Publications

To determine the measurement reproducibility of perfusion fraction f, pseudodiffusion coefficient D (*) and diffusion coefficient D in colorectal liver metastases and normal liver.

Imaging is a key component in the management of brain tumours, with MRI being the preferred modality for most clinical scenarios. However, although conventional MRI provides mainly structural information, such as tumour size and location, it leaves many important clinical questions, such as tumour type, aggressiveness and prognosis, unanswered. An increasing number of studies have shown that additional information can be obtained using functional imaging methods (which probe tissue properties), and that these techniques can give key information of clinical importance. These techniques include diffusion imaging, which can assess tissue structure, and perfusion imaging and magnetic resonance spectroscopy, which measures tissue metabolite profiles. Tumour metabolism can also be investigated using PET, with 18F-deoxyglucose being the most readily available tracer. This Review discusses these methods and the studies that have investigated their clinical use. A strong emphasis is placed on the measurement of quantitative parameters, which is a move away from the qualitative nature of conventional radiological reporting and presents major challenges, particularly for multicentre studies.

Picture archiving and communication systems (PACS) provide limited flexibility for the development of novel research methods. By contrast, the research model of data access is more flexible but has vulnerabilities in numerous areas. No single monolithic application can fulfill the diverse and rapidly changing needs of the clinical imaging research community. Instead, the focus should be on the interoperability of preexisting systems. To a large extent, this can be achieved by means of a unified interface for storing and retrieving data. The concept of a research PACS combines the advantages of the clinical and research models of data access while eliminating the disadvantages. A research PACS streamlines the data management process. Instead of a single software program, it consists of a confederation of independent applications brought together by the ability to store and retrieve data in a common database. A prototype research PACS has been developed that is based on the Extensible Neuroimaging Archive Toolkit (XNAT) in association with two new in-house tools: a data selection tool and a data archiving tool. By taking as an example the comparison of regions of interest in multifunctional liver data, it was demonstrated that this framework allows a number of in-house and open-source applications originally designed to work on a stand-alone basis to be integrated into a unified workflow, with minimal redevelopment effort.

It is recommended that BRCA1/2 mutation carriers undergo breast cancer screening using MRI because of their very high cancer risk and the high sensitivity of MRI in detecting invasive cancers. Clinical observations suggest important differences in the natural history between breast cancers due to mutations in BRCA1 and BRCA2, potentially requiring different screening guidelines.

To assess baseline reproducibility and compare performance of dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging versus DCE computed tomographic (CT) measures of early vascular response in the same patients treated with cediranib (30 or 45 mg daily).

OBJECTIVE: We examine the clinical impetus for whole-body diffusion-weighted MRI and discuss how to implement the technique with clinical MRI systems. We include practical tips and tricks to optimize image quality and reduce artifacts. The interpretative pitfalls are enumerated, and potential challenges are highlighted. CONCLUSION: Whole-body diffusion-weighted MRI can be used for tumor staging and assessment of treatment response. Meticulous technique and knowledge of potential interpretive pitfalls will help to avoid mistakes and establish this modality in radiologic practice.

The vascular disrupting agent (VDA) combretastatin A4 phosphate (CA4P) induces significant tumor necrosis as a single agent. Preclinical models have shown that the addition of an anti-VEGF antibody to a VDA attenuates the revascularization of the surviving tumor rim and thus significantly increases antitumor activity.

Mammographic density adjusted for age and body mass index (BMI) is a heritable marker of breast cancer susceptibility. Little is known about the biologic mechanisms underlying the association between mammographic density and breast cancer risk. We examined whether common low-penetrance breast cancer susceptibility variants contribute to interindividual differences in mammographic density measures.

Silicone breast prostheses prove technically challenging when performing diffusion-weighted MR imaging in the breasts. We describe a combined fat and chemical suppression scheme to achieve dual suppression of fat and silicone, thereby improving the quality of diffusion-weighted images in women with breast implants.

Many therapeutic approaches to cancer affect the tumour vasculature, either indirectly or as a direct target. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has become an important means of investigating this action, both pre-clinically and in early stage clinical trials. For such trials, it is essential that the measurement process (i.e. image acquisition and analysis) can be performed effectively and with consistency among contributing centres. As the technique continues to develop in order to provide potential improvements in sensitivity and physiological relevance, there is considerable scope for between-centre variation in techniques. A workshop was convened by the Imaging Committee of the Experimental Cancer Medicine Centres (ECMC) to review the current status of DCE-MRI and to provide recommendations on how the technique can best be used for early stage trials. This review and the consequent recommendations are summarised here. Key Points • Tumour vascular function is key to tumour development and treatment • Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can assess tumour vascular function • Thus DCE-MRI with pharmacokinetic models can assess novel treatments • Many recent developments are advancing the accuracy of and information from DCE-MRI • Establishing common methodology across multiple centres is challenging and requires accepted guidelines.

To evaluate dynamic contrast-enhanced (DCE) magnetic resonance (MR) imaging for monitoring and assessing treatment response in patients with neuroendocrine liver metastases treated using yttrium 90 ((90)Y)-labeled octreotide ((90)Y-DOTATOC).

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.

Histone deacetylase (HDAC) inhibitors are currently approved for cutaneous T-cell lymphoma and are in mid-late stage trials for other cancers. The HDAC inhibitors LAQ824 and SAHA increase phosphocholine (PC) levels in human colon cancer cells and tumor xenografts as observed by magnetic resonance spectroscopy (MRS). In this study, we show that belinostat, an HDAC inhibitor with an alternative chemical scaffold, also caused a rise in cellular PC content that was detectable by (1)H and (31)P MRS in prostate and colon carcinoma cells. In addition, (1)H MRS showed an increase in branched chain amino acid and alanine concentrations. (13)C-choline labeling indicated that the rise in PC resulted from increased de novo synthesis and correlated with an induction of choline kinase α expression. Furthermore, metabolic labeling experiments with (13)C-glucose showed that differential glucose routing favored alanine formation at the expense of lactate production. Additional analysis revealed increases in the choline/water and phosphomonoester (including PC)/total phosphate ratios in vivo. Together, our findings provide mechanistic insights into the impact of HDAC inhibition on cancer cell metabolism and highlight PC as a candidate noninvasive imaging biomarker for monitoring the action of HDAC inhibitors.

To describe the appearances of colorectal liver metastases on diffusion-weighted MRI (DW-MRI) and to compare these appearances with histopathology.

To determine the T(2) relaxation time of colorectal hepatic metastases and changes in T(2) relaxation times following chemotherapy.

In this study, we introduce a novel, robust and accurate computerized algorithm based on volumetric principal component maps and template matching that facilitates lesion detection on dynamic contrast-enhanced MR. The study dataset comprises 24,204 contrast-enhanced breast MR images corresponding to 4034 axial slices from 47 women in the UK multi-centre study of MRI screening for breast cancer and categorized as high risk. The scans analysed here were performed on six different models of scanner from three commercial vendors, sited in 13 clinics around the UK. 1952 slices from this dataset, containing 15 benign and 13 malignant lesions, were used for training. The remaining 2082 slices, with 14 benign and 12 malignant lesions, were used for test purposes. To prevent false positives being detected from other tissues and regions of the body, breast volumes are segmented from pre-contrast images using a fast semi-automated algorithm. Principal component analysis is applied to the centred intensity vectors formed from the dynamic contrast-enhanced T1-weighted images of the segmented breasts, followed by automatic thresholding to eliminate fatty tissues and slowly enhancing normal parenchyma and a convolution and filtering process to minimize artefacts from moderately enhanced normal parenchyma and blood vessels. Finally, suspicious lesions are identified through a volumetric sixfold neighbourhood connectivity search and calculation of two morphological features: volume and volumetric eccentricity, to exclude highly enhanced blood vessels, nipples and normal parenchyma and to localize lesions. This provides satisfactory lesion localization. For a detection sensitivity of 100%, the overall false-positive detection rate of the system is 1.02/lesion, 1.17/case and 0.08/slice, comparing favourably with previous studies. This approach may facilitate detection of lesions in multi-centre and multi-instrument dynamic contrast-enhanced breast MR data.

To describe computed diffusion weighted (DW) magnetic resonance (MR) imaging as a method for obtaining high-b-value images from DW MR imaging performed at lower b values and to investigate the feasibility of the technique to improve lesion detection in oncologic cases.

Rational drug discovery and development requires biomarkers to inform on target modulation and treatment efficacy. Many aspects of metabolism are altered in cancer, compared to normal tissues, and are often regulated by oncogene activation. Non-invasive imaging of spatio-temporal effects of molecularly targeted anticancer agents on tumor metabolism has considerable potential in the development and use of personalized molecular medicine approaches to cancer treatment. Here we describe how non-invasive monitoring of metabolism, using primarily magnetic resonance spectroscopy (MRS), can be used to follow treatment with novel molecularly targeted anticancer agents. We discuss how the regulation of metabolic pathways by oncogenic signaling can affect MRS-detectable metabolic signals together with the physiological factors that can influence the measured changes. Finally, the translation of these metabolic measurements from pre-clinical models to patients will be discussed.

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. Copyright © 2010 John Wiley & Sons, Ltd.

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 © 2011 John Wiley & Sons, Ltd.

PURPOSE The hepatocyte growth factor/c-MET axis is implicated in tumor cell proliferation, survival, and angiogenesis. ARQ 197 is an oral, selective, non-adenosine triphosphate competitive c-MET inhibitor. A phase I trial of ARQ 197 was conducted to assess safety, tolerability, and target inhibition, including intratumoral c-MET signaling, apoptosis, and angiogenesis. PATIENTS AND METHODS Patients with solid tumors amenable to pharmacokinetic and pharmacodynamic studies using serial biopsies, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and circulating endothelial cell (CEC) and circulating tumor cell (CTC) enumeration were enrolled. Results Fifty-one patients received ARQ 197 at 100 to 400 mg twice per day. ARQ 197 was well tolerated, with the most common toxicities being grade 1 to 2 fatigue, nausea, and vomiting. Dose-limiting toxicities included grade 3 fatigue (200 mg twice per day; n = 1); grade 3 mucositis, palmar-plantar erythrodysesthesia, and hypokalemia (400 mg twice per day; n = 1); and grade 3 to 4 febrile neutropenia (400 mg twice per day, n = 2; 360 mg twice per day, n = 1). The recommended phase II dose was 360 mg twice per day. ARQ 197 systemic exposure was dose dependent and supported twice per day oral dosing. ARQ 197 decreased phosphorylated c-MET, total c-MET, and phosphorylated focal adhesion kinase and increased terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) staining in tumor biopsies (n = 15). CECs decreased in 25 (58.1%) of 43 patients, but no significant changes in DCE-MRI parameters were observed after ARQ 197 treatment. Of 15 patients with detectable CTCs, eight (53.3%) had ≥ 30% decline in CTCs after treatment. Stable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST), ≥ 4 months was observed in 14 patients, with minor regressions in gastric and Merkel cell cancers. CONCLUSION ARQ 197 safely inhibited intratumoral c-MET signaling. Further clinical evaluation focusing on combination approaches, including an erlotinib combination in non-small-cell lung cancer, is ongoing.

Neuroendocrine hepatic metastases exhibit various contrast uptake enhancement patterns in dynamic contrast-enhanced MRI. Using a dual-input two-compartment distributed parameter model, we analyzed the dynamic contrast-enhanced MRI datasets of seven patient study cases with the aim to relate the tumor contrast uptake patterns to parameters of tumor microvasculature. Simulation studies were also performed to provide further insights into the effects of individual microcirculatory parameter on the tumor concentration-time curves. Although the tumor contrast uptake patterns can be influenced by many parameters, initial results indicate that hepatic blood flow and the ratio of fractional vascular volume to fractional interstitial volume may potentially distinguish between the patterns of neuroendocrine hepatic metastases. Magn Reson Med 65: 250-260, 2011. (C) 2010 Wiley-Liss, Inc.

BACKGROUND: As part of the Magnetic Resonance Imaging for Breast Screening (MARIBS), Study women with a family history of breast cancer were assessed psychologically to determine the relative psychological impact and acceptability of annual screening using magnetic resonance imaging (MRI) and conventional X-ray mammography (XRM).METHODS: Women were assessed psychologically at baseline (4 weeks before MRI and XRM), immediately before, and immediately after, both MRI and XRM, and at follow-up (6 weeks after the scans).RESULTS: Overall, both procedures were found to be acceptable with high levels of satisfaction (MRI, 96.3% and XRM, 97.7%; NS) and low levels of psychological morbidity throughout, particularly at 6-week follow-up. Low levels of self-reported distress were reported for both procedures (MRI, 13.5% and XRM, 7.8%), although MRI was more distressing (P = 0.005). Similarly, higher anticipatory anxiety was reported before MRI than before XRM (P = 0.003). Relative to XRM, MRI-related distress was more likely to persist at 6 weeks after the scans in the form of intrusive MRI-related thoughts (P = 0.006) and total MRI-related distress (P = 0.014). More women stated that they intended to return for XRM (96.3%) than for MRI (88%; P < 0.0005). These effects were most marked for the first year of screening, although they were also statistically significant in subsequent years.CONCLUSION: Given the proven benefits of MRI in screening for breast cancer in this population, these data point to the urgent need to provide timely information and support to women undergoing MRI. British Journal of Cancer (2011) 104, 578-586. doi:10.1038/bjc.2011.1 www.bjcancer.com (C) 2011 Cancer Research UK

Pharmacokinetic parameters from dynamic contrast-enhanced MRI (DCE-MRI) were used to assess the perfusion effects due to treatment response using a tyrosine kinase inhibitor. A Bayesian hierarchical model (BHM) is proposed, as an alternative to voxel-wise estimation procedures, to test for a treatment effect while explicitly modeling known sources of variability.Nine subjects from a randomized, blinded, placebo-controlled, multicenter, phase II study of lapatinib were examined before and after treatment. Kinetic parameters were estimated, with an extended compartmental model and subject-specific arterial input function, on a voxel-by-voxel basis.The group treated with lapatinib had a decrease in median K (trans) of 0.17min(-1), when averaged across all voxels in the tumor ROIs, compared with no change in the placebo group based on nonlinear regression. A hypothesis test of equality between pre- and posttreatment K (trans) could not be rejected against a one-sided alternative (P = 0.09). Equality between median K (trans) in placebo and lapatinib groups posttreatment could also not be rejected using the BHM (P = 0.32). Across all scans acquired in the study, estimates of K (trans) at one site were greater on average than those at the other site by including a site effect in the BHM. The inter-voxel variability is of similar order (within 15%) when compared to the inter-patient variability.Though the study contained a small number of subjects and no significant difference was found, the Bayesian hierarchical model provided estimates of variability from known sources in the study and confidence intervals for all estimated parameters. We believe the BHM provides a straightforward and thorough interrogation of the imaging data at the level of voxels, patients or sites in this multicenter clinical study.

A major challenge in cancer biology is to monitor and understand cancer metabolism in vivo with the goal of improved diagnosis and perhaps therapy. Because of the complexity of biochemical pathways, tracer methods are required for detecting specific enzyme-catalyzed reactions. Stable isotopes such as C-13 or N-15 with detection by nuclear magnetic resonance provide the necessary information about tissue biochemistry, but the crucial metabolites are present in low concentration and therefore are beyond the detection threshold of traditional magnetic resonance methods. A solution is to improve sensitivity by a factor of 10,000 or more by temporarily redistributing the populations of nuclear spins in a magnetic field, a process termed hyperpolarization. Although this effect is short-lived, hyperpolarized molecules can be generated in an aqueous solution and infused in vivo where metabolism generates products that can be imaged. This discovery lifts the primary constraint on magnetic resonance imaging for monitoring metabolism-poor sensitivity-while preserving the advantage of biochemical information. The purpose of this report was to briefly summarize the known abnormalities in cancer metabolism, the value and limitations of current imaging methods for metabolism, and the principles of hyperpolarization. Recent preclinical applications are described. Hyperpolarization technology is still in its infancy, and current polarizer equipment and methods are suboptimal. Nevertheless, there are no fundamental barriers to rapid translation of this exciting technology to clinical research and perhaps clinical care.

Developing rational targeted cancer drugs requires the implementation of pharmacodynamic (PD), preferably non-invasive, biomarkers to aid response assessment and patient follow-up. Magnetic resonance spectroscopy (MRS) allows the non-invasive study of tumour metabolism. We describe the MRS-detectable PD biomarkers resulting from the action of targeted therapeutics, and discuss their biological significance and future translation into clinical use.

The phosphoinositide 3-kinase (PI3K) pathway is a major target for cancer drug development. PI-103 is an isoform-selective class I PI3K and mammalian target of rapamycin inhibitor. The aims of this work were as follows: first, to use magnetic resonance spectroscopy (MRS) to identify and develop a robust pharmacodynamic (PD) biomarker for target inhibition and potentially tumor response following PI3K inhibition; second, to evaluate mechanisms underlying the MRS-detected changes. Treatment of human PTEN null PC3 prostate and PIK3CA mutant HCT116 colon carcinoma cells with PI-103 resulted in a concentration- and time-dependent decrease in phosphocholine (PC) and total choline (tCho) levels (P < 0.05) detected by phosphorus ((31)P)- and proton ((1)H)-MRS. In contrast, the cytotoxic microtubule inhibitor docetaxel increased glycerophosphocholine and tCho levels in PC3 cells. PI-103-induced MRS changes were associated with alterations in the protein expression levels of regulatory enzymes involved in lipid metabolism, including choline kinase alpha (ChoK(alpha)), fatty acid synthase (FAS), and phosphorylated ATP-citrate lyase (pACL). However, a strong correlation (r(2) = 0.9, P = 0.009) was found only between PC concentrations and ChoK(alpha) expression but not with FAS or pACL. This study identified inhibition of ChoK(alpha) as a major cause of the observed change in PC levels following PI-103 treatment. We also showed the capacity of (1)H-MRS, a clinically well-established technique with higher sensitivity and wider applicability compared with (31)P-MRS, to assess response to PI-103. Our results show that monitoring the effects of PI3K inhibitors by MRS may provide a noninvasive PD biomarker for PI3K inhibition and potentially of tumor response during early-stage clinical trials with PI3K inhibitors.

Molecular chaperone heat shock protein 90 (Hsp90) inhibitors are promising targeted cancer therapeutic drugs, with the advantage that they deplete multiple oncogenic client proteins and modulate all the classical hallmarks of cancer. They are now in clinical trial and show potential for activity in melanoma and other malignancies. Here we explore the metabolic response to Hsp90 inhibition in human melanoma cells using magnetic resonance spectroscopy. We show that, concomitant with growth inhibition and re-differentiation, Hsp90 inhibition in human melanoma cells is associated with increased glycerophosphocholine content. This was seen with both the clinical geldanamycin-based Hsp90 drug 17-AAG and the structurally dissimilar Hsp90 inhibitor CCT018159. The effect was noted in both BRAF mutant SKMEL28 and BRAF wildtype CHL-1 melanoma cells. Elevated content of the -CH2+CH3 fatty acyl chains and cytoplasmic mobile lipid droplets was also observed in 17-AAG-treated SKMEL28 cells. Importantly, the phospholipase A2 inhibitor bromoenol lactone prevented the rise in glycerophosphocholine seen with 17-AAG, suggesting a role for phospholipase A2 activation in the Hsp90 inhibitor-induced metabolic response. Our findings provide a basis for using metabolic changes as non-invasive indicators of Hsp90 inhibition and potentially as biomarkers of anticancer activity with Hsp90 drugs in malignant melanoma and possibly in other cancers.

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.

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 (31)P 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-isoquinolinesulphonamide (H-89), an agent commercialized as a specific cyclic-AMP-dependent protein kinase A (PKA) inhibitor.

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.

Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) is a valuable tool for assessing treatment response to novel cancer therapeutics. With appropriate data acquisition, quantitative functional parameter estimates can be obtained by fitting a model to the data. This research focuses on applying a dual-input single-compartment pharmacokinetic model to breath-hold DCE-MRI imaging of the liver. In this paper, the use of two breath-holds, providing greater temporal information, is compared with a single breath-hold approach. Computer simulations are used to assess the accuracy, precision and sensitivity to input function errors obtained for parameters estimated from the two imaging protocols. Data from ten patients were analysed to assess the noise statistics obtained from the two breath-hold protocols. The noise statistics were used with a pharmacokinetic liver model to simulate data, from which the estimation accuracy, precision and sensitivity for the two protocols were assessed. Data from the ten patients were also analysed, and the estimates were compared with literature values. This work demonstrates the feasibility of obtaining functional liver perfusion estimates over a 3D volume using a sequential breath-hold protocol. The simulation results show that the protocol consisting of two images per breath-hold is to be preferred as it requires identical patient co-operation, but provides parameter estimates that have superior accuracy and precision.

Gadolinium contrast agents are known to affect the outer-sphere relaxivities of nuclei other than protons. We have investigated the heteronuclear relaxivities of four commercial gadolinium contrast agents (Magnevist, Omniscan, Dotarem and Gadovist) on the relaxation of (13)C in glycine, (13)C in pyruvate and (15)N in choline with long relaxation times. Marked differences in the relaxivities were found between different contrast agents and are attributed to electrostatic effects. This methodology may find applications in the field of hyperpolarized magnetic resonance and by way of example we show that injection of a bolus of contrast agent into an aqueous solution containing hyperpolarized (15)N labeled tetramethylammonium or (13)C labeled pyruvate leads to a predictable shortening of the lifetime of the hyperpolarized signal.

Phosphoinositide-specific phospholipase Cγ1 (PLCγ1) is activated downstream of many receptor tyrosine kinases to promote cell motility. Inhibition of this protein is being explored as a therapeutic strategy for blocking cancer cell invasion and metastasis. The clinical development of such cytostatic therapies requires the implementation of pharmacodynamic biomarkers of target modulation. In this study, we use magnetic resonance spectroscopy to explore metabolic biomarkers of PLCγ1 down-regulation in PC3LN3 prostate cancer cells. We show that inhibition of PLCγ1 via an inducible short hairpin RNA system causes a reduction in phosphocholine levels by up to 50% relative to the control as detected by (1)H and (31)P magnetic resonance spectroscopy analyses. This correlated with a rounded-up morphology and reduced cell migration. Interestingly, the fall in phosphocholine levels was not recorded in cells with constitutive PLCγ1 knockdown where the rounded-up phenotype was no longer apparent. This study reveals alterations in metabolism that accompany the cellular effects of PLCγ1 knockdown and highlights phosphocholine as a potential pharmacodynamic biomarker for monitoring the action of inhibitors targeting PLCγ1 signaling.

Carboxypeptidase G2 (CPG2) is a bacterial enzyme that is currently employed in a range of targeted cancer chemotherapy strategies such as gene-directed enzyme prodrug therapy (GDEPT). Employing dynamic nuclear polarization (DNP) and natural abundance (13)C magnetic resonance spectroscopy (MRS), we observed the CPG2-mediated conversion of a novel hyperpolarized reporter probe 3,5-difluorobenzoyl-L-glutamic acid (3,5-DFBGlu) to 3,5-difluorobenzoic acid (3,5-DFBA) and L-glutamic acid (L-Glu) in vitro. Isotopic labeling of the relevant nuclei with (13)C in 3,5-DFBGlu or related substrates will yield a further factor of 100 increase in the signal-to-noise. We discuss the feasibility of translating these experiments to generate metabolic images of CPG2 activity in vivo.

SR4554 is a fluorine-containing 2-nitroimidazole, designed as a hypoxia marker detectable with 19F magnetic resonance spectroscopy (MRS). In an initial phase I study of SR4554, nausea/vomiting was found to be dose-limiting, and 1400 mg m(-2) was established as MTD. Preliminary MRS studies demonstrated some evidence of 19F retention in tumour. In this study we investigated higher doses of SR4554 and intratumoral localisation of the 19F MRS signal.

Radiotherapy dose escalation improves tumour control in prostate cancer but with increased toxicity. Boosting focal tumour only may allow dose escalation with acceptable toxicity. Intensity-modulated radiotherapy can deliver this, but visualization of the tumour remains limiting. CT or conventional MRI techniques are poor at localizing tumour, but dynamic contrast-enhanced MRI (DCE-MRI) may be superior. 18 patients with prostate cancer had T(2) weighted (T2W) and DCE-MRI prior to prostatectomy. The prostate was sectioned meticulously so as to achieve accurate correlation between imaging and pathology. The accuracy of DCE-MRI for cancer detection was calculated by a pixel-by-pixel correlation of quantitative DCE-MRI parameter maps and pathology. In addition, a radiologist interpreted the DCE-MRI and T2W images. The location of tumour on imaging was compared with histology, and the accuracy of DCE-MRI and T2W images was then compared. Pixel-by-pixel comparison of quantitative parameter maps showed a significant difference between the benign peripheral zone and tumour for the parameters K(trans), v(e) and k(ep). Calculation of areas under the receiver operating characteristic curve showed that the pharmacokinetic parameters were only "fair" discriminators between cancer and benign gland. Interpretation of DCE-MRI and T2W images by a radiologist showed DCE-MRI to be more sensitive than T2W images for tumour localization (50% vs 21%; p = 0.006) and similarly specific (85% vs 81%; p = 0.593). The superior sensitivity of DCE-MRI compared with T2W images, together with its high specificity, is arguably sufficient for its use in guiding radiotherapy boosts in prostate cancer.

To review imaging features of screening-detected cancers on images from diagnostic and prior examinations to identify specific abnormalities to aid earlier detection of or facilitate differentiation of cancers in BRCA1 and BRCA2 carriers and in women with a high risk for breast cancer.

This article presents a method to reconstruct liver MRI data acquired continuously during free breathing, without any external sensor or navigator measurements. When the deformations associated with k-space data are known, generalized matrix inversion reconstruction has been shown to be effective in reducing the ghosting and blurring artifacts of motion. This article describes a novel method to obtain these nonrigid deformations. A breathing model is built from a fast dynamic series: low spatial resolution images are registered and their deformations parameterized by overall superior-inferior displacement. The correct deformation for each subset of the subsequent imaging data is then found by comparing a few lines of k-space with the equivalent lines from a deformed reference image while varying the deformation over the model parameter. This procedure is known as image deformation recovery using overlapping partial samples (iDROPS). Simulations using 10 rapid dynamic studies from volunteers showed the average error in iDROPS-derived deformations within the liver to be 1.43 mm. A further four volunteers were imaged at higher spatial resolution. The complete reconstruction process using data from throughout several breathing cycles was shown to reduce blurring and ghosting in the liver. Retrospective respiratory gating was also demonstrated using the iDROPS parameterization. Magn Reson Med 62:440-449, 2009. (C) 2009 Wiley-Liss, Inc.

Introduction: A UK multicenter study compared the performance of contrast enhanced-magnetic resonance imaging with X-Ray Mammography in women at high-risk of breast cancer commencing in 1997. Selection criteria were used to identify women with at least 0.9% annual risk of breast cancer.Methods: Women at high breast cancer risk, with a strong family history and/or high probability of a BRCA1/BRCA2/TP53 mutation, were recruited from 22 centers. Those not known as gene carriers were asked to give a blood sample, which was tested anonymously for mutations. Women ages 35 to 49 years were offered annual screening for 2 to 7 years. Study eligibility at entry was assessed retrospectively by detailed examination of pedigrees and overall eligibility accounting for computer risk assessment and mutation results.Results: Seventy-eight of 837 (9%) women entered for screening were ineligible using the strict entry criteria. Thirty-nine cancers were detected in 1,869 women-years in study (incidence 21 per 1,000). Including 3,561 further years follow-up, 28 more breast cancers were identified (12 of 1,000). Incidence rates for 759 eligible women were 22 of 1,000 in study and 13 of 1,000 in total follow-up, compared with 9 of 1,000 and 4 of 1,000, respectively, in 78 ineligible women. Breast cancer rates were higher for BRCA2 than BRCA1 after testing anonymized samples in this selected population at 65 of 1,000 in study and 36 of 1,000 in total follow-up for BRCA2 compared with 44 of 1,000 and 27 of 1,000 for BRCA1.Conclusions: Strict enforcement of study criteria would have minimally improved the power of the study, whereas testing for BRCA1/2 in advance would have substantially increased the detection rates. (Cancer Epidemiol Biomarkers Prev 2009;18(7):2123-31)

Residual magnetisation is one of the major sources of artefacts in single point imaging sequences with short repetition times. The unwanted signal is caused by non-dephased transverse magnetisation excited in preceding acquisition cycles. Therefore, the problem emerges mainly around the centre of k-space and has been solved in the past by additional spoiling gradients. In this Work, unwanted residual magnetisation acquired with the SPRITE sequence was investigated and a new method for the suppression of residual magnetisation is presented. It is shown that residual magnetisation experiences a different phase encoding leading to residual images with a different FOV. A phase cycling filter is able to eliminate the unwanted signal. Furthermore, a description of all signal components that occur is presented using all operator notation. The notation is new in this field with respect to its completeness. That is, the signal description is based on an understanding of single point imaging sequences, such as SPRITE, by the use of all extended phase encode graph.A prominent in vivo example is that of sodium imaging in biological tissue where transverse relaxation times are Such that unwanted coherences call Occur and therefore residual magnetisation becomes a significant problem. For instance, sodium in biological tissue has two transverse relaxation times of approximately 3 ms and 15 ins at 4 T and this call result in significant artefacts if the encoding time is short and TR << 3 ms. (c) 2009 Published by Elsevier Inc.

The purpose was to determine the reproducibility of apparent diffusion coefficient (ADC) measurements in a two-centre phase I clinical trial; and to track ADC changes in response to the sequential administration of the vascular disrupting agent, combretastatin A4 phosphate (CA4P), and the anti-angiogenic drug, bevacizumab. Sixteen patients with solid tumours received CA4P and bevacizumab treatment. Echo-planar diffusion-weighted MRI was performed using six b values (b = 0-750 s/mm(2)) before (x2), and at 3 and 72 h after a first dose of CA4P. Bevacizumab was given 4 h after a second dose of CA4P, and imaging performed 3 h post CA4P and 72 h after bevacizumab treatment. The coefficient of repeatability (r) of ADC total (all b values), ADC high (b = 100-750) and ADC low (b = 0-100) was calculated by Bland-Altman analysis. The ADC total and ADC high showed good measurement reproducibility (r% = 13.3, 14.1). There was poor reproducibility of the perfusion-sensitive ADC low (r% = 62.5). Significant increases in the median ADC total and ADC high occurred at 3 h after the second dose of CA4P (p < 0.05). ADC measurements were highly reproducible in a two-centre clinical trial setting and appear promising for evaluating the effects of drugs that target tumour vasculature.

Mammographic breast density is one of the strongest known risk factors for breast cancer. We present a novel technique for estimating breast density based on 3D T1-weighted Magnetic Resonance Imaging (MRI) and evaluate its performance, including for breast cancer risk prediction, relative to two standard mammographic density-estimation methods.

Purpose: Hypoxia in patients with head-and-neck cancer (HNC) is well established and known to cause radiation resistance and treatment failure in the management of HNC. This study examines the role of parameters derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and perfusion computed tomography (CT) as surrogate markers of intratumoral hypoxia, defined by using the exogenous marker of hypoxia pimonidazole and the endogenous marker carbonic anhydrase 9 (CA9).Methods and Materials: Patients with HNC underwent preoperative DCE-MRI, perfusion CT, and pimonidazole infusion. Imaging parameters were correlated with pimonidazole and CA9 staining. The strength of correlations was tested by using a two-tailed Spearman's rank correlation coefficient.Results: Twenty-three regions of interest were analyzed from the 7 patients who completed the DCE-MRI studies. A number of statistically significant correlations were seen between DCE-MRI parameters (volume transfer between blood plasma and extracellular extravascular space [EES], volume of EES, rate constant between EES and blood plasma, time at arrival of contrast inflow, time to peak, average gradient, and time to onset) and areas with a pimonidazole score of 4. In the case of CA9 staining, only a weak correlation was shown with wash-in rate. There were no significant correlations between perfusion CT parameters and pimonidazole staining or CA9 expression.Conclusion: Intratumoral hypoxia in patients with HNC may be predicted by using DCE-MRI; however, perfusion CT requires further investigation. (C) 2009 Elsevier Inc.

Conventional structural imaging provides limited information on tumor characterization and prognosis. Advances in neurosurgical techniques, radiotherapy planning and novel drug treatments for brain tumors have generated increasing need for reproducible, noninvasive, quantitative imaging biomarkers. This review considers the role of physiological MRI and PET molecular imaging in understanding metabolic processes associated with tumor growth, blood flow and ultrastructure. we address the utility of various techniques in distinguishing between tumors and non-neoplastic processes, in tumor grading, in defining anatomical relationships between tumor and eloquent brain regions and in determining the biological substrates of treatment response. Much of the evidence is derived from limited case series in individual centers. Despite their 'added value', the effect of these techniques as an adjunct to structural imaging in clinical research and practice remains limited.

A description of the vascular input function is needed to obtain tissue kinetic parameter estimates from dynamic contrast enhanced MRI (DCE-MRI) data. This paper describes a general modelling framework for defining compact functional forms to describe vascular input functions. By appropriately specifying the components of this model it is possible to generate models that are realistic, and that ensure that the tissue concentration curves can be analytically calculated. This means that the computations necessary to estimate parameters from measured data are relatively efficient, which is important if such methods are to become of use in clinical practice. Three models defined by four parameters, using exponential, gamma-variate and cosine descriptions of the bolus, are described and their properties investigated using simulations. The results indicate that if there is no plasma fraction, then the proposed models are indistinguishable. When a small plasma fraction is present the exponential model gives parameter estimates that are biassed by up to 50%, while the other two models give very little bias; up to 10% but less than 5% in most cases. With a larger plasma fraction the exponential model is again biassed, the gamma-variate model has a small bias, but the cosine model has a very little bias and is indistinguishable from the model used to generate the data. The computational speed of the analytic approaches is compared with a fast-Fourier-transform-based numerical convolution approach. The analytic methods are nearly 10 times faster than the numerical methods for the isolated computation of the convolution, and around 4-5 times faster when used in an optimization routine to obtain parameter estimates. These results were obtained from five example data sets, one of which was examined in more detail to compare the estimates obtained using the different models, and with literature values.

Choline is a precursor of cellular phospholipid metabolism that provides Magnetic Resonance (MR) and Positron Emission Tomography (PET) biomarkers for cancer detection and response assessment. Employing Dynamic Nuclear Polarization we show that the MR signal of 15N in choline can be enhanced by at least 4 orders of magnitude with a relaxation time of ca. 4 min, providing a method to observe the action of choline kinase, an important target for novel cancer therapeutics.

Hepatic metastases are arterially supplied, resulting in an elevated hepatic perfusion index (HPI). The purpose of this study was to use dynamic contrast-enhanced (DCE) MR imaging to quantify the HPI of metastases and the liver before and after treatment with a novel antiangiogenic drug. Ten patients with known metastatic liver disease underwent DCE-MR studies. HPIs of metastases and whole liver were derived using regions of interest (ROIs) and calculated on a pixel-by-pixel basis from quantified changes in gadopentetate dimeglumine (Gd-DTPA) concentration. The HPI measurement error prior to treatment was derived by the Bland-Altman analysis. The median HPI before and after treatment with antiangiogenic drug BIBF 1120 were compared using the Wilcoxon signed rank test. Prior to treatment, the median HPI of metastases, 0.75 +/- 0.14, was significantly higher than that of the whole liver, 0.66 +/- 0.16 (p < 0.01). Bland-Altman reproducibility coefficients of the median HPI from metastases and whole liver were 13.0 and 5.1% respectively. The median HPI of metastases decreased significantly at 28 days after treatment with BIBF 1120 (p < 0.05). This pilot study demonstrates that HPI determined using quantified Gd-DTPA concentration is reproducible and may be useful for monitoring antiangiogenic treatment response of hepatic metastases.

To compare the diagnostic accuracy of MnDPDP MR imaging and diffusion-weighted imaging (DWI), alone and in combination, for detecting colorectal liver metastases in patients with suspected metastatic disease. Thirty-three consecutive patients with suspected colorectal liver metastases underwent MR imaging. Three image sets (MnDPDP, DWI and combined MnDPDP and DWI) were reviewed independently by two observers. Lesions were scored on a five-point scale for malignancy and the areas (Az) under the receiver operating characteristic curves were calculated for each observer and image set. The sensitivity and specificity for lesion detection were calculated for each image set and compared. There were 83 metastases, 49 cysts and 1 haemangioma. Using the combined set resulted in the highest diagnostic accuracy for both observers (Az=0.94 and 0.96), with improved averaged sensitivity of lesion detection compared with the DWI set (p=0.01), and a trend towards improved sensitivity compared with the MnDPDP set (p=0.06). There was no difference in the averaged specificity using any of the three image sets (p > 0.5). Combination of MnDPDP MR imaging and DWI resulted in the highest diagnostic accuracy and can increase sensitivity without loss in specificity.

The aim of this work was to use phosphorus magnetic resonance spectroscopy (P-31 MRS) to investigate the pharmacodynamic effects of LAQ824, a histone deacetylase (HDAC) inhibitor. Human HT29 colon carcinoma cells were examined by 31P MRS after treatment with LAQ824 and another HDAC inhibitor, suberoylanilide hydroxamic acid. HT29 xenografts and tumor extracts were also examined using P-31 MRS, pre- and post-LAQ824 treatment. Histone H3 acetylation was determined using Western blot analysis, and tumor microvessel density by immunohistochemical staining of CD31. Phosphocholine showed a significant increase in HT29 cells after treatment with LAQ824 and suberoylanilide hydroxamic acid. In vivo, the ratio of phosphomonoester/total phosphorus (TotP) signal was significantly increased in LAQ824-treated HT29 xenografts, and this ratio was inversely correlated with changes in tumor volume. Statistically significant decreases in intracellular pH, beta-nucleoside triphosphate (beta-NTP)/TotP, and beta-NTP/inorganic phosphate (Pi) and an increase in Pi/TotP were also seen in LAQ824-treated tumors. Tumor extracts showed many significant metabolic changes after LAQ824 treatment, in parallel with increased histone acetylation and decreased microvessel density. Treatment with LAQ824 resulted in altered phospholipid metabolism and compromised tumor bioenergetics. The phosphocholine and phosphomonoester increases may have the potential to act as pharmacodynamic markers for noninvasively monitoring tumor response after treatment with LAQ824 or other HDAC inhibitors.

Purpose: A method and computer tool to estimate percentage magnetic resonance (MR) imaging (MRI) breast density using three-dimensional T-1-weighted MRI is introduced, and compared with mammographic percentage density [X-ray mammography (XRM)].Materials and Methods: Ethical approval and informed consent were obtained. A method to assess MRI breast density as percentage volume occupied by water-containing tissue on three-dimensional T-1-weighted MR images is described and applied in a pilot study to 138 subjects who were imaged by both MRI and XRM during the Magnetic Resonance Imaging in Breast Screening study. For comparison, percentage mammographic density was measured from matching XRMs as a ratio of dense to total projection areas scored visually using a 21-point score and measured by applying a two-dimensional interactive program (CUMULUS). The MRI and XRM percent methods were compared, including assessment of left-right and interreader consistency.Results: Percent MRI density correlated strongly (r = 0.78; P < 0.0001) with percent mammographic density estimated using Cumulus. Comparison with visual assessment also showed a strong correlation. The mammographic methods overestimate density compared with MRI volumetric assessment by a factor approaching 2.Discussion: MRI provides direct three-dimensional measurement of the proportion of water-based tissue in the breast. It correlates well with visual and computerized percent mammographic density measurements. This method may have direct application in women having breast cancer screening by breast MRI and may aid in determination of risk.

Reference tissues are currently used to analyse dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data. The assessment of tumour response to treatment with anti-cancer drugs is a particularly important application of this type of analysis and requires a measure of reproducibility to define a level above which a significant change due to therapy can be inferred. This study compares the reproducibility of such quantification strategies with that found using a published, group-averaged uptake curve. It is shown that reference tissue quantification gives poorer reproducibility for most parameters than that found using a group-averaged plasma curve (a change in K(trans) of greater than 41.8% and 16.4% would be considered significant in the two approaches, respectively), but successfully incorporates some of the variability observed in plasma kinetics between visits and provides vascular input functions that, across the group, are comparable with the group-averaged curve. This study therefore provides an indirect validation of the methodology.

The quantification of dynamic contrast-enhanced (DCE) MRI data conventionally requires a conversion from signal intensity to contrast agent concentration by measuring a change in the tissue longitudinal relaxation rate, R(1). In this paper, it is shown that the use of a spoiled gradient-echo acquisition sequence (optimized so that signal intensity scales linearly with contrast agent concentration) in conjunction with a reference tissue-derived vascular input function (VIF), avoids the need for the conversion to Gd-DTPA concentration. This study evaluates how to optimize such sequences and which dynamic time-series parameters are most suitable for this type of analysis. It is shown that signal difference and relative enhancement provide useful alternatives when full contrast agent quantification cannot be achieved, but that pharmacokinetic parameters derived from both contain sources of error (such as those caused by differences between reference tissue and region of interest proton density and native T(1) values). It is shown in a rectal cancer study that these sources of uncertainty are smaller when using signal difference, compared with relative enhancement (15 +/- 4% compared with 33 +/- 4%). Both of these uncertainties are of the order of those associated with the conversion to Gd-DTPA concentration, according to literature estimates.

When applying pharmacokinetic (PK) models to dynamic contrast enhanced MRI (DCE-MRI) data it is important to appropriately deal with the enhancement onset time, because errors in the onset time will affect the PK parameter estimates. This paper presents a Bayesian approach to the estimation of the PK parameters k(ep) and K(trans) that robustly treats the onset time. This approach involves the computation of an analytically intractable integral, so two approximate methods are developed. The first uses adaptive numerical quadrature, which produces results accurate to a given tolerance, and the other a simple approximation with a summation. These approaches are compared with each other, and with the standard least-squares (LS) approach. The results of a Monte Carlo experiment show that the LS approach produces biased estimates when k(ep) is large and K(trans) is small, whereas both the Bayesian methods are unbiased. The two Bayesian methods produce very similar estimates, but the simple summation method requires less than half the computation time of either the LS, or the quadrature approximation. The standard deviation of the LS estimates is shown to be larger than either of the Bayesian estimates, while uncertainty estimates based around a Hessian approximation are shown to be too small for all three methods. A more detailed method of assessing the uncertainty of the Bayesian approach is described, and the results show that this is a more accurate description of the estimation uncertainty.

Pimonidazole is one of a series of nitroimidazole compounds that is widely used as a marker for qualitative and quantitative assessment of tumour hypoxia. We have observed a novel dynamic conformational exchange process in this molecule in aqueous solution. By a combination of 1H, 13C, two-dimensional 1H-1H EXchange SpectroscopY (EXSY) and spectral simulation, we unambiguously attribute the conformational exchange process to flipping of the six-membered heterocyclic ring.

To determine if magnetic field exposure close to two clinical 1.5 T magnetic resonance imaging (MRI) scanners during image acquisition and when moving in the spatially-varying static magnetic field is compliant with European Union (EU) Directive 2004/40/EC (the Directive).

Purpose: To assess the reproducibility of intrinsic relaxivity and both relaxivity- and susceptibility-based dynamic contrast enhanced (DCE) MRI in pelvic tumors; to correlate kinetic parameters obtained and to assess whether acute antivascular effects are seen in response to cisplatin- or taxane-based chemotherapy.Materials and Methods: T-1-weighted and T-2*-weighted DCE-MRI and basal R-2* measurements were performed on three consecutive days in women with gynecological tumors. The third scan was 21.0 (range 17.3-23.5) hours after the first cycle of chemotherapy. Kinetic parameter estimates were obtained and correlated between techniques. Test-retest reproducibility and response to treatment were assessed.Results: Relative blood volume (rBV) and relative blood flow (rBF) correlated strongly with transfer constant (K-trans), k(ep), and the initial area under the gadopentetate dimeglumine (Gd-DTPA) concentration-time curve (IAUGC) (all P < 0.01). The group 95% confidence interval (CI) for change was -10.8 to +12.1%; +/- 5.1%; -9.5 to +10.5%; +/- 7.5%; for K-trans, V-e, k(ep), and IAUGC, respectively, and 13.6%, +/- 2.4%, +/- 11.6%, and +/- 11.0%, for rBV, mean transit time (MTF), rBF, and R-2*, respectively. There were no significant acute changes in kinetic parameter estimates in response to treatment on group analysis, apart from a small decrease in v(e).Conclusion: The results confirm the dominant influence of flow on K-trans in untreated gynecological tumors. There is no evidence of an acute, large magnitude antivascular effect caused by cisplatin- or taxane-based chemotherapy.

OBJECTIVE. The purposes of this study were to determine whether the pretreatment apparent diffusion coefficients (ADCs) of hepatic metastatic lesions from colorectal cancer are predictive of response to chemotherapy and to compare the ADCs of metastatic lesions before and after chemotherapy.SUBJECTS AND METHODS. Twenty patients with potentially operable hepatic lesions larger than 1 cm in diameter metastatic from colorectal carcinoma were prospectively evaluated with diffusion-weighted imaging at three b values before and after chemotherapy. Quantitative ADC maps were calculated with images with b values of 0, 150, and 500 s/mm(2) (ADC0-500) and with images with b values of 150 and 500 s/mm(2) (ADC150-500). Regions of interest were drawn around metastatic lesions and randomly over liver. The mean ADC0-500 and mean ADC150-500 of metastatic lesions before and after chemotherapy were compared according to response defined by Response Evaluation Criteria in Solid Tumors criteria.RESULTS. Twenty-five responding and 15 nonresponding metastatic lesions were evaluated. Nonresponding lesions had a significantly higher pretreatment mean ADC0-500 and mean ADC150-500 than did responding lesions (Mann-Whitney U test, p < 0.002). There was a linear regression relation (r(2) = 0.34, p = 0.02) between percentage size reduction of metastatic lesions and pretreatment mean ADC150-500. After chemotherapy, responding lesions had a significant increase in mean ADC0-500 and ADC150-500 (Wilcoxon's signed rank, p = 0.025). No significant change was observed in nonresponding metastatic lesions (Wilcoxon's signed rank, p > 0.5) or in normal liver parenchyma (Wilcoxon's signed rank, p > 0.4).CONCLUSION. High pretreatment mean ADC0-500 and mean ADC150-500 of colorectal hepatic metastatic lesions were predictive of poor response to chemotherapy. A significant increase in mean ADC0-500 and ADC150-500 was observed in metastatic lesions that responded to chemotherapy. These findings may have implications for development of individualized therapy.

New evidence on breast Magnetic Resonance Imaging (MRI) screening has become available since the American Cancer Society (ACS) last issued guidelines for the early detection of breast cancer in 2003. A guideline panel has reviewed this evidence and developed new recommendations for women at different defined levels of risk. Screening MR1 is recommended for women with an approximately 20-25% or greater lifetime risk of breast cancer, including women with a strong family history of breast or ovarian cancer and women who were treated for Hodgkin disease. There are several risk subgroups for which the available data are insufficient to recommend for or against screening, including women with a personal history of breast cancer, carcinoma in situ, atypical hyperplasia, and extremely dense breasts on mammography. Diagnostic uses of MRI were not considered to be within the scope of this review.

The purpose of this study was to adapt the hepatic perfusion index (HPI) methodology previously developed for MRI to derive 3D parametric maps of HPI, and to investigate apparent differences in HPI maps between a group of colorectal cancer patients and controls. To achieve this, a new and simpler approach to HPI calculation which does not require measurements from the aorta or portal vein is introduced, and assessed with large liver regions of interest (ROIs) in patients and controls. Several example HPI maps showing localized variation are then presented. The subject group consisted of 12 patients with known colorectal metastases, and 13 control subjects referred for routine contrast-enhanced spine imaging with no history of neoplastic disease. HPI was evaluated from serial T-1 volume acquisitions acquired over the course of a Gd-DTPA bolus injection. Regions of abnormal perfusion were visible on the HPI maps derived for the patient group, manifested as areas of locally increased HPI extending around the visible margins of known metastases evident on the conventional contrast-enhanced images. This method for MR voxel-based parametric mapping of HPI has the potential to demonstrate regional variations in perfusion at the segmental and subsegmental level.

In this paper, we present an evaluation study of a set of registration strategies for the alignment of sequences of 3D dynamic contrast-enhanced magnetic resonance breast images. The accuracy of the optimal registration strategies was determined on unseen data. The evaluation is based on the simulation of physically plausible breast deformations using finite element methods and on contrast-enhanced image pairs without visually detectable motion artifacts. The configuration of the finite element model was chosen according to its ability to predict in vivo breast deformations for two volunteers. We computed transformations for ten patients with 12 simulated deformations each. These deformations were applied to the postcontrast image to model patient motion occurring between pre- and postcontrast image acquisition. The original precontrast images were registered to the corresponding deformed postcontrast images. The performance of several registration configurations (rigid, affine, B-spline based nonrigid, single-resolution, multi-resolution, and volume-preserving) was optimized for five of the ten patients. The images were most accurately aligned with volume-preserving single-resolution nonrigid registration employing 40 or 20 mm control point spacing. When tested on the remaining five patients the optimal configurations reduced the average mean registration error from 1.40 to 0.45 mm for the whole breast tissue and from 1.20 to 0.32 mm, for the enhancing lesion. These results were obtained on average within 26 (81) min for 40 (20) mm, control point spacing. The visual appearance of the difference images from 30 patients was significantly improved after 20 mm volume-preserving single-resolution nonrigid registration in comparison to no registration or rigid registration. No substantial volume changes within the region of the enhancing lesions were introduced by this nonrigid registration. (c) 2007 American Association of Physicists in Medicine.

The European Union (EU) Physical Agents (EMF) Directive [1] must be incorporated into UK law in 2008. The directive, which applies to employees working in MRI, sets legal exposure limits for two of the three types of EMF exposure employed in MRI; time-varying gradient fields and radiofrequency (RF) fields. Limits on the static field are currently not included but may be added at a later date. Conservative action values have been set for all three types of exposure including the static field. The absolute exposure limits will exclude staff from the scanner bore and adjacent areas during scanning, impacting on many clinical activities such as anaesthetic monitoring during sedated scans, paediatric scanning and interventional MRI. When the legislation comes into force, NHS Trusts, scanner companies and academic institutions will be required to show compliance with the law. We present results of initial measurements performed on a 1.5 T clinical MRI scanner. For the static field, the proposed action value is exceeded at 40 cm from the scanner bore and would be exceeded when positioning a patient for scanning. For the RF field, the action values were only exceeded within the bore at distances of 40 cm from the scanner ends during a very RF intensive sequence; MRI employees are unlikely to be in the bore during an acquisition. For the time-varying gradient fields the action values were exceeded 52 cm out from the mouth of the bore during two clinical sequences, and estimated current densities show the exposure limit to be exceeded at 40 cm for frequencies above 333 Hz. Limiting employees to distances greater than these from the scanner during acquisition will have a severe impact on the future use and development of MRI.

Polarization transfer has become a commonplace technique for the enhancement of a variety of nuclei in high field nuclear magnetic resonance (NMR). In this paper the homonuclear Hartmann-Hahn method for polarization transfer is revisited and it is shown that a 90% transfer of polarization can be achieved experimentally between a pair of scalar coupled C-13 nuclei in a sample of isotopically enriched glycine. This may show particular utility in the field of dynamic nuclear polarization (DNP) and could be used as an addendum to already established DNP techniques allowing the favourable enhancement to be 'stored' on long-lived nuclei and subsequently transferred to shorter-lived nuclei prior to observation.

Purpose: Magnetic resonance imaging (MRI) screening enables early detection of breast cancers in women with an inherited predisposition. Interval cancers occurred in women with a BRCA1 mutation, possibly due to fast tumor growth. We investigated the effect of a BRCA1 or BRCA2 mutation and age on the growth rate of breast cancers, as this may influence the optimal screening frequency.Experimental Design: We reviewed the invasive cancers from the United Kingdom, Dutch, and Canadian MRI screening trials for women at hereditary risk, measuring tumor size at diagnosis and on preceding MRI and/or mammography. We could assess tumor volume doubling time (DT) in 100 cancers.Results: Tumor DT was estimated for 43 women with a BRCA1 mutation, 16 women with a BRCA2 mutation, and 41 women at high risk without an identified mutation. Growth rate slowed continuously with increasing age (P = 0.004). Growth was twice as fast in BRCA1 (P = 0.003) or BRCA2 (P = 0.03) patients as in high-risk patients of the same age. The mean DT for women with BRCA1/2 mutations diagnosed at ages : 40, 41 to 50, and > 50 years was 28, 68, and 81 days, respectively, and 83, 121, and 173 days, respectively, in the high-risk group. Pathologic tumor size decreased with increasing age (P = 0.001). Median size was 15 mm for patients ages <= 40 years compared with 9 mm in older patients (P = 0.003); tumors were largest in young women with BRCA1 mutations.Conclusion: Tumors grow quickly in women with BRCA1 mutations and in young women. Age and risk group should be taken into account in screening protocols.

The purpose of this study was to evaluate distortion-corrected MRI as a radiotherapy planning tool for prostate cancer and the resultant implications for dose sparing of organs at risk. 11 men who were to be treated with radical conformal radiotherapy for localized prostate cancer had an MRI scan under radiotherapy planning conditions, which was corrected for geometric distortion. Radiotherapy plans were created for planning target volumes derived from the MRI- and CT-defined prostate. Dose volume histograms were produced for the rectum, bladder and penile bulb. The mean volume of the prostate as defined on CT and MRI was 41 cm3 and 36 cm3, respectively (p = 0.009). The predicted percentage of the rectum treated to dose levels of 45-65 Gy was significantly lower for plans delineating the prostate with MRI than for those with CT. The rectal-sparing effect was confined to the lowermost 4 cm of the rectum (anal canal). There were no differences between the predicted doses to bladder or penile bulb (as defined using MRI) between plans. In conclusion, prostate radiotherapy planning based on distortion-corrected MRI is feasible and results in a smaller target volume than does CT. This leads to a lower predicted proportion of the rectum, in particular the lower rectum (anal canal), treated to a given dose than with CT.

In this work we propose a method for automatically discriminating between different types of tissue in MR mammography datasets. This is accomplished by employing a wavelet-based multiscale analysis. After the data has been wavelet-transformed unsupervised machine learning methods are employed to identify typical patterns in the wavelet domain. To demonstrate the potential of the proposed approach we apply a filtering procedure that extracts the wavelet-based image information related to tumour tissue. In this way we obtain a robust segmentation of suspicious tissue in the MR image.

Registration of dynamic contrast-enhanced magnetic resonance images (DCE-MRI) of soft tissue is difficult. Conventional registration cost functions that depend on information content are compromised by the changing intensity profile, leading to misregistration. We present a new data-driven model of uptake patterns formed from a principal components analysis (PCA) of time-series data, avoiding the need for a physiological model. We term this process progressive principal component registration (PPCR). Registration is performed repeatedly to an artificial time series of target images generated using the principal components of the current best-registered time-series data. The aim is to produce a dataset that has had random motion artefacts removed but long-term contrast enhancement implicitly preserved. The procedure is tested on 22 DCE-MRI datasets of the liver. Preliminary assessment of the images is by expert observer comparison with registration to the first image in the sequence. The PPCR is preferred in all cases where a preference exists. The method requires neither segmentation nor a pharmacokinetic uptake model and can allow successful registration in the presence of contrast enhancement.

MN58b is a novel anticancer drug that inhibits choline kinase, resulting in inhibition of phosphocholine synthesis. The aim of this work was to develop a noninvasive and robust pharmacodynamic biomarker for target inhibition and, potentially, tumor response following MN58b treatment. Human HT29 (colon) and MDA-MB-231 (breast) carcinoma cells were examined by proton (1H) and phosphorus (31P) magnetic resonance spectroscopy (MRS) before and after treatment with MN58b both in culture and in xenografts. An in vitro time course study of MN58b treatment was also carried out in MDA-MB-231 cells. In addition, enzymatic assays of choline kinase activity in cells were done. A decrease in phosphocholine and total choline levels (P < 0.05) was observed in vitro in both cell lines after MN58b treatment, whereas the inactive analogue ACG20b had no effect. In MDA-MB-231 cells, phosphocholine fell significantly as early as 4 hours following MN58b treatment, whereas a drop in cell number was observed at 48 hours. Significant correlation was also found between phosphocholine levels (measured by MRS) and choline kinase activities (r2 = 0.95, P = 0.0008) following MN58b treatment. Phosphomonoesters also decreased significantly (P < 0.05) in both HT29 and MDA-MB-231 xenografts with no significant changes in controls. 31P-MRS and 1H-MRS of tumor extracts showed a significant decrease in phosphocholine (P < or = 0.05). Inhibition of choline kinase by MN58b resulted in altered phospholipid metabolism both in cultured tumor cells and in vivo. Phosphocholine levels were found to correlate with choline kinase activities. The decrease in phosphocholine, total choline, and phosphomonoesters may have potential as noninvasive pharmacodynamic biomarkers for determining tumor response following treatment with choline kinase inhibitors.

Phosphoinositide 3-kinase (PI3K) is an attractive target for novel mechanism-based anticancer treatment. We used magnetic resonance (MR) spectroscopy (MRS) to detect biomarkers of PI3K signaling inhibition in human breast cancer cells. MDA-MB-231, MCF-7, and Hs578T cells were treated with the prototype PI3K inhibitor LY294002, and the (31)P MR spectra of cell extracts were monitored. In every case, LY294002 treatment was associated with a significant decrease in phosphocholine levels by up to 2-fold (P < 0.05). In addition, a significant increase in glycerophosphocholine levels by up to 5-fold was also observed (P <or= 0.05), whereas the content of glycerophosphoethanolamine, when detectable, did not change significantly. Nucleotide triphosphate levels did not change significantly in MCF-7 and MDA-MB-231 cells but decreased by approximately 1.3-fold in Hs578T cells (P = 0.01). The changes in phosphocholine and glycerophosphocholine levels seen in cell extracts were also detectable in the (31)P MR spectra of intact MDA-MB-231 cells following exposure to LY294002. When treated with another PI3K inhibitor, wortmannin, MDA-MB-231 cells also showed a significant decrease in phosphocholine content by approximately 1.25-fold relative to the control (P < 0.05), whereas the levels of the remaining metabolites did not change significantly. Our results indicate that PI3K inhibition in human breast cancer cells by LY294002 and wortmannin is associated with a decrease in phosphocholine levels.

To prospectively document changes in contrast agent kinetics in patients with primary breast cancer treated with systemic chemotherapy after one or two cycles and to determine whether kinetic measures can be used to predict final clinicopathologic response.

Magnetic Resonance Imaging Workbench (MRIW) allows analysis of T1- and T2*-weighted dynamic contrast-enhanced magnetic resonance imaging data sets to extract tissue permeability and perfusion characteristics by using standard pharmacokinetic models. Parametric maps are calculated from individual pixel enhancement curves in regions of interest (ROIs) and displayed as color overlays on the anatomic images. User-defined ROIs can be saved to ensure consistency of later reanalysis. Individual parametric maps are visualized together with user-selected parameter time-series plots. The following selections are available: overall ROI enhancement curve and fit, histogram, and individual pixel enhancement curve and fit. Summary data (transfer constant, leakage space, rate constant, integrated area under the gadolinium curve after 60 seconds, relative blood volume, relative blood flow, and mean transit time) may be exported to permanent storage along with per-pixel results for statistical analysis. Numerical values for parameters are displayed below the plot for easy reference. The dynamic range of plots and parametric map overlays is interactively adjustable. Viewing individual enhancement curves and parametric maps allows radiologists to investigate the heterogeneity of contrast agent kinetics for lesion characterization and to scrutinize serial changes in response to therapy. MRIW is written in IDL, enabling it to be used on a variety of computer systems.

The first detailed evaluation is presented of high-resolution (31)P 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 (1)H MRS, (31)P 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 14 T. Metabolite stability was evaluated using four sequential 28-min acquisitions. High-resolution MRS was performed on extracts of the same tissue samples. (31)P 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.

Clinical trials of new cancer drugs should ideally include measurements of parameters such as molecular target expression, pharmacokinetic (PK) behavior, and pharmacodynamic (PD) endpoints that can be linked to measures of clinical effect. Appropriate PK/PD biomarkers facilitate proof-of-concept demonstrations for target modulation; enhance the rational selection of an optimal drug dose and schedule; aid decision-making, such as whether to continue or close a drug development project; and may explain or predict clinical outcomes. In addition, measurement of PK/PD biomarkers can minimize uncertainty associated with predicting drug safety and efficacy, reduce the high levels of drug attrition during development, accelerate drug approval, and decrease the overall costs of drug development. However, there are many challenges in the development and implementation of biomarkers that probably explain their disappointingly low implementation in phase I trials. The Pharmacodynamic/Pharmacokinetic Technologies Advisory committee of Cancer Research UK has found that submissions for phase I trials of new cancer drugs in the United Kingdom often lack detailed information about PK and/or PD endpoints, which leads to suboptimal information being obtained in those trials or to delays in starting the trials while PK/PD methods are developed and validated. Minimally invasive PK/PD technologies have logistic and ethical advantages over more invasive technologies. Here we review these technologies, emphasizing magnetic resonance spectroscopy and positron emission tomography, which provide detailed functional and metabolic information. Assays that measure effects of drugs on important biologic pathways and processes are likely to be more cost-effective than those that measure specific molecular targets. Development, validation, and implementation of minimally invasive PK/PD methods are encouraged.

Developments in magnetic resonance spectroscopy (MRS) at The Royal Marsden Hospital and The Institute of Cancer Research are reviewed in the context of preceding developments in nuclear magnetic resonance (NMR) and MRS, and some of the early developments in this field, particularly those leading to human measurements. The early development of technology, and associated techniques for human measurement and assessment will be discussed, with particular reference to experience at out institutions. Applications using particular nuclei will then be described and related to other experimental work where appropriate. Contributions to the development of MRS that have been published in Physics in Medicine and Biology will be discussed.

The initial area under the gadolinium curve (IAUGC) is often used in addition to or as an alternative to parameters derived from pharmacokinetic modelling of T1-weighted dynamic contrast-enhanced (DCE) MRI data in the assessment of response to treatment of cancer. However, the physiological meaning of the IAUGC has not been rigorously defined with respect to model-based parameters. Here, simulations of DCE-MRI data were used to investigate the relationship between IAUGC and the parameters K(trans) (transfer constant), v(e) (fractional extravascular extracellular volume) and v(p) (fractional plasma volume), using two vascular input functions. It is shown that IAUGC is a mixed parameter that can display correlation with K(trans), v(e) and v(p) and ultimately has an intractable relationship with all three. Furthermore, it is demonstrated that the range over which IAUGC is taken and the nature of the vascular input function do not significantly affect this relationship.

Following advances in conformal radiotherapy, a key problem now facing radiation oncologists is target definition. While MRI and CT provide images of excellent spatial resolution, they do not always provide sufficient contrast to identify tumour extent or to identify regions of high cellular activity that might be targeted with boost doses. Magnetic resonance spectroscopy (MRS) is an alternative approach that holds great promise for aiding target definition for radiotherapy treatment planning, and for evaluation of response and recurrence. MRS is able to detect signals from low molecular weight metabolites such as choline and creatine that are present at concentrations of a few mM in tissue. Spectra may be acquired from single voxels, or from a 2D or 3D array of voxels using spectroscopic imaging. The current state of the art achieves a spatial resolution of 6-10 mm in a scan time of about 10-15 min. Co-registered MR images are acquired in the same examination. The method is currently under evaluation, in particular in brain (where MRS has been shown to differentiate between many tumour types and grades) and in prostate (where cancer may be distinguished from normal tissue and benign prostatic hypertrophy). The contrast achieved with MRS, based on tissue biochemistry, therefore provides a promising alternative for identifying tumour extent and regions of high metabolic activity. It is anticipated that MRS will become an essential tool for treatment planning where other modalities lack the necessary contrast.

A version of the chirp z-transform (CZT) enabling signal intensity and phase-preserving field-of-view scaling has been programmed. The algorithm is important for all single-point imaging sequences such as SPRITE when used with multiple data acquisition for T; mapping or signal averaging. CZT has particular utility for SPRITE imaging of nuclei with short relaxation times such as sodium at high field. Here, a complete theory of the properties of CZT is given. This method operates entirely in k-space. It is compared with a conventional interpolation approach that works in image space after the application of a fast Fourier transformation. (c) 2005 Elsevier Inc. All rights reserved.

Recently it has been suggested that finite element methods could be used to predict breast deformations in a number of applications, including comparison of multimodality images, validation of image registration and image guided interventions. Unfortunately knowledge of the mechanical properties of breast tissues is limited. This study evaluated the accuracy with which biomechanical breast models based on finite element methods can predict the displacements of tissue within the breast in the practical clinical situation where the boundaries of the organ might be known reasonably accurately but there is some uncertainty on the mechanical properties of the tissue. For two datasets, we investigate the influence of tissue elasticity values, Poisson's ratios, boundary conditions, finite element solvers and mesh resolutions. Magnetic resonance images were acquired before and after compressing each volunteer's breast by about 20%. Surface displacement boundary conditions were derived from a three-dimensional nonrigid image registration. Six linear and three nonlinear elastic material models with and without skin were tested. These were compared to hyperelastic models. The accuracy of the models was evaluated by assessing the ability of the model to predict the location of 12 corresponding anatomical landmarks. The accuracy was most sensitive to the Poisson's ratio and the boundary condition. Best results were achieved for accurate boundary conditions, appropriate Poisson's ratios and models where fibroglandular tissue was at most four times stiffer than fatty tissue. These configurations reduced the mean (maximum) distance of the landmarks from 6.6 mm (12.4 mm) to 2.1 mm (3.4 mm) averaged over all experiments. (C) 2006 American Association of Physicists in Medicine.

Purpose: To evaluate prospectively the accuracy of a lesion classification system designed for use in a magnetic resonance (MR) imaging high-breast-cancer-risk screening study.Materials and Methods: All participating patients provided written informed consent. Ethics committee approval was obtained. The results of 1541 contrast material-enhanced breast MR imaging examinations were analyzed; 1441 screening examinations were performed in 638 women aged 24 - 51 years at high risk for breast cancer, and 100 examinations were performed in 100 women aged 23 - 81 years. Lesion analysis was performed in 991 breasts, which were divided into design (491 breasts) and testing (500 breasts) sets. The reference standard was histologic analysis of biopsy samples, fine-needle aspiration cytology, or minimal follow- up of 24 months. The scoring system involved the use of five features: morphology (MOR), pattern of enhancement (POE), percentage of maximal focal enhancement (PMFE), maximal signal intensity-time ratio (MITR), and pattern of contrast material washout (POCW). The system was evaluated by means of (a) assessment of interreader agreement, as expressed in kappa statistics, for 315 breasts in which both readers analyzed the same lesion, (b) assessment of the diagnostic accuracy of the scored components with receiver operating characteristic curve analysis, and (c) logistic regression analysis to determine which components of the scoring system were critical to the final score. A new simplified scoring system developed with the design set was applied to the testing set.Results: There was moderate reader agreement regarding overall lesion outcome (ie, malignant, suspicious, or benign) (kappa = 0.58) and less agreement regarding the scored components. The area under the receiver operating characteristic curve (AUC) for the overall lesion score, 0.88, was higher than the AUC for any one component. The components MOR, POE, and POCW yielded the best overall result. PMFE and MITR did not contribute to diagnostic utility. Applying a simplified scoring system to the testing set yielded a nonsignificantly (P = .2) higher AUC than did applying the original scoring system (sensitivity, 84%; specificity, 86.0%).Conclusion: Good diagnostic accuracy can be achieved by using simple qualitative descriptors of lesion enhancement, including POCW. In the context of screening, quantitative enhancement parameters appear to be less useful for lesion characterization.

Objectives: The aim of this study was to assess the consistency and performance of radiologists interpreting breast magnetic resonance imaging (MRI) examinations.Materials and Methods: Two test sets of eight cases comprising cancers, benign disease, technical problems and parenchymal enhancement were prepared from two manufacturers' equipment (X and Y) and reported by 15 radiologists using the recording form and scoring system of the UK MRI breast screening study [(MAgnetic Resonance Imaging in Breast Screening (MARIBS)]. Variations in assessments of morphology, kinetic scores and diagnosis were measured by assessing intraobserver and interobserver variability and agreement. The sensitivity and specificity of reporting performances was determined using receiver operating characteristic (ROC) curve analysis.Results: Intraobserver variation was seen in 13 (27.7%) of 47 of the radiologists' conclusions (four technical and seven pathological differences). Substantial interobserver variation was observed in the scores recorded for morphology, pattern of enhancement, quantification of enhancement and washout pattern. The overall sensitivity of breast MRI was high [88.6%, 95% confidence interval (CI) 77.4-94.7%], combined with a specificity of 69.2% (95% CI 60.5-76.7%). The sensitivities were similar for the two test sets (P=.3), but the specificity was significantly higher for the Manufacturer X dataset (P <.001). ROC curve analysis gave an area under the curve of 0.85 (95% CI 0.79-0.92)Conclusions: Substantial variation in all elements of the scoring system and in the overall diagnostic conclusions was observed between radiologists participating in MARIBS. High overall sensitivity was achieved with moderate specificity. Manufacturer-related differences in specificities possibly occurred because the numerical thresholds set for the scoring system were not optimised for both equipment manufacturers. Scoring systems developed on one equipment software may not be transferable to other manufacturers. (c) 2006 Elsevier Inc. All rights reserved.

The purpose of this study was to obtain quantitative measurements of the apparent diffusion coefficient (ADC1), flow insensitive apparent diffusion coefficient (ADC2) and perfusion fraction ( F) of colorectal hepatic metastases using DWI and to compare these measurements with those obtained in liver parenchyma. Forty patients with 66 hepatic metastases from colorectal carcinoma were prospectively evaluated using DWI with three b values. Quantitative maps of the ADC1 ( using b= 0, 150, 500 s/mm(2)images), ADC2 ( using b= 150, 500 s/mm(2) images) and fractional variation ( F) between ADC1 and ADC2, which reflects perfusion fraction, were calculated. The ADC1, ADC2 and F derived from metastases and liver parenchyma were compared. The mean ADC1 values of liver parenchyma and metastases were significantly higher than the mean ADC2 values ( P< 0.0001, paired t-test). Colorectal metastases were found to have higher mean ADC1 and ADC2 values compared with liver ( P< 0.0001, Mann-Whitney test). However, the estimated F was found to be lower in metastases compared to liver (P= 0.03, Mann-Whitney test). Colorectal hepatic metastases were characterised by higher ADC1 and ADC2 values, but lower F values compared to liver.

Contrast enhanced magnetic resonance imaging (CE MRI) is the most sensitive tool for screening women who are at high familial risk of breast cancer. Our aim in this study was to assess the cost-effectiveness of X-ray mammography (XRM), CE MRI or both strategies combined. In total, 649 women were enrolled in the MARIBS study and screened with both CE MRI and mammography resulting in 1881 screens and 1-7 individual annual screening events. Women aged 35-49 years at high risk of breast cancer, either because they have a strong family history of breast cancer or are tested carriers of a BRCA1, BRCA2 or TP53 mutation or are at a 50% risk of having inherited such a mutation, were recruited from 22 centres and offered annual MRI and XRM for between 2 and 7 years. Information on the number and type of further investigations was collected and specifically calculated unit costs were used to calculate the incremental cost per cancer detected. The numbers of cancer detected was 13 for mammography, 27 for CE MRI and 33 for mammography and CE MRI combined. In the subgroup of BRCA1 (BRCA2) mutation carriers or of women having a first degree relative with a mutation in BRCA1 (BRCA2) corresponding numbers were 3 (6), 12 (7) and 12 (11), respectively. For all women, the incremental cost per cancer detected with CE MRI and mammography combined was 28 pound 284 compared to mammography. When only BRCA1 or the BRCA2 groups were considered, this cost would be reduced to 11 pound 731 (CE MRI vs mammography) and 15 pound 302 (CE MRI and mammography vs mammography). Results were most sensitive to the unit cost estimate for a CE MRI screening test. Contrast-enhanced MRI might be a cost-effective screening modality for women at high risk, particularly for the BRCA1 and BRCA2 subgroups. Further work is needed to assess the impact of screening on mortality and health-related quality of life.

Knowledge of the accuracy of dose calculations in intensity-modulated radiotherapy of the head and neck is essential for clinical confidence in these highly conformal treatments. High dose gradients are frequently placed very close to critical structures, such as the spinal cord, and good coverage of complex shaped nodal target volumes is important for long term-local control.A phantom study is presented comparing the performance of standard clinical pencil-beam and collapsed-cone dose algorithms to Monte Carlo calculation and three-dimensional gel dosimetry measurement. Calculations and measurements are individually normalized to the median dose in the primary planning target volume, making this a purely relative study The phantom simulates tissue, air and bone for a typical neck section and is treated using an inverse-planned 5-field IMRT treatment, similar in character to clinically used class solutions.Results indicate that the pencil-beam algorithm fails to correctly model the relative dose distribution surrounding the air cavity, leading to an overestimate of the target coverage. The collapsed-cone and Monte Carlo results are very similar, indicating that the clinical collapsed-cone algorithm is perfectly sufficient for routine clinical use. The gel measurement shows generally good agreement with the collapsed-cone and Monte Carlo calculated dose, particularly in the spinal cord dose and nodal target coverage, thus giving greater confidence in the use of this class solution.

To measure hepatic concentrations of the fluorine-containing antimicrobial, sitafloxacin, using in vivo(19)F magnetic resonance spectroscopy (MRS).

Several mitogen-activated protein kinase (MAPK) signaling inhibitors are currently undergoing clinical trial as part of novel mechanism-based anticancer treatment strategies. This study was aimed at detecting biomarkers of MAPK signaling inhibition in human breast and colon carcinoma cells using magnetic resonance spectroscopy. We investigated the effect of the prototype MAPK kinase inhibitor U0126 on the (31)P-MR spectra of MDA-MB-231, MCF-7 and Hs578T breast, and HCT116 colon carcinoma cells. Treatment of MDA-MB-231 cells with 50 micromol/L U0126 for 2, 4, 8, 16, 24, 32, and 40 hours caused inhibition of extracellular signal-regulated kinases (ERK1/2) phosphorylation from 2 hours onwards. (31)P-MR spectra of extracted cells indicated that this was associated with a significant drop in phosphocholine levels to 78 +/- 8% at 8 hours, 74 +/- 8% at 16 hours, 66 +/- 7% at 24 hours, 71 +/- 10% at 32 hours, and 65 +/- 10% at 40 hours post-treatment. In contrast, the lower concentration of 10 micromol/L U0126 for 40 hours had no significant effect on either P-ERK1/ 2 or phosphocholine levels in MDA-MB-231 cells. Depletion of P-ERK1/2 in MCF-7 and Hs578T cells with 50 micromol/L U0126 also produced a drop in phosphocholine levels to 51 +/- 17% at 40 hours and 23 +/- 12% at 48 hours, respectively. Similarly, in HCT116 cells, inhibition with 30 micromol/L U0126 caused depletion of P-ERK1/2 and a decrease in phosphocholine levels to 80 +/- 9% at 16 hours and 61 +/- 4% at 24 hours post-treatment. The reduction in phosphocholine in MDA-MB-231 and HCT116 cells correlated positively with the drop in P-ERK1/2 levels. Our results show that MAPK signaling inhibition with U0126 is associated with a time-dependent decrease in cellular phosphocholine levels. Thus, phosphocholine has potential as a noninvasive pharmacodynamic marker for monitoring MAPK signaling blockade.

To develop a method of processing non-formalin fixed prostate specimens removed at radical prostatectomy to obtain fresh tissue for research and for correlating diagnostic and molecular results with preoperative imaging.

Vascular and angiogenic processes provide an important target for novel cancer therapeutics. Dynamic contrast-enhanced magnetic resonance imaging is being used increasingly to noninvasively monitor the action of these therapeutics in early-stage clinical trials. This publication reports the outcome of a workshop that considered the methodology and design of magnetic resonance studies, recommending how this new tool might best be used.

Biliary excretion is a significant component in the metabolism of many drugs, but remains difficult to detect and characterise non-invasively. A previous publication recently described the detection of metabolites of ifosfamide in gall bladder in a guinea pig model using in vivo 1H-decoupled 31P 3-D magnetic resonance spectroscopic imaging and a clinical 1.5 T MR scanner.. Here high-resolution 31P magnetic resonance spectroscopy (MRS) of extracted bile identifies peaks as parent ifosfamide (1.19+/-1.47 mM; mean+/-sd), carboxyifosfamide (2.04+/-1.04 mM) and a major contribution from a previously unreported peak at 16.0 ppm (4.05+/-2.38 mM). The unknown resonance was identified using liquid chromatography-mass spectrometry (LCMS) as the glutathione conjugate of ifosfamide (MW=531). This was confirmed by analysing products from the reaction of glutathione with ifosfamide using LCMS and MRS. These results demonstrate how combined in vivo and analytical MRS, together with mass spectrometry, can help identify visceral routes of drug metabolism, thereby aiding understanding of +/-drug disposition and mechanisms of action and toxicity. In particular, the distribution of ifosfamide and its metabolites into bile may be related to oxazophosphorine-related cholecystitis reported in patients.

Women genetically predisposed to breast cancer often develop the disease at a young age when dense breast tissue reduces the sensitivity of X-ray mammography. Our aim was, therefore, to compare contrast enhanced magnetic resonance imaging (CE MRI) with mammography for screening.

To develop 2D 1H-MRS measurement sequences for the evaluation of bone marrow lipids, and to assess these measurement sequences in healthy and diseased bone marrow.

Double resonance techniques such as INEPT (insensitive nuclei enhanced by polarization transfer) and JCP (J cross-polarization) have previously been applied in vitro to enhance the SNR of low-sensitivity nuclei and detect altered metabolism, for example, with 13C magnetic resonance spectroscopy (MRS), where the 1H-13C scalar couplings are of the order of 130 Hz. The aim of the present study was to investigate the potential advantage of using JCP for the detection of phosphomonoesters (PME) and phosphodiesters (PDE) with 31P MRS in vivo. These metabolites are involved in membrane metabolism and their concentration is altered in tumors and other pathologies. JCP has been implemented and compared with INEPT and pulse-and-acquire in vivo both in unlocalized and in localized spectra in order to select the optimum method for in vivo applications for PME and PDE detection. The results suggest that JCP can give up to 20% more signal in the PME region and up to 70% more signal in the PDE region, with 20 to 70% lower power deposition than INEPT. Such enhancement could be used to reduce the measurement times for equivalent signal-to-noise ratios. The JCP sequence is, however, slightly more sensitive than INEPT to RF field inhomogeneities, as predicted from theory.

In this work we present a gel dosimeter based on 2-Hydroxyethyl Methacrylate (HEMA). The gel dosimeter is manufactured in normal atmospheric oxygen (normoxic) and undergoes a measurable change after irradiation. The gel is shown to provide a signal to noise ratio of up to at least 35 and have a linear change in transverse relaxation rate up to 70 Gy when measured with magnetic resonance imaging.

Relaxation measurements performed at high magnetic field in magnetic resonance (MR) may be adversely affected by the influence of radiation damping in concentrated samples such as water. We consider how the measured value of T1 is affected by this phenomenon for a gadolinium-doped water sample and for an undoped water sample and consider the implications for evaluating contrast agents. A simple method involving the application of a pulsed field gradient to de-phase residual transverse components of the magnetization is shown to be an effective method for suppressing this effect. Given the central role that measurement of the T1 of water plays in the assessment of contrast agents as well as a host of other MR applications, care should always be employed when measuring and interpreting T1 measurements at high magnetic fields.

Imaging plays a fundamental role in the management of children with brain tumours. A series of new techniques, commonly grouped under the heading functional imaging, promise to give information on the properties and biological characteristics of tissues thereby adding to the structural information available from current imaging. The EPSRC funded a workshop to bring together clinicians from the UK Children's Cancer Study Group and scientific experts in the field to identify clinical problems in childhood brain tumours that may be addressed by functional imaging and to develop a clinical test bed for applying, evaluating and developing this new technology. The presentations and discussion sessions from the workshop are summarised and a review of the current 'state of the art' for this rapidly developing area provided. A key output of the workshop was agreement on a series of hypotheses which can be tested in carefully designed clinical Studies. (C) 2004 Wiley-Liss, Inc.

Purpose: We have shown previously that carbogen (95% 0(2), 5% CO2) breathing by rodents can increase uptake of anticancer drugs into tumours. The aim of this study was to extend these observations to other rodent models using the anticancer drug 5-fluorouracil (5FU). 5FU pharmacokinetics in tumour and plasma and physiological effects on the tumour by carbogen were investigated to determine the locus of carbogen action on augmenting tumour uptake of 5FU. Methods: Two different tumour models were used, rat GH3 prolactinomas xenografted s.c. into nude mice and rat H9618a hepatomas grown s.c. in syngeneic Buffalo rats. Uptake and metabolism of 5FU in both tumour models with or without host carbogen breathing was studied non-invasively using fluorine-19 magnetic resonance spectroscopy (F-19-MRS), while plasma samples from Buffalo rats were used to construct a NONMEM pharmacokinetic model. Physiological effects of carbogen on tumours were studied using P-31-MRS for energy status (NTP/Pi) and pH, and gradient-recalled echo magnetic resonance imaging (GRE-MRI) for blood flow and oxygenation. Results: In both tumour models, carbogan-induced GRE-MRI signal intensity increases of similar to 60% consistent with an increase in tumour blood oxygenation and/or flow. In GH3 xenografts, F-19-MRS showed that carbogen had no significant effect on 5FU uptake and metabolism by the tumours, and P-31-MRS showed there was no change in the NTP/Pi ratio. In H9618a hepatomas, F-19-MRS showed that carbogen had no effect on tumour 5FU uptake but significantly (p = 0.0003) increased 5FU elimination from the tumour (i.e. decreased the t(1/2)) and significantly (p = 0.029) increased (53%) the rate of metabolism to cytotoxic fluoronucleotides (FNuct). The pharmacokinetic analysis showed that carbogen increased the rate of tumour uptake of 5FU from the plasma but also increased the rate of removal. P-31-MRS showed there were significant (pless than or equal to 0.02) increases in the hepatoma NTP/Pi ratio of 49% and transmembrane pH gradient of 0.11 units. Conclusions: We suggest that carbogen can transiently increase tumour blood flow, but this effect alone may not increase uptake of anticancer drugs without a secondary mechanism operating. In the case of the hepatoma, the increase in tumour energy status and pH gradient may be sufficient to augment 5FU metabolism to cytotoxic FNuct, while in the GH3 xenografts this was not the case. Thus carbogen breathing does not universally lead to increased uptake of anticancer drugs.

New anticancer therapeutics that target tumor blood vessels promise improved efficacy and tolerability in humans. Early phase I drug trials have shown that the maximum tolerated dose may be inappropriate for more advanced clinical studies with efficacy endpoints. More advanced clinical trials have demonstrated that morphologic assessments of tumor response are of limited value for gauging the efficacy. of treatment. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can serve as pharmacodynamic indicator of biological activity for antivascular cancer drugs by helping to define the biologically active dose. DCE-MRI studies may also predict the efficacy of treatment on the basis of changes observed. If DCE-MRI is to be used for the selection of antivascular drugs that advance into efficacy trials, then it will be necessary to develop standardized approaches to measurement and robust analytic approaches with clear accepted endpoints specified prospectively that have biological validity. Such developments will be essential for multicenter trials in which it will be necessary to establish effective cross-site standardization of measurements and evaluation.

Objective: In this work, methods utilizing supervised and unsupervised machine learning are applied to analyze radiologically derived morphological and calculated kinetic tumour features. The features are extracted from dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) time-course data.Material: The DCE-MRI data of the female breast are obtained within the UK Multicenter Breast Screening Study. The group of patients imaged in this study is selected on the basis of an increased genetic risk for developing breast cancer.Methods: The k-means clustering and self-organizing maps (SOM) are applied to analyze the signal structure in terms of visualization. We employ k-nearest neighbor classifiers (k-nn), support vector machines (SVM) and decision trees (DT) to classify features using a computer aided diagnosis (CAD) approach.Results: Regarding the unsupervised techniques, clustering according to features indicating benign and malignant characteristics is observed to a limited extend. The supervised approaches classified the data with 74% accuracy (DT) and providing an area under the receiver-operator-characteristics (ROC) curve (AUC) of 0.88 (SVM).Conclusion: It was found that contour and wash-out type (WOT) features determined by the radiologists lead to the best SVM classification results. Although a fast signal uptake in early time-point measurements is an important feature for malignant/benign classification of tumours, our results indicate that the wash-out characteristics might be considered as important. &COPY; 2004 Elsevier B.V. All rights reserved.

MR images are known to be distorted because of both gradient nonlinearity and imperfections in the B-0 field, the latter caused either by an imperfect shim or sample-induced distortions. This paper describes in detail a method for correcting the gradient warp distortion, based on a direct field mapping using a custom-built phantom with three orthogonal grids of fluid-filled rods. The key advance of the current work over previous contributions is the large volume of the mapping phantom and the large distortions (&GT; 25 mm) corrected, making the method suitable for use with large field of view, extra-cranial images. Experimental measurements on the Siemens AS25 gradient set, as installed on a Siemens Vision scanner, are compared with a theoretical description of the gradient set, based on the manufacturer's spherical harmonic coefficients. It was found that over a volume of 320 x 200 x 340 mm(3) distortions can be successfully mapped to within the voxel resolution of the raw imaging data, whilst outside this volume, correction is still good but some systematic errors are present. The phenomenon of through-plane distortion (also known as 'slice warp') is examined in detail, and the perturbation it causes to the measurements is quantified and corrected. At the very edges of the region of support provided by the phantom, through-plane distortion is extreme and only partially corrected by the present method. Solutions to this problem are discussed. Both phantom and patient data demonstrate the efficacy of the gradient warp correction.

Dynamic contrast enhanced MRI (DCE-MRI) is being used increasingly in clinical trials to demonstrate that vascular disruptive and antiangiogenic agents target tumour microcirculation. Significant reductions in DCE-MRI kinetic parameters are seen within 4 - 24 and 48 h of treatment with vascular disruptive and antiangiogenic agents, respectively. It is important to know whether cytotoxic agents also cause significant acute reductions in these parameters, for reliable interpretation of results. This study investigated changes in transfer constant ( K trans) and the initial area under the gadolinium curve (IAUGC) following the first dose of chemotherapy in patients with mostly gynaecological tumours. A reproducibility analysis on 20 patients ( using two scans performed on consecutive days) was used to determine the significance of DCE-MRI parameter changes 24 h after chemotherapy in 18 patients. In 11 patients who received platinum alone or with a taxane, there were no significant changes in K trans or IAUGC in either group or individual patient analyses. When the remaining seven patients ( treated with a variety of agents including platinum and taxanes) were included ( n = 18), there were also no significant changes in K trans. Therefore, if combination therapy does show changes in DCE-MRI parameters then the effects can be attributed to antivascular therapy rather than chemotherapy.

We consider the use of adiabatic half-passage pulses (AHP) for the uniform excitation of highly non-equilibrium spin-systems such as spin-exchange optically pumped (SEOP) Xe-129. The method simplifies a number of problems that are encountered for these systems, notably the non-renewable nature of the magnetization, the need for accurate pulse calibration and the influence of radiation damping. This is shown to be a straightforward method for achieving the maximum obtainable signal and thereby for measuring the degree of polarization on a 1.5 T clinical MRI scanner. (c) 2005 Elsevier B.V. All rights reserved.

PURPOSE: To prospectively determine sensitivity and specificity of breast magnetic resonance (MR) imaging in a screening and symptomatic population by using independent double reading, with histologic or cytologic results or a minimum 18-month follow-up as the standard.MATERIALS AND METHODS: Informed consent and ethical approval were obtained. Reader performance was analyzed in 44 radiologists at 18 centers from 1541 examinations, including 1441 screening examinations in 638 high-risk women aged 24-51 years (mean, 40.5 years) and 100 examinations in symptomatic women aged 23-81 years (mean, 49.2 years). A screening protocol of dynamic T1-weighted three-dimensional imaging and 0.2 mmol/kg gadolinium-based intravenous contrast agent was used. Logistic and Poisson regressions were used to analyze reader performance in relation to experience. Correlation between readers was determined with K statistics. Sensitivity and specificity were analyzed according to reader, field strength, machine type, and histologic results.RESULTS: The proportion of studies with lesions analyzed reduced significantly with reader experience (odds ratio, 0.84 per 6 months; P < .001), and number of regions per lesion analyzed also diminished (incidence rate ratio, 0.98 per 6 months; P = .047). The two readers for each study agreed 87% of the time, with a moderately good K statistic of 0.52 (95% confidence interval [CI]: 0.45, 0.58). By taking the reading with the highest score (most likely to be malignant) from each double-read study, sensitivity was 91% (95% CI: 83%, 96%) and specificity was 81% (95% CI: 79%, 83%). Single readings had 7% lower sensitivity (95% CI: 4%, 11%) and 7% higher specificity (95% CI: 6%, 7%). Sensitivity did not differ between MR imager manufacturers or between 1.0- and 1.5-T field strength, but there were significant differences in specificity for machine type (P = .001) and for field strength adjusted for manufacturer (P =.001). Specificity, but not sensitivity, was higher in women younger than 50 years (P = .02).CONCLUSION: Independent double reading by 44 radiologists blinded to mammography results showed sensitivity and specificity acceptable for screening; sensitivity was higher when two readings were used, at the cost of specificity. Interreader correlation was moderately good, and evidence of learning was seen. Equipment manufacturer, field strength, and age affected specificity but not sensitivity. (c) RSNA, 2005

A new EPI-based method is presented which features optimized sampling of k-space enabling the integrated acquisition of two gradient echo images. The first of these images is predominantly T, weighted and the second is T-2* weighted. The new method combines echo sharing of sparsely acquired high spatial frequency components with the keyhole technique and half-Fourier image reconstruction. The feasibility of acquiring high spatial and temporal resolution in vivo images for perfusion mapping is demonstrated. In contrast to most current perfusion methods, which acquire the T-1- and T-2*-weighted images in separate acquisitions, the need for image co-registration here is obviated since both sets of images are EPI-based and are acquired within the same measurement.

SU5416 (Z-3-[(2,4-dimethylpyrrol-5-yl) methylidenyl]-2-indolinone; semaxanib) is a small molecule inhibitor of the vascular endothelial growth factor receptor (VEGFR2). A Phase I dose escalation study was performed. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used as a pharmacodynamic assessment tool. In all, 27 patients were recruited. SU5416 was administered twice weekly by fixed rate intravenous infusion. Patients were treated in sequential cohorts of three patients at 48, 65, 85 110 and 145 mg m(-2). A further dose level of 190 mg m(-2) after a 2-week lead in period at a lower dose was completed; thereafter, the cohort at 145 mg m(-2) was expanded. SU5416 showed linear pharmacokinetics to 145 mg m(-2) with a large volume of distribution and rapid clearance. A significant degree of interpatient variability was seen. SU5416 was well tolerated, by definition a maximum-tolerated dose was not defined. No reproducible changes were seen in DCE-MRI end points. Serial assessments of VEGF in a cohort of patients treated at 145 mg m(-2) did not show a statistically significant treatment-related change. Parallel assessments of the impact of SU5416 on coagulation profiles in six patients showed a transient effect within the fibrinolytic pathway. Clinical experience showed that patients who had breaks of therapy longer than a week could not have treatment reinitiated at a dose of 190 mg m(-2) without unacceptable toxicity. The 145 mg m(-2) dose level is thus the recommended dose for future study.

Radiotherapy treatment planning relies on the use of geometrically correct images. This paper presents a fully automatic tool for correcting MR images for the effects of B(0) inhomogeneities. The post-processing method is based on the gradient-reversal technique of Chang and Fitzpatrick (1992 IEEE Trans. Med. Imaging 11 319-29) which combines two identical images acquired with a forward- and a reversed read gradient. This paper demonstrates how maximization of mutual information for registration of forward and reverse read gradient images allows the elimination of user interaction for the correction. Image quality is preserved to a degree not reported previously.

Intermolecular multiple-quantum coherences (iMQCs) have been reported to offer a sensitivity to sample structure at a specific user-defined length scale down to the order of 10 microm. When assessing this novel contrast mechanism in controlled phantom experiments, we have observed three different mechanisms whereby residual single-quantum coherences (SQCs) arising from intense high spatial frequencies, stimulated echoes and strong spatially encoding gradients can produce significant changes in signal contrast at particular length scales. These changes which only appear when components arising from SQCs and iMQCs are both present in the detected signal, are similar to changes previously attributed to iMQCs alone. We demonstrate each mechanism by which these residual SQCs arise and describe methods for their suppression.

Assessment of low-grade glioma treatment response remains as much of a challenge as the treatment itself. Proton magnetic resonance spectroscopy ((1)H-MRS) and imaging were incorporated into a study of patients receiving temozolomide therapy for low-grade glioma in order to evaluate and monitor tumour metabolite and volume changes during treatment. Patients (n=12) received oral temozolomide (200 mg m(-2) day(-1)) over 5 days on a 28-day cycle for 12 cycles. Response assessment included baseline and three-monthly magnetic resonance imaging studies (pretreatment, 3, 6, 9 and 12 months) assessing the tumour size. Short (TE (echo time)=20 ms) and long (TE=135 ms) echo time single voxel spectroscopy was performed in parallel to determine metabolite profiles. The mean tumour volume change at the end of treatment was -33% (s.d.=20). The dominant metabolite in long echo time spectra was choline. At 12 months, a significant reduction in the mean choline signal was observed compared with the pretreatment (P=0.035) and 3-month scan (P=0.021). The reduction in the tumour choline/water signal paralleled tumour volume change and may reflect the therapeutic effect of temozolomide.

In recent years there has been a large amount of research into the potential use of radiation sensitive gels for three-dimensional verification of clinical radiotherapy doses. In this paper we report the use of a MAGIC gel dosimeter (Fong et al 2001 Phys. Med. Biol. 46 3105) for the verification of a specific patient's radiation therapy dose distribution. A 69-year-old male patient presented with a squamous cell carcinoma extending approximately 180 degrees across the top of the scalp (anterior to posterior) and from just over midline to 90 degrees left of the skull. The patient's treatment was commenced using two electron fields. For gel dosimetry, phantoms were produced in which the outer surface spatially corresponded to the outer contours of the patient's anatomy in the region of irradiation. The phantoms were treated with either electrons or intensity modulated radiation therapy (IMRT) with photons. The results identified a hot spot between the matched electron fields and confirmed the more homogeneous dose distribution produced by the IMRT planning system. The IMRT plan was then clinically implemented. The application of a clinical dose to a phantom shaped to a specific patient as well as the ability to select a slice at will during phantom imaging means that gel dosimetry can no longer be considered to simply have potential alone, but is now in fact a useful dosimetric tool.

Dose resolution, DdeltaP, is becoming a common method for characterizing the performance of a gel dosimeter. In this note we examine how the goodness of fit of the calibration function affects DdeltaP and show that its inclusion in the calculation of DdeltaP is essential to avoid overestimating the performance of the gel.

The aim of this study was to investigate the microenvironmental factors likely to influence the longitudinal relaxation time of MR visible drugs or compounds in vivo at 1.5 T. The relative influence that viscosity, albumin and paramagnetic contrast agent concentrations have on the observed longitudinal relaxation times of three 19F MR detectable drugs and compounds have been investigated. Our data show that for 5-fluorouracil, flucloxacillin and tetrafluorosuccinic acid-containing phantoms, the presence of albumin at normal physiological concentrations will have relaxation effects of the same order of magnitude as that of a commonly clinically administered contrast agent, gadolinium diethylenetriamine pentaacetic acid. The contribution of viscosity is shown, in the examples studied here, to be of minor importance, contributing less than 6.5% to the observed relaxation effects. It is also demonstrated that in the presence of competitive binding of other ligands for common binding sites on albumin, the 19F longitudinal relaxation time of 5-fluorouracil can increase by up to 340% from its value in the absence of the competing ligand. The relevance of the findings to in vivo studies is discussed.

A single large dose of megavoltage x-rays delivered through a grid is currently being utilized by some centres for palliative radiotherapy treatments of large tumours. In this note, we investigate the dosimetry of grid therapy using two-dimensional film dosimetry and three-dimensional gel dosimetry. It is shown that the radiation dose is attenuated more rapidly with depth in a grid field than an open field, and that even shielded regions receive approximately 25% of the dose to the unshielded areas.

Purpose: Previous studies have shown that tumor response to capecitabine strongly correlates with tumor thymidine phosphorylase (TP). The aims of our study were to (a) investigate the pharmacological role of TP by measuring the pharmacokinetics (PK) of capecitabine in a human bladder tumor model that was characterized by the overexpression of TP and (b) develop the use of PK measurements for capecitabine by fluorine-19 magnetic resonance spectroscopy as a noninvasive surrogate marker for determining TP levels in tumors and for predicting tumor response to capecitabine in patients.Experimental Design: TP overexpressing (2T10) and control tumors were grown s.c. in nude mice. Mice were given a dose of capecitabine or 5'-deoxy-5-fluorouridine (5'DFUR). F-19 tumor spectra were acquired for determination of rate constants of capecitabine breakdown and buildup and subsequent breakdown of intermediates, 5'-deoxy-5-fluorocytidine (5'DFCR) and 5'DFUR. The rate constant of 5'DFUR breakdown was also evaluated.Results: The rate constant of breakdown of intermediates was significantly faster in 2T10 tumors than controls (P < 0.003). No significant differences in the rate of capecitabine breakdown or intermediate buildup were observed. The rate constant of 5'DFUR breakdown in the 2T10 tumors was doubled compared with controls (P < 0.001).Conclusions: This study confirmed the expected pathway of capecitabine metabolism and showed that the level of TP was related to the rate of 5'DFUR conversion. Using in vivo fluorine-19 magnetic resonance spectroscopy to measure the PK of capecitabine and its intermediate metabolites in tumors may provide a noninvasive surrogate method for determining TP levels in tumors and for predicting tumor response to capecitabine in patients.

This work describes the development of a quality control protocol, which can be implemented to assess the accuracy, precision and reproducibility of the apparent diffusion coefficient (ADC) measurement on a clinical magnetic resonance imaging (MRI) system. The precision and accuracy of the ADC measurement are analysed with regard to MRI system noise, signal reproducibility and differences between nominal and effective b values. Two aqueous test-solutions of CuSO4 and sucrose are prepared for the quality control protocol. ADC measurement with the CuSO4 Solution is more sensitive to differences between nominal and effective b values, on account of the solution's high ADC. ADC measurement with the sucrose solution is more sensitive to signal reproducibility due to the solution's low baseline signal intensity. The ADC of the test-solutions is measured on an MRI system at our centre with a sequence used for clinical studies using diffusion imaging. Two parameters, Q and R, are defined for the analysis of the quality control ADC values. The Q parameter is the ratio of the standard deviation of the quality control mean ADC values over time to the optimal standard deviation, as derived from the effect of thermal noise on the ADC measurement uncertainty. Analysis with the Q parameter indicates that signal reproducibility errors contribute to ADC variations on our MRI system when imaging with high b values (b > 500 mm s(-2)), whereas differences between nominal and effective b values have a greater impact on the ADC measurement when imaging with low b values (b < 500 mm s(-2)). The R parameter is defined as the ratio of the directional variation of the ADC quality control values to the uncertainty of the ADC measurement. Analysis with the R parameter shows that the effect of directional variation of the ADC measurement on our MRI system is more pronounced when imaging with low b values. The quality control protocol identified a systematic error, which introduced a small system-induced anisotropy in the ADC measurement. This error is currently taken into account in the analysis of clinical studies employing the diffusion imaging sequence used in this quality control protocol.

In this study, the dose distribution delivered by low dose rate Cs-137 brachytherapy sources was investigated using Monte Carlo (MC) techniques and polymer gel dosimetry. The results obtained were compared with a commercial treatment planning system (TPS). The 20 mm and the 30 mm diameter Selectron vaginal applicator set (Nucletron) were used for this study. A homogeneous and a heterogeneous-with an air cavity-polymer gel phantom was used to measure the dose distribution from these sources. The same geometrical set-up was used for the MC calculations. Beyond the applicator tip, to the presence of stainless steel in the applicator and source set, which are not considered by the TPS calculations. Beyond the air cavity, differences in dose of around 5% were noted, due to the TPS assuming a homogeneous water medium. The polymer gel results were in good agreement with the MC calculations for all the cases investigated.

A multi-institutional group has been created to demonstrate the utility of in vivo P-31 magnetic resonance spectroscopy (P-31-MRS) to study human cancers in vivo. This review is concerned with the novel problems concerning quality control in this large multinational trial of P-31 MRS. Our results show that the careful and systematic performance of the quality control tests depicted here (standardized dual H-1/P-31 tuned radiofrequency probe, quality control procedures, routine use of H-1 irradiation while acquiring P-31 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 P-31 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. Copyright (C) 2004 John Wiley Sons, Ltd.

Accurate anatomical delineation of the gross tumour volume (GTV) is crucial for effective radiotherapy (RT) treatment of prostate cancers. Although reference to pelvic magnetic resonance (MR) for improved delineation of the prostate is a regular practice in some clinics, MR has not replaced CT due to its geometrical distortions and lack of electron-density information. The possibility and practicality of using MR only for RT treatment planning were studied.

This brief review considers to what extent Magnetic Resonance Spectroscopy (MRS) can play a role in monitoring early tumour response with examples of preclinical studies and selected clinical studies in tumours of children and young adults. An early non-invasive indicator of tumour response to therapy would provide useful information regarding the effectiveness of therapy. This might be a relevant prognostic factor in new patients and in phase II studies could facilitate recommendations at an early stage as to whether to continue treatment. This review suggests that several markers and ratios are emerging as potential prognostic markers, but larger prospective studies are needed before translating this into clinical practice.

The potential clinical role of in vivo (1)H-MRS ((1)H-magnetic resonance spectroscopy) lipid methylene resonance measurements of human glioma has been assessed. 20 patients, 14 with low grade and 6 with high grade gliomas have been investigated using single voxel (1)H-MRS. Three of the low grade group had undergone transformation by clinical and imaging criteria. Short echo time (TE=20 ms, TR=2500 ms) single voxel Stimulated Echo Acquisition (STEAM) spectra with (acquisitions=64) and without (acquisitions=4) water suppression were acquired. Additionally, T(1) weighted (T(1)W) water spectra (TE=20 ms, TR=888 ms) were acquired pre- and post-injection of Gd-DTPA (0.2 mmol x kg(-1)). The T(1)W water spectra were used to determine the water proton enhancement occurring within the spectroscopic voxel. The enhancement expressed as a percentage was compared with the lipid methylene peak. All the high grade tumours had significantly higher levels of lipid than low grade tumours (p=0.002). Low grade tumours had significantly less water proton enhancement than transformers (p=0.04) and high grade tumours (p=0.001). The lipid methylene signal correlated strongly with the voxel water enhancement (r(2)=0.74, p<0.0001). The data support the view that the spectroscopically detected lipid methylene signal may be a useful criterion in grading glioma. The correlation of the lipid methylene signal with blood-brain barrier breakdown suggests that detection of a previously absent (1)H-MRS lipid methylene signal in low grade tumours might be an early indicator of transformation.

The aim of the work is to evaluate a magnetic resonance imaging (MRI) thermometry sequence suitable for targeting of focused ultrasound (FUS) when used in vascular occlusion studies. A sliding window dual gradient echo (SW-dGRE) sequence was used. This sequence has the capability of monitoring both T1 relaxation and phase changes, which vary with temperature. Preliminary work involved quantification of the changes in T1 relaxation time with temperature and obtaining the PRF shift coefficient in polyacrylamide gel as it underwent an exothermic reaction during polymerization (avoiding the use of an external heat source). Temperature changes were visualized using thermal maps acquired with the sequence. For FUS guidance a thermal imaging technique is required with a temporal resolution <5 s, a spatial resolution of approximately 1 mm and a temperature resolution of approximately 5 degrees C. The sequence was optimized to improve the CNR (contrast to noise ratio) and SNR (signal to noise ratio) in the phase and magnitude images respectively. The PRF coefficient obtained for the polyacrylamide gel was -9.98 +/- 0.24 ppb degrees C(-1), whilst deltaT1 and temperature change were related by a proportionality factor, the T1 temperature coefficient, of 102.3 +/- 2.9 ms degrees C(-1). The sequence produces an image at every 1.4 s interval. In both magnitude and phase data, the in-plane resolution is +/- 1.2 mm and the temperature resolution is approximately 2 degrees C. The advantage of this sequence is that the temperature obtained from the magnitude data can be confirmed independently using the phase data and vice versa. Thus the sequence can essentially be crosschecked.

Several (31)P MRS studies in tumors in vivo have shown that levels of phosphocholine (PC) and other phosphomonoesters (PME) and phosphodiesters (PDE) are useful prognostic or early-response indicators. To improve sensitivity for such measurements, four polarization transfer (PT) sequences (insensitive nuclei enhanced by PT (INEPT), distortionless enhancement by PT (DEPT), reverse-INEPT, and heteronuclear single-quantum coherence (HSQC)) were assessed theoretically and experimentally. The presence of homonuclear ((1)H-(1)H) and heteronuclear ((31)P-(1)H) couplings of similar magnitude makes theoretical analysis very sensitive to precise model parameters, especially for the (1)H-detected sequences. The (1)H-(1)H coupling causes the splitting of (1)H peaks, and hence reduces the proton spectral resolution. This effect and a 50% signal loss from gradient-enhanced water suppression negate the usual advantages of (1)H-detection. Among the PT methods, INEPT gave the higher signal enhancement. However, T(2) losses during the long echo times (TEs) required by the weak coupling limited the resulting signals from PC.

Proton (hydrogen 1) magnetic resonance (MR) spectroscopy was used to study model and porcine bile in vitro. The method was subsequently developed to facilitate the acquisition of in vivo 1H MR spectra from the gallbladder bile of 10 human volunteers. Signals attributable to phosphotidylcholine and conjugated bile acid protons were observed in eight of the 10 volunteers. Phosphotidylcholine concentrations were estimated, and five values (mean = 35.8 mmol/L, SD = 9.8) were within the expected range of levels in human bile. Findings in this preliminary investigation indicate that human gallbladder bile can be qualitatively and quantitatively studied noninvasively with 1H MR spectroscopy.

To perform a Phase I study of SR-4554, a fluorinated 2-nitroimidazole noninvasive probe of tumor hypoxia detected by (19)F magnetic resonance spectroscopy (MRS).

Polymer gel dosimetry has been used to measure the radiotherapy dose homogeneity in a breast phantom for two different treatment methods. The first 'standard' method uses two tangential wedged fields while the second method has three static fields shaped by multileaf collimators (MLCs) in addition to the standard wedged fields to create intensity modulated fields. Gel dose distributions from the multileaf modulation treatment show an improved dose uniformity in comparison to the standard treatment with a decreased volume receiving doses over 105%.

This paper presents a novel method for validation of nonrigid medical image registration. This method is based on the simulation of physically plausible, biomechanical tissue deformations using finite-element methods. Applying a range of displacements to finite-element models of different patient anatomies generates model solutions which simulate gold standard deformations. From these solutions, deformed images are generated with a range of deformations typical of those likely to occur in vivo. The registration accuracy with respect to the finite-element simulations is quantified by co-registering the deformed images with the original images and comparing the recovered voxel displacements with the biomechanically simulated ones. The functionality of the validation method is demonstrated for a previously described nonrigid image registration technique based on free-form deformations using B-splines and normalized mutual information as a voxel similarity measure, with an application to contrast-enhanced magnetic resonance mammography image pairs. The exemplar nonrigid registration technique is shown to be of subvoxel accuracy on average for this particular application. The validation method presented here is an important step toward more generic simulations of biomechanically plausible tissue deformations and quantification of tissue motion recovery using nonrigid image registration. It will provide a basis for improving and comparing different nonrigid registration techniques for a diversity of medical applications, such as intrasubject tissue deformation or motion correction in the brain, liver or heart.

We have compared the efficiency of spin polarisation-induced nuclear Overhauser effect (SPINOE) and low-field thermal mixing (TM) for enhancing the C-13 NMR signal by polarisation transfer from hyperpolarised xenon. In our experiments of TM, the carbon NMR signal was increased by up to a factor of 390, about five times larger than the maximum enhancement obtained using SPINOE in liquid hyperpolarised xenon. Moreover, we show that the enhanced C-13 nuclear polarisation survives a solid/liquid transition, and the subsequent separation of the carbon compound from hyperpolarised xenon, thus opening the possibility of producing hyperpolarised carbon compounds for NMR applications in biological systems and materials science. (C) 2003 Elsevier Science B.V. All rights reserved.

MRS has considerable potential for the measurement of drug pharmacokinetics in vivo. In this study single- and double-resonance P-31 MRS was used to investigate the biodistribution, pharmacokinetics, and metabolism of ifosfamide following administration of 500 mg/kg ifosfamide in guinea pigs. H-1-decoupling was found to nearly double the signal of detected peaks. However, in contrast to studies of ifosfamide in solution, the polarization transfer sequence gave no further signal enhancements. This was attributed to significantly reduced relaxation times in vivo. Chemical shift imaging (CSI) measurements showed that significant proportions of ifosfamide-related P-31 MRS signals arose from the liver, as expected, but also from the gall bladder, which was not predicted from the current literature. Signals were observed within 5 min of the end of administration. The half life in liver was approximately 74 min, whereas in gall bladder there was no measurable signal decay during the 2.5-hr studies. High-resolution P-31 MRS of bile showed that the "ifosfamide" peak in vivo consists of at least two compounds. The lower-concentration peak is ifosfamide, and an investigation is under way to identify the higher-concentration peak. Other peaks observed in bile are tentatively assigned to carboxy-ifosfamide and dechloroethyl-ifosfamide. Overall, H-1-decoupled P-31 MRS has proved to be a useful tool for investigating the metabolism of ifosfamide in vivo. (C) 2003 Wiley-Liss, Inc.

17-allylamino,17-demethoxygeldanamycin (17AAG) is a novel anticancer drug that inhibits heat shock protein 90 (Hsp90), resulting in proteasomal degradation of several oncogenic proteins. We used phosphorus magnetic resonance spectroscopy (31P-MRS) to determine whether 17AAG treatment leads to alterations in phospholipids that could serve as pharmacodynamic markers for tumor response to 17AAG.

The sampling of gall bladder bile for analytical studies remains an invasive procedure. We demonstrate the application of the non-invasive methodology of H-1-MR spectroscopy to the qualitative and quantitative assessment of human gall bladder bile in vivo. Spectral profiles in vivo are shown in relation to model and porcine gall bladder bile and the quantitation in man of the trimethylamine (choline) and lecithin concentrations were estimated to range from 25.9 mM to 48.4 mM (mean: 35.8 mM, standard deviation: 9.8). The composition of human gall bladder bile together with the quantitation of various constituents can be studied non-invasively in vivo.

The aim was to determine if a specific inhibitor of vacuolar H(+)-ATPases (V-ATPases), Bafilomycin A1 (BFM), could increase the low extracellular pH (pHe) typical of solid tumours and thus inhibit their growth in vivo. BFM inhibited the proliferation of various human cells and rat pituitary GH3 tumour cells in vitro (IC50: 2.5-19.2 nM), and flow cytometry on GH3 cells showed a marked increase in S and G2M phases after 16-48 h, but no evidence of increased apoptosis. BFM caused significant inhibition of GH3 xenograft growth, and histomorphometry showed a 30% decrease in mitosis but no change in apoptosis. 31P-magnetic resonance spectroscopy (MRS) in vivo of GH3 xenografts showed that BFM increased pHe, but did not affect pHi, resulting in a decrease in the negative pH gradient (-delta pH). BFM decreased lactate formation suggesting a reduction in glycolysis. We suggest that BFM reduces extracellular H(+)-transport by inhibition of V-ATPases leading to an increase in pHe and decreased glycolysis, and thus reduced tumour cell proliferation. 19F-MRS in vivo showed that a smaller -delta pH was associated with decreased retention of 5-fluorouracil (5FU) which was consistent with our previous data in vivo implying the -delta pH controls tumour retention of 5 FU.

When summing the spectra acquired with phased array coils, signals with low signal-to-noise ratio or wrongly corrected phase may degrade the overall signal-to-noise ratio (SNR). Here we present a mathematical expression predicting the dependence of combined SNR on the signal-to-noise ratios and errors in phase correction of composite signals. Based on this equation, signals that do not lead to an overall increase in signal-to-noise ratio can be identified and excluded from the weighted sum of signals. This tool is particularly useful for the combination of large numbers of signals. Additionally, a simple and robust algorithm for calculating the complex weighting factors necessary for the signal-to-noise weighted combination of spectroscopic data is presented. Errors in the calculation and correction of relative phase differences between composite spectra are analysed. The errors have a negligible effect on the overall spectral SNR for typical clinical magnetic resonance spectroscopy (MRS). The signal combination routine developed here has been applied to the first in vivo MRS study of human rectal adenocarcinomas at 1.5 T (Dzik-Jurasz A S K, Murphy P S, George M, Prock T, Collins D J, Swift I and Leach M O 2001 Magn. Reson. Med. at press), showing improvements of combined spectral SNR of up to 34% over the maximum SNR from a single element.

The aim of the study was to establish the normal range 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(e)) 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(e) 18.5% and MCMA 0.164 mmol/kg). Muscle parameters values were lower (K(trans) 0.126-0.137 min(-1), v(e) 10.6-11.5% and MCMA 0.077-0.086 mmol/kg). The mean difference between paired examinations was not significantly different from zero for any parameter. v(e) and MCMA had the lowest wCV (between 19 and 29%). For individuals, a log(10) K(trans) change of approximately 0.90 in muscles and 0.52 in the ischium would be statistically significant. The corresponding absolute changes for v(e) 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(e) 1.5% and ischium log(10) K(trans) 0.123 and v(e) 3.1%). Fat and the femoral head are unreliable tissues from which to obtain kinetic parameter estimates due to poor enhancement. v(e) 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.

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 T(1)- and T(2)*-weighted images with a time resolution of 1.1 s.

The longitudinal (R1) and transverse (R2) relaxivities of the clinically used contrast agents Gd(DTPA)2-, Gd(DOTA)- and Gd(DTPA-BMA) have been determined in mixed aqueous metabolite solutions for choline, creatine and N-acetylaspartate. Measurements were performed at 1.5 T using a STEAM sequence on 25 mM metabolite solutions at pH = 7.4 and 22 degrees C. The data showed that for all the contrast agents and metabolites, R1 approximately = R2. The largest range of relaxivity values was found for Gd(DTPA)2-, where R2 = 6.8 +/- 0.3 mM(-1) s(-1) for choline and 1.5 +/- 0.4 mM(-1) s(-1) for N-acetylaspartate. Variation in relaxivity values was attributed primarily to differences between the charges of the paramagnetic agent and metabolite. The maximum potential influence of the contrast agents on in vivo metabolite signals was calculated using the measured relaxivities.

In this note we describe and evaluate the performance of a novel approach to information recovery that involves consecutive projection onto convex sets (POCS). The method is applied to a time series of medical image data and the results are compared to images reconstructed using the standard POCS reconstruction method. The consecutive POCS method converges in a desired step-wise manner producing reconstructed images of superior quality compared to the standard scheme and can speed up the reconstruction process. The proposed method is of value for many finite sampling imaging problems including, in particular, fast-scan magnetic resonance imaging applications.

This study was designed to determine whether 1H-MR spectra of locally advanced human rectal adenocarcinoma could be acquired in vivo at 1.5 T. Despite the relatively large size of these neoplasms, only six out of 21 tumors accommodated a voxel size of 8 cm3. This was due to air pockets within the tumor mass, which limited voxel positioning. Localized proton spectra were acquired at short (20 ms) and long (135 ms) echo times (TEs) using a single-voxel technique. The most commonly detected metabolites were choline and lipid.

The influence of Gd-DTPA on T(1)-weighted (T(1)W) proton MR spectra has been investigated in 19 patients with histologically verified low (n = 13) or high-grade (n = 6) gliomas. Repeat measurements were performed on 9 patients (7 low-grade and 2 high-grade), with 28 examinations performed in total. Comparison of spectra obtained before and after 0.2 mmol/kg Gd-DTPA showed contrast agent induced broadening of the choline signal without significant signal area change. Lack of enhancement of the choline signal with the T(1)-weighted acquisitions implies that the contrast agent and the trimethylamine-containing species do not undergo significant direct interaction. Contrast agent induced changes in the choline signal observed in this and previous studies may, therefore, be attributable to T2*/susceptibility-based effects.

Surface coils are widely used in magnetic resonance (MR) studies due to their superior signal to noise properties. Application of excessive power levels to transmit surface coils may result in local tissue damage. A homogeneous muscle tissue model for the conservative prediction of surface coil specific absorption rate (SAR) is introduced. Based on this model, sequence parameters can be limited to provide operational levels within safety guidelines. It is demonstrated that this model provides worst-case SAR estimates at MR frequencies of 25.75 MHz and 63.6 MHz. The dependence of SAR on model structure and geometry is analysed and conclusions on the relationship between SAR levels and local anatomy are drawn. By making a worst-case assumption for the tissue parameters the model provides safe operational levels for all tissue types. Power-demanding proton-decoupled 31P magnetic resonance spectroscopy experiments are possible based on the SAR estimates provided. To date SAR values are calculated for 1 g of tissue. Changes in regulations to calculate SAR values for 10 g tissue masses, and the according averaging of local SAR over a larger volume, have been proposed by the International Electrotechnical Commission. A comparative study shows that up to 100% more energy may be applied to surface coils if SAR values are determined for 10 g tissue masses rather than 1 g tissue masses.

The imaging protocol of the UK multicentre magnetic resonance imaging study for screening in women at genetic risk of breast cancer aims to assist in detecting and diagnosing malignant breast lesions. In this paper, we evaluate a three-layer, feed-forward, backpropagation neural network as an artificial radiological classifier using receiver operating characteristic (ROC) curve analysis and compare the results with those obtained using a proposed radiological scoring system for the study which currently supplements the radiologist's clinical opinion, in comparison with histological diagnosis. Based on the 76 symptomatic cases evaluated, descriptive features scored by radiologists showed considerable overlap between benign and malignant, although some features such as irregular contours and heterogeneous enhancement were more often associated with malignant pathology. In this preliminary evaluation, ROC analysis showed that the proposed scoring scheme did not perform well, indicating further refinement is required. When all 23 features were used in the neural network, its performance was poorer than that of the scoring scheme. When only ten features were used, limited to descriptors of enhancement characteristics, the neural network performed similar to the scoring scheme. This comparison shows that the neural network approach to clinical diagnosis has considerable potential and warrants further development.

Monitoring therapeutic efficacy is essential in oncological practice. We have investigated the feasibility of using proton (1)H MR spectroscopy (MRS), localized to malignant lymphoma and germ cell lesions outside the cranial cavity, to monitor tumour metabolism in vivo during chemotherapy treatment. (1)H single voxel MRS, (stimulated echo acquisition mode, repetition time/echo time=2000/20 ms) was performed prior to treatment in patients with lymphoma or germ cell tumours, and during the first cycle of chemotherapy. Patient response was assessed by independent clinical follow-up at a median of 57 days (range 44-93 days) post-treatment. All 12 non-cystic lesions scanned showed a signal assigned to choline-containing metabolites (tCho); 9 were scanned both pre- and post-treatment. Changes in the tCho:water ratio following treatment were found to predict subsequent patient response. In seven of these nine patients, the tCho:water ratio decreased in the first post-treatment scan, and all subsequently achieved a partial response to treatment. In the remaining two patients, both of whom progressed on treatment, the tCho:water ratio did not change significantly. Normalized to pre-treatment values, the non-responder group values (1.07 and 0.97) were clearly distinct from the responder group, whose values ranged from 0.43 to below detection level. To our knowledge, this is the first report of (1)H MR spectra from these tumour types and sites. These preliminary results indicate that metabolite signals can be detected using (1)H MRS in these tumour types and locations, as has already been established in the brain, breast and prostate. Moreover, the differential changes observed in the tCho region of the spectrum suggest that (1)H MRS could provide an early and sensitive indicator of metabolic response to chemotherapy.

Magnetic resonance imaging provides a range of powerful techniques for assessing breast cancer. Contrast enhanced MRI has been shown to provide a sensitive method for assessing primary breast cancer, with increasing emphasis on performing dynamic analysis, and using quantitative analysis techniques. Magnetic resonance spectroscopy provides information on tumour metabolism and has been investigated as a method of assessing response to therapy. The response of metastatic disease from bone cancer has been assessed using T1 weighted methods. MRI provides information on response to treatment early in the course of chemotherapy. Following chemotherapy it provides a sensitive method of assessing residual disease. Both, with conventional treatments and with new antiangiogenic, antivascular and cytostatic treatments, there is a growing role for functional methods of assessing tumour response to treatment.

The UK national study of magnetic resonance imaging as a method of screening for breast cancer (MARIBS) is in progress. The study design, accrual to date, and related research projects are described. Revised accrual rates and expected recruitment are given. 15 cancers have been detected to date, from a total of 1236 screening measurements. This event rate and the tumour grades reported are compared with recent reports from other studies in women at high risk of breast cancer.

Magnetic resonance spectroscopy is increasingly used as a non-invasive method to investigate apoptosis. Apoptosis was induced in Jurkat T-cells by Fas mAb. H-1 magnetic resonance spectra of live cells showed an increase in methylene signal as well as methylene/methyl ratio of fatty acid side chains at 5 and 24 h following induction of apoptosis. To explain this observation, H-1 magnetic resonance spectra of cell extracts were investigated. These demonstrated a 70.0+/-7.0%, 114.0+/-8.0% and 90.0+/-5.0% increase in the concentration of triacyiglycerols following 3, 5 and 7 h of Fas mAb treatment (P<0.05). Confocal microscopy images of cells stained with the lipophilic dye Nile Red demonstrated the presence of lipid droplets in the cell cytoplasm. Quantification of the stained lipids by flow cytometry showed a good correlation with the magnetic resonance results (Pgreater than or equal to0.05 at 3, 5 and 7 h). P-31 magnetic resonance spectra showed a drop in phosphatidylcholine content of apoptosing cells, indicating that alteration in phosphatidylcholine metabolism could be the source of triacylglycerol accumulation during apoptosis. In summary, apoptosis is associated with an early accumulation of mobile triacylglycerols mostly in the form of cytoplasmic lipid droplets. This is reflected in an increase in the methylene/methyl ratio which could be detected by magnetic resonance spectroscopy, (C) 2002 Cancer Research UK.

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 chances in the pattern of enhancement to pharmacokinetic modelling of contrast agent uptake. The combination of results front different institutions is therefore difficult and the sensitivities of different methods, have not been compared. The purpose of this study is to investigate correlation,, between qualitatative 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, v(e), were determined. In addition. hole 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 as 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 re-ion-of-interest analysis. The absolute change in the K-trans values correlated negatively with the pretreatment values. particularly for responding patients. Thus. for higher pre-treatment K-trans values. a greater decrease as observed. Greater changes were observed in the upper extremes of the K-trans histogram than in the median values after one Course of treatment. Copyright (C) 2002 John Wiley Sons. Ltd.

Breast screening acceptability is dependent on sensitivity and recall rate. We aimed to establish the recall rate for MRI and mammography, separately and together, when screening a cohort of women at high genetic risk. Women aged 35-49 years in the MARIBS study form the cohort. We analysed the recall rate, the number of extra tests and their effectiveness. Wilcoxon Rank test was used to estimate the effect of age and logistic regression with robust variance the effect of mammographic density on recall rates.The first 726 screening studies took place in 415 women. Following 86 of these recall occurred, comprising 140 additional investigations. 28 of the cases were resolved without further MRI, and 18 women had more than 2 additional tests. Neither age nor mammographic density was associated with recall. MRI had a recall of rate of 10.19%, and mammography 4.00%. The two techniques largely recalled different cases and 10 cases only (11.62% of those recalled) were abnormal by both tests. The two together had a recall rate of 11.85%. Recall rates varied widely between centres of the study.Breast MRI in asymptomatic high-risk women age 35-49 years largely recalls different women from mammography. The combined figure of approximately 12% may be acceptable for screening and will be useful for planning similar studies. (C) 2002 Elsevier Science Inc. All rights reserved.

To assess magnetic resonance (MR) measures of vascular permeability of prostate cancer treated with androgen deprivation and to correlate these with morphologic appearances and serum prostate-specific antigen (PSA) levels.

Ras is frequently mutated in cancer, and novel therapies are being developed to target Ras signalling. To identify non-invasive surrogate markers of Ras activation and inhibition, we used(31)P magnetic resonance spectroscopy (MRS) and investigated NIH 3T3 cells compared to a mutant ras transfected counterpart. The MR spectra indicated that phosphocholine (PC) levels increased significantly from 3 +/- 2 fmol cell(-1)in NIH 3T3 cells to 13 +/- 4 fmol cell(-1)in the transfected cells. The PC/NTP ratio increased significantly from 0.3 +/- 0.1 to 0.7 +/- 0.3. This could not be explained by either a faster proliferation rate or by alterations in cell cycle distribution. Both cell lines were treated with simvastatin, 17-AAG and R115777, agents which inhibit Ras signalling. Cell proliferation was inhibited in both cell lines. The spectrum of NIH 3T3 cells was not affected by treatment. In contrast, in the ras transfected cells growth inhibition was associated with an average 35 +/- 5% drop in PC levels and a comparable drop in PC/NTP. Thus the MRS visible increase in phosphocholine is associated with Ras activation, and response to treatment is associated with partial reversal of phosphocholine increase in ras transfected cells. MRS might therefore be a useful tool in detecting Ras activation and its inhibition following targeted therapies.

The use of magnetic resonance spectroscopy (MRS) to investigate breast tumour biochemistry in vivo is reviewed. To this end, results obtained both from patients in vivo and from tumour extracts and model systems are discussed. An association has been observed between transformation and an increase in phosphomonoesters (PMEs) detected in the 31P MRS spectrum, as well as an increase in choline-containing metabolites detected in the 1H spectrum. A decrease in PME content after treatment is associated with response to treatment as assessed by tumour volume. Experiments in model systems aimed at understanding the underlying biochemical processes are presented, as well as data indicating the usefulness of MRS in monitoring the uptake and metabolism of some chemotherapeutic agents.

Magnetic resonance imaging (MRI) techniques enable vascular function to be mapped with high spatial resolution. Current methods for imaging in breast cancer are described, and a review of recent studies that compared dynamic contrast-enhanced MRI with histopathological indicators of tumour vascular status is provided. These studies show correlation between in vivo dynamic contrast measurements and in vitro histopathology. Dynamic contrast-enhanced MRI is also being applied to assessment of the response of breast tumours to treatment.

Surface coils are widely used in magnetic resonance studies due to their superior signal to noise (SNR) properties. When shaping planar coils to cylindrical surfaces, the region with maximum sensitivity migrates from the coil plane towards the centre of the shaping radius. The influence of the coil current, the probe and tissue dimensions, the electrical tissue properties and the operating frequency on the B1 field strength of a coil has been studied using statistical methods. This analysis allows the dependence of the axial SNR distribution of circular and square surface coils on shaping radius and coil dimensions to be evaluated quantitatively using 3D finite element methods. An empirically derived equation describing the dependence of the SNR distributions on coil geometry and depth allows the optimum coil dimensions to be predicted for a given shaping radius and desired optimized depth of sensitivity. Simulations are validated experimentally using both B1 and SNR mapping techniques. A comparison between the axial SNR of circular and square coils demonstrated equal SNR distributions of coils with equivalent area at depth.

The first in vivo hyperpolarized 129Xe NMR study in experimental tumors is presented. Hyperpolarized 129Xe was dissolved in solutions, and was injected intratumorally in GH-3 prolactinomas in rats and RIF-1 fibrosarcomas in mice. The 129Xe NMR spectra and apparent spin-lattice relaxation times in the two tumor types present characteristic differences. These differences are discussed in terms of xenon exchange between the carrier medium and the tissue compartments.

Magnetic resonance imaging (MRI) has emerged as a powerful tool in medical diagnosis and research. Although high spatial resolution images are essential in medical diagnosis and image analysis, high temporal resolution is equally important in applications of dynamic contrast-enhanced MRI or functional brain MRI. In particular, in breast MRI the ability to differentiate between benign and malignant lesions depends, in part, on the temporal resolution of the dynamic image acquisition. New applications of MRI such as multi-feature analysis of image time series data and full 3D functional MRI or event-related functional MRI require high spatial and high temporal resolution for accurate image analysis on a voxel-by-voxel basis. Currently available partial Fourier reconstruction techniques. which effectively improve the time resolution, suffer from a reduced signal to noise ratio in the reconstructed image, a decrease in spatial resolution or reconstruction artefacts, making numerical image analysis difficult. In this work we present an image reconstruction algorithm based on image recovery theory which effectively doubles the temporal resolution and results in an image quality sufficient for further numerical analysis. The developed algorithm requires a full Fourier space acquisition of a pre-contrast or baseline image prior to the reconstruction procedure of the time series partial Fourier data.

Background: Phosphorus magnetic resonance spectroscopy (P-31 MRS) allows for the measurement of phospholipids and their breakdown products in the human brain. Fairly mobile membrane phospholipids give rise to a broad signal that co-resonates with metabolic phosphodiesters. Chronic alcohol exposure increases the rigidity of isolated brain membranes and, thus, may affect the amount and transverse relaxation times (T-2) of MRS-detectable phospholipids. We tested the hypothesis that subjects who were heavy drinkers have stiffer membranes than controls who were light drinkers, as reflected in a smaller broad signal component and a shorter T-2 of the broad signal in P-31 MR spectra of the brain.Methods: Thirteen alcohol-dependent heavy drinkers (mean age 44 years) were studied by localized P-31 MRS in the centrum semiovale and compared with 17 nondependent light drinkers of similar age. The broad component signal was separated from the metabolite signal by convolution difference, which is based on the large difference in line widths of these two signals. Longitudinal and T-2 relaxation times were measured using standard methods.Results: The broad component integral was 13% lower in the brain of heavy drinkers compared with light drinkers (p < 0.001) and remained significantly smaller after corrections for both longitudinal and transverse relaxations (p < 0.01). The T-2 distribution of the broad component consistently showed two resolvable components in both groups. The fast relaxing component had the same T-2 in both groups (T-2 = 1.9 msec). The slower relaxing component T-2 was 0.6 msec shorter in heavy drinkers compared with light drinkers (p = 0.08).Conclusions: These results, observed in the absence of white matter volume loss, are consistent with biochemical alterations and higher rigidity of white matter phospholipids associated with long-term chronic alcohol abuse. The observed smaller broad signal component in these relatively young heavy drinkers is a sensitive measure of white matter phospholipid damage.

Antiangiogenic and antivascular agents provide new approaches to treating tumours. These may avoid many of the problems experienced with current approaches such as inherent and acquired resistance to treatment. Tumours do not grow beyond 1-2 mm(3) in size without the development of new vessels (Folkman, 1971). Such neo-vascularization (angiogenesis) allows tumour cells to increase their nutrient supply, survive and proliferate despite the new vessels often having structural and functional differences compared to normal tissue vasculature. Treatments targeted at tumour vasculature have produced impressive results in animal models (Lindsay et al, 1996; Watson et al, 1996; O'Reilly, 1997; Horsman et al, 1998). These therapies are now entering clinical trials, However, the successful introduction of these therapies into clinical practice will require the development of reliable ways to assess angiogenesis and its modification or inhibition in vivo. Here we discuss some of the emerging imaging techniques that may be useful. (C) 2001 Cancer Research Campaign.

F-19-MR-imaging has been used to quantitate albumin concentration in a phantom at 1.5 T. The experimentally derived relationship between albumin concentration and the T1 relaxation time of a fluorinated marker, tetrafluorosuccinic acid (TFSA) was used to calculate the albumin concentration from a quantitative F-19 T1 map acquired using a gradient echo sequence. There was close correlation between calculated and actual BSA concentrations (r = 0.99, SE = 0.15), The potentially interfering effect of paramagnetic species on T1 relaxation times was also investigated. Relaxivity data show that albumin concentration measurements should be per-formed prior to any contrast agent administration. (C) 2001 Elsevier Science Inc. All rights reserved.

Background: In vivo phosphorus magnetic resonance spectroscopy (P-31 MRS) at a magnetic field strength of 1.5 T allows measurement of fairly mobile membrane phospholipids in the human brain. We previously showed that subjects who are heavy drinkers had a smaller signal and a shorter transverse relaxation time (T-2) of white matter phospholipids than light drinkers, which suggested lower concentrations and molecular mobility of phospholipids in heavy drinkers. The purpose of the present study was to measure if such chronic alcohol-induced white matter tissue changes are persistent in long-term abstinent alcoholics.Methods: Fourteen abstinent alcoholics (mean age 45 years, seven men and seven women) were studied by localized P-31 MRS in the centrum semiovale and were compared with 13 male, alcohol-dependent, heavy drinkers and 23 nondependent light drinkers (17 men, 6 women) of similar age. Methods for measurements of the broad membrane phospholipid signal and its relaxation time were described previously.Results: Phospholipid concentrations and relaxation times in alcoholics abstinent for an average of 31 months were not significantly different from those measured in light drinkers. The contribution of fast and slowly relaxing signal components to the broad phospholipid signal, however, was still different in abstinent alcoholics compared with light drinkers. No effects of sex or of family history of alcoholism were noted on any of our spectroscopic measures within the light-drinking or abstinent groups.Conclusions: Most of our results suggest at least partial recovery of chronic alcohol-induced white matter phospholipid damage with long-term abstinence. They offer myelination changes and/or dendritic, rearborization as a possible mechanism for the commonly observed white matter volume gain with prolonged abstinence. But the results also suggest a persistent abnormality in the nature and/or physical properties of white matter phospholipids in long-term abstinent alcoholics.

For optimal performance of P-31 MRS at 1.5 Tesla, the use of a double resonant probe is essential to enable the application of H-1 decoupling and Nuclear Overhauser Enhancement. This note describes the design, evaluation and safety validation of a versatile and compact probe optimized for H-1 decoupled P-31 MRS studies of tumors close to the surface of the body, in particular the head and neck region. (C) 2001 Elsevier Science Inc. All rights reserved.

To quantify MRI enhancement characteristics of normal and abnormal prostatic tissues and to correlate these with tumour stage, histological grade and tumour markers.

We present a method for reducing the image point-spread function and measuring T(1) using saturation recovery turboFLASH (SRTF) with centric-ordered k-space and a k-space correction filter designed to compensate for longitudinal magnetisation evolution during image acquisition. The method provides a two point T(1) measurement that reduces inaccuracies and image artefacts caused by longitudinal magnetisation evolution in conventional turboFLASH methods. The method is designed for use in rapid, quantitative measurements of contrast agent uptake in vivo.

Optically enhanced NMR with (129)Xe and (3)He is emerging as a novel and promising technique for medical imaging of lungs and other tissues. Here it is shown that hyperpolarized (129)Xe NMR provides a powerful means of measuring blood oxygenation quantitatively and noninvasively. The interaction of xenon with hemoglobin is responsible for an oxygen-dependent NMR shift of (129)Xe in red blood cells, in sharp contrast to the current model of xenon-hemoglobin binding. This effect could be exploited in brain functional studies, and in the assessment of conditions and diseases affected by blood oxygenation.

Polarization transfer methods can substantially enhance NMR signals from nuclei of low gamma, which are J-coupled to nuclei of high gamma, but to date have had limited application for in vivo (31)P MRS studies. They require both accurate flip angles and good localization in order to achieve their potential. Described here is an implementation of the insensitive nuclei enhanced by polarization transfer (INEPT) polarization transfer method using segmented adiabatic BIR4 RF pulses. Localization uses ISIS, applied to the coupled (1)H spins. Detailed analysis is performed to evaluate the specific absorption rate power deposition when using surface coils. Polarization transfer, localization capability, and use with surface coils are demonstrated using suitable test objects. Finally, in vivo data are presented from the liver of a normal volunteer in which the signals from the phosphodiester peaks are substantially enhanced.

Proton spectroscopy has been evaluated as a method for quantifying radiation induced changes in polyacrylamide gel dosimeters. A calibration was first performed using BANG-type gel samples receiving uniform doses of 6 MV photons from 0 to 9 Gy in 1 Gy intervals. The peak integral of the acrylic protons belonging to acrylamide and methylenebisacrylamide normalized to the water signal was plotted against absorbed dose. Response was approximately linear within the range 0-7 Gy. A large gel phantom irradiated with three, coplanar 3 x 3 cm square fields to 5.74 Gy at isocentre was then imaged with an echo filter technique to map the distribution of monomers directly. The image, normalized to the water signal, was converted into an absolute dose map. At the isocentre the measured dose was 5.69 Gy (SD = 0.09) which was in good agreement with the planned dose. The measured dose distribution elsewhere in the sample shows greater errors. A T2 derived dose map demonstrated a better relative distribution but gave an overestimate of the dose at isocentre of 18%. The data indicate that MR measurements of monomer concentration can complement T2-based measurements and can be used to verify absolute dose. Compared with the more usual T2 measurements for assessing gel polymerization, monomer concentration analysis is less sensitive to parameters such as gel pH and temperature, which can cause ambiguous relaxation time measurements and erroneous absolute dose calculations.

Polyacrylamide gels are a powerful tool to measure radiation dose by quantifying the NMR T2 relaxation times of the irradiated gel. The exploitation of these radiation sensitive gels in clinical radiotherapy requires accurate mapping of T2 values. This paper describes the optimization strategy used to identify accurate and practical methods of measuring the range of T2 values typical of gel dosimeters (140-700 ms). The MR imaging techniques used to measure T2 values and the choice of image acquisition parameters are described. Four sequences are compared and the results are analysed in terms of accuracy, signal-to-noise ratio and acquisition time. A multiple spin echo sequence was found to yield the most accurate results (98.9%). Single spin echo sequences, such as Hahn spin echo and EPI spin echo, were found to measure gel T2 values with an accuracy of 90.1%. This paper reports the importance of careful selection and optimization of the MR imaging sequences for accurate and reliable polyacrylamide gel dosimetry.

The spin-lattice relaxation time, T(1), of hyperpolarized (129)Xe in blood is sensitive to blood oxygenation. In particular, it has been shown that (129)Xe T(1) is shorter in venous blood than in arterial blood. We have studied the T(1) of hyperpolarized (129)Xe dissolved in human blood as a function of blood oxygenation level, sO(2), in the physiological oxygenation range. We show that the (129)Xe relaxation rate, T(1)(-1), varies in a nonlinear fashion as a function of sO(2). This finding suggests that direct interaction of xenon with the paramagnetic heme group of deoxyhemoglobin is not the dominant oxygenation-dependent relaxation mechanism for (129)Xe in blood. These results corroborate the idea that the oxygenation-dependence of (129)Xe T(1) is determined by conformational changes of hemoglobin induced by oxygen binding.

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.

Time-share modulation has been implemented successfully on a clinical 1.5 T nuclear magnetic resonance (NMR) system to perform in vivo (19)F[-(1)H] decoupling. It uses commercially available radiofrequency (RF) filters, a transistor-transistor logic (TTL)-controlled attenuator, and a double-resonant RF surface coil suitable for (19)F magnetic resonance spectroscopy (MRS) studies in vivo. This decoupling scheme gives a threefold improvement in signal-to-noise ratio performance compared with the conventional WALTZ-4 decoupling scheme, when significant interaction exists between the decoupler and the receiver. It can also eliminate receiver saturation (i.e., saturation due to coupling of the strong proton decoupling pulse to the (19)F coil) without the need for a high-isolation coil system, thus allowing flexibility in coil geometry. This method has been demonstrated in vivo in patients receiving 5-fluorouracil chemotherapy. Magn Reson Med 44:5-9, 2000.

Magnetic resonance spectroscopic imaging (MRSI) studies in the abdomen or breast are acquired in the presence of respiratory motion. This modifies the point spread function (PSF) and hence the reconstructed spectra. We evaluated the quantitative effects of both periodic and aperiodic motion on spectra localized by MRSI. Artefactual signal changes, both the modification of native to a voxel and spurious signals arising elsewhere, depend primarily upon the motion amplitude relative to the voxel dimension. A similar dependence on motion amplitude was observed for simple harmonic motion (SHM), quasi-periodic motion and random displacements. No systematic dependence upon the period or initial phase of SHM or on the array size was found. There was also no significant variation with motion direction relative to the internal and external phase-encoding directions. In measured excursion ranges of 20 breast and abdominal tumours, 70% moved < or = 5 mm, while 30% moved 6-23 mm. The diaphragm and fatty tissues in the gut typically moved approximately 15-20 mm. While tumour/organ excursions less than half the voxel dimension do not substantially affect native signals, the bleeding in of strong lipid signals will be problematic in 1H studies. MRSI studies in the abdomen, even of relatively well-anchored tumours, are thus likely to benefit from the addition of respiratory triggering or other motion compensation strategies.

Image distortion is an important consideration in the use of magnetic resonance (MR) images for radiotherapy planning. The distortion is a consequence of system distortion (arising from main magnetic field inhomogeneity and nonlinearities in the applied magnetic field gradients) and of effects arising from the object/patient being imaged. A two stage protocol has been developed to correct both system and object-induced distortion in pelvic images which incorporates measures to maintain the quality, accuracy and consistency of the imaging and correction procedures. The first stage of the correction procedure is described here and involves the removal of system distortion. Object- (patient-) induced effects will be described in a subsequent work. Images are acquired with the patient lying on a flat rigid bed, which reproduces treatment conditions. A frame of marker tubes surrounding the patient and attached to the bed provides quality assurance data in each image. System distortions in the three orthogonal planes are mapped using a separate phantom, which fits closely within the quality control frame. Software has been written which automates the measurement and checking of the many marker positions which the test objects generate and which ensures that patient data are acquired using a consistent imaging protocol. Results are presented which show that the scanner and the phantoms used in measuring distortion give highly reproducible results with mean changes of the order of 0.1 mm between repeated measurements of marker positions in the same imaging session. Effective correction for in plane components of system distortion is demonstrated.

Many studies suggest that changes in the uptake of the glucose analog FDG after therapy, compared with pretreatment uptake, predicts tumor response to therapy. However, clinical interpretation is compromised by a limited understanding of the effect of therapy on FDG and 2-deoxy-D-glucose (DG) uptake at the tumor cell level.

In MRS studies using surface transmit coils, accurate assessment of local SAR and RF heating represents a difficult problem involving the coil geometry and electromagnetic and geometric tissue properties. Methodologies to determine the optimum operating parameters for dual-resonant surface coil measurements are presented, based on a standardized coil and protocol used in a multicenter (31)P MRS clinical trial, using adiabatic pulses and bilevel proton decoupling. Spatial distributions of absorbed radiation in human calf and in a tissue-equivalent gel phantom were modeled using finite-element simulations and realistic conductivity and permittivity values. Local SAR in worst-case 1 cm(3) volumes of interest (VOIs) in calf is predicted to be below international guidelines, and the temperature at the skin surface was found to increase due to the RF by less than 2 degrees C and remain below 37 degrees C. The heating rate and maximum temperature in the gel, at positions guided by the simulations, were within guideline values for both extremities and trunk and in reasonable agreement with that predicted.

New, complex radiotherapy delivery techniques require dosimeters that are able to measure complex three-dimensional dose distributions accurately and with good spatial resolution. Polymer gel is an emerging new dosimeter being applied to these challenges. The aim of this review is to present a practical overview of polymer gel dosimetry, including gel manufacture, imaging, calibration and application to radiotherapy verification. The dosimeters consist of a gel matrix within which is suspended a solution of acrylic molecules. These molecules polymerize upon exposure to radiation, with the degree of polymerization being proportional to absorbed dose. The polymer distribution can be measured in two or three dimensions using MRI or optical tomography and, after calibration, the images can be converted into radiation dose distributions. Manufacture of the gel is reported to be reproducible, and measured dose in the range 0-10 Gy is accurate to within 3-5%. In-plane image resolution of 1 mm x 1 mm, with image slice thicknesses of between 2-5 mm, is typically achievable using clinical 1.5 T MR scanners and standard T2 weighted imaging sequences. The gels have been used to verify a number of conventional and novel radiotherapy modalities, including brachytherapy, intensity modulated radiotherapy and stereotactic radiosurgery. All the studies have confirmed the value and versatility of the dosimetry technique.

The characteristics of a new formulation of polymer gel are assessed for MRI-based radiotherapy dosimetry. The gel, based on the first BANG gel formulation, replaces acrylamide with the less toxic monomer sodium methacrylate. The relationship between MR T2 relaxation time and radiation dose for the gel formulation was studied using spin-echo imaging. Proton magnetic resonance spectroscopy was also used to assess the gel composition as a function of dose. The effect of gel pH on the dose-response and baseline R2 was then investigated. A calibration performed on gel without pH modulation (pH = 6.6) revealed a dose-response of 0.14 s(-1) Gy(-1) within the range 0-8 Gy. The baseline R2 increases with pH above neutrality, rising from 1.2 s(-1) at pH = 5.1 to 5.0 s(-1) at pH = 10.1. The dose-response is also pH dependent, having a minimum value of 0.09 s(-1) Gy(-1) at pH = 10.1 and peaking at 0.21 s(-1) Gy(-1) at pH = 7.7. Undertaking proton spectroscopy on the gels enabled resonances associated with the monomer and co-monomer to be studied. By integrating the peaks from the respective monomers and normalizing to the signal at 0 Gy it was shown that only 50% of the methacrylate monomer was used at 10 Gy, whereas 80% of the co-monomer was used at this dose. The data indicate that this gel has a reduced toxicity and a comparable dose response to the previously reported BANG gel. In addition, the performance of the gel can be optimized by controlling the pH. MR spectroscopy revealed that the crosslinking co-monomer is consumed more readily than the monomer, which is in agreement with previous compositional studies.

In 1994, the UK National Health Service identified as a research priority that magnetic resonance imaging (MRI) should be assessed as a screening tool for young, pre-menopausal women who are at a high genetic risk of developing breast cancer. In 1997 a national multicentre study was established to compare MRI with X-ray mammography as a method for screening for breast cancer in this group of women. This paper reviews the relevant literature and describes the rationale that led to the setting up of this study.

The protocol of the national multicentre study of Magnetic Resonance Imaging (MRI) as a method of screening for breast cancer in women at genetic risk is described. The sensitivity and specificity of contrast-enhanced MRI will be compared with two-view X-ray mammography in a comparative trial. Approximately 500 women below the age of 50 at high genetic risk of breast cancer will be recruited per year for 3 years, with annual MRI and X-ray examination continuing for up to 5 years. A symptomatic cohort will be measured in the initial phase of the study to ensure consistent reporting between centres. The MRI examination will comprise an initial high-sensitivity screening measurement, followed by a high-specificity measurement in equivocal cases. Retrospective analysis will identify the most specific indicators of malignancy. Sensitivity and specificity, together with diagnostic performance, diagnostic impact and therapeutic impact will be assessed with reference to pathology, follow-up and changes in diagnostic certainty and therapeutic decisions. The psychological impact of screening in this high-risk group will be ascertained.

This study was undertaken to investigate the ability of focused ultrasonic surgery to occlude blood flow in vivo.

The reproducibility of polyacrylamide gel (PAG) dosimetry has been evaluated when used to verify two radiotherapy treatment plans of increasing complexity. The plans investigated were a three-field coplanar arrangement, using the linac jaws for field shaping, and a four-held, conformal, non-coplanar plan using precision-cast lead alloy shielding blacks. Each treatment was performed three times using phantoms and calibration gels manufactured in-house. Two phantoms were specially designed for this work to aid accurate positioning of the gels for irradiation and imaging.All gels were imaged post-irradiation using a Siemens Vision 1.5T MR scanner. T-2 relaxation images were calibrated to absorbed dose distributions using a number of smaller calibration vessels to produce distribution maps of relative dose. The relative dose distributions were found to be reproducible, with the standard deviation on the mean areas enclosed by the greater than or equal to 50% isodose lines measured in three orthogonal planes being 6.4% and 4.1% for the coplanar and non-coplanar plans respectively. The measured distributions were also consistent with those planned, with isodose lines generally agreeing to within a few millimetres. However, the measured absolute doses were on average 23.5% higher than those planned.Although the polyacrylamide gel dosimetry technique has some limitations, particularly when calibrating distributions to absolute dose, the ability to resolve sharp dose gradients in three dimensions with millimetre precision is invaluable when verifying complex conformal treatment plans, where avoidance of proximal, critical structures is a treatment criterion.

In order to evaluate the role of proton MR spectroscopy (H-1-MRS) in the diagnosis and assessment of long-term radiation-related neurotoxicity, 14 children who had received cranial irradiation for the treatment of childhood leukaemia (n=6) or brain tumours (n=8) underwent H-1-MRS, MRI and neuropsychological assessment. Short-term effects at 2 months following treatment were studied in a further three patients. MRI abnormalities were observed in nine patients. No statistically significant differences between patients and controls (n=17) were seen in any of the calculated H-1-MRS metabolite ratios, in any of the three patient groups. On multivariate logistic regression analysis there was a correlation between the choline/water ratio and a low IQ. It is concluded that any systematic radiation-induced changes in the H-1 MRS metabolites must be below the detection threshold of this study.

There is a clinical need fur early detection of tumor response to therapy. This study aimed to determine whether metabolites of fluorodeoxyglucose (FDG) detected in solid mouse tumors in situ by F-19 magnetic resonance spectroscopy (F-19 MRS) correlated with response to 5-fluorouracil chemotherapy, After injection of FDG (1.4 mmol/kg i.p.), uptake and metabolism was monitored for 2 h in RIF-1 tumors. FDG was detectable immediately. and after 10 min, a second broad peak was detected 5-6 ppm upfield, F-19 MRS analysis of cell and tumor extracts in vitro showed that the upfield peak (greater than or equal to 15% of the total detectable F-19 signal) consisted of the epimer alpha-fluorodeoxymannose (FDM) and various conjugates, Mice treated with 5-fluorouracil (130 mg/kg) received, 48 h later, a repeat dose of FDG. The change in the rate of FDM formation, but not the FDG or total F-19 signal, correlated significantly with the response to 5-fluorouracil (P = 0.032), suggesting that F-19 MRS of FDM metabolism in vivo may be a novel means of predicting tumor response.

Ifosfamide and cyclophosphamide are P-31-containing alkylating agents used widely in the treatment of cancer. In this communication it is demonstrated that signals from these agents may be detected in the livers of patients undergoing treatment using P-31 MRS at 1.5 T, In vitro, signals are enhanced 4-fold by use of H-1-decoupling, with a B-1 field of 100 Hz at -150 Hz relative to water. Polarization transfer (BINEPT) enhances signals in vitro by a further factor of 5.5, Preliminary results using the double-resonance methods in vivo show that the technique is practicable although enhancements may be less than observed in vitro. Factors affecting signal enhancement in vivo are evaluated, Magn Reson Med 44:180-184, 2000, (C) 2000 Wiley-Liss, Inc.

The spin-lattice relaxation time, T-1, of hyperpolarized Xe-129 in blood is sensitive to blood oxygenation. In particular, it has been shown that Xe-129 T-1 is shorter in venous blood than in arterial blood. We have studied the T-1 of hyperpolarized Xe-129 dissolved in human blood as a function of brood oxygenation level, sO(2), in the physiological oxygenation range. We show that the Xe-129 relaxation rate, T-1(-1) 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 Xe-129 in blood. These results corroborate the idea that the oxygenation-dependence of Xe-129 T-1 is determined by conformational changes of hemoglobin induced by oxygen binding. Copyright (C) 2000 John Wiley Br Sons, Ltd.

The hepatobiliary distribution of 5-fluorouracil (5FU) catabolites was investigated in nine patients. Using fluorine 3D-chemical shift imaging, four patients receiving protracted venous infusion of 5FU demonstrated catabolite localized to the gallbladder. No hepatobiliary fluorine signals were detected in three patients whose gallbladders were absent or abnormal, Signals from the gallbladder showed a 2.2-2.4 ppm high-frequency shift from alpha-fluoro-beta-alanine, suggesting the presence of alpha-fluoro-beta-alanine-bile-acid conjugates. 3D-chemical shift imaging of two patients receiving bolus 5FU revealed alpha-fluoro-beta-alanine to be localized to the liver within 1 hr of administration, In one patient examined 4 hr after bolus administration, catabolite signal was detected only in the gallbladder. (C) 2000 Wiley-Liss, Inc.

The imaging and analysis protocol of the UK multicentre study of magnetic resonance imaging (MRI) as a method of screening for breast cancer in women at genetic risk is described. The study will compare the sensitivity and specificity of contrast-enhanced MRI with two-view x-ray mammography. Approximately 500 women below the age of 50 at high genetic risk of breast cancer will be recruited per year for three years, with annual MRI and x-ray mammography continuing for up to 5 years. A symptomatic cohort will be measured in the first year to ensure consistent reporting between centres. The MRI examination comprises a high-sensitivity three-dimensional contrast-enhanced assessment, followed by a high-specificity contrast-enhanced study in equivocal cases. Multiparametric analysis will encompass morphological assessment, the kinetics of contrast agent uptake and determination of quantitative pharmacokinetic parameters. Retrospective analysis will identify the most specific indicators of malignancy. Sensitivity and specificity, together with diagnostic performance, diagnostic impact and therapeutic impact will be assessed with reference to pathology, follow-up and changes in diagnostic certainty and therapeutic decisions. Mammography, lesion localisation, pathology and cytology will be performed in accordance with the UK NHS Breast Screening Programme quality assurance standards. Similar standards of quality assurance will be applied for MR measurements and evaluation. (C) 2000 Elsevier Science Inc. All rights reserved.

To avoid the late sequelae associated with cranial radiation therapy in childhood, intermediate- or high-dose intravenous methotrexate (HDMTX) has found increasing application as a means of preventing the development of overt central nervous system disease in childhood acute leukaemia. However, acute and chronic neurotoxicity has been described following HDMTX therapy, and the long-term intellectual outcome in children treated in this way is inadequately documented. Proton magnetic resonance spectroscopy ((1)H-MRS) of the brain is a noninvasive, quantitative way of assessing aspects of cerebral metabolism, which has not previously been applied to the study of children undergoing central nervous system directed therapy.

The nuclear spin polarization of 129Xe can be enhanced by several orders of magnitude by using optical pumping techniques. The increased sensitivity of xenon NMR has allowed imaging of lungs as well as other in vivo applications. The most critical parameter for efficient delivery of laser-polarized xenon to blood and tissues is the spin-lattice relaxation time (T1) of xenon in blood. In this work, the relaxation of laser-polarized xenon in human blood is measured in vitro as a function of blood oxygenation. Interactions with dissolved oxygen and with deoxyhemoglobin are found to contribute to the spin-lattice relaxation time of 129Xe in blood, the latter interaction having greater effect. Consequently, relaxation times of 129Xe in deoxygenated blood are shorter than in oxygenated blood. In samples with oxygenation equivalent to arterial and venous blood, the 129Xe T1s at 37 degrees C and a magnetic field of 1.5 T were 6.4 s +/- 0.5 s and 4.0 s +/- 0.4 s, respectively. The 129Xe spin-lattice relaxation time in blood decreases at lower temperatures, but the ratio of T1 in oxygenated blood to that in deoxygenated blood is the same at 37 degrees C and 25 degrees C. A competing ligand has been used to show that xenon binding to albumin contributes to the 129Xe spin-lattice relaxation in blood plasma. This technique is promising for the study of xenon interactions with macromolecules.

The use of perfluorooctyl bromide (PFOB) emulsions as delivery media for hyperpolarized xenon has been investigated. Emulsion droplet size was controlled by varying the content of egg yolk phospholipid (EYP), which served as an emulsifier. Hyperpolarized 129Xe nuclear magnetic resonance (NMR) spectra of the dissolved gas were obtained. The NMR spectra were found to be correlated strongly with the emulsion droplet size distribution. The NMR line width is determined by xenon exchange between the PFOB droplets and the aqueous environment. Our findings show that, in a 1.5-Tesla field, relatively narrow 129Xe NMR spectra are obtained for droplet sizes larger than 5 microm. Preliminary results on animal models show that PFOB emulsions have potential as hyperpolarized 129Xe carriers for in vivo magnetic resonance applications.

To evaluate the dynamic interrelationship between rectal distension and rectal movements, and to determine the effect of rectal movement on the position of the prostatic gland using cine magnetic resonance imaging (MRI).

Apoptosis was induced by treating L1210 leukaemia cells with mechlorethamine, and SW620 colorectal cells with doxorubicin. The onset and progression of apoptosis were monitored by assessing caspase activation, mitochondrial transmembrane potential, phosphatidylserine externalization, DNA fragmentation and cell morphology. In parallel, 31P magnetic resonance (MR) spectra of cell extracts were recorded. In L1210 cells, caspase activation was detected at 4 h. By 3 h, the MR spectra showed a steady decrease in NTP and NAD, and a significant build-up of fructose 1,6-bisphosphate (F-1,6-P) dihydroxyacetonephosphate and glycerol-3-phosphate, indicating modulation of glycolysis. Treatment with iodoacetate also induced a build-up of F-1,6-P, while preincubation with two poly(ADP-ribose) polymerase inhibitors, 3-aminobenzamide and nicotinamide, prevented the drop in NAD and the build-up of glycolytic intermediates. This suggested that our results were due to inhibition of glyceraldehyde-3-phosphate dehydrogenase, possibly as a consequence of NAD depletion following poly(ADP-ribose) polymerase activation. Doxorubicin treatment of the adherent SW620 cells caused cells committed to apoptosis to detach. F-1,6-P was observed in detached cells, but not in treated cells that remained attached. This indicated that our observations were not cell line- or treatment-specific, but were correlated with the appearance of apoptotic cells following drug treatment. The 31P MR spectrum of tumours responding to chemotherapy could be modulated by similar effects.

Few quantitative data are available on the kinetics of polymerization reactions in polymer gel (PAG) dosimeters and their long-term stability. Post-irradiation polymerization reactions have been found to continue for several weeks, posing questions regarding dosimeter stability and its achievement. In this paper we report an investigation of polymerization kinetics in PAG dosimeters and the effect of diffusing oxygen into the dosimeter, post irradiation, as a potential method of inhibiting further polymerization and stabilizing the dose distribution. Results show continuous post-irradiation changes in transverse relaxation rate R2 with time over the five week study period and that a steady-state may not be reached for a period of months. An assessment is made of the appropriate time to image the dosimeter which shows that after three to four days the polymerization change is slow compared with imaging time. The implications of the time delay between irradiation and imaging are discussed in terms of the resultant sensitivity of the dosimeter and accuracy of the dose measured. In pairs of dosimeters, one sealed the other open to air, oxygen diffusing into the dosimeter arrests polymerization. However, the diffusion rate is too slow to make this method practicable. The slow diffusion means that while in regions near the air/gel interface polymerization is quickly arrested, in deeper regions it may continue for many hours, causing artefacts in the dose distribution. In the companion paper to this from a collaborating team, a study focusing on modelling oxygen diffusion in dosimeter gel will be presented.

It is well known that the experimental dosimetry of brachytherapy sources presents a challenge. Depending on the particular-dosimeter used, measurements can suffer from poor spatial resolution (ion chambers), lack of 3D information (film) or errors due to the presence of the dosimeter itself distorting the radiation flux. To avoid these problems, we have investigated the dosimetry of a clinical 192Ir source using a polyacrylamide gel (PAG) dosimeter. Experimental measurements of dose versus radial distance from the centre of the source (cross-line plots) were compared with calculations produced with a Nucletron NPS planning system. Good agreement was found between the planning system and gel measurements in planes selected for analysis. Gel dosimeter measurements in a coronal plane through the phantom showed a mean difference between measured absorbed dose and calculated dose of 0.17 Gy with SD = 0.13 Gy. Spatially, the errors at the reference point remain within one image pixel (1.0 mm). The use of polymer gel dosimetry shows promise for brachytherapy applications, offering complete, three-dimensional dose information, good spatial resolution and small measurement errors. Measurements close to the source, however, are difficult, due to some of the limiting properties of the polyacrylamide gel.

The effect of gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) on the proton relaxation properties of choline, creatine and N-acetylaspartate has been assessed quantitatively. The compounds studied, either directly or indirectly as chemical constituents of other compounds, contribute to proton MR spectroscopy observable metabolite resonances. The longitudinal and transverse Gd-DTPA proton relaxivities of the methyl groups of choline, creatine, and N-acetylaspartate have been determined at 1.5 T. The longitudinal relaxivity of lactate has also been measured. Longitudinal and transverse relaxivity values were found to vary in the order N-acetylaspartate < creatine < choline. Using choline as an example, the maximum possible signal enhancement predicted in vivo in the presence of 0.5 mM Gd-DTPA (using a T(1)-weighted sequence, TR = 888 msec, TE = 20 msec) was found to be approximately 100 %. For a T(2)-weighted sequence (TR = 3000 msec, TE = 270 msec) a maximum signal loss of 53 % was calculated. The present study indicates why the use of contrast agents in spectroscopic investigations may lead to significant changes in signal intensities. Magn Reson Med 42:1155-1158, 1999.

This feasibility study was performed to evaluate the suitability of MRI in defining appropriate pelvic radiotherapy treatment volumes, and to compare MRI sequences with CT for prostate cancer radiotherapy. Five patients with localized prostate cancer, imaged with four MRI sequences (spin echo (SE) T1, turbo SE (TSE) T2, high resolution TSE (HR) T2, and FLASH 3D (F3D)), compared with their corresponding CT planning scans. Segmentation ability of the following pelvic structures: prostatic apex (PA), prostate, rectum, bladder and seminal vesicles (SV), were evaluated by three independent observers. They used a five point grading scale based on the anatomical definition of the organ boundary, tissue contrast and multiplanar display. Results were averaged for the group and for each sequence. There was no significant interobserver variation in the assessed scores (p > 0.1). The average scores (+/- 1 SD) for all pelvic structures assessed by each imaging sequence were CT 1.3 +/- 0.6; SE T1 2.4 +/- 0.9; TSE T2 2.4 +/- 0.7; HR T2 2.2 +/- 0.7 and F3D 3.4 +/- 0.6. Compared with CT, the average MR score for each assessed pelvic structure was higher with a trend for all transaxial MR sequences to provide improved segmentation of the PA and rectum. The F3D sequence scored highest as it provided multiplanar views and avoided the problem of partial volume averaging. MRI, compared with CT, appears to provide improved definition of pelvic treatment volumes but further work is required to confirm this and to address the issues of MRI associated distortion and dosimetry before MRI can be used routinely for pelvic radiotherapy planning.

In this paper we present a new approach for the nonrigid registration of contrast-enhanced breast MRI, A hierarchical transformation model of the motion of the breast has been developed. The global motion of the breast is modeled by an affine transformation while the local breast motion is described by a free-form deformation (FPD) based on B-splines. Normalized mutual information is used as a voxel-based similarity measure which is insensitive to intensity changes as a result of the contrast enhancement, Registration is achieved by minimizing a cost function, which represents a combination of the cost associated with the smoothness of the transformation and the cost associated with the image similarity, The algorithm has been applied to the fully automated registration of three-dimensional (3-D) breast MRI in volunteers and patients. In particular, we have compared the results of the proposed nonrigid registration algorithm to those obtained using rigid. and affine registration techniques, The results clearly indicate that the nonrigid registration algorithm is much better able to recover the motion and deformation of the breast than rigid or affine registration algorithms.

Oxygen contamination of a polyacrylamide gel (PAG) dosimeter can have a significant detrimental effect upon the performance characteristics of the gel as a dosimeter. Oxygen contamination can occur during preparation, but can also arise from the diffusion of atmospheric oxygen through vessel walls. Even 'trace' amounts of oxygen present in any gaseous space (usually nitrogen filled) between the surface of the PAG and the vessel seal can have a detectable effect. This paper describes a method used to quantify the detrimental effects of a range of oxygen concentrations upon the performance of the PAG. The results of diffusion studies for air and pure oxygen diffusing into the PAG over time are presented and coupled with a novel method of calculating oxygen concentrations in the PAG. Results obtained suggest that the diffusion is Fickian. The coefficient of diffusion D has been calculated to be (8+/-2) x 10(-6) cm(2) s(-1) for oxygen diffusing into PAG stored at 4 degrees C, under the assumption that the diffusion mechanism is independent of the concentration of the diffusing species. In addition, a quantitative relation has been established between the transverse relaxation rate R-2 of the PAG and the concentration of oxygen present. The implications of these findings for polymer gel dosimetry are discussed.

Precise measurement of pH(e) in vivo may be of clinical value for both diagnosis and selection of therapy. pH(e) measurements made by the P-31 probe 3-aminopropylphosphonate (3-APP) were compared with those made by the F-19 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 pH(e) were compared at 20-60 min post administration, although very low pH(e) values (ca. 6.0) were recorded in two out of eight Lettre tumours by ZK-150471. The more rapid pH(e) measurements possible using ZK-150471 showed that during the first 20 min postadministration significant increases occurred in pH(e) which were greatest in the more necrotic rumours. Since isolated cell experiments showed that ZK-150471 was non-toxic and did not enter the cells, this early increase in pH(e) 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 pH(e) by ZK-150471 compared to 3-APP. These characteristics suggest that ZK-150471 is currently the preferred pH(e) probe for non-invasive MRS. Copyright (C) 1999 John Wiley & Sons, Ltd.

Focused ultrasound surgery (FUS) is being developed clinically for the non-invasive treatment of soft tissue tumours of the prostate, bladder, liver, kidney, muscle and breast. In the work described in this paper, the application of FUS is extended to investigate the potential to induce vascular occlusion, with the aim of applying the technique to problems in fetal medicine and oncology.

Purpose: A new nonrigid registration method, designed to reduce the effect of movement artifact in subtraction images from breast MR, is compared with existing rigid and affine registration methods.Method: Nonrigid registration was compared with rigid and affine registration methods and unregistered images using 54 gadolinium-enhanced 3D breast MR data sets. Twenty-seven data sets had been previously reported normal, and 27 contained a histologically proven carcinoma. The comparison was based on visual assessment and ranking by two radiologists.Results: When analyzed by two radiologists independently, all three registration methods gave better-quality subtraction images than unregistered images (p < 0.01), but nonrigid registration gave significantly better results than the rigid and affine registration methods (p < 0.01). There was no significant difference between rigid and affine registration methods.Conclusion: Nonrigid registration significantly reduces the effects of movement artifact in subtracted contrast-enhanced breast MRI. This may enable better visualization of small tumors and those. within a glandular breast.

A simple pyramidal tube phantom has been designed to allow accurate location of a selected slice along the desired axis of a magnetic resonance scanner and to provide a check of the quality of slice selection. It is particularly helpful in locating the origin of any out-of-slice ghost artefacts. The geometry of the phantom allows the slice positions to be calculated readily.

A software package called the Magnetic Resonance Imaging Workbench has been developed to characterize contrast agent uptake in vivo following T1-weighted magnetic resonance (MR) imaging with qualitative analysis of changes in signal intensity or quantitative analysis of changes in contrast agent concentration over time. Various descriptors may be calculated from the analysis of dynamic contrast agent-enhanced MR studies and visualized as false-color overlays, which allow the immediate display and interpretation of information taken from a series of images acquired over time. Qualitative descriptors include onset of enhancement, initial gradient, mean gradient, maximum enhancement, and washout. These parameters can be particularly useful in the investigation of multifocal or widespread disease. Quantitative descriptors include capillary permeability-surface area product, extracellular volume, and T1 and may be used to monitor changes in the disease state and to assess the efficacy of treatment. In addition, they allow comparison of data obtained from different patients, from independent MR studies, or from studies performed with different modalities. Analysis of contrast enhancement during MR imaging in terms of such qualitative or quantitative parameters is a promising new method of data analysis in radiology.

BANG-gel dosimetry offers the potential for measuring the dose delivered by a radiotherapy treatment technique, in three dimensions, with high spatial resolution and good accuracy. The ability to measure comprehensively a 3D dose distribution is a major advantage of the gel dosimeter over conventional planar and point-based dosimeter devices, particularly when applied to the verification of complex dose distributions characteristic of intensity-modulated radiotherapy (IMRT). In this paper an in-house manufactured BANG-gel dosimeter was applied to study the dose distributions of two irradiation experiments for which the distributions were known: (i) a dosimetrically simple parallel-opposed irradiation, and (ii) a more complex nine-field 'static tomotherapy' intensity-modulated irradiation delivered with the Nomos MIMiC. The uniform distribution in (i) allowed a study of the magnetic resonance (MR) imaging parameters to achieve an optimal trade-off between noise and image resolution (optimum image resolution for the Siemens 1.5T Vision system was determined to be approximately 0.8 mm2 with a slice thickness of 2 mm). The spatial uniformity of gel sensitivity to radiation was found to depend strongly on the presence of oxygen, which must be eliminated for the gel dosimeter to be of use. The gel dosimeter was found to agree well with predicted dose distributions and accurately measured the steep penumbral fall-off of dose, even after many days, proving its potential for the verification of IMRT distributions. In the nine-field IMRT delivery (ii) the predicted dose was computed by both an in-house 'component-delivery' dose algorithm and the Peacock planning-system dose algorithm. Good agreement was found between the two algorithms despite the latter's omission of the change in penumbral characteristics with aperture-size during delivery, lack of inhomogeneity correction and approximate modelling of leaf leakage. These effects were found to be small for the problem studied. The predicted distribution agreed well with the gel-measured distribution at medium and high doses (50-90% isodose lines) although differences of up to 10% were observed at lower doses (30% isodose line). The gel dosimeter was found to have the potential to verify IMRT distributions but required considerable care to achieve accurate results. Attention was required to achieve uniformity of gel sensitivity (to prevent oxygen contamination), and in the calibration process.

A new method of calibrating gel dosimeters (applicable to both Fricke and polyacrylamide gels) is presented which has intrinsically higher accuracy than current methods, and requires less gel. Two test-tubes of gel (inner diameter 2.5 cm, length 20 cm) are irradiated separately with a 10 x 10 cm2 field end-on in a water bath, such that the characteristic depth-dose curve is recorded in the gel. The calibration is then determined by fitting the depth-dose measured in water, against the measured change in relaxivity with depth in the gel. Increased accuracy is achieved in this simple depth-dose geometry by averaging the relaxivity at each depth. A large number of calibration data points, each with relatively high accuracy, are obtained. Calibration data over the full range of dose (1.6-10 Gy) is obtained by irradiating one test-tube to 10 Gy at dose maximum (Dmax), and the other to 4.5 Gy at Dmax. The new calibration method is compared with a 'standard method' where five identical test-tubes of gel were irradiated to different known doses between 2 and 10 Gy. The percentage uncertainties in the slope and intercept of the calibration fit are found to be lower with the new method by a factor of about 4 and 10 respectively, when compared with the standard method and with published values. The gel was found to respond linearly within the error bars up to doses of 7 Gy, with a slope of 0.233 +/- 0.001 s(-1) Gy(-1) and an intercept of 1.106 +/- 0.005 Gy. For higher doses, nonlinear behaviour was observed.

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<0.001), PDE (p = 0.01), TP (p = 0.001) and TNTP (p = 0.007) at week 3 (+/-1). PME at week 3 (+/-1) was also significantly associated with the best volume response to treatment (p = 0.03). A reproducibility analysis of results from the observation of normal breast metabolism in four volunteers showed a mean coefficient of variation of 25%, after correcting for changes resulting from the menstrual cycle. Reproducibility studies in four patients with breast cancer showed a mean coefficient of variation of 33%, with the reproducibility being better in patients measured on different days (difference in TP was -6%) compared with those measured on the same day (difference in TP was -29%).

The purpose of this study was to examine the effect of carbogen gas (95% O-2-5% CO2) on uptake and metabolism of 5-fluorouracil (5FU) in murine RIF-1 tumors and their growth in vivo, In addition, we have explored the mechanisms by which carbogen can transiently affect the physiology of RIF-1 tumors.After i.p. injection of 1 mmol/kg 5FU into C3H mice, the uptake and metabolism of the drug by s.c. RIF-1 tumors was followed for 2 h noninvasively using F-19-magnetic resonance spectroscopy (MRS). In all animals, irrespective of tumor size, carbogen caused a significant increase in the half-life (t(1/2)) of the elimination of 5FU by the tumor and a significant increase in growth inhibition, In 2-3-g tumors (group II), carbogen also caused increased 5FU uptake and metabolism to the cytotoxic 5-fluoronucleotides, whereas in 0.8-1.5-g tumors (group I), only the t(1/2) was slightly increased, These results suggested that tumor size was an important factor in the effect of carbogen on tumor physiology.Measurements of RIF-1 tumor vascular and necrotic volume showed no significant differences between group I and group II tumors, However, H-1-MR images of RIF-1 tumors showed that carbogen caused a transient decrease in signal intensity, which correlated positively (P = 0.02) with tumor size, suggesting that larger tumors responded to carbogen by transiently increasing O-2 uptake from the blood. F-19-MRS was used to measure RIF-1 tumor retention of the fluorinated nitroimidazole SR-4554. These studies also showed a positive correlation (P = 0.001) with tumor size, implying greater hypoxia in larger tumors, We propose that carbogen may transiently open nonfunctional blood vessels in the tumor, allowing increased leakage of 5FU from the plasma into the extracellular space, 5FU transport is known to be pH dependent, Intra- and extracellular tumor pH was measured using P-31- and F-19-MRS, which showed that carbogen caused a significant decrease in the extracellular pH of 0.1 unit in group II tumors and a consequent increase in the negative pH gradient across the tumor plasma membrane, which can cause increased 5FU uptake, The pH gradient was unaffected in group I tumors.We conclude that carbogen breathing can increase tumor uptake of 5FU by two independent mechanisms involving changes in tumor blood pow and pH, which consequently cause increased formation of 5-fluoronucleotides and cytotoxicity. The effect seems more pronounced in hypoxic tumors, implying that carbogen would be a valuable aid in clinical chemotherapy.

To investigate the possible dependence of 5-fluorouracil (5FU) uptake in tumours on the intra- (pH(i)) and extracellular (pH(e)) pH, a pH gradient (Delta pH) was imposed across the plasma membrane of ascites tumour cells in vitro, similar to that known to occur in some solid tumours in vivo, by incubation in media of pH(e) 5-8. A greater than or equal to 2:1 (intracellular/extracellular) accumulation of radiolabelled 5FU occurred after 5 min incubation of the cells with 0.5 mM 5FU at pH(e) of 5.0, 5.5 or 6.0. 5FU metabolism is slow under these conditions, and 5FU uptake was not affected by longer incubations up to 20 min, nor by the absence of a sodium gradient. pH, was estimated from the distribution of the weak acid, 5,5-dimethyl-2,4-oxazolidione ([C-14]DMO) across the cell membrane. There was significant correlation between the intracellular/extracellular 5FU ratio and pH(e) (from pH(e) 6-8), Delta pH and pH(i) (P < 0.02). Similar results were obtained with HT29 cells. incubation with a drug that made plasma membranes permeable to H+ significantly decreased 5FU uptake in Lettre cells. The co-transport of 5FU may occur on a proton symport using the proton motive force of the Delta pH.

The demagnetizing field produced by the nuclear polarization can induce refocusing of multiple spin echoes. We show that multiple spin echoes can be observed in vivo with a clinical MR system at 1.5 T. Strategies for the spatial localization of the multiple spin echo signals are considered. Multiple spin echo studies in brain white matter and skeletal muscle in healthy volunteers are reported. The dependence of the signal amplitudes on the experimental parameters is compared with the theory. The sources of contrast for MRI and the perspectives for medical applications are discussed. (C) 1998 Academic Press.

A hyperpolarized Xe-129 Nuclear Magnetic Resonance (NMR) technique for measuring diffusion of xenon in solution is presented. The dramatically enhanced NMR signal of hyperpolarized Xe-129 makes it possible to measure the xenon self-diffusion coefficient with a single-shot NMR experiment. Diffusion constants of xenon in various solvents are reported. A value of (2.2 +/- 0.4) x 10(-5) cm(2) s(-1) was measured for xenon in water at room temperature. The potential applications of this technique to in vivo experiments are discussed. (C) 1998 Elsevier Science B.V. All rights reserved.

Metabolite concentrations determined from MR spectra provide more specific information than peak area ratios. This paper presents a method of quantification that allows metabolite concentrations to be determined from in vivo 31P MR spectra acquired using a surface coil and ISIS localization. Corrections for the effects of B1 field inhomogeneity produced by surface coils are based on a measured and calibrated spatial sensitivity field map for the coil. Account is taken of imperfections in pulse performance, coil loading effects and relaxation effects, the latter making use of published metabolite relaxation times. The technique is demonstrated on model solutions. The concentrations of the main 31P metabolites in normal human calf muscle measured using this method are [PCr] = 26.9 +/- 4.1 mM; [Pi] = 3.6 +/- 1.2 mM; [NTP] = 6.8 +/- 1.8 mM. Quantification of spectra acquired from soft-tissue tumours in patients both pre- and post-treatment showed that changes in metabolite concentrations are more sensitive to metabolic changes than changes in peak area ratios.

High intensity, focused ultrasound has considerable potential as a non-invasive surgical technique, with applications which include the treatment of benign prostatic hyperplasia and the elimination of metastatic disease in the liver. In this study, the use of MRI for treatment planning and subsequent monitoring of ultrasound therapy in the liver has been evaluated. In an experimental model both tumour bearing and normal liver lobes were treated invasively with high intensity focused beam ultrasound surgery. Subsequent changes in the tissue properties were investigated using MRI, in combination with the intravenous contrast agent, Gd-DTPA. The repair of ultrasound damaged tissue was followed until 8 weeks after treatment. The appearance of the MR images was compared with histological sections prepared from parallel experiments. Imaging and histology results showed excellent agreement, illustrating that MRI is well suited to the non-invasive observation of the effects of high intensity focused ultrasound therapy on tissue. Thus, as the clinical potential of ultrasound surgery is realized, MRI, together with the use of contrast agents, will be invaluable both in treatment planning and in monitoring the progress of a treated tumour.

This paper describes a measurement protocol for acquiring quantitative dynamic MRI data and novel analysis and display software (Magnetic Resonance Imaging Workbench (MRIW)). Proton density-weighted and T1-weighted two-dimensional gradient echo images are used to quantify tissue contrast agent concentration. The dynamic studies last approximately 7 minutes, with 10-second temporal resolution. Analyses of signal and concentration changes with time are performed, allowing capillary permeability-surface area product, tissue leakage space, enhancement onset time, mean enhancement gradient and maximum enhancement level to be mapped as false-color parametric overlays registered with anatomic images. Quantification of permeability and leakage space provides a method for comparing physiology in patients between visits or for intersite comparisons.

FOCI pulses are a variant of hyperbolic secant pulses in which the RF amplitude, RF frequency, and gradient waveform are all modulated by the same function A(t). This increases the usable gradient amplitude without requiring a corresponding increase in RF amplitude. In this paper the implementation and inversion profiles of FOCI pulses on a clinical MR system are described, showing improved slice definition and chemical-shift offset behavior. Their adiabatic behavior is confirmed, and their use with an ISIS sequence for localized MRS is illustrated. Finally the effects of waveform digitization are considered, and the implications for SAR and dB/dt are discussed.

F-19-MRS (magnetic resonance spectroscopy) was used to study the pharmacokinetics of 5-fluorouracil (5-FU) in human (HT29) tumour xenografts, with and without pretreatment of the mice using either thymidine (40 min) or interferon-alpha (2 and 24h). A 200 mg/kg i.p. bolus dose of 5-FU was eliminated from control tumours with a t(1/2) of 25.4 +/- 2 min (mean +/- SEM, n = 11), while both thymidine (500 mg/kg) and interferon (50 000 IU/mouse) significantly increased t(1/2) to 36.5 +/- 6.1 (n = 5) and 48.1 +/- 13.6 min (n = 4), respectively (P = 0.04, Gabriel's ANOVA). Thymidine increased 5-FU anabolism to cytotoxic 5-fluoronucleotides, and decreased the amount of tumour catabolites; the latter probably recirculated from liver since isolated HT29 cells did not catabolise 5-FU. These in vivo observations were confirmed by F-19-MRS quantification of tumour extracts. Interferon did not significantly affect 5-FU metabolism in the tumour or liver, nor the 5-FU t(1/2) in liver. Treatment of tumours with 5-FU or interferon had no effect on tumour growth, whereas the combination strongly inhibited growth. P-31-MRS of HT29 tumours showed that 2 and 24 h after i.p. injections of interferon there was a significant increase in the pH(int), of 0.3 +/- 0.04 units (P = 0.002), while pH(ext) and the tumour NTP/Pi ratio were unchanged. The large increase in the negative pH gradient (-Delta pH) across the tumour plasma membrane caused by interferon suggests the a pH may be a factor in tumour retention of 5-FU, as recently shown in isolated tumour cells. (C) 1997 Elsevier Science Ltd.

The emerging utilisation of conformal radiotherapy (RT) planning requires sophisticated imaging modalities. Magnetic resonance imaging (MRI) has introduced several added imaging benefits that may confer an advantage over the use of computed tomography (CT) in RT planning such as improved soft tissue definition, unrestricted multiplannar and volumetric imaging as well as physiological and biochemical information with magnetic resonance (MR) angiography and spectroscopy. However, MRI has not yet seriously challenged CT for RT planning in most sites. The reasons for this include: (1) the poor imaging of bone and the lack of electron density information from MRI required for dosimetry calculations; (2) the presence of intrinsic system-related and object-induced MR image distortions; (3) the paucity of widely available computer software to accurately and reliably integrate and manipulate MR images within existing RT planning systems. In this review, the basic principals of MRI with its present potential and limitations for RT planning as well as possible solutions will be examined. Methods of MRI data acquisition and processing including image segmentation and registration to allow its application in RT planning will be discussed. Despite the difficulties listed, MRI has complemented CT-based RT planning and in some regions of the body especially the brain, it has been used alone with some success. Recent work with doped gel compounds allow the MRI mapping of dose distributions thus potentially providing a quality assurance tool and in a manner analogous to CT, the production of dose-response information in the form of dose volume histograms. However, despite the promise of MRI, much development research remains before its full potential and cost-effectiveness can be assessed.

Measurements of tumour extracts and tumour cell lines using 1H and 31P MRS have demonstrated the potential of the technique to distinguish different types of tumour, and in a range of tumours to provide information on degree of malignancy, grade and prognosis. In vivo studies have shown that changes in the energetic status of tumours, and in the phospholipid metabolites, correlate with the response of tumours to treatment, providing the potential to monitor the effectiveness of cancer treatment. Routine application of these techniques in clinical measurements depends upon the development of robust equipment and measurement methods to aid clinical measurements. Considerable advances have been made. Imaging can now be performed very rapidly, and a range of localisation technique have been established. Equipment provides for automatic set up and shimming, and coils with increased sensitivity are available. Improvements in hardware provide more sensitive receive coils; and shielded gradients which provide for a more robust performance. 31P studies are being improved by the use of NOE enhancement and 1H decoupling, increasing the specificity and sensitivity of the techniques. These advances in instrumentation need to be complemented by advances in our understanding of the biochemical processes in tumours giving rise to the observed spectral changes. In this paper, recent reports of NMR spectroscopy in cancer are reviewed, together with the requirements for tumour measurements.

A sequence for simultaneous acquisition of 1H STEAM and 31P ISIS spectra is described, and 1H and 31P spectra obtained simultaneously from the same volume of interest in both a phantom and a volunteer are presented. The STEAM and ISIS parts of the sequence use a common gradient scheme that is also used during the localized shimming process, partially compensating for eddy current effects. It is demonstrated that this method of simultaneous multinuclear spectroscopy does not compromise the localization performance of the sequence.

To measure plasma 5-fluorouracil (5-FU) levels using high-performance liquid chromatography (HPLC) and compare the findings to the tissue metabolism of 5-FU evaluated using 19F magnetic resonance spectroscopy (MRS), during a protracted venous infusion (PVI) with or without interferon-alpha.

Measurements of MR spin-lattice (T1), and spin-spin (T2) relaxation times in lumbar vertebrae have been performed in a pilot study on six adult patients, treated for acute myeloid leukaemia (AML). All patients were treated with initial chemotherapy and then proceeded to bone marrow transplantation (BMT), conditioned with Melphalan and total body irradiation (TBI). MR measurements were made between 21 and 89 months after TBI. The relaxation times in the six patients were compared with those in six healthy age-matched volunteers to establish whether there were differences between the two groups. Average T1 values in the vertebrae of the treated patients are significantly shorter (p < 0.01) than in the healthy volunteers. This is consistent with the observation of a relatively hyperintense vertebral bone marrow in the T1 weighted images and is likely to be a consequence of treatment induced fatty replacement of marrow. Shorter T1 values tend to be distributed within the centre of the lumbar vertebrae compatible with observations, made by others, which suggest that the peripheral zone of the vertebral body has been repopulated with bone marrow cells whereas the central zone, around the basivertebral vein, is predominantly fat. Histogram displays of vertebral body relaxation time distributions (T1, T2) for both patients and healthy age-matched volunteers are similar in that both patients and volunteers give histograms that are only slightly skewed. This similarity is probably a reflection of the fact that the patients have been in remission for over a year and have generally healthy bone marrow.

The three most widely used single-volume NMR localization techniques (ISIS, STEAM and PRESS) are assessed quantitatively for 1H spectroscopy using an EEC localization test object. Signal selection efficiency, suppression of outer volume signals and contamination are measured on a 1.5 T whole-body Siemens GBS1 system. The ISIS signal selection efficiency (volume of interest (VOI), 1-125 cm3) ranged from 90% to 95%, with T1 relaxation during the sequence shown to account for the observed 5-10% signal loss. Contamination for ISIS was found to be higher for smaller VOIS and ranged from approximately 45% (VOI = 1 cm3) to approximately 9% (VOI = 125 cm3). For PRESS, contamination ranged from 7% to 12% and it was between 3% and 8% for STEAM. However, the maximum signal selection efficiency for the latter two techniques (echo time, 270 ms) was relatively low (10-17%), and limited by T2 losses and the non-rectangular slice profiles of sinc pulses.

Stimulated echo (STEAM) localisation yields up to 50% of the full magnetisation. It is shown that given the good magnetic field homogeneity now obtained in clinical MRS, and with a slight modification to the gradient pattern, the localised signal may be nearly doubled, although at the expense of introducing a frequency-dependent amplitude for peaks in the final spectrum. A two-step phase cycle is also required. The principle is demonstrated on a clinical MR system, and the relative merits of the sequence are discussed.

Quantification of MRS signals obtained with surface coils is difficult due to the inhomogeneous response of these coils. This inhomogeneity results in the measured signal from a defined volume of interest (VOI) being spatially dependent. To account for the sensitivity variation with position from the surface coil, we have developed a method of calculating correction factors for defined VOIs based on an experimentally obtained 3D sensitivity coil map. These factors may then be applied to spectra obtained from these VOIs to accurately take into consideration the varying coil sensitivity resulting in a reduction of measured signal. This method is demonstrated here to be able to correct for the inhomogeneity of surface coils over a range of two coil radii to within 4% accuracy.

Based on the requirements of test protocols developed to evaluate clinical MRS single slice and volume localisation sequences, two clinical test objects, STO1 and STO2 have been developed. The properties of a range of potential construction materials have been assessed, demonstrating that the water/Perspex interface produced minimum susceptibility effects. The design of the objects has been evaluated in trials on different magnetic resonance instruments, with size and loading being adjusted to allow use on currently available equipment. Appropriate test solutions for 31P and 1H measurements have been developed and their properties evaluated.

1H decoupling using the WALTZ-4 decoupling scheme is a popular means of improving spectral resolution in 31P NMR spectroscopy. At the same time, sensitivity in the proton decoupled 31P spectra is enhanced by the nuclear Overhauser effect. The authors show that when using WALTZ-4 decoupling in a uniform decoupler RF field, the degree of sensitivity enhancement is critically dependent on whether the decoupling interval contains an odd or an even number of WALTZ decoupling elements. This effect is demonstrated both in phantoms and in vivo.

The anticancer agent temozolomide labeled with C-13 (8-Carbamoyl-3-C-13-methylimidazo-[5,1-d]-1,2,3,5-tetrazin-4-(3H)-one), was noninvasively detected in subcutaneous RIF-1 tumors by a selective cross polarization C-13 NMR method, at a field strength of 9.4T., Pharmacokinetics of the drug, at a dose of 150 mg/kg, were determined for intravenous and intraperitoneal modes of administration (three animals per mode), The half-life of the drug in the tumors was approximately 60 min. The uptake and clearance of the drug, however, varied significantly between individual hosts, for both modes of administration, These results demonstrate the feasibility of obtaining pharmacokinetics of anticancer agents for individual tumors without the need for a label that might modify drug activity (e.g., fluorine), The variability of the in vivo measurements, even within the same tumor model, demonstrates the necessity of directly monitoring the tumor to evaluate drug pharmacokinetics.

Magnetic resonance spectroscopy provides a means of non-invasively measuring the behaviour of a range of compounds of biochemical significance. With the development of a range of spatial localization and mapping techniques, the method has a range of promising applications in oncology. 31P and 1H spectroscopy are of value in observing the metabolism of both tumours and normal tissues. 19F spectroscopy has been used to monitor the metabolism of fluorine containing anticancer drugs, and 13C may find application in this field, particularly in pre-clinical studies. In vivo clinical measurements are complemented by pre-clinical studies, high resolution measurements of extracts from tissue samples and also the measurement of biofluids, which can provide additional metabolic and pharmacokinetic information. The application of these techniques to oncology is reviewed, with particular emphasis on their clinical role.

A gradient scheme is presented which may be used for STEAM or ISIS localization. One application of the scheme is to perform single-shot STEAM shimming prior to data acquisition with STEAM and ISIS, using identical gradient amplitudes and durations. Using conventional STEAM to shim for ISIS can produce line-shape distortions induced by different eddy currents in the two sequences; with this gradient scheme the problem is minimized. Line-shape improvements of STEAM and ISIS localized data obtained after volume localized shimming with the proposed STEAM sequence are demonstrated. The localization performance of the STEAM and ISIS sequences are demonstrated on phantoms and in vivo for 1H and 31P metabolites.

Since 5-fluorouracil (5-FU) was synthesized in the late 1950s it has become an important component of many anticancer treatment regimens. The increasing volume of literature accumulating about this drug is evidence that the optimal administration schedule and its combination with modulators has yet to be determined. Much of the investigation of 5-FU, particularly in the clinical setting, has been in the development of administration schedules based on plasma pharmacokinetic data. Particularly with the development of modulators of 5-FU, investigators are looking more closely at its intracellular tissue pharmacology and metabolism. To study the tissue metabolism of 5-FU (and other drugs), patients often have to be willing to undergo invasive procedures, sometimes with significant discomfort, usually with little direct benefit to their management. The ability to conduct an investigation of the cellular effects of a drug in both tumor and normal tissue non-invasively will not only be more acceptable to patients, resulting in better compliance to protocols, but will give information about the in situ tissue which is not subject to the problems of invasive sampling techniques. Magnetic resonance spectroscopy is a non-invasive technique that has recently started to show potential in the area of investigating 5-FU metabolism and its impact on tumor and patient outcome. Further development of this method may ultimately have an impact on the investigation of any new anticancer agent.

Robust and accurate methods of measuring relaxation times on commercial scanners have recently been developed. Such methods overcome many machine and sequence dependent errors, but are still subject to errors arising from motion artifacts. This paper considers methods of decreasing the effect of motion artifacts in in vivo T-1 and T-2 measurements. Three conventional techniques:for reducing such artifacts are assessed for their use with relaxation time measurement sequences. It is shown that these techniques do not adversely affect the accuracy of phantom T-1 measurements made with the spin echo/inversion recovery sequence, and of T-2 measurements made using the PHAPS sequence. For in vivo measurements of T-1 it is also shown that these techniques reduce the standard deviation of T-1 measurements in regions of interest and improve the reproducibility of such measurements overall. Two other techniques for reducing motion artifacts were found not to be compatible with the accurate measurement of relaxation times.

Robust and accurate methods of measuring relaxation times on commercial scanners have recently been developed. Such methods overcome many machine and sequence dependent errors, but are still subject to errors arising from motion artifacts. This paper considers methods of decreasing the effect of motion artifacts in in vivo T1 and T2 measurements. Three conventional techniques for reducing such artifacts are assessed for their use with relaxation time measurement sequences. It is shown that these techniques do not adversely affect the accuracy of phantom T1 measurements made with the spin echo/inversion recovery sequence, and of T2 measurements made using the PHAPS sequence. For in vivo measurements of T1 it is also shown that these techniques reduce the standard deviation of T1 measurements in regions of interest and improve the reproducibility of such measurements overall. Two other techniques for reducing motion artifacts were found not to be compatible with the accurate measurement of relaxation times.

A method has been developed that uses dynamic MR imaging to measure simultaneously the changes in signal intensity due to paramagnetic contrast agent in blood and tissue, using interleaved single-angle projection and imaging sequences. The basic projection/image sequence has a projection time resolution of 50 ms and can measure rapid changes in the blood signal intensity. Variants with a tissue suppression slab have time resolutions of 57 or 75 ms. Orientation of the projection and image planes can be defined independently. This technique will facilitate functional measurements using MR contrast agents, allowing the blood input function to be determined with excellent time resolution.

The concentration of phospholipid metabolites was determined in chemical extracts from two types of rat mammary tumours and compared with proliferation data (S-phase fraction). One of the tumours was an oestrogen-sensitive transplanted tumour. In this tumour the concentration of phosphocholine (PC) and glycerophosphorylcholine (GPC) correlated strongly with the S-phase fraction but not with the number of cells actively synthesizing DNA. Oestrogen ablation resulted in tumour regression. Regressing tumours contained less PC and more GPC than those actively growing. The other tumour was induced in rats by intravenous administration of N-methyl N-nitrosourea. Phosphoethanolamine (PE), PC and GPC levels were not associated with the S-phase fraction in this tumour. Oestrogen ablation resulted in tumour regression. There was no significant difference between the regressing and growing tumours in PE, PC or GPC content.

The content of the phospholipid metabolites, phosphocholine, phosphoethanolamine, glycerophosphorylcholine and glycerophosphorylethanolamine was measured in chemical extracts from 46 human breast carcinoma using P-31 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.

Background: 5-Fluorouracil (5-FU) is the most widely used cytotoxic drug in oncology and the only one useful in the management of colorectal cancer - a leading cause of cancer death worldwide. Recent studies of 5-FU have focused on increasing efficacy and reducing toxicity by varying the delivery schedule and combining it with modulators. With the development of whole body magnetic resonance systems it is now possible to examine the metabolism of 5-FU in vivo by exploiting the magnetic properties of the fluorine atom which is an integral component of the drug.Patients and methods: Magnetic Resonance Spectroscopy (MRS) was used to non-invasively monitor the metabolism of 5-FU in the liver metastases of colorectal cancer patients. The patients were treated with a continuous low dose intravenous infusion of 5-FU until the point of refractory disease, at which time interferon-alpha was added with the objective of modulating 5-FU activity. MRS was performed at specific phases of the treatment.Results: Twenty-six patients were treated with 5-FU, 11 (42%) achieving partial response. Of the 15 given interferon when disease became refractory to 5-FU, 4 showed signs of further response. In patients observed by MRS during the first 8 weeks of 5-FU treatment, those with a visible 5-FU signal were likely to respond to treatment (p = 0.017). At the time of interferon-a addition, MRS showed that 7 patients developed new or increased 5-FU signals, and 4 patients showed a signal from the active metabolites of 5-FU. The patients who exhibited a new or increased 5-FU signal were more likely to show further response to interferon-alpha (p = 0.007).Conclusions: MRS is a powerful technique for monitoring intratumoural metabolism and modulation of 5-FU enabling prediction of tumour outcome. Direct metabolic information may facilitate the rapid development of optimal clinical schedules for 5-FU and its modulators, thus maximising antitumour effect and minimising toxicity to the patient. This technique may be applied to other areas of clinical medicine where knowledge of the tissue metabolism of a fluorinated drug is of interest.

The two-dimensional mapping of the effective diffusion coefficient of water in tissues may provide a useful method of tissue characterization to complement T1 and T2 relaxation time studies for diagnostic purposes. Current diffusion techniques rely on the application of large gradient strengths and long echo times to achieve the required sensitivity. This, in turn, limits the applicability of the technique to tissues having long T2s with rapid water diffusion. In addition, the inherent directionality of these methods results in only the partial encoding of diffusion information. A modified diffusion sequence is presented, radial diffusion mapping (RAD), which provides enhanced sensitivity diffusion maps by employing gradient sensitization in three orthogonal directions. Results in both phantoms and volunteers are presented, together with an investigation of the effects of T2 on the measurement accuracy. Using RAD, a two- to five-fold improvement in sensitivity was achieved, thus significantly enhancing the dynamic range of the method and allowing more accurate in vivo diffusion measurements to be carried out.

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.

"Conformal" spectroscopy is a method for the acquisition of accurately localized NMR spectra from noncuboidal regions with optimum signal-to-noise ratio, and is based upon the localization of volumes defined by a number of oblique intersecting selected slices. We have previously demonstrated conformal localization of volumes with convex surfaces. In this paper we extend the technique to the localization of concave volumes.

A technique is reported for generating the quantitative area under selected peaks within a 31P NMR spectrum. A numerical iterative method generates the fitted curve so as to minimize the RMS deviation between the fit and the experimental data. The curve is constructed from elemental grains of spectral density ('spexels'), each of which represents an elemental Lorentzian distribution, where the centre frequency and line width of the spexel may be varied within predetermined limits. This provides a fit that in principle is not restricted to a Lorentzian model. The method allows peak areas to be estimated, including the case of overlapping peaks. The method has been tested using simulated spectra containing six overlapping spectral lines each of known amplitude (ranging from 367 to 661 mV) and area; together with additional Gaussian noise with a standard deviation ranging from 30 to 646 mV. The results of fitting both unfiltered and filtered spectra were compared. The variation of quality of fit with spectral noise and filtering has been evaluated. In all cases, the method fitted the peak amplitudes to within 1% of the simulated value. The optimization processes provide an excellent non-linear spectrum filtering algorithm. Provided the noise in the spectra did not exceed ca 400 mV, prefiltered data could be adequately fitted.

Spin inversion produced by hyperbolic secant RF pulses is independent of pulse amplitude once a threshold value is exceeded. A semi-empirical formula for these pulses has been derived by application of analytical solutions to the Bloch equations. This predicts the required coil voltages for inversion as a function of inversion bandwidth and side-to-width parameter-mu, based on knowledge of a reference voltage for the loaded coil. The voltage required is shown to increase linearly with bandwidth but to fall with the mu, approximately as (1/mu)0.4. Experimental confirmation is presented, and factors affecting choice of pulse parameters are discussed.

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 T1 s 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. P-31 spectra and T1 values of P(i), phosphocreatine and alpha-, beta- and gamma-NTP metabolites from the calf muscle of healthy volunteers were obtained with the sequence employing B1-insensitive excitation pulses and a surface coil. The T1 values fall within the range of published values obtained by other techniques.

pH measurements require a suitable pH reference within the 31P NMR spectrum with respect to which the chemical shift of Pi, and hence pH, may be calculated. In muscle spectra PCr is prominent and provides a reference frequency. However, recent localized tumor studies have reported the absence of PCr, for example, in breast tumors. The use of the alpha-, beta-, and gamma-ATP peaks as suitable references has been suggested, but the position of the beta- and gamma-ATP peaks is dependent upon the intracellular Mg2+ concentration. The alpha-ATP is not affected by ionic concentrations; however, it contains UDPG and NAD+, the presence of which can lead to peak-shape distortion. This paper considers the use of the H2O resonance from the proton spectrum used for shimming as a suitable pH reference, provided this is also localized to the same region of interest, using a sequence giving rise to eddy current effects comparable to those of the 31P NMR sequence. Localized in vivo measurements in the muscle and brain of volunteers indicate good agreement between the proton and phosphorus chemical shifts, allowing the PCr position to be predicted to within 0.01 ppm in all cases.

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.

A simple scheme for the polarity correction of absolute images from inversion recovery multi-image T1 measurement sequences is described and demonstrated. This method is less sensitive to errors from eddy currents than the conventional full phase correction schemes and does not involve an increase in measurement time as it requires no additional scans.

An in vivo P-31 NMR spectrum was obtained from each of four human breast tumours. The phosphomonoester and phosphodiester region of each spectrum consisted of a broad peak. Chemical extracts from samples of each of the tumours obtained at resection were examined on a high field strength NMR system. The phosphomonoester region in the spectrum from each extract resolved into three peaks consisting of phosphocholine, phosphoethanolamine and a nucleoside monophosphate. The phosphodiester region resolved into two components, glycerophosphorylcholine and glycerophosphorylethanolamine. Comparing the in vivo and in vitro data from each tumour showed that the contribution of phosphodiester was much lower in the in vitro spectra. We believe this to be a consequence of phospholipid, which would not appear in the aqueous extract, contributing to the phosphodiester peak in vivo.

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.

An oestrogen sensitive rat mammary tumour was grown in two groups of female and one group of male hooded rats. The male group and one of the female groups were supplemented with oestrogen. The tumours grew most rapidly in the female supplemented group. When the tumours reached 1.5 cm in diameter they were harvested and the cell cycle distribution and number of cells actively synthesising DNA (bromodeoxyuridine (BrdU) labelling index) determined in each case. Chemical extracts were prepared from each tumour and the concentration of phosphorus-containing metabolites determined using high resolution NMR spectroscopy. The concentration of phosphocholine was found to correlate strongly with the number of cells in S-phase and the number of cells labelled with BrdU, whilst a highly significant negative correlation was observed between these two parameters and glycerophosphocholine. The concentration of phosphoethanolamine did not correlate with either of these measures of proliferation rate. The concentration of glycerophosphorylethanolamine showed a weak negative correlation with the number of cells in S-phase.

Lonidamine is a substituted indazole carboxylic acid with a unique mechanism of action and early clinical studies have reported anti-tumour activity. In a phase II study 32 patients with previously treated advanced breast cancer were given Lonidamine in a daily divided oral dose of 600 mg. Of 28 patients evaluable for response, three (11%) achieved a partial response (4-24+ months) and three (11%) a minor response. Two patients have stable disease (greater than 3 months) and 20 progressed. Toxicity was very mild. Sixteen (53%) of 31 patients had myalgia which lasted a median of 2 weeks. This was investigated with nuclear magnetic resonance spectroscopy in four patients but the changes were unrelated to the degree of myalgia. No other major side-effect was seen, and no dose reduction was required. Lonidamine pharmacokinetics have been investigated in 17 patients 1 month after the start of therapy. Lonidamine was detected in the plasma of all patients, but there was no clear relationship between Lonidamine levels and clinical response or toxicity. Lonidamine appears to be active against advanced breast cancer and its low toxicity would allow combination studies with chemotherapy.

The presence of hypoxia and low pH in tumours is known to influence several treatment modalities including radiotherapy, chemotherapy and hyperthermia. Hypoxic and acidic regions have been demonstrated in tumours using pH and pO2 microelectrodes. The technique has shown marked heterogeneity within individual tumours. A non-invasive measure of intracellular pH is provided by 31P nuclear magnetic resonance (NMR) spectroscopy from determination of the chemical shift of inorganic phosphate, and is being increasingly applied to the study of human tumours in vivo. Based upon the assumption that hypoxic cells are also acidic, we have assessed the ability of a whole-body NMR spectrometer to detect acidic subpopulations within a tumour using simulated tumour spectra. In these simulations the size of the acidic subpopulation, assigned pH values from 5.0 to 7.0, was varied between 5% and 50% of the neutral "control" population. Gaussian noise was added to the simulated spectra giving signal-to-noise ratios for the neutral control inorganic phosphate peak of 3, 5 and 7, which are typical of values encountered in human tumour measurements. From the results of the simulations it seems unlikely that human hypoxic, and presumably acidic, cell fractions, typically 1-15%, will be detected by this method in the presence of signal-to-noise levels characteristic of current equipment. Therefore, whole-body in vivo 31P NMR spectroscopy may fail to identify significant pH heterogeneity within human tumours. Improvements in signal-to-noise and line separation owing to improvements in technique and higher field strength instruments may improve sensitivity to heterogeneous populations.

An ambient-temperature control system, designed to maintain small, anaesthetized animals at physiological temperatures during long examination times, is described. The system is suitable for installation in large bore, whole-body magnets and can be positioned close to the animal under study. Design details and a description of the equipment used is given. The system proved to be satisfactory in maintaining mice at physiological temperatures.

The result of conservative management of breast cancer is strongly dependent on the homogeneity of the dose delivered a schedule of post-surgical radiotherapy. In addition to improvements in local control, late normal-tissue effects should be minimised by achieving a good dose homogeneity. The Royal Marsden Hospital prototype CT simulator has been used to image patients in the treatment position. With the CT data incorporated into the planning process a quantitative measure of the dose homogeneity was made. There are strong indications that unless tissue compensators are used and/or conformation therapy is performed, the dose inhomogeneity in a widely used treatment geometry is too large to be clinically acceptable.