Optimal combinations of ultrasound-based and serum markers of disease severity in patients with chronic hepatitis C.

Combinations of noninvasive markers may improve discrimination of chronic liver disease severity. The aims of this study were to compare four validated serum and ultrasound-based markers of hepatic disease severity head-to-head with liver biopsy and to assess optimal combinations with consideration of cost. A total of 67 patients with biopsy-proven chronic hepatitis C underwent all four techniques on the same visit [aspartate aminotransferase (AST) to platelet ratio index (APRI); Enhanced Liver Fibrosis (ELF) panel; transient elastography (TE) and ultrasound microbubble hepatic transit times (HTT)]. Markers were combined according to increasing financial cost and ordinal regression used to determine contributions. APRI, ELF, TE and HTT predicted cirrhosis with diagnostic accuracy of 86%, 91%, 90% and 83% respectively. ELF and TE were the most reliable tests with an intra-class correlation of 0.94 each. Either ELF or TE significantly enhanced the prediction of fibrosis stage when combined with APRI, but when combined together, did not improve the model further. Addition of third or fourth markers did not significantly improve prediction of fibrosis. Combination of APRI with either ELF or TE effectively predicts fibrosis stage, but combinations of three or more tests lead to redundancy of information and increased cost.

The role of clinical imaging in oncological drug development.

Clinical imaging has the potential to provide key biomarkers to inform decision-making in drug development. There is considerable optimism that emerging functional imaging techniques will substantially add to the conventional morphological depiction of disease. The discovery, development and qualification of clinical imaging biomarkers remain a considerable undertaking. Once an imaging biomarker is developed, it must be implemented with a high degree of consistency to ensure the collection of robust clinical trial data. The aim of such a development and implementation process is to deliver sufficient confidence in an imaging biomarker to support "go/no-go" decisions made in a drug development programme. This article outlines the drug development process, with a focus on the current impact of clinical imaging on drug development and its probable future direction.

Monitoring temozolomide treatment of low-grade glioma with proton magnetic resonance spectroscopy.

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.

Could assessment of glioma methylene lipid resonance by in vivo (1)H-MRS be of clinical value?

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.

Human rectal adenocarcinoma: demonstration of 1H-MR spectra in vivo at 1.5 T.

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.

A modified polymer gel for radiotherapy dosimetry: assessment by MRI and MRS.

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.

Radiation dosimetry using polymer gels: methods and applications.

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 reproducibility of polyacrylamide gel dosimetry applied to stereotactic conformal radiotherapy.

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-field, conformal, non-coplanar plan using precision-cast lead alloy shielding blocks. 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. T2 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 > or = 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.

Proton spectroscopic imaging of polyacrylamide gel dosimeters for absolute radiation dosimetry.

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.

Signal modulation in (1)H magnetic resonance spectroscopy using contrast agents: proton relaxivities of choline, creatine, and N-acetylaspartate.

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.

Experimental 3D dosimetry around a high-dose-rate clinical 192Ir source using a polyacrylamide gel (PAG) dosimeter.

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.

Effect of nutrition education on nutrition counseling practices of family physicians.

The effects of completing a comprehensive nutrition curriculum on the nutrition counseling practices of family physicians trained at the University of Manitoba were investigated by sending a questionnaire to a group of these physicians who had completed the nutrition curriculum and a group that had not. The 48 responding family practice residency-trained physicians who had completed the nutrition curriculum, and the 41 responding hospital-trained physicians who had not, reported counseling practices that were not significantly different (p greater than .05). Implications and recommendations for future teaching of nutrition counseling skills to physicians during residency training are presented.