). For repeatability measurements, healthy subjects were scanned twice on the same day. The patient was only scanned once. Test–retest 31P MRSI data of pancreas and liver voxels (segmented on 1H MRI) of healthy subjects were quantified by fitting in the time domain and signal amplitudes were normalized to γ‐adenosine triphosphate. In addition, the PME/PDE ratio was calculated. Metabolite levels were averaged over all voxels within the pancreas, right liver lobe and left liver lobe, respectively. Statistical Tests: Repeatability of test–retest data from healthy pancreas was assessed by paired t‐tests, Bland–Altman analyses, and calculation of the intrasubject coefficients of variation (CoVs). Significant differences between healthy pancreas and right and left liver lobes were assessed with a two‐way analysis of variance (ANOVA) for repeated measures. A P‐value <0.05 was considered statistically significant. Results: The intrasubject CoVs for PME, PDE, and PME/PDE in healthy pancreas were below 20%. Furthermore, PME and PME/PDE were significantly higher in pancreas compared to liver. In the patient with pancreatic cancer, qualitatively, elevated relative PME signals were observed in comparison with healthy pancreas. Data Conclusion: In vivo31P MRSI of the human healthy pancreas and in pancreatic cancer may be feasible at 7 T. Evidence Level: 3 Technical Efficacy: Stage 2 [ABSTRACT FROM AUTHOR]

The neuronal tricarboxylic acid and glutamate/glutamine (Glu/Gln) cycles play important roles in brain function. These processes can be measured in vivo using dynamic 1H–[13C] MRS during administration of 13C‐labeled glucose. Proton‐observed carbon‐edited (POCE) MRS enhances the signal‐to‐noise ratio (SNR) compared with direct 13C‐MRS. Ultra‐high field further boosts the SNR and increases spectral dispersion; however, even at 7 T, Glu and Gln 1H‐resonances may overlap. Further gain can be obtained with selective POCE (selPOCE). Our aim was to create a setup for indirect dynamic 1H–[13C] MRS in the human brain at 7 T. A home‐built non‐shielded transmit–receive 13C‐birdcage head coil with eight transmit–receive 1H‐dipole antennas was used together with a 32‐channel 1H‐receive array. Electromagnetic simulations were carried out to ensure that acquisitions remained within local and global head SAR limits. POCE‐MRS was performed using slice‐selective excitation with semi‐localization by adiabatic selective refocusing (sLASER) and stimulated echo acquisition mode (STEAM) localization, and selPOCE‐MRS using STEAM. Sequences were tested in a phantom containing non‐enriched Glu and Gln, and in three healthy volunteers during uniformly labeled 13C‐glucose infusions. In one subject the voxel position was alternated between bi‐frontal and bi‐occipital placement within one session. [4‐13C]Glu‐H4 and [4‐13C]Gln‐H4 signals could be separately detected using both STEAM‐POCE and STEAM‐selPOCE in the phantom. In vivo, [4,5‐13C]Glx could be detected using both sLASER‐POCE and STEAM‐POCE, with similar sensitivities, but [4,5‐13C]Glu and [4,5‐13C]Gln signals could not be completely resolved. STEAM‐POCE was alternately performed bi‐frontal and bi‐occipital within a single session without repositioning of the subject, yielding similar results. With STEAM‐selPOCE, [4,5‐13C]Glu and [4,5‐13C]Gln could be clearly separated. We have shown that with our setup indirect dynamic 1H–[13C] MRS at 7 T is feasible in different locations in the brain within one session, and by using STEAM‐selPOCE it is possible to separate Glu from Gln in vivo while obtaining high quality spectra. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Quantitative three‐dimensional (3D) imaging of phosphorus (31P) metabolites is potentially a promising technique with which to assess the progression of liver disease and monitor therapy response. However, 31P magnetic resonance spectroscopy has a low sensitivity and commonly used 31P surface coils do not provide full coverage of the liver. This study aimed to overcome these limitations by using a 31P whole‐body transmit coil in combination with a 16‐channel 31P receive array at 7 T. Using this setup, we determined the repeatability of whole‐liver 31P magnetic resonance spectroscopic imaging (31P MRSI) in healthy subjects and assessed the effects of principal component analysis (PCA)‐based denoising on the repeatability parameters. In addition, spatial variations of 31P metabolites within the liver were analyzed. 3D 31P MRSI data of the liver were acquired with a nominal voxel size of 20 mm isotropic in 10 healthy volunteers twice on the same day. Data were reconstructed without denoising, and with PCA‐based denoising before or after channel combination. From the test–retest data, repeatability parameters for metabolite level quantification were determined for 12 31P metabolite signals. On average, 31P MR spectra from 100 ± 25 voxels in the liver were analyzed. Only voxels with contamination from skeletal muscle or the gall bladder were excluded and no voxels were discarded based on (low) signal‐to‐noise ratio (SNR). Repeatability for most quantified 31P metabolite levels in the liver was good to excellent, with an intrasubject variability below 10%. PCA‐based denoising increased the SNR ~ 3‐fold, but did not improve the repeatability for mean liver 31P metabolite quantification with the fitting constraints used. Significant spatial heterogeneity of various 31P metabolite levels within the liver was observed, with marked differences for the phosphomonoester and phosphodiester metabolites between the left and right lobe. In conclusion, using a 31P whole‐body transmit coil in combination with a 16‐channel 31P receive array at 7 T allowed 31P MRSI acquisitions with full liver coverage and good to excellent repeatability. [ABSTRACT FROM AUTHOR]

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 (31P) magnetic resonance spectroscopy (MRS). Purpose: To conduct a quantitative analysis of the available literature on 31P 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: 31P MRS. Assessment: The PubMed, EMBASE, and Cochrane library databases were systematically searched for studies published to 17 March 17, 2022. All 31P MRS studies in hepatopancreatobiliary cancer reporting 31P metabolite levels were included. Statistical Tests: Relative differences in 31P metabolite levels/ratios between patients before therapy and healthy controls, and the relative changes in 31P 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, 31P MRS has not been applied in pancreatic cancer. In liver cancer, alterations in levels of 31P 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: 31P MRS has great potential for treatment monitoring in oncology. Future studies are needed to correlate the changes in 31P metabolite levels in hepatopancreatobiliary tumors with treatment response. Evidence Level: 3 Technical Efficacy: Stage 2 [ABSTRACT FROM AUTHOR]

Patient‐derived cancer cells cultured in vitro are a cornerstone of cancer metabolism research. More recently, the introduction of organoids has provided the research community with a more versatile model system. Physiological structure and organization of the cell source tissue are maintained in organoids, representing a closer link to in vivo tumor models. High‐resolution magic angle spinning magnetic resonance spectroscopy (HR MAS MRS) is a commonly applied analytical approach for metabolic profiling of intact tissue, but its use has not been reported for organoids. The aim of the current work was to compare the performance of HR MAS MRS and extraction‐based nuclear magnetic resonance (NMR) in metabolic profiling of wild‐type and tumor progression organoids (TPOs) from human colon cancer, and further to investigate how the sequentially increased genetic alterations of the TPOs affect the metabolic profile. Sixteen metabolites were reliably identified and quantified both in spectra based on NMR of extracts and HR MAS MRS of intact organoids. The metabolite concentrations from the two approaches were highly correlated (r = 0.94), and both approaches were able to capture the systematic changes in metabolic features introduced by the genetic alterations characteristic of colorectal cancer progression (e.g., increased levels of lactate and decreased levels of myo‐inositol and phosphocholine with an increasing number of mutations). The current work highlights that HR MAS MRS is a well‐suited method for metabolic profiling of intact organoids, with the additional benefit that the nondestructive nature of HR MAS enables subsequent recovery of the organoids for further analyses based on nucleic acids or proteins. [ABSTRACT FROM AUTHOR]

The transduction function for ADP stimulation of mltochondrial ATP synthesis in skeletal muscle was reconstructed in vivo and in silico to investigate the magnitude and origin of mitochondrial sensitivity to cytoplasmic ADP concentration changes. Dynamic in vivo measurements of human leg muscle phosphocreatine (PCr) content during metabolic recovery from contractions were performed by [sup.31]P-NMR spectroscopy. The cytoplasmic ADP concentration ([ADP]) and rate of oxidative ATP synthesis (Jp) at each time point were calculated from creatine kinase equilibrium and the derivative of a monoexponential fit to the PCr recovery data, respectively. Reconstructed [ADP]-Jp relations for individual muscles containing more than 100 data points were kinetically characterized by nonlinear curve fitting yielding an apparent kinetic order and ADP affinity of 1.9 [+ or -] 0.2 and 0.022 [+ or -] 0.003 mM, respectively (means [+ or -] SD; n = 6). Next, in silico [ADP]-Jp relations for skeletal muscle were generated using a computational model of muscle oxidative ATP metabolism whereby model parameters corresponding to mitochondrial enzymes were randomly changed by 50-150% to determine control of mitochondrial ADP sensitivity. The multiparametric sensitivity analysis showed that mitochondrial ADP ultrasensitivity is an emergent property of the integrated mitochondrial enzyme network controlled primarily by kinetic properties of the adenine nucleotide translocator. mitochondria; nuclear magnetic resonance; mathematical modeling; regulation; adenosine 5'-diphosphate

[sup.31]P magnetic resonance spectroscopy provides the possibility of obtaining bioenergetic data during skeletal muscle exercise and recovery. The time constant of phosphocreatine (PCr) recovery ([[tau].sub.PCr]) has been used as a measure of mitochondrial function. However, cytosolic pH has a strong influence on the kinetics of PCr recovery, and it has been suggested that [[tau].sub.PCr] should be normalized for end-exercise pH. A general correction can only be applied if there are no intersubject differences in the pH dependence of [[tau].sub.PCr]. We investigated the pH dependence of [[tau].sub.PCr] on a subject-by-subject basis. Furthermore, we determined the kinetics of proton efflux at the start of recovery. Intracellular acidosis slowed PCr recovery, and the pH dependence of [[tau].sub.PCr] differed among subjects, ranging from -33.0 to -75.3 s/pH unit. The slope of the relation between [[tau].sub.PCr] and end-exercise pH was positively correlated with both the proton efflux rate and the apparent proton efflux rate constant, indicating that subjects with a smaller pH dependence of [[tau].sub.PCr] have a higher proton efflux rate. Our study implies that simply correcting [[tau].sub.PCr] for end-exercise pH is not adequate, in particular when comparing patients and control subjects, because certain disorders are characterized by altered proton efflux from muscle fibers. [sup.31]P magnetic resonance spectroscopy; skeletal muscle; oxidative capacity; mitochondrial function; intracellular pH doi:10.1152/ajpcell.00023.2006