MRT-gestützte Thermometrie in der regionalen Tiefenhyperthermie und interstitiellen Laserthermotherapie

PURPOSE: To demonstrate the potential of quantitative MRI-assisted thermometry for the treatment of tumor patients with regional hyperthermia (RHT) and interstitial laser thermotherapy (ILTT). METHODS: Two patients and seven tissue samples were investigated using the T1-relaxation time and the chemical shift of the proton resonance frequency (PRF) as temperature sensitive MRI-parameters at 0.2 and 1.5 T. Thermotherapy was applied using either a dedicated MRI-hyperthermia hybrid system or a temperature controlled laser with 830 nm. RESULTS: Both patients were treated successfully showing clinical benefit. T1 and PRF are depending on the applied thermotherapy method and on the MR-system suitable for MRI-assisted thermometry. The clinical application based on phantom results is not necessarily adequate. CONCLUSION: Clinical application and phantom experiments of RHT and ILTT show the potential of MRI-assisted thermometry for further improvement of both minimal invasive thermotherapy methods. Further investigations concerning optimization of the MRI-techniques, the influence of perfusion or the determination of threshold values are necessary.     

Magnetic resonance imaging of frozen tissues: temperature-dependent MR signal characteristics and relevance for MR monitoring of cryosurgery.

Previously, the magnetic resonance (MR) imaging appearance of frozen tissues created during cryosurgery has been described as a signal void. In this work, very short echo times (1.2 msec) allowed MR signals from frozen tissues to be measured at temperatures down to -35 degrees C. Ex vivo bovine liver, muscle, adipose tissue, and water were imaged at steady-state temperatures from -78 degrees to +6 degrees C. Signal intensity, T2*, and T1 were measured using gradient-echo imaging. Signal intensity and T2* decrease monotonically with temperature. In the future, these MR parameters may be useful for mapping temperatures during cryosurgery.     

Thermosensitive paramagnetic liposomes for temperature control during MR imaging-guided hyperthermia: in vitro feasibility studies

RATIONALE AND OBJECTIVES: Magnetic resonance (MR) imaging-based temperature monitoring has gained interest for use in general hyperthermia treatment of tumors. Such therapy requires an accurate control of the temperature, which should range from 41 degrees to 45 degrees C. A novel type of thermosensitive MR agent is proposed: liposome-encapsulated gadolinium chelates whose temperature response is linked to the phase-transition properties of the liposome carrier. In vitro relaxometry and MR imaging were used to evaluate the thermosensitivity of the contrast properties of liposomal gadolinium diethylenetriaminepentaacetic acid bis(methylamide) (Gd-DTPA-BMA). MATERIALS AND METHODS: T1 relaxivity (rl) measurements of liposomal Gd-DTPA-BMA were undertaken at 0.47 T and at temperatures of 20 degrees-48 degrees C. MR imaging was performed at 2.0 T with a gel phantom containing inserts of liposomes. Diffusion-weighted and T1-weighted gradient-recalled echo images were acquired as the phantom was heated from 22 degrees to about 65 degrees C. RESULTS: At ambient temperature, the r1 of liposomal Gd-DTPA-BMA was exchange limited due to slow water exchange between the liposome interior and exterior. A sharp, marked increase in r1 occurred as the temperature reached and exceeded the gel-to-liquid crystalline phase-transition temperature (Tm) of the liposomes (42 degrees C). The relaxation enhancement was mainly attributable to the marked increase in transmembrane water permeability, yielding fast exchange conditions. There was good correlation between the relaxometric and imaging results; the signal intensity on T1-weighted gradient-recalled echo images increased markedly as the temperature approached Tm. The temperature sensitivity of the diffusion-weighted technique differed from that of the liposome-based T1-weighted approach, with an apparent water diffusion coefficient increasing linearly with temperature. CONCLUSION: Since the transition from low to high signal intensity occurred in the temperature range of 38 degrees - 42 degrees C, the investigated paramagnetic liposomes have a potential role as "off-on" switches for temperature control during hyperthermia treatment.     

A sensitive PARACEST contrast agent for temperature MRI: Eu3+-DOTAM-glycine (Gly)-phenylalanine (Phe).

Tissue temperature is a fundamental physiological parameter that can provide insight into pathological processes. The purpose of this study was to develop and characterize a novel paramagnetic chemical exchange saturation transfer (CEST) agent suitable for in vivo temperature mapping at 9.4T. The CEST properties of the europium (Eu(3+)) complex of the DOTAM-Glycine (Gly)-Phenylalanine (Phe) ligand were studied in vitro at 9.4T as a function of temperature, pH, and agent concentration. The transfer of magnetization (CEST effect) from the bound water to bulk water pools was approximately 75% greater for Eu(3+)-DOTAM-Gly-Phe compared to Eu(3+)-DOTAM-Gly at physiologic temperature (38 degrees C) and pH (7.0 pH units) when using power level sufficiently low for in vivo imaging. Unlike Eu(3+)-DOTAM-Gly, whose CEST effect decreased with increasing temperature in the physiologic range, the CEST effect of Eu(3+)-DOTAM-Gly-Phe was optimal at body temperature. A strong linear dependence of the chemical shift of the bound water pool on temperature was observed (0.3 ppm/ degrees C), which was insensitive to pH and agent concentration. Temperature maps with SDs < 1 degrees C were acquired at 9.4T in phantoms containing: 1) phantom A, an aqueous solution of 10 mM Eu(3+)-DOTAM-Gly-Phe; 2) phantom B, 5% bovine serum albumin (BSA) with 15 mM Eu(3+)-DOTAM-Gly-Phe; and 3) phantom C, mouse brain tissue with 4 mM Eu(3+)-DOTAM-Gly-Phe. The temperature sensitivity combined with the high CEST effect observed at low concentration using low saturation power (B(1)) suggests this compound may be a good choice for in vivo temperature mapping at 9.4T.     

Investigation of proton density for measuring tissue temperature

PURPOSE: To examine the temperature dependence of the proton density (PD) in both adipose and muscle tissues, and the application of the PD as a thermometry parameter in breast tissues. MATERIALS AND METHODS: Porcine fat samples and bovine muscle samples were successively heated to temperatures ranging from 30 degrees C to 76 degrees C and then cooled. They were then imaged with a dual-echo spin-echo sequence. T1 and T2 effects were carefully corrected from the images. The apparent PD (APD) in regions of interest (ROIs) and the sum of the APD in all pixels (Sum_APD) were measured and analyzed by linear regression. RESULTS: APD in adipose tissue is linear and reversible, and changes with a 0.3%/ degrees C to 0.45%/ degrees C temperature variation. The temperature coefficient of Sum_APD in adipose tissue is approximately 0.29%/ degrees C, as predicted from the Boltzmann distribution. However, the results in muscle tissue are more variable. There is an offset in both APD and Sum_APD between heating and cooling phases, as well as different temperature coefficients between these two phases. CONCLUSION: The Sum_APD in adipose tissue validates the 1/T dependence on temperature. The APD is a potentially useful parameter for fat thermometry; however, its application in muscle tissue requires further investigation.     

Factors controlling T2 mapping from partially spoiled SSFP sequence: optimization for skeletal muscle characterization

A fast and robust methodology for in vivo T(2) mapping is presented. The approach is based on the partially spoiled steady state free precession technique recently proposed by Bieri et al. (Magn Reson Med 2011). The accuracy of this method was demonstrated in simulations and phantom experiments. Variations in skeletal muscle T(2) relaxation time have been correlated with cell damage and inflammatory response. Nonetheless, the lack of easily implementable, fast, accurate and reproducible methods has hampered the adoption of T(2) measurement as a noninvasive tool for skeletal muscle characterization. The applicability of the partially spoiled steady state free precession method for tissue characterization in muscle disease is illustrated in this work by several examples. Quantitative MRI, in particular T(2) mapping based on partially spoiled steady state free precession acquisitions, might provide objective markers of muscle damage and degenerative changes, and an alternative to serial muscle biopsies.     

500-element ultrasound phased array system for noninvasive focal surgery of the brain: a preliminary rabbit study with ex vivo human skulls.

The aim of this study was to test a prototype MRI-compatible focused ultrasound phased array system for trans-skull brain tissue ablation. Rabbit thigh muscle and brain were sonicated with a prototype, hemispherical 500-element ultrasound phased array operating at frequencies of 700-800 kHz. An ex vivo human skull sample was placed between the array and the animal tissue. The temperature elevation during 20-30-sec sonications was monitored using MRI thermometry. The induced focal lesions were observed in T2 and contrast-enhanced T1-weighted fast spin echo images. Whole brain histology evaluation was performed after the sonications. The results showed that sharp temperature elevations can be produced both in the thigh muscle and in the brain. High-power sonications (600-1080 W) produced peak temperatures up to 55 degrees C and focal lesions that were consistent with thermal tissue damage. The lesion size was found to increase with increasing peak temperature. The device was then modified to operate in the orientation that will be used in the clinic and successfully tested in phantom experiments. As a conclusion, this study demonstrates that it is possible to create ultrasound-induced lesions in vivo through a human skull under MRI guidance with this large-scale phased array.     

Measurement of changes in tissue temperature using MR imaging

The spin-lattice relaxation time T1 of tissue has been measured as a function of temperature using a magnetic resonance imager. Both in vitro and in vivo tissues have been heated within the imager using radiofrequency power applied to either implanted electrodes or capacitive plates. The temperature distribution was monitored with implanted thermocouples and T1 was found to have a linear dependence with temperature with a slope of 5-10 ms/degrees C. The uncertainty in T1 corresponds to a temperature resolution of 1-2 degrees C, which combined with a spatial resolution of 4-5 mm and scan time of 1 min suggests the method should be valuable for noninvasive temperature mapping in clinical hyperthermia.     

Temperature mapping with MR imaging of molecular diffusion: application to hyperthermia

Efficacy and safety considerations for hyperthermia (HT) cancer therapy require accurate temperature measurements throughout the heated volume. Noninvasive thermometry methods have been proposed, including magnetic resonance (MR) imaging based on the temperature dependence of the relaxation time T1. However, the temperature accuracy achieved to date with T1 measurements does not fulfill the HT requirements (1 degree C/cm). The authors propose to use molecular diffusion, for which temperature dependence is well known. Molecular diffusion is more sensitive than T1 and can be determined with high accuracy with MR imaging. Diffusion and derived temperature images were obtained with a 2 X 2-mm pixel size in a polyacrylamide gel phantom heated inside the head coil of a clinical 0.5-T whole-body MR imaging system by means of a modified clinical HT device made compatible with the system. Temperatures determined from these images with 0.8-cm2 regions of interest were found to be within 0.5 degrees C of those recorded with thermocouples placed inside the gel. The utility of this method in clinical hyperthermia is enhanced by its potential to also help monitor blood perfusion.     

Temperature quantification using the proton frequency shift technique: In vitro and in vivo validation in an open 0.5 tesla interventional MR scanner during RF ablation

Open magnetic resonance (MR) scanners allow MR-guided targeting of tumors, as well as temperature monitoring of radio frequency (RF) ablation. The proton frequency shift (PFS) technique, an accurate and fast imaging method for temperature quantification, was used to synthesize thermal maps after RF ablation in an open 0.5 T MR system under ex vivo and in vivo conditions. Calibration experiments with 1.5% agarose gel yielded a chemical shift factor of 0.011 +/- 0.001 ppm/ degrees C (r2 = 0.96). Three gradient echo (GRE) pulse sequences were tested for thermal mapping by comparison with fiberoptic thermometer (Luxtron Model 760) readings. Temperature uncertainty decreased from high to low bandwidths (BW): +/-5.9 degrees C at BW = 15.6 kHz, +/-1.4 degrees C at BW = 3.9 kHz, and +/-0.8 degrees C at BW = 2.5 kHz. In vitro experiments (N = 9) in the paraspinal muscle yielded a chemical shift factor of 0.008 +/- 0.001 ppm/ degrees C. Temperature uncertainty was determined as +/-2.7 degrees C (BW = 3.9 kHz, TE = 19.3 msec). The same experiments carried out in the paraspinal muscle (N = 9) of a fully anesthetized pig resulted in a temperature uncertainty of +/-4.3 degrees C (BW = 3.9 kHz, TE = 19.3 msec), which is higher than it is in vitro conditions (P < 0.15). Quantitative temperature monitoring of RF ablation is feasible in a 0.5 T open-configured MR scanner under ex vivo and in vivo conditions using the PFS technique.     

Single-shot diffusion-weighted RARE sequence: Application for temperature monitoring during hyperthermia session

A diffusion-sensitive single-shot RARE (rapid acquisition with relaxation enhancement) sequence was implemented on a 2T whole-body MRI system. The sequence was optimized for diffusion-based MR thermometry, both on a conventional whole-body gradient system and on a high-performance gradient insert. The use of spin-echo versus stimulated-echo diffusion weighting is discussed as a function of gradient performance. Diffusion-based temperature mapping was used to observe the effect of the geometry of the antenna used for radiofrequency (RF) hyperthermia on the temperature distribution. Temperature changes of ±.5°C in gel and ±2°C in a muscle sample in vitro could be detected within 16 seconds (gel) or 1 minute (muscle) at a spatial resolution of 2 × 2 × 8 mm. Temperature changes in vivo were also observed on human muscle cooled with ice with comparable sensitivity for the measured apparent diffusion coefficient (ADC) values.     

Temperature changes induced in human muscle by radio-frequency H-1 decoupling: measurement with an MR imaging diffusion technique. Work in progress.

To investigate temperature increases in tissues during magnetic resonance (MR) imaging or spectroscopy, the authors measured temperature changes in vitro and in vivo (leg of a volunteer) in a condition simulating hydrogen-1 decoupling in MR spectroscopy. Noninvasive measurements were obtained by using the temperature dependence of the translational diffusion coefficient of water. Temperature was measured at 0.5 T (86 MHz) by using a stimulated-echo sequence that included intense gradient pulses and a procedure reducing sensitivity to bulk tissue motion. Calibration curves of the diffusion coefficient against thermocouple-measured temperature were obtained for a gelatin phantom and bovine muscle. Temperature changes were 5.3 degrees C +/- 0.5 at 2.5 cm from the coil in gelatin and 7.7 degrees C +/- 0.5 at 0.7 cm in bovine muscle. The temperature changed by 4.9 degrees C +/- 1.9 at 2.2 cm from the coil in the calf muscle of a volunteer. The H-1 decoupling protocol can be adapted (modifications in transmission power, duty cycle) to reduce heating effects to below safety recommendations.     

Using a phantom to compare MR techniques for determining the ratio of intraabdominal to subcutaneous adipose tissue

OBJECTIVE: Patients who have a greater distribution of intraabdominal adipose tissue as compared with subcutaneous adipose tissue and an increased ratio of intraabdominal adipose tissue to subcutaneous adipose tissue are at greater risk for developing cardiovascular disease and type 2 diabetes mellitus. In previous MR investigations, researchers have used conventional T1-weighted spin-echo images to determine the ratio of intraabdominal adipose tissue to subcutaneous adipose tissue. However, no investigation, to our knowledge, has been performed to determine the accuracy of using different MR sequences to estimate adipose distribution. The purpose of our investigation was to compare MR imaging and segmentation techniques in calculating the ratio of intraabdominal to subcutaneous adipose tissue using an adiposity phantom. MATERIALS AND METHODS: A phantom was created to simulate the distribution of subcutaneous and intraabdominal fat (with known volumes). Axial MR images were obtained twice through the phantom using a 5-mm slice thickness and zero gap for the following T1-weighted sequences: spin-echo, fast Dixon, and three-dimensional (3D) spoiled gradient-echo. An in-house computer software program was then used to segment the volumes of fat and calculate the volume of intraabdominal adipose tissue and subcutaneous adipose tissue and the ratio of intraabdominal to subcutaneous adipose tissue. Each imaging data set was segmented three times, so six sets of data were yielded for each imaging technique. The percentage predicted of the true volume was calculated for each MR imaging technique for each fat variable. The mean percentages for each variable were then compared using one-factor analysis of variance to determine whether differences exist among the three MR techniques. RESULTS: The three MR imaging techniques had statistically significant different means for the predicted true volume of two variables: volume of subcutaneous adipose tissue (p < 0.001) and volume of intraabdominal adipose tissue (p = 0.0426). Estimates based on fast Dixon images were closest to the true volumes for all the variables. All MR imaging techniques performed similarly in estimating the ratio of intraabdominal adipose tissue to subcutaneous adipose tissue (p = 0.9117). The acquisition time for the 3D spoiled gradient-echo images was 10-22 times faster than for the other sequences. CONCLUSION: Conventional T1-weighted spin-echo MR imaging, the current sequence used in practice for measuring visceral adiposity, may not be the optimal MR sequence for this purpose. We found that the T1-weighted fast Dixon sequence was the most accurate at estimating all fat volumes. The T1-weighted 3D spoiled gradient-echo sequence generated similar ratios of intraabdominal to subcutaneous adipose tissue in a fraction of the acquisition time.     

Analysis of changes in MR properties of tissues after heat treatment.

To characterize changes in the MR parameters of tissues due to thermal coagulation, a series of T(1), T(2), diffusion, and magnetization transfer measurements were performed on a variety of ex vivo tissues: murine slow twitch skeletal muscle, murine cardiac muscle, murine cerebral hemisphere, bovine white matter, murine liver tissue, bovine retroperitoneal adipose tissue, hen egg white, human prostate and human blood. Standardized heat treatments were performed for each tissue type, over the temperature range from 37 degrees C to 90 degrees C. For all tissues, changes in each MR measurement resulting from thermal coagulation were observed above a threshold temperature of approximately 60 degrees C. These changes are explained based on biophysical knowledge of thermal damage mechanisms and the MR properties of normal tissues, and are particularly relevant for interpreting the changes in image contrast that are observed when MRI is used to guide and monitor thermal coagulation therapy procedures. Magn Reson Med 42:1061-1071, 1999.     

Local delivery of magnetic resonance (MR) contrast agent in kidney using thermosensitive liposomes and MR imaging-guided local hyperthermia: a feasibility study in vivo

PURPOSE: To investigate the feasibility of local delivery of a magnetic resonance (MR) contrast agent in vivo using paramagnetic thermosensitive liposomes and infrared (IR) laser-induced local hyperthermia under real-time MR thermometry on rabbit kidney. MATERIALS AND METHODS: Respiratory gated, radio frequency (RF)-spoiled gradient-echo sequences were used for precise MR temperature mapping (SD = 1 degrees C). In vivo heating experiments confirmed local release of MR contrast agent from liposomes. RESULTS: T1 decreased from 800 msec to about 500 msec, as measured after tissue cooling, in those locations where the renal parenchyma was heated above the phase transition temperature of the liposome membrane. CONCLUSION: The release of MR contrast agent has been demonstrated in rabbit kidney in vivo. This may be used as a reporter for simultaneous release of therapeutic agents.     

Real-time MR temperature mapping of rabbit liver in vivo during thermal ablation.

It has been shown that quantitative MRI thermometry using the proton resonance frequency (PRF) method can be used to noninvasively monitor the evolution of tissue temperature, and to guide minimally-invasive tumor ablation based on local hyperthermia. Although hepatic tumors are among the main targets for thermal ablation, PRF-based temperature MRI of the liver is difficult to perform because of motion artifacts, fat content, and low T(*) (2). In this study the stability of real-time thermometry was tested on a clinical 1.5 T scanner for rabbit liver in vivo. The fast segmented EPI principle was used together with respiratory gating to limit respiratory motion artifacts. Lipid signal suppression was achieved with a binomial excitation pulse. Saturation slabs were applied to suppress artifacts due to flowing blood. The respiratory-gated MR thermometry in the rabbit liver in vivo showed a standard deviation (SD) of 1-3 degrees C with a temporal resolution of 3 s per slice and 1.4 mm x 1.9 mm spatial resolution in plane (slice thickness = 5 mm). The method was used to guide thermal ablation experiments with a clinical infrared laser. The estimated size of the necrotic area, based on the thermal dose calculated from MR temperature maps, corresponded well with the actual lesion size determined by histology and conventional MR images obtained 5 days posttreatment. These results show that quantitative MR temperature mapping can be obtained in the liver in vivo, and can be used for real-time control of thermal ablation and for lesion size prediction.     

Temperature measurement using echo-shifted FLASH at low field for interventional MRI

We investigated the feasibility of using echo-shifted fast low-angle shot (FLASH) for temperature-monitored thermo-therapeutic procedures in a 0.2 T interventional magnetic resonance (MR) scanner. Based on the proton resonance frequency shift technique, modified echo-shifted FLASH has sufficiently high signal-to-noise ratio to provide accurate temperature maps with short scan times, i.e., 5 seconds in phantoms (TR = 20.5 msec; effective TE = 30 msec; one echo shift; NSA = 2) and ex vivo experiments (TR = 19.4 msec; effective TE = 28.9 msec; one echo shift; NSA = 2) and 3 seconds (TR = 19.4 msec; effective TE = 28.9 msec, one echo shift; NSA 1) for an in vivo case. The proton resonance frequency shifts with temperature observed in a 0.2 T MR scanner using this sequence were -0.0072 ppm/degrees C (temperature uncertainty = +/-2.5 degrees C) for polyacrylamide phantoins and -0.0086 ppm/degrees C (temperature uncertainty = +/- 1 degrees C) for ex vivo bovine liver. These experiments demonstrated that echo-shifted FLASH is a viable method for low-field temperature monitoring despite the decreased signal and decreased phase sensitivity compared with its counterpart in a 1.5 T MR imaging system. The improved temporal resolution of temperature images, now possible in low-field interventional MR systems using echo-shifted FLASH, will allow clinicians more accurate monitoring of interstitial ablation in MR-guided interventional procedures.     

Observation by MR imaging of in vivo temperature changes induced by radio frequency hyperthermia

Volunteers have undergone radio frequency hyperthermia in a magnetic resonance (MR) imaging system to investigate which of several possible MR parameters would be most convenient and sensitive to use to observe in vivo temperature changes. Measurements were made for T1, T2, and perfusion and diffusion variations, although the number of sequences needed at each temperature meant that the number of data points obtainable was limited. However, in the temperature range studied (around 28-42 degrees C), changes in both T1 and the diffusion coefficient were observed that agreed quite well with those predicted theoretically (respectively around 1.3%/degrees C and 2.4/degrees C).     

Production of a human-tissue-equivalent MRI phantom: optimization of material heating

PURPOSE: We conceived a 2-stage heating method to dissolve the ingredients of magnetic resonance (MR) imaging phantoms to overcome issues of uneven quality in conventional MR imaging phantoms, and we evaluated uniformity and the reproducibility of our method. METHODS: We used a 3-liter capacity, column-shaped, enamel-coated porcelain container to produce a muscle-equivalent phantom (diameter, 160 mm; height, 100 mm; volume, 2 liters). The phantom contained: 1) carrageenan as a gelling agent; 2) agarose as a T2 modifier; 3) GdCl3 as a T1 modifier; 4) NaN3 as an antiseptic; and 5) distilled water. We applied both direct heating and 2-stage heating of pre-soaked materials. We placed powdered materials directly into hot water for direct heating but soaked them in water one day before use (post-swelling) in 2-stage heating. The materials in the container were melted in a silicone oil bath of 120 or 140 degrees C under various conditions, then allowed to gel by natural cooling. We observed the resulting gel phantoms macroscopically using a CCD camera and evaluated their uniformity by microscopy and MR imaging. RESULTS: We found it necessary to raise the temperature inside the phantom to 100.0 degrees C, to produce a uniform gel with stable homogeneity and few bubbles. Use of an enamel-coated porcelain container required setting the temperature of the oil bath at 140 degrees C. CONCLUSION: A uniform and reproducible human tissue-equivalent phantom with few bubbles can be manufactured using our 2-stage heating method, which employs pre-soaking in a silicone oil bath at 140 degrees C for 30 min. We then added the swollen carrageenan to the agarose solution, which heating the temperature to 140 degrees C for 30 min while continuously stirring at 120 rpm, following with natural cooling.     

Real-time control of focused ultrasound heating based on rapid MR thermometry

RATIONALE AND OBJECTIVES: Real-time control of the heating procedure is essential for hyperthermia applications of focused ultrasound (FUS). The objective of this study is to demonstrate the feasibility of MRI-controlled FUS. METHODS: An automatic control system was developed using a dedicated interface between the MR system control computer and the FUS wave generator. Two algorithms were used to regulate FUS power to maintain the focal point temperature at a desired level. RESULTS: Automatic control of FUS power level was demonstrated ex vivo at three target temperature levels (increase of 5 degrees C, 10 degrees C, and 30 degrees C above room temperature) during 30-minute hyperthermic periods. Preliminary in vivo results on rat leg muscle confirm that necrosis estimate, calculated on-line during FUS sonication, allows prediction of tissue damage. CONCLUSIONS. The feasibility of fully automatic FUS control based on MRI thermometry has been demonstrated.