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.
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.
This study aimed to demonstrate the feasibility of 31P MRSI with full liver coverage to assess 31P metabolite levels and chemotherapy‐induced changes in liver metastases of gastro‐esophageal cancer at 7 T, using a 31P whole‐body transmit coil and 31P body receive array. Before chemotherapy, PME was higher in metastases compared with healthy liver. After 2 weeks of chemotherapy, PME remained elevated or increased further, resulting in increased PME/PDE ratios, in correspondence with clinical assessment of progressive disease after 2 months of chemotherapy.
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.
Tumor progression organoids (TPOs) representing the genetic alterations in colorectal cancer were analyzed by two methods: extraction NMR and high‐resolution magic angle spinning (HR MAS) MRS. Correlation analysis and principal component analysis from MR spectra show that the two methods can be useful in the metabolic profiling of organoids. NMR analysis of the TPOs indicates that metabolic changes occur at an early stage during tumor progression.
Purpose
Metabolic MRI is a noninvasive technique that can give new insights into understanding cancer metabolism and finding biomarkers to evaluate or monitor treatment plans. Using this technique, a ...previous study has shown an increase in pH during neoadjuvant chemotherapy (NAC) treatment, while recent observation in a different study showed a reduced amide proton transfer (APT) signal during NAC treatment (negative relation). These findings are counterintuitive, given the known intrinsic positive relation of APT signal to pH.
Methods
In this study we combined APT MRI and 31P‐MRSI measurements to unravel the relation between the APT signal and pH in breast cancer. Twenty‐two breast cancer patients were scanned with a 7 T MRI before and after the first cycle of NAC treatment. pH was determined by the chemical shift of inorganic phosphate (Pi).
Results
While APT signals have a positive relation to pH and amide content, we observed a direct negative linear correlation between APT signals and pH in breast tumors in vivo.
Conclusions
As differentiation of cancer stages was confirmed by observation of a linear correlation between cell proliferation marker PE/Pi (phosphoethanolamine over inorganic phosphate) and pH in the tumor, our data demonstrates that the concentration of mobile proteins likely supersedes the contribution of the exchange rate to the APT signal.
31P‐MRS and CEST‐MRI were acquired in 22 breast cancer patients with a 7 T MRI. While APT signals have a positive relation to pH and amide content, we observed a direct negative linear correlation between APT signals and pH in breast tumors in vivo. Our data demonstrates that the concentration of mobile proteins likely supersedes the contribution of the exchange rate to the APT signal.
The purpose of this work was to investigate whether noninvasive early detection (after the first cycle) of response to neoadjuvant chemotherapy (NAC) in breast cancer patients was possible. 31P‐MRSI ...at 7 T was used to determine different phosphor metabolites ratios and correlate this to pathological response.
31P‐MRSI was performed in 12 breast cancer patients treated with NAC. 31P spectra were fitted and aligned to the frequency of phosphoethanolamine (PE). Metabolic signal ratios for phosphomonoesters/phosphodiesters (PME/PDE), phosphocholine/glycerophosphatidylcholine (PC/GPtC), phosphoethanolamine/glycerophosphoethanolamine (PE/GPE) and phosphomonoesters/in‐organic phosphate (PME/Pi) were determined from spectral fitting of the individual spectra and the summed spectra before and after the first cycle of NAC. Metabolic ratios were subsequently related to pathological response. Additionally, the correlation between the measured metabolic ratios and Ki‐67 levels was determined using linear regression.
Four patients had a pathological complete response after treatment, five patients a partial pathological response, and three patients did not respond to NAC. In the summed spectrum after the first cycle of NAC, PME/Pi and PME/PDE decreased by 18 and 13%, respectively. A subtle difference among the different response groups was observed in PME/PDE, where the nonresponders showed an increase and the partial and complete responders a decrease (P = 0.32). No significant changes in metabolic ratios were found. However, a significant association between PE/Pi and the Ki‐67 index was found (P = 0.03).
We demonstrated that it is possible to detect subtle changes in 31P metabolites with a 7 T MR system after the first cycle of NAC treatment in breast cancer patients. Nonresponders showed different changes in metabolic ratios compared with partial and complete responders, in particular for PME/PDE; however, more patients need to be included to investigate its clinical value.
We demonstrated that changes in 31P metabolites can be detected by 7 T MRI after the first cycle of neoadjuvant chemotherapy in breast cancer patients. Already, after the first cycle, patient groups with different pathological responses can potentially be distinguished based on the different metabolic ratios, of which phosphomonoesters/phosphodiesters is most likely to discriminate nonresponders from the partial and complete responders.
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.
31P MRS can be used in liver disease diagnosis and treatment monitoring. However, 31P MRS has a low intrinsic sensitivity and commonly used 31P surface coils do not provide full liver coverage. We demonstrated that a 31P whole‐body transmit coil in combination with a 16‐channel 31P receive array improves field‐of‐view coverage, allowing full liver 31P MRSI acquisitions. We showed good repeatability for most quantified 31P metabolite levels, and significant differences for PME and PDE between the left and right lobe.
In vivo water‐ and fat‐suppressed 1H magnetic resonance spectroscopy (MRS) and 31P magnetic resonance adiabatic multi‐echo spectroscopic imaging were performed at 7 T in duplicate in healthy ...fibroglandular breast tissue of a group of eight volunteers. The transverse relaxation times of 31P metabolites were determined, and the reproducibility of 1H and 31P MRS was investigated. The transverse relaxation times for phosphoethanolamine (PE) and phosphocholine (PC) were fitted bi‐exponentially, with an added short T2 component of 20 ms for adenosine monophosphate, resulting in values of 199 ± 8 and 239 ± 14 ms, respectively. The transverse relaxation time for glycerophosphocholine (GPC) was also fitted bi‐exponentially, with an added short T2 component of 20 ms for glycerophosphatidylethanolamine, which resonates at a similar frequency, resulting in a value of 177 ± 6 ms. Transverse relaxation times for inorganic phosphate, γ‐ATP and glycerophosphatidylcholine mobile phospholipid were fitted mono‐exponentially, resulting in values of 180 ± 4, 19 ± 3 and 20 ± 4 ms, respectively. Coefficients of variation for the duplicate determinations of 1H total choline (tChol) and the 31P metabolites were calculated for the group of volunteers. The reproducibility of inorganic phosphate, the sum of phosphomonoesters and the sum of phosphodiesters with 31P MRS imaging was superior to the reproducibility of 1H MRS for tChol. 1H and 31P data were combined to calculate estimates of the absolute concentrations of PC, GPC and PE in healthy fibroglandular tissue, resulting in upper limits of 0.1, 0.1 and 0.2 mmol/kg of tissue, respectively.
Proton (1H) and phosphorus (31P) spectroscopy of the human breast were performed in a group of eight healthy volunteers at 7 T, in duplicate, and the results were combined to calculate upper limit concentrations of phosphomonoesters and phosphodiesters. In addition, transverse relaxation times for 31P metabolites were determined, together with coefficients of variation for the measured metabolite signal intensities.
Phosphorus MRS offers a non‐invasive tool for monitoring cell energy and phospholipid metabolism and can be of additional value in diagnosing cancer and monitoring cancer therapy. In this study, we ...determined the transverse relaxation times of a number of phosphorous metabolites in a group of breast cancer patients by adiabatic multi‐echo spectroscopic imaging at 7 T. The transverse relaxation times of phosphoethanolamine, phosphocholine, inorganic phosphate (Pi), glycerophosphocholine and glycerophosphatidylcholine were 184 ± 8 ms, 203 ± 17 ms, 87 ± 8 ms, 240 ± 56 ms and 20 ± 10 ms, respectively. The transverse relaxation time of Pi in breast cancer tissue was less than half that of healthy fibroglandular tissue. This effect is most likely caused by an up‐regulation of glycolysis in breast cancer tissue that leads to interaction of Pi with the GAPDH enzyme, which forms part of the reversible pathway of exchange of Pi with gamma‐adenosine tri‐phosphate, thus shortening its apparent transverse relaxation time. As healthy breast tissue shows very little glycolytic activity, the apparent T2 shortening of Pi due to malignant transformation could possibly be used as a biomarker for cancer.
Transverse relaxation times of phosphorous metabolites were determined in breast cancer tissue at 7 T. The apparent T2 of Pi was less than half that of healthy fibroglandular tissue. This effect is most likely caused by an up‐regulation of glycolysis in breast cancer tissue that leads to increased interaction of Pi with the GADPH enzyme, thus shortening its apparent T2. As healthy breast tissue shows very little glycolytic activity, the observed effect may serve as a biomarker for cancer.
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
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