Combined magnetic resonance imaging and magnetic resonance spectroscopy imaging in the diagnosis of prostate cancer: a systematic review and meta-analysis

CONTEXT: Magnetic resonance imaging (MRI) combined with magnetic resonance spectroscopy imaging (MRSI) emerged as a promising test in the diagnosis of prostate cancer and showed encouraging results. OBJECTIVE: The aim of this systematic review is to meta-analyse the diagnostic accuracy of combined MRI/MRSI in prostate cancer and to explore risk profiles with highest benefit. EVIDENCE ACQUISITION: The authors searched the MEDLINE and EMBASE databases and the Cochrane Library, and the authors screened reference lists and contacted experts. There were no language restrictions. The last search was performed in August 2008. EVIDENCE SYNTHESIS: We identified 31 test-accuracy studies (1765 patients); 16 studies (17 populations) with a total of 581 patients were suitable for meta-analysis. Nine combined MRI/MRSI studies (10 populations) examining men with pathologically confirmed prostate cancer (297 patients; 1518 specimens) had a pooled sensitivity and specificity on prostate subpart level of 68% (95% CI, 56-78%) and 85% (95% CI, 78-90%), respectively. Compared with patients at high risk for clinically relevant cancer (six studies), sensitivity was lower in low-risk patients (four studies) (58% [46-69%] vs 74% [58-85%]; p>0.05) but higher for specificity (91% [86-94%] vs 78% [70-84%]; p<0.01). Seven studies examining patients with suspected prostate cancer at combined MRI/MRSI (284 patients) had an overall pooled sensitivity and specificity on patients level of 82% (59-94%) and 88% (80-95%). In the low-risk group (five studies) these values were 75% (39-93%) and 91% (77-97%), respectively. CONCLUSIONS: A limited number of small studies suggest that MRI combined with MRSI could be a rule-in test for low-risk patients. This finding needs further confirmation in larger studies and cost-effectiveness needs to be established.

Quantitative 1H-magnetic resonance spectroscopy of human brain: Influence of composition and parameterization of the basis set in linear combination model-fitting

Localized short-echo-time (1)H-MR spectra of human brain contain contributions of many low-molecular-weight metabolites and baseline contributions of macromolecules. Two approaches to model such spectra are compared and the data acquisition sequence, optimized for reproducibility, is presented. Modeling relies on prior knowledge constraints and linear combination of metabolite spectra. Investigated was what can be gained by basis parameterization, i.e., description of basis spectra as sums of parametric lineshapes. Effects of basis composition and addition of experimentally measured macromolecular baselines were investigated also. Both fitting methods yielded quantitatively similar values, model deviations, error estimates, and reproducibility in the evaluation of 64 spectra of human gray and white matter from 40 subjects. Major advantages of parameterized basis functions are the possibilities to evaluate fitting parameters separately, to treat subgroup spectra as independent moieties, and to incorporate deviations from straightforward metabolite models. It was found that most of the 22 basis metabolites used may provide meaningful data when comparing patient cohorts. In individual spectra, sums of closely related metabolites are often more meaningful. Inclusion of a macromolecular basis component leads to relatively small, but significantly different tissue content for most metabolites. It provides a means to quantitate baseline contributions that may contain crucial clinical information.

{\it In vivo\/} magnetic resonance studies of experimental liver disease: Carbon tetrachloride hepatotoxicity and alcohol-induced fatty liver in rat

Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) were used to non-invasively determine if cirrhosis induced by carbon tetrachloride (CCl$\sb4$) and phospholipase-D (PLD) could be distinguished from fatty infiltration in rat. MRS localization and water suppression methods were developed, implemented and evaluated in terms of their application to in vivo proton NMR studies of experimental liver disease. MRS studies were also performed to quantitate fatty infiltration resulting from carbon tetrachloride (CCl$\sb4$) or alcohol (ethanol) administration and the MRS results were confirmed using biochemical total lipid analysis and histology. $\rm T\sb1$ weighted MR images acquired weekly, 48 hours post administration, demonstrated only a slight increase in overall liver intensity with CCl$\sb4$ or alcohol administration, which is consistent with previously reported results. The MR images were able to detect nodules resulting from CCl$\sb4$+PLD induced cirrhosis as hypointense regions, also consistent with previous reports. Localized in vivo water and lipid proton $\rm T\sb1$ relaxation time measurements were performed and demonstrated no statistically significant trends for either agent. In vivo proton spectra were also acquired using stimulated echo techniques to quantitatively follow the changes in liver lipid content. The changes in liver lipid content observed using MRS were verified by total lipid analysis using the Folch technique and histology. The in vivo $\rm T\sb1$ and lipid quantification data str inconsistent with the previous hypothesis that the changes in $\rm T\sb1$ weighted images were the result of increased "free" water content and, therefore, increased water $\rm T\sb1$ relaxation times. These data indicate that the long term changes are more likely the result of changes in lipid content. The data are also shown to agree with the accepted hypothesis that the time course and mechanism of fatty infiltration are different for CCl$\sb4$ and alcohol. The hypothesis that the lipids resulting from either protocol are from the same lipid fraction(s), presumably triglycerides, is also supported. And lastly, on the basis of MR images and quantitative MRS lipid information, it was shown that cirrhosis could be distinguished from fatty infiltration. ^

Neuromuscular disuse and atrophy: {\it In vivo\/} magnetic resonance studies of intramuscular lipid metabolism and fluid shift changes

We postulated that neuromuscular disuse results in deleteriously affected tissue-vascular fluid exchange processes and subsequently damages the important oxidative bioenergetic process of intramuscular lipid metabolism. The in-depth research reported in the literature is somewhat limited by the ex vivo nature and sporadic time-course characterization of disuse atrophy and recovery. Thus, an in vivo controlled, localized animal model of disuse atrophy was developed in one of the hindlimbs of laboratory rabbits (employing surgically implanted tetrodotoxin (TTX)-filled mini-osmotic pump-sciatic nerve superfusion system) and tested repeatedly with magnetic resonance (MR) throughout the 2-week period of temporarily induced disuse and during the recovery period (following explantation of the TTX-filled pump) for a period of 3 weeks. Controls consisted of saline/"sham"-implanted rabbit hindlimbs. The validity of this model was established with repeated electrophysiologic nerve conduction testing using a clinically appropriate protocol and percutaneously inserted small needle stimulating and recording electrodes. Evoked responses recorded from proximal (P) and distal (D) sites to the sciatic nerve cuff in the TTX-implanted group revealed significantly decreased (p $<$ 0.001) proximal-to-distal (P/D) amplitude ratios (as much as 50-70% below Baseline/pre-implanted and sham-implanted group values) and significantly increased (p $<$ 0.01) differential latency (PL-DL) values (as much as 1.5 times the pre- and sham-implanted groups). By Day 21 of recovery, observed P/D and PL-DL levels matched Baseline/sham-implemented levels. MRI-determined cross-sectional area (CSA) values of Baseline/pre-implanted, sham- or TTX-implanted, and recovering/explanted and the corresponding contralateral hindlimb tibialis anterior (TA) muscles normalized to tibial bone (TB) CSA (in TA/TB ratios) revealed that there was a significant decline (indicative of atrophic response) from pre- and sham-implanted controls by as much as 20% (p $<$ 0.01) at Day 7 and 50-55% (p $<$ 0.001) at Day 13 of TTX-implantation. In the non-implanted contralaterals, a significant increase (indicative of hypertrophic response) by as much as 10% (p $<$ 0.025) at Day 7 and 27% (p $<$ 0.001) at Day 13 + TTX was found. The induced atrophic/hypertrophic TA muscles were observed to be fully recovered by Day 21 post-explantation as evidenced by image TA/TB ratios. End-point biopsy results from a small group of rabbits revealed comprehensive atrophy of both Type I and Type II fibers, although the heterogeneity of the response supports the use of image-guided, volume-localized proton magnetic resonance spectroscopy (MRS) to noninvasively assess tissue-level metabolic changes. MRS-determined results of a 0.25cc volume of tissue within implanted limb TA muscles under resting/pre-ischemic, ischemic-stressed, and post-ischemic conditions at timepoints during and following disuse atrophy/recovery revealed significantly increased intramuscular spectral lipid levels, as much as 2-3 times (p $<$ 0.01) the Baseline/pre-implanted values at Day 7 and 6-7 times (p $<$ 0.001) at Day 13 + TTX, which approached normal levels (compared to pre- and sham-implanted groups) by Day 21 of post-explanation recovery. (Abstract shortened by UMI.) ^

Increased levels of choline metabolites are an early marker of docetaxel treatment response in BRCA1-mutated mouse mammary tumors: an assessment by ex vivo proton magnetic resonance spectroscopy.

BACKGROUND Docetaxel is one of the most frequently used drugs to treat breast cancer. However, resistance or incomplete response to docetaxel is a major challenge. The aim of this study was to utilize MR metabolomics to identify potential biomarkers of docetaxel resistance in a mouse model for BRCA1-mutated breast cancer. METHODOLOGY High resolution magic angle spinning (HRMAS) (1)H MR spectroscopy was performed on tissue samples obtained from docetaxel-sensitive or -resistant BRCA1-mutated mammary tumors in mice. Measurements were performed on samples obtained before treatment and at 1-2, 3-5 and 6-7 days after a 25 mg/kg dose of docetaxel. The MR spectra were analyzed by multivariate analysis, followed by analysis of the signals of individual compounds by peak fitting and integration with normalization to the integral of the creatine signal and of all signals between 2.9 and 3.6 ppm. RESULTS The HRMAS spectra revealed significant metabolic differences between sensitive and resistant tissue samples. In particular choline metabolites were higher in resistant tumors by more than 50% with respect to creatine and by more than 30% with respect to all signals between 2.9 and 3.6 ppm. Shortly after treatment (1-2 days) the normalized choline metabolite levels were significantly increased by more than 30% in the sensitive group coinciding with the time of highest apoptotic activity induced by docetaxel. Thereafter, choline metabolites in these tumors returned towards pre-treatment levels. No change in choline compounds was observed in the resistant tumors over the whole time of investigation. CONCLUSIONS Relative tissue concentrations of choline compounds are higher in docetaxel resistant than in sensitive BRCA1-mutated mouse mammary tumors, but in the first days after docetaxel treatment only in the sensitive tumors an increase of these compounds is observed. Thus both pre- and post-treatment tissue levels of choline compounds have potential to predict response to docetaxel treatment.

A dual resonance, image -guided, volume localization technique for magnetic resonance spectroscopy

An interleaved, dual resonance, volume localization technique for $\sp1$H/$\sp{31}$P magnetic resonance spectroscopy has been designed, implemented on a 2 T imager/spectrometer, and verified with phantom studies.^ Localization techniques, including several single voxel techniques and spectroscopic imaging, were implemented, and studies were performed to compare the efficiency of each sequence of $\sp1$H/$\sp{31}$P spectral acquisitions. The sequence chosen was a hybrid of the stimulated echo single voxel technique and the spectroscopic imaging technique.^ Water suppression during the $\sp1$H spectral acquisitions was accomplished by the use of three narrow bandwidth RF saturation pulses in combination with three spoiler gradients. The spoiler gradient amplitudes were selected on the basis of a numerical solution of the Bloch equations. A post-acquisition water suppression algorithm was used to minimize any residual water signal.^ For interleaved $\sp1$H/$\sp{31}$P acquisitions, a dual resonance RF coil was constructed and interfaced to the existing RF detection system via a custom-designed dual resonance transcoupler and switching system. Programmable attenuators were incorporated to allow for changes in receiver and transmitter attenuation "on the fly".^ To provide the rapidly switched gradient fields required for the $\sp1$H/$\sp{31}$P acquisitions, an actively screened gradient coil system was designed and implemented. With this system, gradient field rise times on the order of 100 $\mu$s were obtained. These rapid switching times were necessary for minimizing intrasequence delays and for improving localization quality and water suppression efficiency.^ The interleaved $\sp1$H/$\sp{31}$P volume localization technique was tested using a two-compartment phantom. Analysis of the data showed that the spectral contamination was less than three percent. One-to-one spatial correspondence of the $\sp1$H and $\sp{31}$P spectra was verified and allowed for direct correlation of the spectral data with a standard magnetic resonance image. ^

HR Nuclear Magnetic Resonance Spectroscopy for Authentication of Olive Oil Quality

The present work is a preliminary study to settle the optimum experimental conditions and data processing for accomplishing the strategies established by the Action Plan for the EU olive oil sector. The objectives of the work were: a) to monitor the evolution of extra virgin olive oil exposed to indirect solar light in transparent glass bottles during four months; b) to identify spectral differences between edible and lampant virgin olive oil by applying high resolution Nuclear Magnetic Resonance (HR-NMR) Spectroscopy. Pr esent study could contribute to determine the date of minimum storage, their optimum conditions, and to properly characterize olive oil.

Biochemical changes in the frontal lobe of HIV-infected individuals detected by magnetic resonance spectroscopy

We have developed a proton magnetic resonance spectroscopy method that selectively can sample cortical gray matter and adjacent white matter in the frontal lobe. We have used this approach to study a group of patients (n = 7) infected with HIV and clinical manifestations of the AIDS dementia complex (ADC), a group of patients (n = 8) infected with HIV without any indications of ADC, and seven controls. The patients without ADC had a statistically significant increase in the ratio of myo-inositol to creatine in white matter compared with normal controls. In contrast, the group of patients with ADC had almost normal levels of myo-inositol to creatine in both gray matter and white matter and showed a statistically significant decrease in the N-acetylaspartate to creatine ratio in gray matter compared with either the normal controls or the patients without ADC. Patterns of spectral abnormalities correlated with neuropsychological measures of frontal lobe dysfunction, suggesting that the evaluation of frontal lobe metabolism by magnetic resonance spectroscopy can play a role in the early detection of ADC, in determining its progression, and in assessing responses to therapeutic interventions.

31P magnetic resonance spectroscopy of the Sherpa heart: a phosphocreatine/adenosine triphosphate signature of metabolic defense against hypobaric hypoxia.

Of all humans thus far studied, Sherpas are considered by many high-altitude biomedical scientists as most exquisitely adapted for life under continuous hypobaric hypoxia. However, little is known about how the heart is protected in hypoxia. Hypoxia defense mechanisms in the Sherpa heart were explored by in vivo, noninvasive 31P magnetic resonance spectroscopy. Six Sherpas were examined under two experimental conditions [normoxic (21% FiO2) and hypoxic (11% FiO2) and in two adaptational states--the acclimated state (on arrival at low-altitude study sites) and the deacclimating state (4 weeks of ongoing exposure to low altitude). Four lowland subjects were used for comparison. We found that the concentration ratios of phosphocreatine (PCr)/adenosine triphosphate (ATP) were maintained at steady-state normoxic values (0.96, SEM = 0.22) that were about half those found in normoxic lowlanders (1.76, SEM = 0.03) monitored the same way at the same time. These differences in heart energetic status between Sherpas and lowlanders compared under normoxic conditions remained highly significant (P < 0.02) even after 4 weeks of deacclimation at low altitudes. In Sherpas under acute hypoxia, the heart rate increased by 20 beats per min from resting values of about 70 beats per min, and the percent saturation of hemoglobin decreased to about 75%. However, these perturbations did not alter the PCr/ATP concentration ratios, which remained at about 50% of the values expected in healthy lowlanders. Because the creatine phosphokinase reaction functions close to equilibrium, these steady-state PCr/ATP ratios presumably coincided with about 3-fold higher free adenosine diphosphate (ADP) concentrations. Higher ADP concentrations (i.e., lower [PCr]/[ATP] ratios) were interpreted to correlate with the Km values for ADP-requiring kinases of glycolysis and to reflect elevated carbohydrate contributions to heart energy needs. This metabolic organization is postulated as advantageous in hypobaria because the ATP yield per O2 molecule is 25-60% higher with glucose than with free fatty acids (the usual fuels utilized in the human heart in postfasting conditions).

Nuclear magnetic resonance spectroscopy and ultrasound

The work described in this thesis is directed to the examination of the hypothesis that ultrasound may be used to perturb molecular motion in the liquid phase. These changes can then be detected by nuclear magnetic resonance (NMR) in spin-lattice and spin-spin relaxation times. The objective being to develop a method capable of reducing the pulsed NMR acquisition times of slowly relaxing nuclei. The thesis describes the theoretical principles underlying both NMR spectroscopy and ultrasonics with particular attention being paid to factors that impinge on testing the above hypothesis. Apparatus has been constructed to enable ultrasound at frequencies between 1 and 10 mega-hertz with a variable power up to 100W/cm-2 to be introduced in the NMR sample. A broadband high frequency generator is used to drive PZT piezo-electric transducer via various transducer to liquid coupling arrangements. A commercial instrument of 20 kilo-hertz has also been employed to test the above hypothesis and also to demonstrate the usefulness of ultrasound in sonochemistry. The latter objective being, detection of radical formation in monomer and polymer ultrasonic degradation. The principle features of the results obtained are: Ultrasonic perturbation of T1 is far smaller for pure liquids than is for mixtures. The effects appear to be greater on protons (1H) than on carbon-13 nuclei (13C) relaxation times. The observed effect of ultrasonics is not due to temperature changes in the sample. As the power applied to the transducer is progressively increased T1 decreases to a minimum and then increases. The T1's of the same nuclei in different functional groups are influenced to different extents by ultrasound. Studies of the 14N resonances from an equimolar mixture of N, N-dimethylformamide and deuterated chloroform with ultrasonic frequencies at 1.115, 6, 6.42 and 10 MHz show that as the frequency is increased the NMR signal to noise ratio decreases to zero at the Larmor frequency of 6.42 MHz and then again rises. This reveals the surprising indication that an effect corresponding to nuclear acoustic saturation in the liquid may be observable. Ultrasonic irradiation of acidified ammonium chloride solution at and around 6.42 MHz appears to cause distinctive changes in the proton-nitrogen J coupling resonance at 89.56 MHz. Ultrasonic irradiation of N, N-dimethylacetamide at 2 KHz using the lowest stable power revealed the onset of coalescence in the proton spectrum. The corresponding effect achieved by direct heating required a temperature rise of approximately 30oC. The effects of low frequency (20 KHz) on relaxation times appear to be nil. Detection of radical formation proved difficult but is still regarded as the principle route for monomer and polymer degradation. The initial hypothesis is considered proven with the results showing significant changes in the mega-hertz region and none at 20 KHz.

Magnetic resonance spectroscopy. Data analysis for clinical applications

This text is taken from the postgraduate thesis, which one of the authors (A.B.) developed for the degree of Medical Physicist in the School on Medical Physics of the University of Florence. The text explores the feasibility of quantitative Magnetic Resonance Spectroscopy as a tool for daily clinical routine use. The results and analysis comes from two types of hyper spectral images: the first set are hyper spectral images coming from a standard phantom (reference images); and hyper spectral images obtained from a group of patients who have undergone MRI examinations at the Santa Maria Nuova Hospital. This interdisciplinary work stems from the IFAC-CNR know how in terms of data analysis and nanomedicine, and the clinical expertise of Radiologists and Medical Physicists. The results reported here, which were the subject of the thesis, are original, unpublished, and represent independent work.