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Purpose To study cancer associated with abnormal metabolism of phospholipids, of which several have been proposed as biomarkers for malignancy or to monitor response to anticancer therapy. We explored 3D 31P magnetic resonance spectroscopic imaging (MRSI) at high magnetic field for in vivo assessment of individual phospholipids in two patient-derived breast cancer xenografts representing good and poor prognosis (luminal- and basal-like tumors). Materials and Methods Metabolic profiles from luminal-like and basal-like xenograft tumors were obtained in vivo using 3D 31P MRSI at 11.7T and from tissue extracts in vitro at 14.1T. Gene expression analysis was performed in order to support metabolic differences between the two xenografts. Results In vivo 31P MR spectra were obtained in which the prominent resonances from phospholipid metabolites were detected at a high signal-to-noise ratio (SNR >7.5). Metabolic profiles obtained in vivo were in agreement with those obtained in vitro and could be used to discriminate between the two xenograft models, based on the levels of phosphocholine, phosphoethanolamine, glycerophosphocholine, and glycerophosphoethanolamine. The differences in phospholipid metabolite concentration could partly be explained by gene expression profiles. Conclusion Noninvasive metabolic profiling by 3D 31P MRSI can discriminate between subtypes of breast cancer based on different concentrations of choline- and ethanolamine-containing phospholipids. J. Magn. Reson. Imaging 2015;41:601-609. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Purpose Phospholipid metabolites are of importance in cancer studies, and have been suggested as candidate metabolic biomarkers for response to targeted anticancer drugs. The purpose of this study was to develop a phosphorus (31P) high resolution magic angle spinning magnetic resonance spectroscopy protocol for quantification of phosphorylated metabolites in intact cancer tissue. Methods 31P spectra were acquired on a 14.1 T spectrometer with a triplet 1H/13C/31P MAS probe. Quantification of metabolites was performed using the PULCON principle. Basal-like and luminal-like breast cancer xenografts were treated with the dual PI3K/mTOR inhibitor BEZ235, and the impact of treatment on the concentration of phosphocholine, glycerophosphocholine, phosphoethanolamine and glycerophosphoethanolamine was evaluated. Results In basal-like xenografts, BEZ235 treatment induced a significant decrease in phosphoethanolamine (−25.6%, P = 0.01) whilst phosphocholine (16.5%, P = 0.02) and glycerophosphocholine (37.3%, P < 0.001) were significantly increased. The metabolic changes could partially be explained by increased levels of phospholipase A2 group 4A (PLA2G4A). Conclusion 31P high resolution magic angle spinning magnetic resonance spectroscopy is a useful method for quantitative assessment of metabolic responses to PI3K inhibition. Using the PULCON principle for quantification, the levels of phosphocholine, glycerophosphocholine, phosphoethanolamine, and glycerophosphoethanolamine could be evaluated with high precision and accuracy. Magn Reson Med 71:1973-1981, 2014. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Purpose To investigate the effect of bevacizumab treatment on vascular architecture and function in two xenograft models with different angiogenic properties using diffusion-weighted magnetic resonance imaging (DW-MRI) and dynamic contrast-enhanced MRI (DCE-MRI). Materials and Methods Mice carrying basal-like (MAS98.12) or luminal-like (MAS98.06) orthotopic breast cancer xenografts were treated with bevacizumab (5 mg/kg), doxorubicin (8 mg/kg), or both drugs in combination. DW-MRI and DCE-MRI were performed before and 3 days after treatment using a Bruker 7T preclinical scanner. Mean microvessel density (MVD) and proliferating microvessel density (pMVD) in the tumors were determined for evaluation of vascular response to bevacizumab treatment. Results No changes in DCE-MRI or DW-MRI parameters were observed in untreated controls during the experiment period. DW-MRI showed increased apparent diffusion coefficient (ADC) values in all treatment groups in both basal-like and luminal-like xenografts. DCE-MRI showed increased contrast agent uptake, particularly in central regions of the tumors, after bevacizumab/combination treatment in both xenograft models. This was accompanied by decreased MVD and pMVD in basal-like xenografts. Doxorubicin treatment had no effect on DCE-MRI parameters in any of the xenograft models. Conclusion Both DW-MRI and DCE-MRI demonstrated an early response to bevacizumab treatment in the xenograft tumors. Increased contrast agent uptake and reduced MVD/pMVD is consistent with a normalization of vascular function. J. Magn. Reson. Imaging 2013;38:1043-1053. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

MR metabolic profiling of the prostate is promising as an additional diagnostic approach to separate indolent from aggressive prostate cancer. The objective of this study was to assess the relationship between the Gleason score and the metabolic biomarker (choline + creatine + spermine)/citrate (CCS/C) measured by ex vivo high-resolution magic angle spinning MRS (HR-MAS MRS) and in vivo MRSI, and to evaluate the correlation between in vivo- and ex vivo-measured metabolite ratios from spatially matched prostate regions. Patients ( n = 13) underwent in vivo MRSI prior to radical prostatectomy. A prostate tissue slice was snap-frozen shortly after surgery and the locations of tissue samples ( n = 40) collected for ex vivo HR-MAS were matched to in vivo MRSI voxels ( n = 40). In vivo MRSI was performed on a 3T clinical MR system and ex vivo HR-MAS on a 14.1T magnet. Relative metabolite concentrations were calculated by LCModel fitting of in vivo spectra and by peak integration of ex vivo spectra. Spearman's rank correlations ( ρ) between CCS/C from in vivo and ex vivo MR spectra, and with their corresponding Gleason score, were calculated. There was a strong positive correlation between the Gleason score and CCS/C measured both in vivo and ex vivo ( ρ = 0.77 and ρ = 0.69, respectively; p < 0.001), and between in vivo and ex vivo metabolite ratios from spatially matched regions ( ρ = 0.67, p < 0.001). Our data indicate that MR metabolic profiling is a potentially useful tool for the assessment of cancer aggressiveness. Moreover, the good correlation between in vivo- and ex vivo-measured CCS/C demonstrates that our method is able to bridge MRSI and HR-MAS molecular analysis. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Antiangiogenic therapy with bevacizumab has shown varying results in breast cancer clinical trials. Identifying robust biomarkers for selecting patients who may benefit from such treatment and for monitoring response is important for the future use of bevacizumab. Two established xenograft models representing basal-like and luminal-like breast cancer were used to study bevacizumab treatment response on the metabolic and gene expression levels. Tumor samples were obtained from mice treated with bevacizumab, doxorubicin or a combination of the two drugs, and high resolution magic angle spinning magnetic resonance spectroscopy and gene expression microarray analysis was performed. Combination treatment with bevacizumab showed the strongest growth inhibiting effect in basal-like tumors, and this was reflected by a significant change in the metabolomic and transcriptomic profiles. In the luminal-like xenografts, addition of bevacizumab did not improve the effect of doxorubicin. On the global transcriptomic level, the largest gene expression changes were observed for the most efficient treatment in both models. Glycerophosphocholine showed opposite response in the treated xenografts compared with untreated controls; lower in basal-like and higher in luminal-like tumors. Comparing combination therapy with doxorubicin monotherapy in basal-like xenografts, 14 genes showed significant differential expression, including very low density lipoprotein receptor (VLDLR) and hemoglobin, theta 1 (HBQ1). Bevacizumab-treated tumors were associated with a more hypoxic phenotype, while no evidence was found for associations between bevacizumab treatment and vascular invasion or tumor grade. This study underlines the importance of characterizing biological differences between subtypes of breast cancer to identify personalized biomarkers for improved patient stratification and evaluation of response to therapy. [Copyright &y& Elsevier]

MRSI of prostate cancer provides a potential clinical tool to aid in the detection and characterisation of this disease, but its clinical use is limited by the need for the specialist training of radiologists to read these datasets. An essential part of this reading is the assessment of the usability and reliability of MRSI spectra because they can be affected by artefacts such as poor signal to noise, lipid signal contamination and broad resonances that could cause errors of interpretation. We have developed an automated quality control algorithm that classifies every voxel of an MRSI dataset as either acceptable or unacceptable for further analysis, based on the spectral profile alone. The method was trained and tested based on a gold standard of agreement of four experts. It was highly accurate: testing with a novel set of data from MRSI patients produced agreement with the experts' consensus decisions with a specificity of 0.95 and sensitivity of 0.95. This method provides fast quality control of three-dimensional MRSI datasets of the prostate, removing the need for radiologists to perform this time consuming, but necessary, task prior to further analysis. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Breast cancer is a heterogeneous disease with a variable prognosis. Clinical factors provide some information about the prognosis of patients with breast cancer; however, there is a need for additional information to stratify patients for improved and more individualized treatment. The aim of this study was to examine the relationship between the metabolite profiles of breast cancer tissue and 5-year survival. Biopsies from breast cancer patients ( n = 98) were excised during surgery and analyzed by high-resolution magic angle spinning MRS. The data were analyzed by multivariate principal component analysis and partial least-squares discriminant analysis, and the findings of important metabolites were confirmed by spectral integration of the metabolite peaks. Predictions of 5-year survival using metabolite profiles were compared with predictions using clinical parameters. Based on the metabolite profiles, patients with estrogen receptor (ER)-positive breast cancer ( n = 71) were separated into two groups with significantly different survival rates ( p = 0.024). Higher levels of glycine and lactate were found to be associated with lower survival rates by both multivariate analyses and spectral integration, and are suggested as biomarkers for breast cancer prognosis. Similar metabolic differences were not observed for ER-negative patients, where survivors could not be separated from nonsurvivors. Predictions of 5-year survival of ER-positive patients using metabolite profiles gave better and more robust results than those using traditional clinical parameters. The results imply that the metabolic state of a tumor may provide additional information concerning breast cancer prognosis. Further studies should be conducted in order to evaluate the role of MR metabolomics as an additional clinical tool for determining the prognosis of patients with breast cancer. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Altered choline phospholipid metabolism is a hallmark of cancer, leading to malignant choline metabolite profiles consisting of low glycerophosphocholine (GPC) and high phosphocholine (PC) in human breast cancers. Glycerophosphocholine phosphodiesterase (GPC-PDE) catalyzes the degradation of GPC to free choline and glycerol-3-phosphate. The gene(s) encoding for the GPC-PDE(s) responsible for GPC degradation in breast cancers have not yet been identified. Here, we demonstrate for the first time that the GPC-PDE encoded by glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5) is associated with breast cancer malignancy. Two human breast cancer cell lines ( n = 8 and n = 10) and primary human breast tumor samples ( n = 19) were studied with combined MRS and quantitative reverse transcription-polymerase chain reaction to investigate several isoforms of GDPD expression with respect to choline phospholipid metabolite levels. Of the five GDPDs tested, GDPD5 was found to be significantly overexpressed in highly malignant estrogen receptor negative (ER-) compared with weakly malignant estrogen receptor positive (ER+) human breast cancer cells ( p = 0.027) and breast tumors from patients ( p = 0.015). GDPD5 showed significantly positive correlations with PC ( p < 0.001), total choline (tCho) ( p = 0.007) and PC/GPC ( p < 0.001) levels in human breast tumors. GDPD5 showed a trend towards a negative correlation with GPC levels ( p = 0.130). Human breast cancers with malignant choline metabolite profiles consisting of low GPC and high PC levels highly co-expressed GDPD5, choline kinase alpha (CHKA) and phosphatidylcholine-specific phospholipase D1 (PLD1), whereas cancers containing high GPC and relatively low PC levels displayed low co-expression of GDPD5, CHKA and PLD1. GDPD5, CHKA and PLD1 were significantly overexpressed in highly malignant ER- tumors in our patient cohort. Our study identified GDPD5 as a GPC-PDE that probably participates in the regulation of choline phospholipid metabolism in breast cancer, which possibly occurs in cooperation with CHKA and PLD1. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Purpose: To explore tumor pathophysiology with special attention to the microenvironment in two molecular subtypes of human breast cancer using in vivo magnetic resonance imaging (MRI) and histopathology. The impact of tumor growth, size, and the influence of estradiol were also investigated. Materials and Methods: Two orthotopic and directly transplanted human breast cancer models representing luminal-like and basal-like molecular subtypes were characterized by dynamic contrast-enhanced MRI and diffusion-weighted MRI. Ex vivo measurements of vascularization, hypoxia, mitoses, and the level of VEGF activations were associated with the calculated in vivo MRI parameters of the tumors. Results: The vascular permeability and perfusion (Ktrans) was significantly higher in basal-like compared to luminal-like tumors. These findings were confirmed by a 4-fold higher proliferating microvessel density (pMVD) in basal-like tumors, reflecting the difference in aggressiveness between the subtypes. No effect of tumor growth was observed during 6 days of growth in any of the models; however, large tumors had lower Ktrans, higher extracellular extravascular volume fraction (ve), and more hypoxia than medium-sized tumors. Estradiol withdrawal induced increased Ktrans, ve, and tumor water diffusion (ADC) in luminal-like tumors, corresponding to increased VEGFR2 activation, which is likely to cause increased tumor vessel permeability. Conclusion: These novel data confirm the potential of functional MRI methods to map histopathologically proven changes in breast tumor vasculature and microenvironment in vivo. J. Magn. Reson. Imaging 2012;. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Purpose This study aimed to evaluate whether MR metabolic profiling can be used for prediction of long-term survival and monitoring of treatment response in locally advanced breast cancer patients during neoadjuvant chemotherapy (NAC). Methods: High resolution magic angle spinning (HR MAS) MR spectra of pre- and post-treatment biopsies from 33 patients were acquired. Tissue concentrations of choline-containing metabolites (tCho), glycine and taurine were assessed using electronic reference to access in vivo concentration (ERETIC) of the signal and receiver operating characteristic (ROC) curves was used to define their potential to predict patient survival and treatment response. The metabolite profiles obtained by HR MAS spectroscopy were related to long-term survival and treatment response by genetic algorithm partial least squares discriminant analysis (GA PLS-DA). Results Different pre-treatment MR metabolic profiles characterized by higher levels of tCho and lower levels of lactate were observed in patients with long-term survival (≥5 years, survivors) compared to patients who died of cancer recurrence (<5 years, non-survivors). A significant decrease in glycerophosphocholine (GPC) post-treatment was associated with long-term survival ( p = 0.046) and partial response ( p = 0.014) to NAC. Long-term survival was best predicted by GPC using ROC analyses (sens. 66.7%, spec. 62.5%), while taurine had the best predictive value of treatment response (sens. 72.7%, spec. 63.2%). GA PLS-DA multivariate classification models successfully discriminated between survivors and non-survivors, resulting in 82.7% and 90.2% cross-validation (CV) classification accuracy, pre- and post-treatment, respectively. Classification of treatment response using GA PLS-DA was not successful for this patient cohort. Conclusions Our results demonstrate that HR MAS MR metabolic profiles consisting of important metabolic characteristics of breast cancer tumors could potentially assist the classification and prediction of long-term survival in locally advanced breast cancer patients, in addition to being used as an adjunct for evaluation of treatment response to NAC. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Tumor cells have increased glycolytic activity, and glucose is mainly used to form lactate and alanine, even when high concentrations of oxygen are present (Warburg effect). The purpose of the present study was to investigate glucose metabolism in two xenograft models representing basal-like and luminal-like breast cancer using 13C high-resolution-magic angle spinning (HR-MAS) MRS and gene expression analysis. Tumor tissue was collected from two groups for each model: untreated mice ( n = 19) and a group of mice ( n = 16) that received an injection of [1-13C]-glucose 10 or 15 min before harvesting the tissue. 13C HR-MAS MRS was performed on the tumor samples and differences in the glucose/alanine (Glc/Ala), glucose/lactate (Glc/Lac) and alanine/lactate (Ala/Lac) ratios between the models were studied. The expression of glycolytic genes was studied using tumor tissue from the same models. In the natural abundance MR spectra, a significantly lower Glc/Ala and Glc/Lac ratio ( p < 0.001) was observed in the luminal-like model compared with the basal-like model. In the labeled samples, the predominant glucose metabolites were lactate and alanine. Significantly lower Glc/Ala and Glc/Lac ratios were observed in the luminal-like model ( p < 0.05). Most genes contributing to glycolysis were expressed at higher levels in the luminal-like model (fdr < 0.001). The lower Glc/Ala and Glc/Lac ratios and higher glycolytic gene expression observed in the luminal-like model indicates that the transformation of glucose to lactate and alanine occurred faster in this model than in the basal-like model, which has a growth rate several times faster than that of the luminal-like model. The results from the present study suggest that the tumor growth rate is not necessarily a determinant of glycolytic activity. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Purpose: To use dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) MRI at 3 Tesla (T) for early evaluation of treatment effects in breast cancer patients undergoing neoadjuvant chemotherapy (NAC), and assess the reliability of DW-MRI. Materials and Methods: DW- and DCE-MRI acquisitions of 15 breast cancer patients were performed before and after one cycle of NAC. MRI tumor diameter and volume, apparent diffusion coefficient (ADC) and kinetic parameters (Ktrans, ve) were derived. The reliability of ADC before NAC was assessed. Changes in MRI parameters after NAC were analyzed, and logistic regression analysis was used to find the best predictors for pathologic response. Results: The reliability for ADC values was high, with intraclass correlation coefficient of 0.84 ( P = 0.001). After one cycle of NAC, MRI tumor diameter (8%, P = 0.005) and tumor volume (30%, P = 0.008) was reduced for all patients, while ADC mean values increased (0.12 mm2/s, P = 0.008). The best predictor for treatment response was a change in MRI tumor diameter with mean error rate of 0.167 (13% for responders, 5% for nonresponders, P = 0.291). Conclusion: Changes in MRI derived tumor diameter and ADC after only one cycle of NAC could provide a valuable tool for early evaluation of treatment effects in breast cancer patients. J. Magn. Reson. Imaging 2011;. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Purpose: To investigate possible improvements in predicting the response to neoadjuvant chemotherapy (NAC) at 3 T for locally advanced breast cancer (LABC). Materials and Methods: Dynamic contrast-enhanced magnetic resonance (DCE-MR) images acquired before and during NAC were retrospectively analyzed in 85 patients. Tumor volume and diameter, three volumes based on the shape of the enhancement curve, relative signal intensity, area under the curve, and the signal-to-noise ratio were extracted. Differences between responders and nonresponders at the same and between MR timepoints during treatment were evaluated. Results: A higher signal-to-noise ratio was observed on 3 T images compared to 1.5 T, and 3 T revealed more significant findings related to response compared to 1.5 T. The DCE-MRI-derived volume parameters were the earliest predictors of response at both 1.5 and 3 T. Conclusion: Our results show that 3 T provides an improved assessment of the response to NAC in LABC patients, where the MR determined tumor volume reduction before the second cycle of NAC was the strongest and earliest predictor of a response. J. Magn. Reson. Imaging 2011;. © 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

MRS and MRSI are valuable tools for the detection of metabolic changes in tumors. The currently emerging era of molecular medicine, which is shaped by molecularly targeted anticancer therapies combined with molecular imaging of the effects of such therapies, requires powerful imaging technologies that are able to detect molecular information. MRS and MRSI are such technologies that are able to detect metabolites arising from glucose and choline metabolism in noninvasive in vivo settings and at higher resolution in tissue samples. The roles played by MRS and MRSI in the diagnosis of different types of cancer, as well as in the early monitoring of the tumor response to traditional chemotherapies, are reviewed. The emerging roles of MRS and MRSI in the development and detection of novel targeted anticancer therapies that target oncogenic signaling pathways or markers in choline or glucose metabolism are discussed. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Triple-negative breast cancers (TNBC), characterized by absence of estrogen receptor (ER), progesterone receptor (PR) and lack of overexpression of human epidermal growth factor receptor 2 (HER2), are typically associated with poor prognosis, due to aggressive tumor phenotype(s), only partial response to chemotherapy and present lack of clinically established targeted therapies. Advances in the design of individualized strategies for treatment of TNBC patients require further elucidation, by combined ‘omics’ approaches, of the molecular mechanisms underlying TNBC phenotypic heterogeneity, and the still poorly understood association of TNBC with BRCA1 mutations. An overview is here presented on TNBC profiling in terms of expression signatures, within the functional genomic breast tumor classification, and ongoing efforts toward identification of new therapy targets and bioimaging markers. Due to the complexity of aberrant molecular patterns involved in expression, pathological progression and biological/clinical heterogeneity, the search for novel TNBC biomarkers and therapy targets requires collection of multi-dimensional data sets, use of robust multivariate data analysis techniques and development of innovative systems biology approaches. [Copyright &y& Elsevier]

Absolute quantitative measures of breast cancer tissue metabolites can increase our understanding of biological processes. Electronic REference To access In vivo Concentrations (ERETIC) was applied to high resolution magic angle spinning MR spectroscopy (HR MAS MRS) to quantify metabolites in intact breast cancer samples. The ERETIC signal was calibrated using solutions of creatine and TSP. The largest relative errors of the ERETIC method were 8.4%, compared to 4.4% for the HR MAS MRS method using TSP as a standard. The same MR experimental procedure was applied to intact tissue samples from breast cancer patients with clinically defined good ( n = 13) and poor ( n = 16) prognosis. All samples were examined by histopathology for relative content of different tissue types and proliferation index (MIB-1) after MR analysis. The resulting spectra were analyzed by quantification of tissue metabolites (β-glucose, lactate, glycine, myo-inositol, taurine, glycerophosphocholine, phosphocholine, choline and creatine), by peak area ratios and by principal component analysis. We found a trend toward lower concentrations of glycine in patients with good prognosis (1.1 µmol/g) compared to patients with poor prognosis (1.9 µmol/g, p = 0.067). Tissue metabolite concentrations (except for β-glucose) were also found to correlate to the fraction of tumor, connective, fat or glandular tissue by Pearson correlation analysis. Tissue concentrations of β-glucose correlated to proliferation index (MIB-1) with a negative correlation factor (−0.45, p = 0.015), consistent with increased energy demand in proliferating tumor cells. By analyzing several metabolites simultaneously, either in ratios or by metabolic profiles analyzed by PCA, we found that tissue metabolites correlate to patients' prognoses and health status five years after surgery. This study shows that the diagnostic and prognostic potential in MR metabolite analysis of breast cancer tissue is greater when combining multiple metabolites (MR Metabolomics). Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate the use of dynamic contrast-enhanced (DCE) MRI, in vivo 1H MRS and ex vivo high resolution magic angle spinning (HR MAS) MRS of tissue samples as methods to detect early treatment effects of docetaxel in a breast cancer xenograft model (MCF-7) in mice. MCF-7 cells were implanted subcutaneously in athymic mice and treated with docetaxel (20, 30, and 40 mg/kg) or saline six weeks later. DCE-MRI and in vivo 1H MRS were performed on a 7 T MR system three days after treatment. The dynamic images were used as input for a two-compartment model, yielding the vascular parameters Ktrans and ve. HR MAS MRS, histology, and immunohistochemical staining for proliferation (Ki-67), apoptosis (M30 cytodeath), and vascular/endothelial cells (CD31) were performed on excised tumor tissue. Both in vivo spectra and HR MAS spectra were used as input for multivariate analysis (principal component analysis (PCA) and partial least squares regression analysis (PLS)) to compare controls to treated tumors. Tumor growth was suppressed in docetaxel-treated mice compared to the controls. The anti-tumor effect led to an increase in Ktrans and ve values in all the treated groups. Furthermore, in vivo MRS and HR MAS MRS revealed a significant decrease in choline metabolite levels for the treated groups, in accordance with reduced proliferative index as seen on Ki-67 stained sections. In this study DCE-MRI, in vivo MRS and ex vivo HR MAS MRS have been used to demonstrate that docetaxel treatment of a human breast cancer xenograft model results in changes in the vascular dynamics and metabolic profile of the tumors. This indicates that these MR methods could be used to monitor intra-tumoral treatment effects. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Purpose: To assess the reproducibility of 1H-MR spectroscopic imaging (MRSI) of the human brain at 3T with volume selection by a double spin echo sequence for localization with adiabatic refocusing pulses (semi-LASER). Materials and Methods: Twenty volunteers in two different institutions were measured twice with the same pulse sequence at an echo time of 30 msec. Magnetic resonance (MR) spectra were analyzed with LCModel with a simulated basis set including an experimentally acquired macromolecular signal profile. For specific regions in the brain mean metabolite levels, within and between subject variance, and the coefficient of variation (CoV) were calculated (for taurine, glutamate, total N-acetylaspartate, total creatine, total choline, myo-inositol + glycine, and glutamate + glutamine). Results: Repeated measurements showed no significant differences with a paired t-test and a high reproducibility (CoV ranging from 3%-30% throughout the selected volume). Mean metabolite levels and CoV obtained in similar regions in the brain did not differ significantly between two contributing institutions. The major source of differences between different measurements was identified to be the between-subject variations in the volunteers. Conclusion: We conclude that semi-LASER 1H-MRSI at 3T is an adequate method to obtain quantitative and reproducible measures of metabolite levels over large parts of the brain, applicable across multiple centers. J. Magn. Reson. Imaging 2010;31:61-70. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Purpose To evaluate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) as a tool for early prediction of response to neoadjuvant chemotherapy (NAC) and 5-year survival in patients with locally advanced breast cancer. Materials and Methods DCE-MRI was performed in patients scheduled for NAC ( n = 24) before and after the first treatment cycle. Clinical response was evaluated after completed NAC. Relative signal intensity (RSI) and area under the curve (AUC) were calculated from the DCE-curves and compared to clinical treatment response. Kohonen and probabilistic neural network (KNN and PNN) analysis were used to predict 5-year survival. Results RSI and AUC were reduced after only one cycle of NAC in patients with clinical treatment response ( P = 0.02 and P = 0.08). The mean and 10th percentile RSI values before NAC were significantly lower in patients surviving more than 5 years compared to nonsurvivors ( P = 0.05 and 0.02). This relationship was confirmed using KNN, which demonstrated that patients who remained alive clustered in separate regions from those that died. Calibration of contrast enhancement curves by PNN for patient survival at 5 years yielded sensitivity and specificity for training and testing ranging from 80%-92%. Conclusion DCE-MRI in locally advanced breast cancer has the potential to predict 5-year survival in a small patient cohort. In addition, changes in tumor vascularization after one cycle of NAC can be assessed. J. Magn. Reson. Imaging 2009;29:1300-1307. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The goal of this study was to investigate the use of lactate and alanine as metabolic biomarkers of prostate cancer using 1H high-resolution magic angle spinning (HR-MAS) spectroscopy of snap-frozen transrectal ultrasound (TRUS)-guided prostate biopsy tissues. A long-echo-time rotor-synchronized Carr-Purcell-Meiboom-Gill (CPMG) sequence including an electronic reference to access in vivo concentrations (ERETIC) standard was used to determine the concentrations of lactate and alanine in 82 benign and 16 malignant biopsies (mean 26.5% ± 17.2% of core). Low concentrations of lactate (0.61 ± 0.28 mmol/kg) and alanine (0.14 ± 0.06 mmol/kg) were observed in benign prostate biopsies, and there was no significant difference between benign predominantly glandular ( N = 54) and stromal ( N = 28) biopsies between patients with ( N = 38) and without ( N = 44) a positive clinical biopsy. In biopsies containing prostate cancer there was a highly significant ( P < 0.0001) increase in lactate (1.59 ± 0.61 mmol/kg) and alanine (0.26 ± 0.07 mmol/kg), and minimal overlap with lactate concentrations in benign biopsies. This study demonstrates for the first time very low concentrations of lactate and alanine in benign prostate biopsy tissues. The significant increase in the concentration of both lactate and alanine in biopsy tissue containing as little as 5% cancer could be exploited in hyperpolarized 13C spectroscopic imaging (SI) studies of prostate cancer patients. Magn Reson Med 60:510-516, 2008. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The objectives of this study were to (a) explore the spectral characteristics of brain metastases, focusing on the origin of the primary cancer, and (b) evaluate the correlation with clinical outcome using multivariate analysis. High-resolution magic angle spinning (HR-MAS) MR spectra ( n = 26) were obtained from 16 patients with brain metastases using a Bruker Avance DRX600 instrument. Standard pulse-acquired and spin-echo ( TE 32 and 285 ms) 1H spectra were obtained. These were examined using principal component analysis (PCA) and partial least squares regression analysis (PLS) relating spectral data to clinical outcome. The PCA score plot of pulse-acquired HR-MAS spectra showed a trend of clustering due to the origin of the metastases, mainly based on differences in the lipid signals at 1.3 and 0.9 ppm. With PLS, spectra of patients who died less than 5 months after surgery appeared to cluster in the lower left quadrant of the score plot. These preliminary results on brain metastasis classification and prediction of survival must be validated in a larger patient cohort. However, the possibility of differentiating metastases according to origin and predicting survival on the basis of HR-MAS spectra suggests that this method may be useful for diagnosing and planning treatment for brain metastases and also for guiding decisions about terminating further treatment. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Breast cancer is the most frequent form of cancer in women and improved diagnostic methods are desirable. Malignant cells have altered metabolism and metabolic mapping might become a tool in cancer diagnostics. High-resolution magic angle spinning (HR MAS) MR spectroscopy of tissue biopsies provides detailed information on metabolic composition. The 600 MHz 1H HR MAS spectra were acquired of breast cancer tissue from 85 patients and adjacent non-involved tissue from 18 of these patients. Tissue specimens were investigated by microscopy after MR analysis. The resulting spectra were examined by three different approaches. Relative intensities of glycerophosphocholine (GPC), phosphocholine (PC) and choline were compared for cancerous and non-involved specimens. Eight metabolites, choline, creatine, β-glucose, GPC, glycine, myo-inositol, PC and taurine, were quantified from the recorded spectra and compared with tumor histological type and size, patient's lymph node status and tissue composition of sample. The spectra were also compared with tumor histological type and size, lymph node status and tissue composition of samples using principal component analysis (PCA). Tumor samples could be distinguished from non-involved samples (82% sensitivity, 100% specificity) based on relative intensities of signals from GPC, PC and choline in 1H HR MAS spectra. Tissue concentrations of metabolites showed few differences between groups of samples, which can be caused by limitations in the quantification procedure. Choline and glycine concentrations were found to be significantly higher in tumors larger than 2 cm compared with smaller tumors. PCA of MAS spectra from patients with invasive ductal carcinomas indicated a possible prediction of spread to axillary lymph nodes. Metabolite estimates and PCA of MAS spectra were influenced by the percentage of tumor cells in the investigated specimens. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]