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1H MRS measurements of lactate are often confounded by overlapping lipid signals. Double-quantum (DQ) filtering eliminates lipid signals and permits single-shot measurements, which avoid subtraction artefacts in moving tissues. This study evaluated a single-voxel-localized DQ filtering method qualitatively and quantitatively for measuring lactate concentrations in the presence of lipid, using high-grade brain tumours in which the results could be compared with standard acquisition as a reference. Paired standard acquisition and DQ-filtered 1H MR spectra were acquired at 3T from patients receiving treatment for glioblastoma, using fLASER (localization by adiabatic selective refocusing using frequency offset corrected inversion pulses) single-voxel localization. Data were acquired from 2 × 2 × 2 cm3 voxels, with a repetition time of 1 s and 128 averages (standard acquisition) or 256 averages (DQ-filtered acquisition), requiring 2.15 and 4.3 min respectively. Of 37 evaluated data pairs, 20 cases (54%) had measureable lactate (fitted Cramer–Rao lower bounds ≤ 20%) in either the DQ-filtered or the standard acquisition spectra. The measured DQ-filtered lactate signal was consistently downfield of lipid (1.33 ± 0.03 ppm vs 1.22 ± 0.08 ppm; p = 0.002), showing that it was not caused by lipid breakthrough, and that it matched the lactate signal seen in standard measurements (1.36 ± 0.02 ppm). In the absence of lipid, similar lactate concentrations were measured by the two methods (mean ratio DQ filtered/standard acquisition = 1.10 ± 0.21). In 7/20 cases with measurable lactate, signal was not measureable in the standard acquisition owing to lipid overlap but was quantified in the DQ-filtered acquisition. Conversely, lactate was undetected in seven DQ-filtered acquisitions but visible using the standard acquisition. In conclusion, the DQ filtering method has proven robust in eliminating lipid and permits uncontaminated measurement of lactate. This is important validation prior to use in tissues outside the brain, which contain large amounts of lipid and which are often susceptible to motion.

Measurement of tissue lactate using 1H MRS is often confounded by overlap with intense lipid signals at 1.3 ppm. Single‐voxel localization using PRESS is also compromised by the large chemical shift displacement between voxels for the 4.1 ppm (–CH) resonance and the 1.3 ppm –CH3 resonance, leading to subvoxels with signals of opposite phase and hence partial signal cancellation. To reduce the chemical shift displacement to negligible proportions, a modified semi‐LASER sequence was written (“FOCI‐LASER”, abbreviated as fLASER) using FOCI pulses to permit high RF bandwidth even with the limited RF amplitude characteristic of clinical MRI scanners. A further modification, MQF‐fLASER, includes a selective multiple‐quantum filter to detect lactate and reject lipid signals. The sequences were implemented on a Philips 3 T Achieva TX system. In a solution of brain metabolites fLASER lactate signals were 2.7 times those of PRESS. MQF‐fLASER lactate was 47% of fLASER (the theoretical maximum is 50%) but still larger than PRESS lactate. In oil, the main 1.3 ppm lipid peak was suppressed to less than 1%. Enhanced suppression was possible using increased gradient durations. The minimum detectable lactate concentration was approximately 0.5 mM. Coherence selection gradients needed to be at the magic angle to avoid large water signals derived from intermolecular multiple‐quantum coherences. In pilot patient measurements, lactate peaks were often observed in brain tumours, but not in cervix tumours; lipids were effectively suppressed. In summary, compared with PRESS, the fLASER sequence yields greatly superior sensitivity for direct detection of lactate (and equivalent sensitivity for other metabolites), while the single‐voxel single‐shot MQF‐fLASER sequence surpasses PRESS for lactate detection while eliminating substantial signals from lipids. This sequence will increase the potential for in vivo lactate measurement as a biomarker in targeted anti‐cancer treatments as well as in measurements of tissue hypoxia. Copyright © 2015 John Wiley & Sons, Ltd.

31P magnetic resonance spectroscopy (31P MRS) can measure intracellular pH (pHi) using the chemical shift difference between pH‐dependent inorganic phosphate (Pi) and a pH‐independent reference peak. This study compared three different frequency reference peaks [phosphocreatine (PCr), α resonance of adenosine triphosphate (αATP) and water (using 1H MRS)] in a cohort of 10 volunteers and eight patients with non‐Hodgkin's lymphoma (NHL). Well‐resolved chemical shift imaging (CSI) spectra were acquired on a 1.5T scanner for muscle, liver and tumour. The pH was calculated for all volunteers and patients using the available methods. The consistency of the resulting pH was evaluated. The direct Pi–PCr method was best for those spectra with a very well‐defined PCr, such as muscle (pH=7.05 ± 0.02). In liver, the Pi–αATP method gave more consistent results (pH=7.30 ± 0.06) than the calibrated water‐based method (pH=7.27 ± 0.11). In NHL nodes, the measured pH using the Pi–αATP method was 7.25 ± 0.12. Given that the measured range includes some biological variation in individual patients, treatment‐related changes of the order of 0.1 pH units should be detectable. © 2013 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.

Pyruvate–lactate exchange is mediated by the enzyme lactate dehydrogenase (LDH) and is central to the altered energy metabolism in cancer cells. The measurement of exchange kinetics using hyperpolarized 13C NMR has provided a biomarker of response to novel therapeutics. However, the observable signal is restricted to the exchanging hyperpolarized 13C pools and the endogenous pools of 12C-labelled metabolites are invisible in these measurements. In this study, we investigated an alternative in vitro 1H NMR assay, using [3-13C]pyruvate, and compared the measured kinetics with a hyperpolarized 13C NMR assay, using [1-13C]pyruvate, under the same conditions in human colorectal carcinoma SW1222 cells. The apparent forward reaction rate constants (kPL) derived from the two assays showed no significant difference, and both assays had similar reproducibility (kPL = 0.506 ± 0.054 and kPL = 0.441 ± 0.090 nmol/s/106 cells; mean ± standard deviation; n = 3); 1H, 13C assays, respectively). The apparent backward reaction rate constant (kLP) could only be measured with good reproducibility using the 1H NMR assay (kLP = 0.376 ± 0.091 nmol/s/106 cells; mean ± standard deviation; n = 3). The 1H NMR assay has adequate sensitivity to measure real-time pyruvate–lactate exchange kinetics in vitro, offering a complementary and accessible assay of apparent LDH activity. Copyright © 2013 John Wiley & Sons, Ltd.

Increased expression of choline kinase has frequently been shown in tumours and is thought to be associated with disease progression. Studies using magnetic resonance spectroscopy have shown an increase in total choline-containing metabolites (tCho) in tumour compared with healthy tissue. Subsequent reductions in tCho following successful treatment support the use of tCho as a biomarker of disease and response. However, accurate measurement of tCho using MRS in abdominal tumours is complicated by respiratory motion, blurring the acquisition volume and degrading the lineshape and signal-to-noise ratio (SNR) of metabolites. Motion compensation using prospectively gated acquisitions or offline correction of phase and frequency distortions can help restore the SNR and linewidth of metabolites. Prospectively gated acquisitions have the advantage of confining the volume of acquisition to the prescribed volume but are constrained by the repetition time (TR) of the respiratory motion. In contrast, data acquired for offline correction may use a shorter repetition time and therefore yield an increased SNR per unit time. In this study abdominal spectra acquired from single-voxel ‘free-breathing’ measurements in liver of healthy volunteers and in abdominal tumours of cancer patients were compared with those of prospective gating and with an implementation of offline correction. The two motion compensation methodologies were assessed in terms of SNR, linewidth and repeatability. Our experiments show that prospective gating and offline correction result in a 12–22% reduction in median tCho linewidth, while offline correction also provides a significant increase in SNR. The repeatability coefficient (the expected interval for 95% of repeat measurements) for tCho/water ratio was reduced by 37% (prospective gating) and 41% (offline correction). Both methods of motion compensation substantially improved the reproducibility of the tCho/water measurement and the tCho linewidth. While offline correction also leads to a significant improvement in SNR, it may suffer more from out-of-voxel contamination.

The detection and prognosis of prostate cancer in its early stages are critically important. It is therefore essential to improve the existing dynamic contrast-enhanced MRI (DCE MRI) techniques commonly used for the assessment of the tumour vascular environment. The goal of this study was to describe a method for the estimation of the arterial input function (AIF) in DCE MRI by measuring R-2* values in the femoral artery of patients with early-stage prostate cancer. The calculation of contrast agent concentrations was based on calibration curves determined in whole blood samples for a range of normal haematocrit (HCT) values (HCT 0.35-0.525). Individual AIFs corrected for HCT were compared with individual AIFs calibrated with a mean whole blood [R-2*-Gd-DTPA-BMA] [Gd-DTPA-BMA, gadolinium diethylenetriaminepentaacetate-bis(methylamide) (gadodiamide)] curve at an assumed HCT = 0.44, as well as a population AIF at an assumed HCT = 0.45. The area under the curve of the first-pass bolus ranged between 0.6 min mM at HCT = 0.53 and 1.3 min mM at HCT = 0.39. Significant differences in magnitude at peak contrast agent concentrations (HCT = 0.36, [Gd-DTPA-BMA](max) = 9 +/- 0.4 mM; HCT = 0.46, [Gd-DTPA-BMA](max) = 4.0 +/- 0.2 mM) were found. Using model-based simulations, the accuracy of the kinetic parameters estimated using individual AIFs corrected for HCT demonstrated that, for the use of individual calibration curves with HCT values differing by more than 10%, K-trans and k(ep) values were largely underestimated (up to 60% difference for K-trans). Moreover, blood volume estimates were severely underestimated. Estimates of kinetic parameters in early-stage prostate cancer patients demonstrated that the efflux rate constant (k(ep)) was influenced significantly by the definition of AIF. Regardless of whether an individually calibrated AIF or a population AIF (average of all individually calibrated AIFs) was used, pixel-by-pixel mapping of k(ep) and v(b) in the prostate gland appeared to be more sensitive than with the usual biexponential approach. Copyright (C) 2011 John Wiley & Sons, Ltd.

The pseudomonad protein, carboxypeptidase G2 (CPG2), is a prodrug-activating enzyme utilized in the targeted chemotherapy strategies of antibody- and gene-directed enzyme prodrug therapy (ADEPT and GDEPT). We have developed a noninvasive imaging approach to monitor CPG2 activity in vivo that will facilitate the preclinical and clinical development of CPG2-based ADEPT and GDEPT strategies. Cleavage of the novel reporter probe, 3,5-difluorobenzoyl-L-glutamic acid (3,5-DFBGlu), by CPG2, in human colon adenocarcinoma WiDr xenografts engineered to stably express CPG2, was monitored using (19)F MRSI. The high signal-to-noise ratio afforded by the two MR-equivalent (19)F nuclei of 3,5-DFBGlu, and the 1.4 ppm (19)F chemical shift difference on CPG2-mediated cleavage, enabled the dynamics and quantification of the apparent pharmacokinetics of 3,5-DFBGlu and its CPG2-mediated cleavage in the tumor to be evaluated. In addition, the apparent rate of increase of 3,5-difluorobenzoic acid concentration could also provide a biomarker of CPG2 activity levels in tumors of patients undergoing CPG2-based therapies, as well as a biomarker of treatment response. The addition of in vivo reporter probes, such as 3,5-DFBGlu, to the armamentarium of prodrugs cleaved by CPG2 affords new applications for CPG2 as a gene reporter of transgene expression.

Development and evaluation of new anticancer drugs are expedited when minimally invasive biomarkers of pharmacokinetic and pharmacodynamic behaviour are available. Gene-directed enzyme prodrug therapy (GDEPT) is a suicide gene therapy in which the anticancer drug is activated in the tumor by an exogenous enzyme previously targeted by a vector carrying the gene. GDEPT has been evaluated in various clinical trials using several enzyme/prodrug combinations. The key processes to be monitored in GDEPT are gene delivery and expression, as well as prodrug delivery and activation. {4-[bis(2-chloroethyl)amino]-3,5-difluorobenzoyl}-L-glutamic acid, a prodrug for the GDEPT enzyme carboxypeptidase-G2 (CPG2; K(m) = 1.71 microM; k(cat) = 732 s(-1)), was measured with (19)F magnetic resonance spectroscopy (MRS). The 1 ppm chemical shift separation found between the signals of prodrug and activated drug (4-[bis(2-chloroethyl)amino]-3,5-difluorobenzoic acid) is sufficient for the detection of prodrug activation in vivo. However, these compounds hydrolyze rapidly, and protein binding broadens the MR signals. A new CPG2 substrate was designed with hydroxyethyl instead of chloroethyl groups (K(m) = 3.5 microM, k(cat) = 747 s(-1)). This substrate is nontoxic and stable in solution, has a narrow MRS resonance in the presence of bovine and foetal bovine albumin, and exhibits a 1.1 ppm change in chemical shift upon cleavage by CPG2. In cells transfected to express CPG2 in the cytoplasm (MDA MB 361 breast carcinoma cells and WiDr colon cancer cells), well-resolved (19)F MRS signals were observed from clinically relevant concentrations of the new substrate and its nontoxic product. The MRS conversion half-life (470 min) agreed with that measured by HPLC (500 min). This substrate is, therefore, suitable for evaluating gene delivery and expression prior to administration of the therapeutic agent.

Choline metabolites are widely studied in cancer research as biomarkers of malignancy and as indicators of therapeutic response. However, endogenous phosphocholine levels are determined by a number of processes that confound the interpretation of these measurements, including membrane transport rates and a series of enzyme catalysed reactions in the Kennedy pathway. Employing a dynamic P-31 NMR assay that is specific to choline kinase (ChoK) we have measured the rates of this enzyme reaction in cell lysates of MDA-MB-231 breast, PC-3 prostate and HeLa cervical cancer cells and in solutions of purified human ChoK. The rates are sensitive to inhibition by hemicholinium-3 (HC-3), a competitive ChoK inhibitor, and to N-[2-bromocinnamyl(amino)ethyl]-5-isoquinoline-sulphonamide (H-89), an agent commercialized as a specific cyclic-AMP-dependent protein kinase A (PKA) inhibitor. Copyright (C) 2009 John Wiley & Sons, Ltd.

A series of prospective comparative studies have demonstrated that MRI has approximately twice the sensitivity of X-ray mammography for screening women at high familial risk of breast cancer. In these studies, lesions have often been detected at an early stage, with disease being small and predominantly node negative. The diagnostic features in relation to risk and the biological behaviour of disease with risk category and age are being evaluated. The results of these studies have resulted in revised recommendations for screening for women at high risk of breast cancer. In this article, the results of the UK Magnetic Resonance Imaging in Breast Cancer Screening (MARIBS) study of MRI screening are described, and compared with results from other studies. Risk factors identifying women who would benefit from MRI screening are discussed, MRI measurement methods are described, and the results of studies evaluating MRI and mammographic lesions in different risk groups are reviewed. Recommendations for screening women at high risk of breast cancer published by the American Cancer Society and from the National Institute for Health and Clinical Excellence (NICE) in the UK are summarised.

Evaluation of P-31 high-resolution magic angle spinning of intact tissue samples The first detailed evaluation is presented of high-resolution P-31 MRS using magic angle spinning (MAS) of intact tissue samples and comparison with the conventional method of studying tissue extracts. The main motivation is that MAS leaves the sample intact at the end of the study for histopathological evaluation. While MAS of tissue samples has previously been demonstrated for H-1 MRS P-31 MRS is better suited to study of the phospholipid metabolites of importance in cancer. Samples of rhabdomyosarcoma and RIF-1 experimental tumours were maintained at 4 degrees C, spun at 3 kHz and measured in 28-min acquisitions at 11.7 and 14T. Metabolite stability was evaluated using four sequential 28-min acquisitions. High-resolution MRS was performed on extracts of the same tissue samples. P-31 HR-MAS yielded well-resolved high-resolution spectra, showing peaks from phosphoethanolamine (PE), phosphocholine (PC), inorganic phosphate, glycerophosphoethanolamine and glycerophosphocholine, with linewidths in the range 3-20 Hz. In tumour samples there was no significant change in peak areas over a 2-h period, while peaks sensitive to pH (inorganic phosphate, PE and PC) showed a small change in chemical shift, corresponding to a change of 0.13 +/- 0.06 pH units. Tissue metabolite concentrations showed good agreement with concentrations measured from extracts of the same pieces of tissue. For calculation of metabolite concentrations, the measurement of a reference compound in a separate measurement is more robust than using the signal from a reference compound in the rotor with the sample. Compared with performing tissue extracts, use of MAS of intact tissue samples requires less preparation, is quicker and permits the same sample to be used for subsequent histopathology. The methodology has particular application in studying phospholipid metabolism in cancer and in monitoring tumour response to treatment, where concentrations of phospholipid-related metabolites are found to alter following response to a wide range of anti-cancer therapies. Copyright (C) 2006 John Wiley & Sons, Ltd.

Contains fulltext : 51298.pdf (Publisher’s version ) (Closed access) The standardization and reproducibility of techniques required to acquire anatomically localized 31P MR spectra non-invasively while studying tumors in cancer patients in a multi-institutional group at 1.5 T are reported. This initial group of patients was studied from 1995 to 2000 to test the feasibility of acquiring in vivo localized 31P MRS in clinical MR spectrometers. The cancers tested were non-Hodgkin's lymphomas, sarcomas of soft tissue and bone, breast carcinomas and head and neck carcinomas. The best accrual and spectral quality were achieved with the non-Hodgkin's lymphomas. The initial analysis of the spectral values of the sum of phosphoethanolamine plus phosphocholine normalized by the content of nucleotide triphosphates in a homogeneous sample of 32 NHL patients studied by in vivo (31)P MRS showed good reproducibility among different institutions. No statistical differences were found between the institution with the largest number of cases accrued and the rest of the multi-institutional NHL data (2.28 +/- 0.64, mean +/- standard error; n = 17, vs 2.08 +/- 0.14, n = 15). The preliminary data reported demonstrate that the institutions involved in this trial are obtaining reproducible 31P MR spectroscopic data non-invasively from human tumors. This is a fundamental prerequisite for the international cooperative group to be able to demonstrate the clinical value of the normalized determination of phosphoethanolamine plus phosphocholine by 31P MRS as predictor for treatment response in cancer patients.

The spin-lattice relaxation time, T1, of hyperpolarized 129Xe in blood is sensitive to blood oxygenation. In particular, it has been shown that 129Xe T1 is shorter in venous blood than in arterial blood. We have studied the T1 of hyperpolarized 129Xe dissolved in human blood as a function of blood oxygenation level, sO2, in the physiological oxygenation range. We show that the 129Xe relaxation rate, , varies in a nonlinear fashion as a function of sO2. This finding suggests that direct interaction of xenon with the paramagnetic heme group of deoxyhemoglobin is not the dominant oxygenation-dependent relaxation mechanism for 129Xe in blood. These results corroborate the idea that the oxygenation-dependence of 129Xe T1 is determined by conformational changes of hemoglobin induced by oxygen binding. Copyright © 2000 John Wiley & Sons, Ltd.

There is an increasing interest in the use of hyperpolarized 129-xenon (HpXe) NMR for the measurement of tissue perfusion. In this paper we present a theoretical study designed to assess the merit of intravenous HpXe delivery compared with the existing respiration techniques. A compartmental model was created to describe the behavior of the injected bolus in the circulatory system and in the lungs. The dependence of the tissue concentration on the T 1 and solubility of the Xe in the various compartments, and on injection rate, were evaluated. By this process the critical loss mechanisms are identified. It is shown that the predicted tissue concentrations of HpXe in gray and white matter are comparable using respiration or injection techniques.

Precise measurement of pHein vivo may be of clinical value for both diagnosis and selection of therapy. pHe measurements made by the 31P probe 3-aminopropylphosphonate (3-APP) were compared with those made by the 19F probe, 3-[N-(4-fluor-2-trifluoromethylphenyl)-sulphamoyl]-propionic acid (ZK-150471) in three solid tumour types, human HT29 xenografts, murine RIF-1 fibrosarcomas and Lettre tumours grown subcutaneously in mice. No significant differences were observed when probe measurements of pHe were compared at 20–60 min post-administration, although very low pHe values (ca. 6.0) were recorded in two out of eight Lettre tumours by ZK-150471. The more rapid pHe measurements possible using ZK-150471 showed that during the first 20 min post-administration significant increases occurred in pHe which were greatest in the more necrotic tumours. Since isolated cell experiments showed that ZK-150471 was non-toxic and did not enter the cells, this early increase in pHe may reflect gradual penetration by ZK-150471 of the reportedly alkaline necrotic space in the tumours. The wide chemical shift range, improved signal-to-noise and absence of signal overlap allowed a more rapid and precise measurement of pHe by ZK-150471 compared to 3-APP. These characteristics suggest that ZK-150471 is currently the preferred pHe probe for non-invasive MRS. Copyright © 1999 John Wiley & Sons, Ltd.

A review of the literature has shown that in human breast tumours, large signals from phosphomonoesters (PME) and phosphodiesters (PDE) are evident. In serial measurements in 19 patients with breast cancer, a decrease in PME was significantly associated with a stable or responding disease (p = 0.017), and an increase in PME was associated with disease progression. Extract studies have shown PME to comprise of phosphoethanolamine (PEth) and phosphocholine (PCho), with the PEth to PCho ratio ranging from 1.3 to 12. The PCho content of high grade tumours was found to be higher than low grade tumours. In some animal models, changes in PCho have been shown to correlate with indices of cellular proliferation, and spheroid studies have shown a decrease in PCho content in spheroids with smaller growth fractions. A serial study of 25 patients with advanced primary breast tumours undergoing hormone, chemotherapy or radiotherapy treatments, showed that in this heterogenous group there were significant changes in metabolites that were seen during the first 3 weeks (range 2-4 weeks) of treatment, that correlated with volume change over this period, employed here as a measure of response. Changes in PME (p = 0.003), total phosphate (TP) (p = 0.008) and total nucleoside tri-phosphate (TNTP) (p = 0.02) over 3 (1) weeks were significantly associated with response, as were the levels of PME (p

Pyruvate-lactate exchange is mediated by the enzyme lactate dehydrogenase (LDH) and is central to the altered energy metabolism in cancer cells. The measurement of exchange kinetics using hyperpolarized (13) C NMR has provided a biomarker of response to novel therapeutics. However, the observable signal is restricted to the exchanging hyperpolarized (13) C pools and the endogenous pools of (12) C-labelled metabolites are invisible in these measurements. In this study, we investigated an alternative in vitro (1) H NMR assay, using [3-(13) C]pyruvate, and compared the measured kinetics with a hyperpolarized (13) C NMR assay, using [1-(13) C]pyruvate, under the same conditions in human colorectal carcinoma SW1222 cells. The apparent forward reaction rate constants (kPL ) derived from the two assays showed no significant difference, and both assays had similar reproducibility (kPL = 0.506 ± 0.054 and kPL = 0.441 ± 0.090 nmol/s/10(6) cells; mean ± standard deviation; n = 3); (1) H, (13) C assays, respectively). The apparent backward reaction rate constant (kLP ) could only be measured with good reproducibility using the (1) H NMR assay (kLP = 0.376 ± 0.091 nmol/s/10(6) cells; mean ± standard deviation; n = 3). The (1) H NMR assay has adequate sensitivity to measure real-time pyruvate-lactate exchange kinetics in vitro, offering a complementary and accessible assay of apparent LDH activity.

The content of the phospholipid metabolites, phosphocholine, phosphoethanolamine, glycerophosphorylcholine and glycerophosphorylethanolamine was measured in chemical extracts from 46 human breast carcinoma using 31P NMR spectroscopy. Some patients had received therapy prior to tumour resection. The data were therefore stratified into two groups: (i) all tumours; and (ii) untreated tumours. Three indices of tumour proliferation i.e., mitotic index, Ki67 and S-phase fraction were determined on tissue from the same tumours and were found not to correlate with the content of any of these metabolites. In addition oestrogen-receptor status and density, tumour grade and DNA ploidy were obtained on some tumours. The phosphocholine content was higher in high grade tumours when compared with low grade tumours. There was no apparent relationship between DNA ploidy and the content of any of these metabolites. Glycerophosphorylcholine content of oestrogen-receptor positive tumours correlated with receptor density. However, there was no significant difference between receptor positive and negative tumours in the content of any of the phospholipid metabolites measured.

The pseudomonad protein, carboxypeptidase G2 (CPG2), is a prodrug-activating enzyme utilized in the targeted chemotherapy strategies of antibody- and gene-directed enzyme prodrug therapy (ADEPT and GDEPT). We have developed a noninvasive imaging approach to monitor CPG2 activity in vivo that will facilitate the preclinical and clinical development of CPG2-based ADEPT and GDEPT strategies. Cleavage of the novel reporter probe, 3,5-difluorobenzoyl-L-glutamic acid (3,5-DFBGlu), by CPG2, in human colon adenocarcinoma WiDr xenografts engineered to stably express CPG2, was monitored using (19)F MRSI. The high signal-to-noise ratio afforded by the two MR-equivalent (19)F nuclei of 3,5-DFBGlu, and the 1.4 ppm (19)F chemical shift difference on CPG2-mediated cleavage, enabled the dynamics and quantification of the apparent pharmacokinetics of 3,5-DFBGlu and its CPG2-mediated cleavage in the tumor to be evaluated. In addition, the apparent rate of increase of 3,5-difluorobenzoic acid concentration could also provide a biomarker of CPG2 activity levels in tumors of patients undergoing CPG2-based therapies, as well as a biomarker of treatment response. The addition of in vivo reporter probes, such as 3,5-DFBGlu, to the armamentarium of prodrugs cleaved by CPG2 affords new applications for CPG2 as a gene reporter of transgene expression.

Factors affecting the selection and application of localization methods for measuring tumours by NMR spectroscopy are considered, with particular regard to the S/N ratio and to contaminating signal from outside the volume of interest. Methods of assessing the performance of localization techniques are considered, and their importance for quantitative measurements and comparative studies is discussed.

The concentration of phosphorus-containing metabolites was determined in extracts of multiple samples from six human breast tumours and in samples from normal and inflamed breast tissue. The degree of lymphoid infiltrate, necrotic fraction and tumour cell and normal tissue fraction were determined on sections taken from each of the tumour samples. In four of the tumours there was a very high degree of variation between samples in the absolute concentration of metabolites. Three of these tumours showed a high degree of intra-tumour variation in the distribution of tumour cells and of normal tissue. The other two tumours were relatively homogeneous with respect to both tumour cellularity and the distribution of phosphorus-containing metabolites. Samples from normal breast tissue was found to contain only low concentrations of phosphorus-containing metabolites. However one of the inflamed samples, which consisted predominantly of macrophages, contained high levels of such compounds. The effect of time delay between resection and freezing on the levels of metabolites in human breast tumours was also examined.

31P NMR spectroscopy provides a means of monitoring intracellular pH (pHi). In order to determine the significance of observed pH changes, an assessment of the measurement uncertainty is required. This paper considers the possible sources of error involved, firstly in chemical shift assignment and, secondly, in relating chemical shift to pH. A statistical analysis of these errors is presented and an expression for the accuracy of pH measurements obtained using in vivo 31P NMR spectroscopy is derived. Computer simulations and clinical measurements are considered to determine the likely error in clinical measurements. A comparison of pH measurement methodology using a centre-of-gravity calculation, Gaussian and Lorentzian fitting is also presented and discussed.

Contains fulltext : 57307.pdf (Publisher’s version ) (Closed access) A multi-institutional group has been created to demonstrate the utility of in vivo 31P magnetic resonance spectroscopy (31P-MRS) to study human cancers in vivo. This review is concerned with the novel problems concerning quality control in this large multinational trial of 31P MRS. Our results show that the careful and systematic performance of the quality control tests depicted here (standardized dual 1H/31P tuned radiofrequency probe, quality control procedures, routine use of 1H irradiation while acquiring 31P MR signals) has ensured comparable results between the different institutions. In studies made in vitro, the root-mean-square error was 3.6 %, and in muscle of healthy volunteers in vivo the coefficients of variance for the ratios phosphocreatine/nucleotide-triphosphates, phosphocreatine/noise and nucleotide-triphosphate/noise were 12.2, 7.0 and 10.8 %, respectively. The standardization of the acquisition protocol for in vivo-localized 31P MR spectroscopy across the different institutions has resulted in comparable in vivo data, decreasing the possible problems related to a research study carried out under a multi-institutional setting.

Applications of dynamic contrast enhanced MR imaging are increasing and require both high spatial resolution and high temporal resolution. Perfusion studies using susceptibility contrast in particular require very high temporal resolution. The sliding window reconstruction is a technique for increasing temporal resolution. It has previously been applied to radial and spiral sampling, but these schemes require extensive correction and interpolation during image reconstruction. Fourier raw data can be reconstructed simply and quickly using the fast fourier transform (FFT). This paper presents a new Fourier-based sampling scheme and sliding window reconstruction that facilitates fast scanning without needing correction or interpolation. This technique can be used on virtually any MR scanner since it requires no specialized hardware. It is implemented here as a dual gradient echo sequence providing simultaneous T1- and T2*-weighted images with a time resolution of 1.1 s. Copyright © 2002 John Wiley & Sons, Ltd.

Reproducibility of quantitative dynamic MRI of normal human tissues. The aim of the study was to establish the normal ran-e and to evaluate the reproducibility of dynamic contrast enhanced MRI (DCE-MRI) parameter estimates in normal human pelvic tissues. Nineteen patients with prostate cancer. undergoing androgen deprivation treatment. had paired DCE-MRI examinations of the pelvis using spoiled gradient-echo sequences. Quantitative enhancement parameters were calculated for each examination: transfer constant (K-trans). leakage space (v(c)) and maximum contrast medium accumulation (MCMA) of pelvic muscles bone marrow and fat. Descriptive and reproducibility statistics were calculated: within-patient Standard deviation (wSD), repeatability and within-patient coefficient of variation (wCV). The femoral head and ischiorectal fat showed large numbers of non-enhancing pixels (81 and 88%. respectively). The ischial bone marrow had the highest values of kinetic parameter estimates (K-trans 0.554 min(-1), v(c) 18.5% and MCMA 0.164 mmol/kg). Muscle parameters values were lower (K-trans 0.126- 0.137 min(-1), v(c) 10.6-11.5% and MCMA 0.077-0.086 mmol/kg). The mean difference between paired examination,, was not significantly different from zero for any parameter. v, and MCMA had the lowest wCV (between 19 and 29%). For individuals. a log(10) K-trans chance of approximately 0.90 in muscles and 0.52 in the ischium would be statistically significant. The corresponding absolute changes for v(c) are 6.7% in muscle and 13.6% in the ischium. For a group of 19 patients, small changes are statistically significant (muscle log(10) K-trans 0.208 and v(c) 1.5% and ischium log(10) K-trans 0.123 and v(c) 3.1%). Fat and the femoral head are unreliable tissues from which to obtain kinetic parameter estimates due to poor enhancement. v(c) and MCMA have smaller coefficient of variation than K- trans in muscles and ischium. Reproducibility studies of normal and pathological tissues should be incorporated into clinical research protocols that measure treatment effects by DCE-MRI techniques.

Dynamic contrast-enhanced MRI (DCE-MRI) is widely used in the diagnosis and staging of cancer and is emerging as a promising method for monitoring tumour response to treatment. However, DCE-MR imaging techniques are still evolving and methods of image analysis remain variable and non-standard, and range from relative changes in the pattern of enhancement to pharmacokinetic modelling of contrast agent uptake. The combination of results from different institutions is therefore difficult and the sensitivities of different methods have not been compared. The purpose of this study is to investigate correlations between qualitative and quantitative methods of analysis for DCE-MR images from breast cancer patients undergoing neo-adjuvant chemotherapy. Fifteen patients underwent DCE-MRI examinations before and after one course of chemotherapy. Changes in the temporal pattern of signal enhancement, the rate and amplitude of enhancement and the volume transfer constant of contrast agent between the blood plasma and the extravascular extracellular space (EES), K(trans), and the EES fractional volume, nu(e), were determined. In addition, whole tumour region-of-interest analysis was compared with histogram analysis to investigate the extent of tumour heterogeneity. It was found that changes in the rate of enhancement correlated strongly with changes in K(trans) values (Kendall's tau = 0.68, P < 0.001). Furthermore, it was found that the shape of the signal enhancement curve only changed when the K(trans) values changed by 50% or more. Median K(trans) values determined following histogram analysis of pixel maps of K(trans) were approximately equal to those determined by whole tumour region-of-interest analysis. The absolute change in the K(trans) values correlated negatively with the pre-treatment values, particularly for responding patients. Thus, for higher pre-treatment K(trans) values, a greater decrease was observed. Greater changes were observed in the upper extremes of the K(trans) histogram than in the median values after one course of treatment.

A technique for obtaining T1 values from well localized regions using surface coils and with a clinically practicable measurement time is described. The method uses a two-point Inversion-Recovery/Saturation-Recovery (IR/SR) sequence in conjunction with the image-selected in vivo spectroscopy localization scheme. T1 values are obtained by comparing the ratio of peak areas with those in a pre-computed look-up table. The method was tested by measuring the T1s of six calibrated water phantoms doped with different concentrations of gadolinium. This indicated an accuracy of 3% for T1 values in the range 400-1500 ms. 31P spectra and T1 values of Pi, phosphocreatine and alpha-, beta- and gamma-NTP metabolites from the calf muscle of healthy volunteers were obtained with the sequence employing beta 1-insensitive excitation pulses and a surface coil. The T1 values fall within the range of published values obtained by other techniques.