The use of T2 distribution to study tumor extent and heterogeneity in head and neck cancer

Demarcation of the extent of malignant tissue is essential for planning a course of radiotherapy. MR images may provide additional information for delineating the target volume because of the large difference in the proton magnetic resonance relaxation times between normal and malignant tissues. In 13 patients with head and neck tumors the distribution of the proton spin-spin relaxation times, T2, at 1.5 Tesla were evaluated throughout the physician designated target volume and normal surrounding tissue. The T2 values within the tumor were always elevated compared with normal tissue, the highest values being in the nominal center of the tumor and decreasing toward the periphery. The regional distribution of T2 values within the tumor is a measure of the tissue heterogeneity within the tumor volume. In addition, the large differences in T2 relaxation times between normal and disease tissues were used in a computer algorithm to automatically demarcate the boundary of abnormal tissue in each axial MRI section. This potentially could significantly expedite the time required to identify the target volume on multiple sections and thus remove one of the major time constraints for 3D treatment planning.     

Magnetic resonance of brain tumors: considerations of imaging contrast on the basis of relaxation measurements

Proton spin-lattice and spin-spin relaxation times have been measured in surgically-removed normal CNS tissues and a variety of tumors of the brain. All measurements were made at 20 MHz and 37 degrees C. Between grey and white matter from autopsy human or canine specimens significant differences in T1 or T2 were observed, with greater differences seen in T1. Such discrimination was reduced in samples obtained from live brain-tumor patients due to lengthening in T1 and T2 of white matter near tumorous lesions. Edematous white matter showed T1 and T2 values higher than those of autopsy disease-free white matter. Compared to normal CNS tissues, most brain tumors examined in this study demonstrated elevated T1 and T2 values. Exceptions, however, did exist. No definitive correlation was indicated on a T1 or T2 basis which allowed a distinction to be made between benign and malignant states. Furthermore, considerable variation in relaxation times occurred from tumor to tumor of the same type, suggesting that within a tumor type there are important differences in physiology, biology, and/or pathologic state. Such variation caused partial overlap in relaxation times among certain tumor types and hence may limit the capability of magnetic resonance imaging (MR) alone for the diagnosis of specific disease. Nonetheless, this study predicts that on the basis of T1 or T2 differences most brain tumors are readily detectable by MR via saturation recovery or inversion recovery with appropriate selections of pulse-spacing parameters. In general, tumors can be discriminated against white matter better than grey matter and contrast between glioma and grey matter is usually superior to that between meningioma and grey matter. This work did not consider tissue-associated proton density which should be addressed together with T1 and T2 for a complete treatment of MR contrast.     

Significance of proton relaxation time measurement in brain edema, cerebral infarction and brain tumors

We examined the proton relaxation times in vitro in various neurological diseases using experimental and clinical materials, and consequently obtained significant results for making a fundamental analysis of magnetic resonance imaging (MRI) as followings. 1) In the brain edema and cerebral infarction, T1 prolonged and T2 separated into two components, one fast and one slow. Prolongation of T1 referred to the volume of increased water in tissue. The slow component of T2 reflects both the volume and the content of increased edema fluid in tissue. 2) In the edematous brain tissue with the damaged Blood-Brain-Barrier (BBB), the slow component of T2 became shorter after the injection of Mn-EDTA. Paramagnetic ion could be used as an indicator to demonstrate the destruction of BBB in the brain. 3) After the i.v. injection of glycerol, the slow component of T2 became shorter in the edematous brain with the concomitant decrease of water content. The effects of therapeutic drug could be evaluated by the measurement of proton relaxation times. 4) Almost all tumor tissue showed a longer T1 and T2 values than the normal rat brain, and many of them showed two components in T2. It was difficult to determine the histology of tumor tissue by the relaxation time alone because of an overlap of T1 and T2 values occurred among various types of brain tumors. 5) In vivo T1 values of various brain tumor were calculated from the data of MRIs by zero-crossing method, and they were compared with the in vitro T1 values which were measured immediately after the surgical operation. Though the absolute value did not coincide with each other due to differences in magnetic field strength, the tendency of the changes was the same among all kinds of tumors. It is concluded that the fundamental analysis of proton relaxation times is essentially important not only for the study of pathophysiology in many diseases but also for the interpretation of clinical MRI.     

Breast disease evaluation with fat-suppressed magnetic resonance imaging.

Thirty patients with a variety of pathologically confirmed malignant and benign pathologic lesions of the breast were evaluated with a spectrally selective fat suppression imaging technique to obtain fat-suppressed images of the breast. The technique, a selective partial inversion-recovery (SPIR) method, demonstrated the architectural relationship of malignant and benign tumors with respect to the normal water-containing elements of the breast. These relationships included signs of advanced malignant disease such as tissue retraction, invasive growth, and multicentricity, which appeared on the fat-suppressed images. Fat-suppressed imaging provided useful information for assessing the breasts of both pre- and postmenopausal women, especially in the latter group, where fatty involution of the breast is common. Microcysts, which are normally not visualized by conventional methods, were demonstrated and associated with patients having confirmed fibrocystic disease of the breast. As expected, the SPIR technique did not improve the ability to distinguish between tissues having similar T1 and T2 relaxation time values, such as malignant tumors and normal breast parenchymal tissues. The technique was able to demonstrate that the intense lipid signal, known to be responsible for obscuring the borders of water-fat interfaces and small tumors, could be eliminated in a variety of pathological settings.     

Flow and oxygenation dependent (FLOOD) contrast MR imaging to monitor the response of rat tumors to carbogen breathing

Gradient recalled echo (GRE) images are sensitive to both paramagnetic deoxyhaemoglobin concentration (via T2*) and flow (via T1*). Large GRE signal intensity increases have been observed in subcutaneous tumors during carbogen (5% carbon dioxide, 95% oxygen) breathing. We term this combined effect flow and oxygenation-dependent (FLOOD) contrast. We have now used both spin echo (SE) and GRE images to evaluate how changes in relaxation times and flow contribute to image intensity contrast changes. T1-weighted images, with and without outer slice suppression, and calculated T2, T2* and "flow" maps, were obtained for subcutaneous GH3 prolactinomas in rats during air and carbogen breathing. T1-weighted images showed bright features that increased in size, intensity and number with carbogen breathing. H&E stained histological sections confirmed them to be large blood vessels. Apparent T1 and T2 images were fairly homogeneous with average relaxation times of 850 ms and 37 ms, respectively, during air breathing, with increases of 2% for T1 and 11% for T2 during carbogen breathing. The apparent T2* over all tumors was very heterogeneous, with values between 9 and 23 ms and localized increases of up to 75% during carbogen breathing. Synthesised "flow" maps also showed heterogeneity, and regions of maximum increase in flow did not always coincide with maximum increases in T2*. Carbogen breathing caused a threefold increase in arterial rat blood PaO2, and typically a 50% increase in tumor blood volume as measured by 51Cr-labelled RBC uptake. The T2* increase is therefore due to a decrease in blood deoxyhaemoglobin concentration with the magnitude of the FLOOD response being determined by the vascular density and responsiveness to blood flow modifiers. FLOOD contrast may therefore be of value in assessing the magnitude and heterogeneity of response of individual tumors to blood flow modifiers for both chemotherapy, antiangiogenesis therapy in particular, and radiotherapy.     

Quantitative multivoxel proton chemical shift imaging of the breast

The study of focal pathology by single-voxel magnetic resonance spectroscopy (MRS) is hampered by the impossibility to study tissue heterogeneity or compare the metabolite signals in breast lesion directly to those in unaffected tissue. Multivoxel MRS studies, while potentially allowing for truly quantitative tissue characterization, have up to now also been far from quantitative with, for example, the signal-to-noise ratio of the choline (Cho) signal serving as measure of tumor activity. Shown in this study is that in a standard clinical setting with a regular 1.5-T magnetic resonance scanner, it is possible to perform quantitative multivoxel MRS. With the use of literature values for the T1 and T2 relaxation times of Cho and water in fibroglandular breast tissue and tumors, one can determine the concentrations of Cho in different tumor compartments and surrounding tissues in two brief multivoxel MRS measurements. This opens excellent perspectives to quantitative diagnostic and follow-up studies of focal pathology such as lesions suspected of breast cancer.     

Measurement of proliferation activity in human melanoma xenografts by magnetic resonance imaging

Tumor proliferation may be predictive for malignant progression and response to fractionated therapy of cancer. The purpose of the present work was to investigate whether the proliferation activity of solid tumors can be assessed in vivo from the proton relaxation times, T1 and T2. Tumors of four amelanotic human melanoma xenograft lines were studied. Three parameters were used to represent tumor proliferation activity; the volume doubling time, Tvol, the potential doubling time, Tpot, and the fraction of cells in S-phase. Tvol was determined from volumetric growth data. Tpot and S-phase fraction were determined by flow cytometric analysis of tumor cells after bromodeoxyuridine (BrdU) incorporation in vivo. T1 and T2 were measured by 1H-MRI in vivo, using spin-echo pulse sequences. The proliferation parameters and relaxation times differed considerably among the tumor lines. Significant correlations were found between the proliferation parameters and the relaxation times, regardless of whether Tvol, Tpot, or S-phase fraction was considered. Tumors with short Tvol and Tpot and high S-phase fraction had long T1 and T2 compared to tumors with long Tvol and Tpot and low S-phase fraction. The elongated T1 and T2 of fast growing tumors were probably due to increased interstitial and/or intravascular water content. The present results suggest that in vivo spin-echo 1H-MRI can be used to discriminate between tumors of high and low proliferation activity.     

The influence of macromolecular polymerization of spin-lattice relaxation of aqueous solutions

The docking or polymerization of globular proteins is demonstrated to cause changes in proton NMR spin-lattice (T1) relaxation times. Studies on solutions of lysozyme, bovine serum albumin, actin, and tubulin are used to demonstrate that two mechanisms account for the observed changes in T1. Polymerization displaces the hydration water sheath surrounding globular proteins in solution that causes an increase in T1. Polymerization also slows the average tumbling rate of the proteins, which typically causes a contrary decrease in T1. The crystallization reaction of lysozyme in sodium chloride solution further demonstrates that the "effective" molecular weight can either decrease or increase T1 depending on how much the protein is slowed. The displacement of hydration water increases T1 because it speeds up the mean motional state of water in the solution. Macromolecular docking typically decreases T1 because it slows the mean motional state of the solute molecules. Cross-relaxation between the proteins and bound water provides the mechanism that allows macromolecular motion to influence the relaxation rate of the solvent. Fast chemical exchange between bound, structured, and bulk water accounts for monoexponential spin-lattice relaxation. Thus the spin-lattice relaxation rate of water in protein solutions is a complex reflection of the motional properties of all the molecules present containing proton magnetic dipoles. It is expected, as a result, that the characteristic relaxation times of tissues will reflect the influence of polymerization changes related to cellular activities.     

Prolonged bone marrow T1-relaxation in patients with polycythemia vera

In vitro as well as in vivo studies have shown prolonged T1 relaxation times in patients with acute leukemia. The mechanism behind this finding is not known. In order to evaluate if this was specific for leukemia we examined eight patients with polycythemia vera, representing a condition with a rather benign bone marrow neoplasia. In this group of patients we found prolonged T1 relaxation times but normal T2 relaxation times. This may indicate that the prolonged T1 relaxation time seen in leukemic bone marrow is not due to the malignant cell per se.     

In vivo estimation of relaxation processes in benign hyperplasia and carcinoma of the prostate gland by magnetic resonance imaging

Tissue characterization for separating malignant from benign tissue is a clinically very important potential of magnetic resonance imaging (MRI). In this study quantitative determination of T1- and T2-relaxation processes was accomplished in five healthy volunteers, 10 patients with benign hyperplasia of the prostate gland and eight patients with prostatic carcinoma. Histological verification was obtained in all the patients. The measurements were performed on a wholebody MR-scanner operating at 1.5 T using six inversion recovery sequences (TR = 4000 msec) for T1-determination and a 32 spin-echo sequence (TR = 3000 or 2000 msec) for T2-estimation. The T1-relaxation curves all appeared monoexponential, whereas the T2-curves in most cases showed a multiexponential behaviour. A considerable overlap of the relaxation curves was seen. Consequently, we found no statistically significant differences between the T1- or the T2-relaxation times of the three groups investigated. It is concluded that tissue characterization based on relaxation time measurements with MRI does not seem to have a clinically useful role in prostatic disease.     

Changes of relaxation times T1 and T2 in rat tissues after biopsy and fixation

NMR spectroscopical measurements of relaxation times were conducted on muscle, intestine, fatty tissue and cerebral cortex and white matter of the rat at various time intervals following removal of the tissue. It appeared that most tissues can be stored at 4 degrees C up to 24 hours without noticeable effects on NMR relaxation parameters. Exceptions are the T2 of muscle and the T1 and T2 of intestine, which tended to change in the first hour after biopsy. Relaxation parameters change considerably after fixation of the tissues. Therefore the effects of fixation have to be taken into account when carrying out NMR measurements on fixed tissues.     

Tissue characterization of benign brain tumors: use of NMR-tissue parameters

To evaluate the potentials of NMR tissue parameters for tissue characterization we investigated 68 patients with benign brain tumors. Tissue parameters were accurately measured by a recently developed interlaced triple sequence. Each individual tumor was characterized by a set of three numbers (relaxation times T1 and T2 and proton density Rho). Different tumors exhibited significant overlaps of the three tissue parameters. Therefore a reliable prediction of the histological diagnosis based on the quantitative analysis of tissue parameters alone was not possible. T2-prolongation correlated well with water content and "regressive changes" in meningiomas and neuromas.     

Isointense model for the evaluation of tumor-specific MRI contrast agents

An isointense model has been developed to evaluate the applicability of putative tumor-specific MRI contrast agents. Data for tissue relaxation measurements in the presence of Mn(III)TPPS4 are used to illustrate the model. The concentration of contrast agent in tumor tissue required for a tumor/normal tissue signal difference-to-noise ratio of 5 (delta SNR = 5) is determined for a T1 weighted pulse sequence and several hypothetical tumor/normal tissue pairs. The impact of various contrast agent characteristics including initial tumor/normal tissue relaxation values, differential uptake of contrast agent, and in vivo relaxivity are considered. Isointense tumor/normal tissue with longer initial relaxation times are shown to be more affected by the presence of contrast agent. In addition those with initially longer relaxation times have less rigorous requirements for tumor specificity. Typically, a normal tissue/tumor uptake ratio of 1:2 increases the concentration required for delta SNR = 5 by a factor of two compared to that of exclusive uptake in tumor. For the T1 weighted pulse sequence employed, the concentration required for delta SNR = 5 is shown to be linear with the inverse of in vivo relaxivity for the hypothetical tissues considered. The isointense model is also extended to predict the field dependence of tumor-specific contrast enhancement by Mn(III)TPPS4.     

T2 relaxation of the parotid gland of patients affected by pleomorphic adenoma.

The T2 behavior of parotid gland tissue was investigated in 11 patients affected by pleomorphic adenoma. A protocol that was previously set up to define acquisition and post-processing procedures, reaching an accuracy of 2.5% in phantoms and an in vivo long term reproducibility of 0.9-8.5%, was used for the evaluations. The measurements were carried out on a whole body, superconducting imager, using a neck coil as a receiver. Some reference gel samples were imaged together with the patient and used to correct T2 results. The sequence protocol was a multispin-echo, 16 echoes. Signals were fitted with mono and biexponential decay models and an automatic choice of the best model was performed using the two chisquared comparison. Two T2 maps (T2 monoexponential or short T2 component, and long T2 component) and chisquared maps were then produced. Pathologic and normal tissues showed a dominant monoexponential decay with a good level of biexponentiality (16%-27% of total fitted pixels) due to partial volume effects from the liquid content. Concerning the biexponentiality, no significant differences were found between the fitted pixel fraction of normal and pathologic tissue, because the T2 long component of the lesion was related both to the edema and saliva content, but probably the increase in the first compensated the decrease in the second. Chisquared maps showed that most of the lesions presented a monoexponential core surrounded by a biexponential border probably due to a solid component similar to normal tissue with partial volume effects from saliva content. Ninety-five percent confidence intervals for normal tissue were 69.40-87.80 ms (monoexponential relaxation), 38.19-44.67 ms and 285.84-691.28 ms (short and long components of biexponential relaxation). For pathologic tissue they resulted 172.17-275.83 ms, 53.86-89.98 ms and 442.10-814.58 ms. The monoexponential component, mostly present in the core of the lesion, was the parameter that better characterized pathologic tissue. A comparison was performed between normal tissue of patients and normal tissue of volunteers, whose statistics was collected in a previous study with the same evaluation protocol. Results showed no significant differences in the biexponential fitted fractions and the comparison of relaxation times. We conclude that, for tissue characterization, a multiexponential analysis should be carried out in order to improve accuracy and to obtain more reliable results. Moreover, other than relaxation calculations, a topographical analysis of relaxation distribution, using for instance the chisquared maps, might in the future give us more useful information on tissue structure.     

Magnetic resonance imaging measurements of vascular permeability and extracellular volume fraction of breast tumors by dynamic Gd-DTPA-enhanced relaxometry

Vascular permeability (k(ep), min(-1)) and extracellular volume fraction (v(e)) are tissue parameters of great interest to characterize malignant tumor lesions. Indeed, it is well known that tumors with high blood supply better respond to therapy than poorly vascularized tumors, and tumors with large extracellular volume tend to be more malignant than tumors showing lower extracellular volume. Furthermore, the transport of therapeutic agents depends on both extracellular volume fraction and vessel permeability. Thus, before treatment, these tissue parameters may prove useful to evaluate tumor aggressiveness and to predict responsiveness to therapy and variations during cytotoxic therapies could allow to assess treatment efficacy and early modified therapy schedules in case of poor responsiveness. As a consequence, there is a need to develop methods that could be routinely used to determine these tissue parameters. In this work, blood-tissue permeability and extracellular volume fraction information were derived from magnetic resonance imaging dynamic longitudinal relaxation rate (R(1)) mapping obtained after an intravenous bolus injection of Gd-DTPA in a group of 92 female patients with breast lesions, 68 of these being histologically proven to be with carcinoma. For the sake of comparison, 24 benign lesions were studied. The measurement protocol based on two-dimensional gradient echo sequences and a monoexponential plasma kinetic model was that validated in the occasion of previous animal experiments. As a consequence of neoangiogenesis, results showed a higher permeability in malignant than in benign lesions, whereas the extracellular volume fraction value did not allow any discrimination between benign and malignant lesions. The method, which can be easily implemented whatever the imaging system used, could advantageously be used to quantify lesion parameters (k(ep) and v(e)) in routine clinical imaging. Because of its large reproducibility, the method could be useful for intersite comparisons and follow-up studies.     

Assessment of T1 time course changes and tissue-blood ratios after Gd-DTPA administration in brain tumors

Sequential T1 changes in brain tumor tissue after Gd-DTPA administration were investigated in 10 patients, including 4 meningiomas, 2 gliomas, 3 metastatic cerebral tumors and 1 brain abscess. T1 values were measured serially for 60 minutes following Gd-DTPA injection using a magnetic focusing technique. In vitro T1 of the whole blood samples was also comparatively examined. Time processes in the tissue-blood ratio (TBR) were calculated from two-point relaxation rates at 5 and 30 minutes. The obtained ratios of TBR were ranged from 1.0 to 3.0, probably depending on histological types of brain tumor (the value of 1.0 to 1.5 for meningioma and 1.5 to 3.0 for glioma and metastatic tumor). No significant changes in the T1 value were observed in the examined normal tissue and peritumoral edema. These results indicate that Gd-DTPA plays an important role not only as an image enhancer for tumor tissue but also as an indicator for estimating the blood-brain barrier function.     

T2* measurements in human brain at 1.5, 3 and 7 T

Measurements have been carried out in six subjects at magnetic fields of 1.5, 3 and 7 T, with the aim of characterizing the variation of T2* with field strength in human brain. Accurate measurement of T2* in the presence of macroscopic magnetic field inhomogeneity is problematic due to signal decay resulting from through-slice dephasing. The approach employed here allowed the signal decay due to through-slice dephasing to be characterized and removed from data, thus facilitating an accurate measurement of T2* even at ultrahigh field. Using double inversion recovery turbo spin-echo images for tissue classification, an analysis of T2* relaxation times in cortical grey matter and white matter was carried out, along with an evaluation of the variation of T2* with field strength in the caudate nucleus and putamen. The results show an approximately linear increase in relaxation rate R2* with field strength for all tissues, leading to a greater range of relaxation times across tissue types at 7 T that can be exploited in high-resolution T2*-weighted imaging.     

13C spin-lattice relaxation in natural diamond: Zeeman relaxation at 4.7 T and 300 K due to fixed paramagnetic nitrogen defects

13C spin-lattice relaxation times in the laboratory frame, ranging from 1.4 to 36 h, have been measured on a suite of five natural type Ia and Ib diamonds at 4.7 T and 300 K. Each of the diamonds contains two types of fixed paramagnetic centers with overlapping inhomogeneous electron paramagnetic resonance (EPR) lines. EPR techniques have been employed to identify these defects and to determine their concentrations and relaxation times at X-band. Spin-lattice relaxation behavior of 13C in diamonds containing paramagnetic P1, P2, N2. and N3 centers are discussed. Depending on the paramagnetic impurity types and concentrations present in each diamond, three different nuclear spin-lattice relaxation (SLR) paths exist, namely that due to electron SLR mechanisms and two types of three-spin processes (TSPs). The one three-spin process (TSP1) involves a simultaneous transition of two electron spins belonging to the same hyperfine EPR line and a flip of a 13C spin, while the other process (TSP2) involves two electron spins belonging to different hyperfine EPR lines and a 13C spin. It is shown that the thermal contact between the 13C nuclear Zeeman and electron dipole-dipole interaction reservoirs is field dependent, thus forming a bottleneck in the 13C relaxation path due to TSP1 at high magnetic fields.     

Assessment of scanner performance and normalization of estimated relaxation rate values

The purpose of this study was to develop and test a method for the assessment of Magnetic Resonance (MR) scanner performance suitable for routine brain MR studies and for normalization of calculated relaxation times. We hypothesized that regular monitoring of machine performance changes could provide a helpful normalization tool for calculating tissue MR parameters, thus contributing to support their use for longitudinal and comparative studies of both normal and diseased tissues.The method is based on the acquisition of phantom images during routine brain studies with standard spin-echo sequences. MR phantom and brain tissue parameters were used to assess the influence of machine related changes on relaxation parameter estimates. Experimental results showed that scanner performance may affect relaxation rate estimates. Phantom and in vivo results indicate that the correction method yields a reduction in variability of estimated phantom R1 values up to 29% and of R1 for different brain structures up to 17%. These findings support the validity of using brain coil phantoms for routine system monitoring and correction of tissue relaxation rates.     

Changes in orcine muscle water characteristics during growth--an in vitro low-field NMR relaxation study

This study investigates the effects of developmental stage and muscle type on the mobility and distribution of water within skeletal muscles, using low-field (1)H-NMR transverse relaxation measurements in vitro on four different porcine muscles (M. longissimus dorsi, M. semitendinosus, M. biceps femoris, M. vastus intermedius) from a total of 48 pigs slaughtered at various weight classes between 25 kg and 150 kg. Principal component analysis (PCA) revealed effects of both slaughter weight and muscle type on the transverse relaxation decay. Independent of developmental stage and muscle type, distributed exponential analysis of the NMR T(2) relaxation data imparted the existence of three distinct water populations, T(2b), T(21), and T(22), with relaxation times of approximately 1-10, 45-120, and 200-500 ms, respectively. The most profound change during muscle growth was a shift toward faster relaxation in the intermediate time constant, T(21). It decreased by approx. 24% in all four muscle types during the period from 25 to 150 kg live weight. Determination of dry matter, fat, and protein content in the muscles showed that the changes in relaxation time of the intermediate time constant, T(21), during growth should be ascribed mainly to a change in protein content, as the protein content explained 77% of the variation in the T(21) time constant. Partial least squares (PLS) regression revealed validated correlations in the region of 0.58 to 0.77 between NMR transverse relaxation data and muscle development for all the four muscle types, which indicates that NMR relaxation measurements may be used in the prediction of muscle developmental stage.