Intensity modulated proton therapy: a clinical example.

In this paper, we report on the clinical application of fully automated three-dimensional intensity modulated proton therapy, as applied to a 34-year-old patient presenting with a thoracic chordoma. Due to the anatomically challenging position of the lesion, a three-field technique was adopted in which fields incident through the lungs and heart, as well as beams directed directly at the spinal cord, could be avoided. A homogeneous target dose and sparing of the spinal cord was achieved through field patching and computer optimization of the 3D fluence of each field. Sensitivity of the resultant plan to delivery and calculational errors was determined through both the assessment of the potential effects of range and patient setup errors, and by the application of Monte Carlo dose calculation methods. Ionization chamber profile measurements and 2D dosimetry using a scintillator/CCD camera arrangement were performed to verify the calculated fields in water. Modeling of a 10% overshoot of proton range showed that the maximum dose to the spinal cord remained unchanged, but setup error analysis showed that dose homogeneity in the target volume could be sensitive to offsets in the AP direction. No significant difference between the MC and analytic dose calculations was found and the measured dosimetry for all fields was accurate to 3% for all measured points. Over the course of the treatment, a setup accuracy of +/-4 mm (2 s.d.) could be achieved, with a mean offset in the AP direction of 0.1 mm. Inhalation/exhalation CT scans indicated that organ motion in the region of the target volume was negligible. We conclude that 3D IMPT plans can be applied clinically and safely without modification to our existing delivery system. However, analysis of the calculated intensity matrices should be performed to assess the practicality, or otherwise, of the plan.

Serial proton MR spectroscopy of contrast-enhancing multiple sclerosis plaques: absolute metabolic values over 2 years during a clinical pharmacological study.

BACKGROUND AND PURPOSE: The time courses of total creatine (Cr), N-acetylaspartate (NAA), choline (Cho), and myo-inositol have not previously been investigated in the follow-up of contrast-enhancing multiple sclerosis (MS) plaques. Therefore, over a period of 2 years, we compared the absolute concentrations of these metabolites between patients treated with a placebo or 15 +/- deoxyspergualin (DSG) and between clinical groups with relapsing-remitting or secondary-progressive MS. METHODS: Sixteen patients, recruited from a pharmacological study of DSG, and 11 healthy control subjects were investigated by a stimulated-echo acquisition mode sequence (TR/TE = 3000/20). The selected volume initially contained a contrast-enhancing plaque, which was followed up for a period of 2 years. RESULTS: In contrast-enhancing plaques, Cho was significantly elevated and showed a significant reduction after both 3 and 12 months. The initially normal Cr significantly increased between 3 and 12 months, and was negatively correlated with plaque volume on T1-weighted MR images. NAA initially showed normal values, a significant decrease at 1 month, and a slow recovery over 2 years. Myo-inositol did not show a clear tendency. The placebo group did not differ from the treated group, nor did the relapsing-remitting group differ from the secondary-progressive group. CONCLUSION: The contradictory time courses of Cr and NAA show that an absolute quantification in proton MR spectroscopy in MS is necessary to avoid a false interpretation of reduced NAA/Cr ratios. The increase in Cr is probably due to remyelination. The initial dip and later recovery of NAA seem to be related to diminishing edema and remyelination.

MRS of the brain in patients with anorexia or bulimia nervosa.

Twenty patients with anorexia or bulimia nervosa were prospectively investigated by magnetic resonance spectroscopy (MRS) of the brain. Compared to healthy controls, MRS of those with eating disorders revealed metabolic changes, which seem to be a consequence of their nutritional deficiency.

Initial experience of using an active beam delivery technique at PSI.

At PSI a new proton therapy facility has been assembled and commissioned. The major features of the facility are the spot scanning technique and the very compact gantry. The operation of the facility was started in 1997 and the feasibility of the spot scanning technique has been demonstrated in practice with patient treatments. In this report we discuss the usual initial difficulties encountered in the commissioning of a new technology, the very positive preliminary experience with the system and the optimistic expectations for the future. The long range goal of this project is to parallel the recent developments regarding inverse planning for photons with a similar advanced technology optimized for a proton beam.

Metabolic changes in the brain of patients with anorexia and bulimia nervosa as detected by proton magnetic resonance spectroscopy.

OBJECTIVE: To investigate the brain of patients with anorexia and bulimia nervosa by localized proton magnetic resonance spectroscopy (1H-MRS) and to look for metabolic alterations. METHOD: Twenty patients with anorexia and bulimia nervosa were investigated by magnetic resonance imaging (MRI) and 1H-MRS in three regions of the brain. Age and sex-matched healthy subjects were investigated as controls. RESULTS: 1H-MRS revealed metabolic changes, such as a significant decrease of both myo-inositol and lipid compounds within the frontal white matter. The concentration of these compounds was further reduced with decreasing body mass index. Reduced lipid signals were also found in the occipital gray matter. In the cerebellum, the concentration of all metabolites including water, except lipids, was increased. DISCUSSION: The metabolic changes found in this study seem to be a consequence of nutritional deficiency. It has to be further investigated whether these findings have any relevance for brain function. 1H-MRS might serve as a valuable investigative tool to observe eating disorders as anorexia and bulimia nervosa and to follow the success of therapy.

Assignment of glial brain tumors in humans by in vivo 1H-magnetic resonance spectroscopy and multidimensional metabolic classification.

This study presents a simple approach for the noninvasive assignment of glial brain tumors according to malignancy by single-voxel proton magnetic resonance spectroscopy at short echo times (TE < or = 50 milliseconds). Based on peak area ratios, a five-dimensional data set was obtained for each investigated subject. This vector was then projected along metabolic coordinates in a two-dimensional metabolic space. These coordinates had been determined in a previous study (Hagberg G et al., 1995, Magn Reson Med 34: 242-252). Tumor assignment was done without any knowledge of histology by comparing the location of the new cases to the features of the previous study. All 11 investigated glioblastomas multiforme, as well as 4 of 5 astrocytomas grade II, could easily be assigned to the groups of high- and low-grade tumors, respectively. Classification was more difficult in the case of a cystic astrocytoma grade II and one astrocytoma grade III. Two spectra measured in normal-appearing matter of glioblastoma patients were not classified as healthy. Using single-voxel proton magnetic resonance spectroscopy at short echo times with the knowledge of a base study, a straightforward, fast, and noninvasive differential diagnosis of glial brain tumors is possible.

Single-dose gadolinium with magnetization transfer versus triple-dose gadolinium in the MR detection of multiple sclerosis lesions.

PURPOSE: To compare the efficacy of single-dose gadolinium with magnetization transfer contrast (MTC) with that of triple-dose gadolinium in detecting enhancing multiple sclerosis lesions. METHODS: Twenty-one patients with multiple sclerosis were examined with MR imaging first with 0.1 mmol/kg gadolinium (single dose) and then, after 24 to 72 hours, with 0.3 mmol/kg gadolinium (triple dose). T2-weighted fast spin-echo and T1-weighted spin-echo MR images with and without MTC were obtained before contrast administration followed by either T1-weighted spin-echo images with MTC (single dose) or conventional T1-weighted spin-echo images (triple dose), starting 5, 17, and 29 minutes after contrast administration. All images were evaluated in a blinded fashion and scored in random order by two readers. Outcome parameters included number of enhancing lesions, number of active MR examinations (those containing at least one enhancing lesion), contrast ratio (signal intensity of enhancing lesion divided by signal intensity of normal-appearing white matter), and size of enhancing lesions. RESULTS: Eighty-one percent more enhancing lesions and 49% more active MR examinations were detected when a triple dose of gadolinium was used as compared with a single dose. The level of agreement between readers as to the number of enhancing lesions was significantly higher for triple-dose than for single-dose gadolinium. With triple-dose gadolinium, contrast ratios and areas of enhancement increased by 10% and 33%, respectively. Delayed imaging increased the size of the lesion by 11% on single-dose MTC images and by 18% on triple-dose images. CONCLUSION: Triple-dose gadolinium is more effective (higher sensitivity and interobserver agreement) than single-dose gadolinium in combination with MTC in detecting enhancing multiple sclerosis lesions.

[Results and consequences of frequent quality control of quantitative clinical 1H-MR-spectroscopy]. / Resultate und Konsequenzen regelmässiger Qualitätskontrollen für die quantitative klinische 1H-MR-Spektroskopie.

Different methods exist for an absolute quantification of in vivo proton MR spectra. According to the principle of reciprocity a simple method has been suggested previously, comprising the multiplication of the spectral signals with the unlocalised reference amplitude of the measurement as a correction for the different coil load. Afterwards, the result can be compared to measurements on phantoms in order to obtain in vivo metabolite concentrations. Thus, only one calibration would be sufficient in principle for all measured spectra. However, during a previous serial study on humans and phantoms we observed significant changes in transmitter amplitudes over time, although metabolite peak areas remained quite constant. Hence, the method led to incorrect metabolite concentrations. Since these effects are mostly underestimated or even neglected in clinical spectroscopy, the purpose of the present study was to investigate these instabilities over time in order to find a new correction method for quantitative MRS. According to this new method, the spectra corrected by the coil load have to be modified additionally by dividing by the reference amplitude of a phantom.

1H MRS of liver and brain in a patient with AL amyloidosis.

A patient with AL (amyloid light chain) amyloidosis was investigated in liver and brain by localized magnetic resonance spectroscopy. Liver spectra of the patient were characterized by small line widths, a striking increase of trimethylammonium compounds, and the presence of a further resonance at 3.8 ppm. None of the healthy control subjects showed trimethylammonium levels of comparable intensity. In the brain, the intensities of amino acids was relatively increased in white matter, whereas the concentration of choline, creatine, and N-acetyl-aspartate were reduced.

Proton chemical shift imaging, metabolic maps, and single voxel spectroscopy of glial brain tumors.

Seventeen patients with presumed glial brain tumors were examined with proton chemical shift imaging and single voxel spectroscopy that used different echo times. Metabolite resonances were evaluated by metabolic ratios and absolutely by correcting for coil load and comparison to phantom measurements. Metabolic images were created to visualize the metabolic changes. All patients showed spectra that were different from those measured in healthy control subjects. Spectral changes were also present in normal-appearing matter (NAM) that was distant from lesions. The resonance at 3.55 ppm which is usually assigned to both myo-inositol and glycine, was the only one to allow a discrimination between healthy volunteers, astrocytoma grade II, and glioblastoma multiforme (GBM) (p < 0.02). From the different echo times used we conclude that an increase in this resonance has to be assigned to glycine rather than myo-inositol. This resonance might be used to grade human gliomas more reliably. Total creatine (Cr) decreased more drastically with malignancy than N-acetylated metabolites (NA). This led to a higher NA/Cr ratio in GBM compared to astrocytoma grade II. NA/Cr was thus pseudonormal in GBM due to a change in both nominator and denominator. This study reveals the importance of comparing magnetic resonance spectroscopy data of lesions to spectra measured in identical localizations in healthy control subjects instead of NAM and the importance of quantifying single metabolic peaks instead of creating metabolic ratios in clinical magnetic resonance spectroscopy.

Absolute quantification of the hepatic glycogen content in a patient with glycogen storage disease by 13C magnetic resonance spectroscopy.

Using natural-abundance 13C magnetic resonance spectroscopy (MRS) on a conventional whole-body system operating at 1.5 T, the absolute hepatic glycogen concentration was noninvasively determined in a patient with type Ia glycogen storage disease. Furthermore, to assess the reliability of glycogen determination, hepatic glycogen content was assessed after an overnight fasting period in 35 healthy volunteers divided into two groups, one with a carbohydrate-rich diet, the other without any particular dietary preparation. In the patient, the glycogen concentration was found to be 458 mM. In the healthy subjects, average glycogen concentrations were 229 +/- 34 mM (mean +/- standard deviation) and 257 +/- 31 mM for the group without and with dietary preparation, respectively. The 13C-MRS results are in agreement with those obtained by conventional liver biopsy. 13C MRS in natural abundance may thus serve as a straightforward, fast, and noninvasive tool for quantification of the liver glycogen content in patients.

In vivo proton MR spectroscopy of human gliomas: definition of metabolic coordinates for multi-dimensional classification.

Several multi-dimensional statistical evaluation methods were applied to single-voxel proton MR spectra of glial brain tumors and of healthy volunteers. Metabolic coordinates with histological relevance for future diagnosis were found by which spectra from controls, low-grade tumors, and high-grade tumors were completely separated. Significant differences between low-grade and high-grade glioma patients and controls were found for several metabolic ratios by variance analysis. Cluster analysis both with and without principal component analysis was applied. The outcome of these two approaches depended mainly on the lipid-to-creatine ratio. Two other approaches, discriminant factor analysis and the orthonormal discriminant vector method were then used to find discriminatory metabolic coordinates. It turned out that a linear combination of all evaluable metabolic ratios made it possible to separate the three groups completely. On the basis of these results, a classification method that uses the entire proton MRS spectrum is proposed.

Proton MRS of gadolinium-enhancing MS plaques and metabolic changes in normal-appearing white matter.

Localized short echo time (TE = 20 ms), stimulated echo acquisition mode, and double spin echo (TE = 135 ms) proton spectroscopy were performed in clearly defined, acute Gadolinium (Gd)-enhancing multiple sclerosis (MS) plaques of 22 patients with clinically definite MS. The resonances of N-acetylated metabolites (NA), creatine/phosphocreatine (Cr), choline-containing compounds (Cho), glycine/myo-inositol (Ino), and lactate were evaluated. The ratios of NA/Cr and NA/Cho were significantly decreased, Cho/Cr increased, and Ino/Cr remained unchanged. No marker peaks or elevated lactate levels were found. The measured metabolic changes were practically independent of the relative plaque size within the volume of interest (8 ml). Thus, the spectral changes measured with 1H MRS in acute Gd-enhancing MS plaques originate not only from the lesion as depicted by MRI, but also from the surrounding normal-appearing white matter.