Andrew Brian Gill

Advanced Ovarian Cancer: Multiparametric MR Imaging Demonstrates Response- and Metastasis-specific Effects

PURPOSE To investigate the role of multiparametric magnetic resonance (MR) imaging in the evaluation of response to platinum-based neoadjuvant chemotherapy in advanced ovarian cancer and to compare imaging parameters between primary ovarian mass and metastatic disease. MATERIALS AND METHODS Evaluable patients suspected of having advanced ovarian carcinoma were enrolled in a prospective protocol-driven study. Research ethics committee approval and written informed consent were obtained. Multiparametric MR imaging (diffusion-weighted MR imaging, dynamic contrast material-enhanced [DCE] MR imaging, and hydrogen 1 MR spectroscopy) was performed with a 3.0-T wholebody MR imaging system. Three marker lesions-primary ovarian mass, omental cake, and peritoneal deposit-were outlined by a radiologist on apparent diffusion coefficient (ADC) and vascular signal fraction (VSF) maps and on DCE MR images. Comparisons of mean ADC, mean VSF, DCE MR imaging parameters, and choline concentration between responders and nonresponders were based on Response Evaluation Criteria in Solid Tumors and CA-125 criteria. RESULTS Twenty-two patients were evaluable. The mean ADC for peritoneal metastases was lower than that for ovarian (P = .015) and omental (P = .006) sites. There were no differences in pretreatment DCE MR imaging parameters between tumor sites. After treatment, responders showed a significantly larger increase in ADC (P = .021) and fractional volume of the extravascular extracellular space (v(e)) (P = .025) of ovarian lesions compared with nonresponders, but there was no change in ADC at other sites. Pre- and posttreatment values of choline concentration of ovarian lesions were lower in responders (P = .025) than in nonresponders (P = .010). CONCLUSION The significant differences in baseline ADCs among primary ovarian cancer, omental cake, and peritoneal deposits indicate that diffusivity profiles may be tumor-site dependent, suggesting biologic heterogeneity of disease. ADC and v(e) parameters correlated with the cytotoxic effects of platinum-based therapy and may be useful response markers, while choline concentration predicted but did not reflect response.

DCE and DW MRI in monitoring response to androgen deprivation therapy in patients with prostate cancer: a feasibility study.

Androgen deprivation therapy (ADT) is a key primary treatment for advanced and metastatic prostate cancer and is an important neoadjuvant before radiotherapy. We evaluated 3.0 T dynamic contrast‐enhanced MRI and diffusion‐weighted (DW) MRI in monitoring ADT response. Twenty‐three consecutive patients with prostate cancer treated by primary ADT were included. Imaging was performed at baseline and 3 months posttreatment with ADT. After 3 months therapy there was a significant reduction in all dynamic contrast‐enhanced MRI parameters measured in tumor regions of interest (Ktrans, kep, vp, IAUGC‐90); P < 0.001. Areas of normal‐appearing peripheral zone showed no significant change; P = 0.285–0.879. Post‐ADT, there was no significant change in apparent diffusion coefficient values in tumors, whilst apparent diffusion coefficient values significantly decreased in areas of normal‐appearing peripheral zone, from 1.786 × 10−3 mm2/s to 1.561 × 10−3 mm2/s; P = 0.007. As expected the median Prostate‐Specific Antigen (PSA) significantly reduced from 30 ng/mL to 1.5 ng/mL posttreatment, and median prostate volume dropped from 47.6 cm3 to 24.9 cm3; P < 0.001. These results suggest that dynamic contrast‐enhanced MRI and diffusion‐weighted MRI offer different information but that both could prove useful adjuncts to the anatomical information provided by T2‐weighted imaging. dynamic contrast‐enhanced as a marker of angiogenesis may help demonstrate ADT resistance and diffusion‐weighted imaging may be more accurate in determining presence of tumor cell death versus residual tumor. Magn Reson Med, 2012.

Dynamic contrast-enhanced MRI in ovarian cancer: Initial experience at 3 tesla in primary and metastatic disease

The aim of this study was to develop and demonstrate a methodology for dynamic contrast‐enhanced MRI at 3 T in patients with advanced ovarian cancer and to report the results from pharmacokinetic modeling of the data. Nineteen patients with suspected advanced ovarian carcinoma (FIGO stage 3 or higher) were enrolled in this prospective study. Up to three marker lesions were identified: primary ovarian mass, omental ‘‘cake’’, and peritoneal deposits. Dynamic contrast‐enhanced MRI was performed using a three‐dimensional T1‐weighted gradient‐echo acquisition with a temporal resolution of 1.6 sec, following intravenous administration of 0.1 mmol/kg gadobutrol. Precontrast T1 mapping, using an inversion‐recovery fast gradient‐echo sequence, was also performed. Imaging was completed in 18/19 patients, although two were subsequently excluded based on pathology results. Pharmacokinetic modeling of the data was performed according to the extended Kety model, using an arterial input function formed by concatenation of the Fritz‐Hansen and Weinmann curves. No statistically significant differences were found between the results for the three marker lesions. In the future, this work will allow kinetic modeling results from ovarian dynamic contrast‐enhanced MRI to be correlated with response to treatment. The high temporal resolution allows good characterization of the rapid contrast agent uptake in these vascular tumors. Magn Reson Med 63:1044–1049, 2010.

A comparison of quantitative methods for clinical imaging with hyperpolarized 13C-pyruvate

Dissolution dynamic nuclear polarization (DNP) enables the metabolism of hyperpolarized 13C‐labelled molecules, such as the conversion of [1‐13C]pyruvate to [1‐13C]lactate, to be dynamically and non‐invasively imaged in tissue. Imaging of this exchange reaction in animal models has been shown to detect early treatment response and correlate with tumour grade. The first human DNP study has recently been completed, and, for widespread clinical translation, simple and reliable methods are necessary to accurately probe the reaction in patients. However, there is currently no consensus on the most appropriate method to quantify this exchange reaction. In this study, an in vitro system was used to compare several kinetic models, as well as simple model‐free methods. Experiments were performed using a clinical hyperpolarizer, a human 3 T MR system, and spectroscopic imaging sequences. The quantitative methods were compared in vivo by using subcutaneous breast tumours in rats to examine the effect of pyruvate inflow. The two‐way kinetic model was the most accurate method for characterizing the exchange reaction in vitro, and the incorporation of a Heaviside step inflow profile was best able to describe the in vivo data. The lactate time‐to‐peak and the lactate‐to‐pyruvate area under the curve ratio were simple model‐free approaches that accurately represented the full reaction, with the time‐to‐peak method performing indistinguishably from the best kinetic model. Finally, extracting data from a single pixel was a robust and reliable surrogate of the whole region of interest. This work has identified appropriate quantitative methods for future work in the analysis of human hyperpolarized 13C data.

A functional form for injected MRI Gd-chelate contrast agent concentration incorporating recirculation, extravasation and excretion

A functional form for the vascular concentration of MRI contrast agent after intravenous bolus injection was developed that can be used to model the concentration at any vascular site at which contrast concentration can be measured. The form is based on previous models of blood circulation, and is consistent with previously measured data at long post-injection times, when the contrast agent is fully and evenly dispersed in the blood. It allows the first-pass and recirculation peaks of contrast agent to be modelled, and measurement of the absolute concentration of contrast agent at a single time point allows the whole time course to be rescaled to give absolute contrast agent concentration values. This measure of absolute concentration could be performed at a long post-injection time using either MRI or blood-sampling methods. In order to provide a model that is consistent with measured data, it was necessary to include both rapid and slow extravasation, together with excretion via the kidneys. The model was tested on T(1)-weighted data from the descending aorta and hepatic portal vein, and on T*(2)-weighted data from the cerebral arteries. Fitting of the model was successful for all datasets, but there was a considerable variation in fit parameters between subjects, which suggests that the formation of a meaningful population-averaged vascular concentration function is precluded.

Carbonic Anhydrase Activity Monitored In Vivo by Hyperpolarized 13C-Magnetic Resonance Spectroscopy Demonstrates Its Importance for pH Regulation in Tumors

Carbonic anhydrase buffers tissue pH by catalyzing the rapid interconversion of carbon dioxide (CO2) and bicarbonate (HCO3 (-)). We assessed the functional activity of CAIX in two colorectal tumor models, expressing different levels of the enzyme, by measuring the rate of exchange of hyperpolarized (13)C label between bicarbonate (H(13)CO3(-)) and carbon dioxide ((13)CO2), following injection of hyperpolarized H(13)CO3(-), using (13)C-magnetic resonance spectroscopy ((13)C-MRS) magnetization transfer measurements. (31)P-MRS measurements of the chemical shift of the pH probe, 3-aminopropylphosphonate, and (13)C-MRS measurements of the H(13)CO3(-)/(13)CO2 peak intensity ratio showed that CAIX overexpression lowered extracellular pH in these tumors. However, the (13)C measurements overestimated pH due to incomplete equilibration of the hyperpolarized (13)C label between the H(13)CO3(-) and (13)CO2 pools. Paradoxically, tumors overexpressing CAIX showed lower enzyme activity using magnetization transfer measurements, which can be explained by the more acidic extracellular pH in these tumors and the decreased activity of the enzyme at low pH. This explanation was confirmed by administration of bicarbonate in the drinking water, which elevated tumor extracellular pH and restored enzyme activity to control levels. These results suggest that CAIX expression is increased in hypoxia to compensate for the decrease in its activity produced by a low extracellular pH and supports the hypothesis that a major function of CAIX is to lower the extracellular pH.

Ex vivo study of carotid endarterectomy specimens: quantitative relaxation times within atherosclerotic plaque tissues

PURPOSE Previous studies reporting relaxation times within atherosclerotic plaque have typically used dedicated small-bore high-field systems and small sample sizes. This study reports quantitative T(1), T(2) and T(2) relaxation times within plaque tissue at 1.5 T using spatially co-matched histology to determine tissue constituents. METHODS Ten carotid endarterectomy specimens were removed from patients with advanced atherosclerosis. Imaging was performed on a 1.5-T whole-body scanner using a custom built 10-mm diameter receive-only solenoid coil. A protocol was defined to allow subsequent computation of T(1), T(2) and T(2) relaxation times using multi-flip angle spoiled gradient echo, multi-echo fast spin echo and multi-echo gradient echo sequences, respectively. The specimens were subsequently processed for histology and individually sectioned into 2-mm blocks to allow subsequent co-registration. Each imaging sequence was imported into in-house software and displayed alongside the digitized histology sections. Regions of interest were defined to demarcate fibrous cap, connective tissue and lipid/necrotic core at matched slice-locations. Relaxation times were calculated using Levenberg-Marquardts least squares curve fitting algorithm. A linear-mixed effect model was applied to account for multiple measurements from the same patient and establish if there was a statistically significant difference between the plaque tissue constituents. RESULTS T(2) and T(2) relaxation times were statistically different between all plaque tissues (P=.026 and P=.002 respectively) [T(2): lipid/necrotic core was lower 47 ± 13.7 ms than connective tissue (67 ± 22.5 ms) and fibrous cap (60 ± 13.2 ms); T(2): fibrous cap was higher (48 ± 15.5 ms) than connective tissue (19 ± 10.6 ms) and lipid/necrotic core (24 ± 8.2 ms)]. T(1) relaxation times were not significantly different (P=.287) [T(1): Fibrous cap: 933 ± 271.9 ms; connective tissue (1002 ± 272.9 ms) and lipid/necrotic core (1044 ± 304.0 ms)]. We were unable to demarcate hemorrhage and calcium following histology processing. CONCLUSIONS This study demonstrates that there is a significant difference between qT(2) and qT(2) in plaque tissues types. Derivation of quantitative relaxation times shows promise for determining plaque tissue constituents.

Evaluating Prostate Cancer Using Fractional Tissue Composition of Radical Prostatectomy Specimens and Pre-Operative Diffusional Kurtosis Magnetic Resonance Imaging.

Background Evaluating tissue heterogeneity using non-invasive imaging could potentially improve prostate cancer assessment and treatment. Methods 20 patients with intermediate/high-risk prostate cancer underwent diffusion kurtosis imaging, including calculation of apparent diffusion (Dapp) and kurtosis (Kapp), prior to radical prostatectomy. Whole-mount tissue composition was quantified into: cellularity, luminal space, and fibromuscular stroma. Peripheral zone tumors were subdivided according to Gleason score. Results Peripheral zone tumors had increased cellularity (p<0.0001), decreased fibromuscular stroma (p<0.05) and decreased luminal space (p<0.0001). Gleason score ≥4+3 tumors had significantly increased cellularity and decreased fibromuscular stroma compared to Gleason score ≤3+4 (p<0.05). In tumors, there was a significant positive correlation between median Kapp and cellularity (ρ = 0.50; p<0.05), and a negative correlation with fibromuscular stroma (ρ = -0.45; p<0.05). In normal tissue, median Dapp had a significant positive correlation with luminal space (ρ = 0.65; p<0.05) and a negative correlation with cellularity (ρ = -0.49; p<0.05). Median Kapp and Dapp varied significantly between tumor and normal tissue (p<0.0001), but only median Kapp was significantly different between Gleason score ≥4+3 and ≤3+4 (p<0.05). Conclusions Peripheral zone tumors have increased cellular heterogeneity which is reflected in mean Kapp, while normal prostate has a more homogeneous luminal space and cellularity better represented by Dapp.

Role of PROPELLER-DWI of the prostate in reducing distortion and artefact from total hip replacement metalwork.

OBJECTIVE To compare image quality, artefact, and distortion in standard echo-planar imaging (EPI) with periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) for prostate magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI) in patients with previous total hip replacement (THR). METHODS 21 male subjects with a clinical suspicion for, or known prostate cancer and previous THR were scanned at 1.5 T using a phased-array body coil. DWI was obtained using single-shot EPI and PROPELLER techniques using fat saturation (PROPELLER-DWI-FS), and without (PROPELLER-DWI-NFS). Image quality (the overall impression of diagnostic quality) was compared to T2-weighted (T2WI) imaging using a 5-point Likert scale, with diffusion sequences additionally scored for artefact and distortion according to a 4-point scale, with artefact defined as the amount of prostate affected and distortion as the degree of warping of the organ. The T2W and DW image volumes were compared to produce quantitative distortion maps. A two-sample Wilcoxon test compared the qualitative scores, with inter-reader variability calculated using Cohens kappa. RESULTS 21 patients were included in the study, with an average age of 70.4 years and PSA 9.2 ng/ml. Hip metalwork was present bilaterally in 3 patients, left-sided in 9, and right-sided in 9. PROPELLER-DWI-FS significantly improved image quality (p < 0.01) and reduced distortion (p < 0.01) when compared to standard EP-DWI. Artefact was not shown to be significantly improved. The last 5 patients in the study were additionally imaged with PROPELLER-DWI-NFS, which resulted in a significant reduction in artefact compared to EP-DWI (p < 0.05). Quantitative distortion was significantly lower compared to EP-DWI for both PROPELLER with fat saturation (p < 0.01) and without fat saturation (p < 0.01). CONCLUSION PROPELLER-DWI demonstrates better image quality and decreases both artefact and distortion compared to conventional echo planar sequences in patients with hip metalwork.

The Effect of Different Drinking and Voiding Preparations on Magnetic Resonance Imaging Bladder Distention in Normal Volunteers and Patients

International School ‘‘Medicine of the Future’’, Sechenov First Moscow State Medical University, Moscow, Russia Department of Radiology, Addenbrooke’s Hospital, Cambridge, United Kingdom Department of Public Health and Healthcare Organization, Sechenov First Moscow State Medical University, Moscow, Russia CamPARI Clinic, Addenbrooke’s Hospital and University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom