Andrzej S. K. Dzik-Jurasz

Diffusion MRI for prediction of response of rectal cancer to chemoradiation

Prediction of tumour response before onset of treatment could have considerable clinical benefit. Since the apparent diffusion coefficient (ADC) of a tumours water content can show the extent of necrosis, we looked for a possible correlation of ADC with response to treatment. We measured mean tumour water ADC before and after chemotherapy and chemoradiation in 14 patients with locally advanced rectal cancer, with a quantitative magnetic resonance diffusion imaging sequence. We found a strong negative correlation between mean pretreatment tumour water ADC and percentage size change of tumours after chemotherapy (r=-0.67, p=0.01) and chemoradiation (r=-0.83, p=0.001). Persistence of low ADC in responders after chemotherapy could represent loss of a non-viable fraction of the treated tumour.

Rectal Carcinoma: MRI with Histologic Correlation Before and After Chemoradiation Therapy

OBJECTIVE The purpose of this study was to use MRI to compare the morphologic features of rectal cancer before and 6 weeks after chemotherapy and radiation treatment to correlate the posttreatment MRI appearances with the histologic findings in resected tumors. MATERIALS AND METHODS High-resolution T2-weighted MRI was performed before and immediately after a standardized 5-week course of chemoradiation therapy in the care of 30 patients with locally advanced adenocarcinoma of the rectum. Changes in morphologic features were evaluated with respect to primary tumor and nodal downstaging. The MRI findings after chemoradiation therapy were compared with the histologic findings in the resected specimens with respect to prediction of tumor stage and showing the relation between the tumor and the circumferential margin of resection. RESULTS Tumor shrinkage > 30% was found in 19 (63%; 95% CI, 46-81%) of 30 patients, but changes in MRI T stage occurred in only five (17%; 95% CI, 3-30%) of 30 patients. Tumor regression from the circumferential resection margin was found in five patients, all findings confirmed at histologic examination. Nodal downstaging was observed in 13 (68%; 95% CI, 48-89%) of 19 patients; 11 patients were node free on the basis of both MRI findings and subsequent histologic results. Overall prediction of distance between tumor and circumferential resection margin was good, with a mean difference of -0.2 mm and an interclass correlation coefficient of 0.74. MRI was not useful for gauging disease activity of persistent abnormalities in mucinous tumors that often represented inactive mucin lakes. CONCLUSION Decreases in tumor size and nodal downstaging can be seen on MRI after chemoradiation therapy in approximately two thirds of patients. The surgically more relevant parameter--distance between tumor and circumferential resection margin--can be accurately predicted. Errors were caused by the presence of considerable tumor, rectal wall fibrosis, and mucinous tumors.

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 (1H-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.

The effect of Gd-DTPA on T1-weighted choline signal in human brain tumours

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.

An algorithm for the optimum combination of data from arbitrary magnetic resonance phased array probes

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.

A novel technique to monitor carboxypeptidase G2 expression in suicide gene therapy using 19F magnetic resonance spectroscopy.

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; Km = 1.71 µM; kcat = 732 s−1), was measured with 19F 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 (Km = 3.5 µM, kcat = 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 19F 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. Copyright

Ifosfamide pharmacokinetics and hepatobiliary uptake in vivo investigated using single- and double-resonance 31P MRS

MRS has considerable potential for the measurement of drug pharmacokinetics in vivo. In this study single‐ and double‐resonance 31P MRS was used to investigate the biodistribution, pharmacokinetics, and metabolism of ifosfamide following administration of 500 mg/kg ifosfamide in guinea pigs. 1H‐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 31P 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 halflife in liver was approximately 74 min, whereas in gall bladder there was no measurable signal decay during the 2.5‐hr studies. High‐resolution 31P 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, 1H‐decoupled 31P MRS has proved to be a useful tool for investigating the metabolism of ifosfamide in vivo. Magn Reson Med 50:249–255, 2003.