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Purpose: To automate dynamic contrast-enhanced MRI (DCE-MRI) data analysis by unsupervised pattern recognition (PR) to enable spatial mapping of intratumoral vascular heterogeneity., Methods: Three steps were automated. First, the arrival time of the contrast agent at the tumor was determined, including a calculation of the precontrast signal. Second, four criteria-based algorithms for the slice-specific selection of number of patterns (NP) were validated using 109 tumor slices from subcutaneous flank tumors of five different tumor models. The criteria were: half area under the curve, standard deviation thresholding, percent signal enhancement, and signal-to-noise ratio (SNR). The performance of these criteria was assessed by comparing the calculated NP with the visually determined NP. Third, spatial assignment of single patterns and/or pattern mixtures was obtained by way of constrained nonnegative matrix factorization., Results: The determination of the contrast agent arrival time at the tumor slice was successfully automated. For the determination of NP, the SNR-based approach outperformed other selection criteria by agreeing >97% with visual assessment. The spatial localization of single patterns and pattern mixtures, the latter inferring tumor vascular heterogeneity at subpixel spatial resolution, was established successfully by automated assignment from DCE-MRI signal-versus-time curves., Conclusion: The PR-based DCE-MRI analysis was successfully automated to spatially map intratumoral vascular heterogeneity. Magn Reson Med 79:1736-1744, 2018. © 2017 International Society for Magnetic Resonance in Medicine., (© 2017 International Society for Magnetic Resonance in Medicine.)

An MRI technique is proposed for complete fat signal elimination. This approach exploits the fact that water rapidly exchanges magnetization with protons in protein and membrane phospholipid of tissue and cells but does not exchange magnetization with triglyceride or fat protons in the tissue. Saturation of the proton signal from protein and membrane phospholipid thus results in partial saturation of the water proton signal, allowing acquisition of an image including a portion of the water signal and the full fat signal. Subtraction of this image from the standard image, containing both water and fat signals, results in an image in which all fat signal is cancelled. This fat-free image is sensitive to magnetization transfer and to water density and relaxation time, providing the possibility of additional contrast. Unlike most fat suppression techniques, this method is not compromised by the static or radiofrequency field heterogeneity and is equally efficient for all fat resonances independent of their chemical shift frequency., ((c) 2010 Wiley-Liss, Inc.)

17-Allylamino, 17-demethoxygeldanamycin (17-AAG), an effective inhibitor of the heat shock protein hsp90, preferentially inhibiting tumor hsp90 compared to hsp90 from normal cells, has shown promising results against several cancers, including hormone-resistant prostate cancer. Levels of several oncogenic proteins critical to tumor growth and progression, such as androgen receptor and HER2/neu, were reduced 4 h post 17-allylamino, 17-demethoxygeldanamycin treatment. Posttreatment metabolic changes have also been observed in several tumor cell lines. In this study, total choline distributions in hormone sensitive CWR22 and hormone resistant CWR22r prostate cancer xenograft tumors in mice were measured before and at 4 h and 48 h after a single-bolus 17-allylamino, 17-demethoxygeldanamycin treatment at 100 mg/kg, using proton MR spectroscopy. Our results show that tumor total choline levels declined 4 h after the treatment for CWR22 (P = 0.001) and 48 h post treatment for CWR22r (P = 0.003). Metabolic changes, in particular of total choline intensity detected by proton magnetic resonance spectroscopic imaging (MRSI), are consistent with the observed immunohistochemistry changes, tumor growth inhibition for CWR22r (P = 0.01 at 14 days post treatment), and a constant prostate specific antigen level versus increasing prostate specific antigen for control CWR22 (P = 0.01). Metabolic changes in total choline by proton MRSI can be used as an early biomarker of response for advanced-stage prostate cancer in targeted therapy such as 17-allylamino, 17-demethoxygeldanamycin., ((c) 2009 Wiley-Liss, Inc.)

Tumor vasculature and tissue oxygen pressure can influence tumor growth, metastases, and patient survival. Elevated levels of lactate may be observed during the process of aggressive tumor development accompanied by angiogenesis (the evolution of the microenvironment). The noninvasive MR detection of lactate in tumor tissues as a potential biomarker is difficult due to the presence of co-resonating lipids that are present at high concentrations. Methods were previously reported for lactate editing using the SELective Multiple Quantum Coherence (SelMQC) method. Here we report a sequence "SS-SelMQC," Spectral-Selective SelMQC, which is a modified version of SelMQC using binomial pulses. Binomial pulses were employed in this editing sequence for frequency excitation or inversion of selective lactate resonances. Lactate detection has been demonstrated using SS-SelMQC, both in vitro (30 mM lactate/H(2)O doped with 25 microM Gd-DTPA) and in vivo (Dunning R3337-AT prostate tumors), and compared to similar measurements made with SelMQC. Lactate areas were measured from nonlocalized spectra, one-dimensional (1D) localized spectra, and two-dimensional chemical shift images (CSI) of the localized slice. In data from whole phantoms, the modified pulse sequence yielded enhancement of the lactate signal of 2.4 +/- 0.40 times compared to SelMQC. Similar in vivo lactate signal enhancement of 2.3 +/- 0.24 times was observed in 1D slice-localized experiment.

For clinical dynamic contrast-enhanced (DCE) MRI studies, it is often not possible to obtain reliable arterial input function (AIF) in each measurement. Thus, it is important to find a representative AIF for pharmacokinetic modeling of DCE-MRI data when individual AIF (Ind-AIF) measurements are not available. A total of 16 patients with osteosarcomas in the lower extremity (knee region) underwent multislice DCE-MRI. Reliable Ind-AIFs were obtained in five patients with a contrast injection rate of 2 cc/s and another five patients with a 1 cc/s injection rate. Average AIF (Avg-AIF) for each injection rate was constructed from the corresponding five Ind-AIFs. For each injection rate there are no statistically significant differences between pharmacokinetic parameters of the five patients derived with Ind-AIFs and Avg-AIF. There are no statistically significant changes in pharmacokinetic parameters of the 16 patients when the two Avg-AIFs were applied in kinetic modeling. The results suggest that it is feasible, as well as practical, to use a limited-population-based Avg-AIF for pharmacokinetic modeling of osteosarcoma DCE-MRI data. Further validation with a larger population and multiple regions is desirable., ((c) 2008 Wiley-Liss, Inc.)

In the present study we applied proton-decoupled 31P magnetic resonance spectroscopic imaging (MRSI) to noninvasively assess liver metabolism in patients who had undergone a partial hepatectomy (PH). Proton-decoupled 31P chemical shift imaging was performed in 47 patients 2-28 days following major hepatectomy, and the results were compared with those from eight control subjects. All studies were performed on a 1.5T MR imager (General Electric, Milwaukee, WI) equipped with a stand-alone proton decoupler. A 31P-1H resonator pair was used for data acquisition, and 31P data were obtained in 34 min. Liver regeneration was characterized by increases in phosphoethanolamine (PE), and decreases in nucleoside triphosphates (NTP), glycerophosphoethanolamine (GPE), and glycerophosphocholine (GPC). These alterations were most marked 48-72 hr after hepatectomy and returned to baseline within 3 weeks. The level of PE measured by MRSI was also found to depend on the percentage of liver that was removed, while changes in levels of cellular high energy phosphates were independent of the size of liver resection. Implementation of proton-decoupling was critical for assessing individual phosphomonoester and phosphodiester components. This study demonstrates that 31P MRSI can be used to assess metabolic changes in humans during liver regeneration, and may be useful for assessing derangement of the regenerative process or guiding adjuvant chemotherapies., (2005 Wiley-Liss, Inc)

The frequency-selective multiple-quantum-coherence (Sel-MQC) lactate (Lac) filter offers complete lipid and water suppression in a single scan for robust in vivo detection of tumor Lac, even in the presence of abundant lipids. Conversion of the detected signal into accurate tissue concentrations of Lac requires knowledge of in vivo Lac T1 and T2 relaxation times. This work reports modifications to the Sel-MQC pulse sequence, T1- and T2-Sel-MQC, that facilitate relaxation measurements of Lac. The T1-Sel-MQC sequence combines an inversion prepulse with the Sel-MQC filter. The T2-Sel-MQC sequence incorporates a CH3-selective 180 degrees pulse during the MQ preparation period to overcome the J-modulation effects and allow the insertion of variable echo delays. The performance of these sequences was evaluated with the use of phantoms and subcutaneous murine tumor models in vivo. The present approach will allow investigators to correct for the relaxation-induced Lac signal loss in Sel-MQC experiments for the quantitative mapping of in vivo tumor Lac distribution.

19Fluorine NMRS has the potential to enable noninvasive predictions of tumor response to 5-fluorouracil (5FU) therapy based on tumor pharmacokinetics. Knowledge of the T1's of 5FU and its fluoronucleotide anabolites (FNuc) is required for quantitative spectral analysis and selection of optimal pulse parameters. We used the variable nutation angle (VNA) method to determine T1's of 5FU and FNuc in subcutaneous Walker 256 rat mammary carcinosarcoma tumors transfected with a cytosine deaminase/uracil phosphoribosyltransferase fusion gene. We calibrated in vivo NAs using methoxydifluoroacetate to ensure the accuracy of these measurements. The T1's were calculated based on signal intensities acquired with NAs of 20 degrees, 35 degrees, 45 degrees, 60 degrees, and 75 degrees. The acquisition order of these NAs was shuffled to reduce the effect of signal variations. The determined T1's for 5FU and FNuc (2.3 +/- 0.1 s and 1.3 +/- 0.1 s, respectively) represent the first reported in vivo measurements for these metabolites in tumor., (Copyright 2004 Wiley-Liss, Inc.)

A multiple-mouse solenoidal MR coil was developed for in vivo imaging of up to 13 mice simultaneously to screen for tumors on a 1.5 T clinical scanner. For the coil to be effective as a screening tool, it should permit acquisition of MRIs in which orthotopic tumors with diameters >2 mm are detectable in a reasonable period of time (<1 hr magnet time) and their sizes accurately measured. Using a spin echo sequence, we demonstrated that this coil provides sufficient sensitivity for moderately high resolution images (156-176 microm in plane-resolution, 1.5 mm slice thickness). This spatial resolution permitted detection of primary brain tumors in transgenic/knockout mice and orthotopic xenografts. Brain tumor size as measured by MRI was correlated with size measured by histopathology (P < 0.001). Metastatic tumors in the mouse lung were also successfully imaged in a screening setting. The multiple mouse coil is simple in construction and may be implemented without any significant modification to the hardware or software on a clinical scanner., (Copyright 2003 Wiley-Liss, Inc.)

A fully quadrature dome-shaped resonator is presented that has been dual-tuned for proton and phosphorus operation at 1.5 T. The resonator is 16.5 cm in length and 23 cm in diameter. Phantom studies were performed to demonstrate the utility of the resonator for proton imaging, shimming, and proton-decoupled phosphorus spectroscopy. In human subjects, proton-decoupled phosphorus chemical shift imaging spectra of the brain were acquired at 27 cm3 resolution in 34 min. Volunteer studies demonstrated improved resolution of phosphomonoesters, phosphodiesters, and nucleoside triphosphates due to proton decoupling. Sensitive coverage of the brain extended from the most superior cerebral cortex to the cerebellum. Acquisition of good quality 31P spectra over this volume is due to the dome structure as well as quadrature operation at both proton and phosphorus frequencies.

Spatial maps of the percentage cellularity in pelvic bone marrow were calculated at a resolution of 15.6 mm3 from six volunteers and 10 patients treated for documented hematologic disease using a three-point Dixon MRI pulse sequence. The percentage cellularity calculation was aided by analyzing a two-dimensional feature space consisting of the apparent water fraction (Wa), and the T2 relaxation time of water (T2w). An extracellular water fraction was assigned to each voxel on the basis of a two-component T2w algorithm. In six cases, the method was compared to results obtained from core biopsies or aspirates of the posterior iliac crest. The results indicate that segmentation schemes that combine high-quality phase-contrast imaging with nuclear relaxation time measurements can potentially identify the true fractional marrow volume occupied by hematopoietic elements in a variety of clinical situations.

The results of an initial study on the feasibility of using the phosphonium analog of choline to follow the metabolism of phosphatidylcholine in tumors in vivo using 31P NMR are reported. C3H/He mice bearing a mammary carcinoma tumor on the foot pad were fed a choline-free diet supplemented with the phosphonium analog of choline. Metabolites of this compound, including the phosphonium analogs of phosphatidylcholine, phosphocholine, glycerophosphocholine, and betaine were observed noninvasively in vivo in tumors by 31P NMR after 2-3 weeks of feeding. Clearance of these phosphonium-labeled metabolites from tumors was measured after a change to a choline-containing diet. Significant decreases were seen in the levels of the analogs of betaine (P < 0.003) and phosphatidylcholine (P < 0.004) by Day 4. A significant increase in the level of authentic phosphocholine (P < 0.003) occurred over the same time period.

6-aminonicotinamide (6AN) has been shown to enhance radiosensitivity in vitro, although previous in vivo studies failed to show an effect. 31P NMR spectra were obtained by using a one-dimensional chemical shift imaging technique on a first generation transplant of the CD8FI spontaneous mammary carcinoma tumor model. Spectra were obtained both before and 10 h after treatment with 6AN (20 mg/kg). Changes in pH, nucleoside triphosphate/inorganic phosphate, and phosphocreatine/ inorganic phosphate measured at 10 h post-6AN were not significant. A new peak was detected 10 h post-6AN, which was assigned to 6-phosphogluconate (6PG), indicating inhibition of the pentose phosphate pathway (PPP). Based on the spectral data demonstrating inhibition of the PPP at 10 h post-6AN, tumor-bearing mice were irradiated (15 Gy x 3 fractions) on Days 1, 10 or 11, and 21 10 h after administration of 6-aminonicotinamide (20 mg/kg). Tumor-bearing mice receiving 6AN alone (20 mg/kg x 3), radiation alone (15 Gy x 3), or saline were also studied. Tumor growth delay studies indicated that 6AN alone induced a small but significant tumor growth delay (4.3 +/- 0.8 days). Radiation alone induced a tumor growth delay of 34.5 +/- 2.7 days. Treatment with 6AN followed by radiation induced a tumor growth delay of 57.0 +/- 3.8 days. This was significantly greater than the TGD values for treatment with 6AN alone or radiation (P < 0.01). No complete regressions were noted after treatment with 6AN or radiation alone. Concomitant therapy with 6AN plus radiation yielded 6/28 complete regressions (21%), which was significantly greater than radiation (P < 0.05) or 6AN alone (P < 0.01) on this mammary carcinoma.

A technique is described which reduced the magnetic susceptibility induced line broadening in NMR spectra obtained from three biological systems at 4.7 Tesla. Proton spectra from a sealed suspension of HL60 leukemic myeloblasts yielded minimum linewidths of 1.3 Hz at 200 MHz (0.0065 ppm) after 10 min of automated shimming. 31P spectra from an in vivo murine MCa mammary carcinoma yielded a well-resolved phosphorylcholine resonance without proton decoupling and with the resistive shim coil currents set to zero. 31P spectra from a perfused suspension of RIF-1 fibrosarcoma cells exhibited a gamma-nucleoside triphosphate resonance which was resolved into purine and pyrimidine components.

Volume-localized proton NMR spectroscopy was used to estimate bone marrow cellularity in the posterior iliac crests of patients undergoing treatment with hematopoietic growth factors for a variety of hematologic and neoplastic disorders. Twelve patients were accrued, six of whom were studied more than once, yielding a total of 25 measurements. These data were compared to cellularity assessments derived from conventional bone marrow core biopsies obtained within a 24-h period before or after the NMR exam. The results obtained by the two methods are well correlated (R = 0.94, P less than 0.001), suggesting that this noninvasive technique may preclude the need for biopsies in some cases.

We have used in vivo 19F NMR spectroscopy to study the metabolism of 5-fluorouracil (FUra) in tumors with and without pretreatment with methotrexate (MTX). Using the CD8F1 murine mammary tumor as an in vivo model, we observed signals from FUra, alpha-fluoro-beta-alanine (F beta ALA), alpha-fluoro-beta-ureidopropionic acid (FUPA), and 5-fluorouracil-nucleotides (FUN) after intravenous or intraperitoneal injection of 150 mg/kg FUra. Formation of FUN was increased about 1.7-fold in CD8F1 tumor with methotrexate pretreatment as determined by acid extraction and HPLC analysis. A comparison of in vivo NMR spectra from FUra and sequential MTX + FUra-treated tumors showed a significantly higher ratio of the FUN signal to the initial total 19F signal in the MTX + FUra-treated tumors (p less than 0.001) for animals receiving FUra either intravenously or intraperitoneally. In addition, tumors treated with MTX + FUra had significantly longer time durations during which FUN was detected, independent of the mode of administration. These experiments indicate that in vivo 19F NMR spectroscopy can be used to noninvasively monitor alterations of 5-fluorouracil metabolism that occur with administration of modulating agents such as methotrexate. Further studies, in both murine tumor models and patients, are indicated to determine if these results can be correlated with tumor response.

We have used 31P NMR spectroscopy to study 22 patients with suspected sarcomas prior to any treatment. The spectra are characterized by the same peaks noted in murine tumors. The mean pH was 7.14 +/- 0.08 and PCr/Pi was 1.18 +/- 0.83. Comparison of pH and PCr/Pi ratios in human and a murine tumor with a low hypoxic cell fraction revealed no significant differences. Six patients subsequently received chemotherapy and three responded to therapy (based on pathologic examination and/or tumor reduction greater than 50%). The three responding patients were noted to have significantly lower PDE/PME in their pretreatment spectra than the three nonresponding patients. The three responding patients with sarcomas also showed a rise of greater than 100% in PDE/PME during the first cycle of therapy. Two of the responding patients had an increase of 0.37 pH units during this interval, which was not detected in the nonresponding patients. These data suggest that 31P NMR spectroscopy may be a useful prognostic indicator in conjunction with other clinical parameters.