Assessing Human Embryonic Stem Cell-Derived Dopaminergic Neuron Progenitor Transplants Using Non-invasive Imaging Techniques.

PURPOSE: Human pluripotent stem cell (hPSC)-derived dopaminergic neuron progenitor cells (DAPCs) are a potential therapy for Parkinson's disease (PD). However, their intracranial administration raises safety concerns including uncontrolled proliferation, migration and inflammation. Here, we apply a bimodal imaging approach to investigate the fate of DAPC transplants in the rat striatum. PROCEDURES: DAPCs co-expressing luciferase and ZsGreen or labelled with micron-sized particles of iron oxide (MPIOs) were transplanted in the striatum of RNU rats (n = 6 per group). DAPCs were tracked in vivo using bioluminescence and magnetic resonance (MR) imaging modalities. RESULTS: Transgene silencing in differentiating DAPCs accompanied with signal attenuation due to animal growth rendered the bioluminescence undetectable by week 2 post intrastriatal transplantation. However, MR imaging of MPIO-labelled DAPCs showed that transplanted cells remained at the site of injection for over 120 days. Post-mortem histological analysis of DAPC transplants demonstrated that labelling with either luciferase/ZsGreen or MPIOs did not affect the ability of cells to differentiate into mature dopaminergic neurons. Importantly, labelled cells did not elicit increased glial reactivity compared to non-labelled cells. CONCLUSIONS: In summary, our findings support the transplantation of hPSC-derived DAPCs as a safe treatment for PD.

Dynamic Contrast-Enhanced MRI-Derived Intracellular Water Lifetime (τ i ): A Prognostic Marker for Patients with Head and Neck Squamous Cell Carcinomas.

BACKGROUND AND PURPOSE: Shutter-speed model analysis of dynamic contrast-enhanced MR imaging allows estimation of mean intracellular water molecule lifetime (a measure of cellular energy metabolism) and volume transfer constant (a measure of hemodynamics). The purpose of this study was to investigate the prognostic utility of pretreatment mean intracellular water molecule lifetime and volume transfer constant in predicting overall survival in patients with squamous cell carcinomas of the head and neck and to stratify p16-positive patients based upon survival outcome. MATERIALS AND METHODS: A cohort of 60 patients underwent dynamic contrast-enhanced MR imaging before treatment. Median, mean intracellular water molecule lifetime and volume transfer constant values from metastatic nodes were computed from each patient. Kaplan-Meier analyses were performed to associate mean intracellular water molecule lifetime and volume transfer constant and their combination with overall survival for the first 2 years, 5 years, and beyond (median duration, >7 years). RESULTS: By the last date of observation, 18 patients had died, and median follow-up for surviving patients (n = 42) was 8.32 years. Patients with high mean intracellular water molecule lifetime (4 deaths) had significantly (P = .01) prolonged overall survival by 5 years compared with those with low mean intracellular water molecule lifetime (13 deaths). Similarly, patients with high mean intracellular water molecule lifetime (4 deaths) had significantly (P = .006) longer overall survival at long-term duration than those with low mean intracellular water molecule lifetime (14 deaths). However, volume transfer constant was a significant predictor for only the 5-year follow-up period. There was some evidence (P < .10) to suggest that mean intracellular water molecule lifetime and volume transfer constant were associated with overall survival for the first 2 years. Patients with high mean intracellular water molecule lifetime and high volume transfer constant were associated with significantly (P < .01) longer overall survival compared with other groups for all follow-up periods. In addition, p16-positive patients with high mean intracellular water molecule lifetime and high volume transfer constant demonstrated a trend toward the longest overall survival. CONCLUSIONS: A combined analysis of mean intracellular water molecule lifetime and volume transfer constant provided the best model to predict overall survival in patients with squamous cell carcinomas of the head and neck.

Differentiating Tumor Progression from Pseudoprogression in Patients with Glioblastomas Using Diffusion Tensor Imaging and Dynamic Susceptibility Contrast MRI.

BACKGROUND AND PURPOSE: Early assessment of treatment response is critical in patients with glioblastomas. A combination of DTI and DSC perfusion imaging parameters was evaluated to distinguish glioblastomas with true progression from mixed response and pseudoprogression. MATERIALS AND METHODS: Forty-one patients with glioblastomas exhibiting enhancing lesions within 6 months after completion of chemoradiation therapy were retrospectively studied. All patients underwent surgery after MR imaging and were histologically classified as having true progression (>75% tumor), mixed response (25%-75% tumor), or pseudoprogression (<25% tumor). Mean diffusivity, fractional anisotropy, linear anisotropy coefficient, planar anisotropy coefficient, spheric anisotropy coefficient, and maximum relative cerebral blood volume values were measured from the enhancing tissue. A multivariate logistic regression analysis was used to determine the best model for classification of true progression from mixed response or pseudoprogression. RESULTS: Significantly elevated maximum relative cerebral blood volume, fractional anisotropy, linear anisotropy coefficient, and planar anisotropy coefficient and decreased spheric anisotropy coefficient were observed in true progression compared with pseudoprogression (P < .05). There were also significant differences in maximum relative cerebral blood volume, fractional anisotropy, planar anisotropy coefficient, and spheric anisotropy coefficient measurements between mixed response and true progression groups. The best model to distinguish true progression from non-true progression (pseudoprogression and mixed) consisted of fractional anisotropy, linear anisotropy coefficient, and maximum relative cerebral blood volume, resulting in an area under the curve of 0.905. This model also differentiated true progression from mixed response with an area under the curve of 0.901. A combination of fractional anisotropy and maximum relative cerebral blood volume differentiated pseudoprogression from nonpseudoprogression (true progression and mixed) with an area under the curve of 0.807. CONCLUSIONS: DTI and DSC perfusion imaging can improve accuracy in assessing treatment response and may aid in individualized treatment of patients with glioblastomas.

Prognostic Value of Dynamic Susceptibility Contrast-Enhanced and Diffusion-Weighted MR Imaging in Patients with Glioblastomas.

BACKGROUND AND PURPOSE: Prediction of survival in patients with glioblastomas is important for individualized treatment planning. This study aimed to assess the prognostic utility of presurgical dynamic susceptibility contrast and diffusion-weighted imaging for overall survival in patients with glioblastoma. MATERIALS AND METHODS: MR imaging data from pathologically proved glioblastomas between June 2006 to December 2013 in 58 patients (mean age, 62.7 years; age range, 22-89 years) were included in this retrospective study. Patients were divided into long survival (≥15 months) and short survival (<15 months) groups, depending on overall survival time. Patients underwent dynamic susceptibility contrast perfusion and DWI before surgery and were treated with chemotherapy and radiation therapy. The maximum relative cerebral blood volume and minimum mean diffusivity values were measured from the enhancing part of the tumor. RESULTS: Maximum relative cerebral blood volume values in patients with short survival were significantly higher compared with those who demonstrated long survival (P < .05). No significant difference was observed in the minimum mean diffusivity between short and long survivors. Receiver operator curve analysis demonstrated that a maximum relative cerebral blood volume cutoff value of 5.79 differentiated patients with low and high survival with an area under the curve of 0.93, sensitivity of 0.89, and specificity of 0.90 (P < .001), while a minimum mean diffusivity cutoff value of 8.35 × 10(-4)mm(2)/s had an area under the curve of 0.55, sensitivity of 0.71, and specificity of 0.47 (P > .05) in separating the 2 groups. CONCLUSIONS: Maximum relative cerebral blood volume may be used as a prognostic marker of overall survival in patients with glioblastomas.

Diagnostic utility of diffusion tensor imaging in differentiating glioblastomas from brain metastases.

BACKGROUND AND PURPOSE: Differentiation of glioblastomas and solitary brain metastases is an important clinical problem because the treatment strategy can differ significantly. The purpose of this study was to investigate the potential added value of DTI metrics in differentiating glioblastomas from brain metastases. MATERIALS AND METHODS: One hundred twenty-eight patients with glioblastomas and 93 with brain metastases were retrospectively identified. Fractional anisotropy and mean diffusivity values were measured from the enhancing and peritumoral regions of the tumor. Two experienced neuroradiologists independently rated all cases by using conventional MR imaging and DTI. The diagnostic performances of the 2 raters and a DTI-based model were assessed individually and combined. RESULTS: The fractional anisotropy values from the enhancing region of glioblastomas were significantly higher than those of brain metastases (P < .01). There was no difference in mean diffusivity between the 2 tumor types. A classification model based on fractional anisotropy and mean diffusivity from the enhancing regions differentiated glioblastomas from brain metastases with an area under the receiver operating characteristic curve of 0.86, close to those obtained by 2 neuroradiologists using routine clinical images and DTI parameter maps (area under the curve = 0.90 and 0.85). The areas under the curve of the 2 radiologists were further improved to 0.96 and 0.93 by the addition of the DTI classification model. CONCLUSIONS: Classification models based on fractional anisotropy and mean diffusivity from the enhancing regions of the tumor can improve diagnostic performance in differentiating glioblastomas from brain metastases.

A Bayesian diagnostic system to differentiate glioblastomas from solitary brain metastases.

This paper aimed to construct a Bayesian network-based decision support system to differentiate glioblastomas from solitary metastases, based on multimodality MR examination. We enrolled 51 patients with solitary brain tumors (26 with glioblastomas and 25 with solitary brain metastases). These patients underwent contrast-enhanced T1-weighted magnetic resonance (MR) examination, diffusion tensor imaging (DTI), dynamic susceptibility contrast (DSC) MRI, and fluid-attenuated inversion recovery (FLAIR). We generated a set of MR biomarkers, including relative cerebral blood volume in the enhancing region, and fractional anisotropy measured in the immediate peritumoral area. We then generated a Bayesian network model to represent associations among these imaging-derived predictors, and the group membership variable, (glioblastoma or solitary metastasis). This Bayesian network can be used to classify new patients' tumors based on their MR appearance. The Bayesian network model accurately differentiated glioblastomas from solitary metastases. Prediction accuracy was 0.94 (sensitivity = 0.96, specificity = 0.92) based on leave-one-out cross-validation. The area under the receiver operating characteristic curve was 0.90. A Bayesian network-based decision support system accurately differentiates glioblastomas from solitary metastases, based on MR-derived biomarkers.

Differentiation between oligodendroglioma genotypes using dynamic susceptibility contrast perfusion-weighted imaging and proton MR spectroscopy.

BACKGROUND AND PURPOSE: Oligodendrogliomas with 1p/19q chromosome LOH are more sensitive to chemoradiation therapy than those with intact alleles. The usefulness of dynamic susceptibility contrast-PWI-guided ¹H-MRS in differentiating these 2 genotypes was tested in this study. MATERIALS AND METHODS: Forty patients with oligodendrogliomas, 1p/19q LOH (n = 23) and intact alleles (n = 17), underwent MR imaging and 2D-¹H-MRS. ¹H-MRS VOI was overlaid on FLAIR images to encompass the hyperintense abnormality on the largest cross-section of the neoplasm and then overlaid on CBV maps to coregister CBV maps with ¹H-MRS VOI. rCBVmax values were obtained by measuring the CBV from each of the selected ¹H-MRS voxels in the neoplasm and were normalized with respect to contralateral white matter. Metabolite ratios with respect to ipsilateral Cr were computed from the voxel corresponding to the rCBVmax value. Logistic regression and receiver operating characteristic analyses were performed to ascertain the best model to discriminate the 2 genotypes of oligodendrogliomas. Qualitative evaluation of conventional MR imaging characteristics (patterns of tumor border, signal intensity, contrast enhancement, and paramagnetic susceptibility effect) was also performed to distinguish the 2 groups of oligodendrogliomas. RESULTS: The incorporation of rCBVmax value and metabolite ratios (NAA/Cr, Cho/Cr, Glx/Cr, myo-inositol/Cr, and lipid + lactate/Cr) into the multivariate logistic regression model provided the best discriminatory classification with sensitivity (82.6%), specificity (64.7%), and accuracy (72%) in distinguishing 2 oligodendroglioma genotypes. Oligodendrogliomas with 1p/19q LOH were also more associated with paramagnetic susceptibility effect (P < .05). CONCLUSIONS: Our preliminary results indicate the potential of combing PWI and ¹H-MRS to distinguish oligodendroglial genotypes.

Magnetic Resonance Spectroscopy for Differentiating Pseudo-Progression from True Progression in GBM on Concurrent Chemoradiotherapy.

Neoadjuvant chemo-radiation therapy including temozolomide is commonly used for the treatment of gliomas. However, increased lesion size and contrast enhancement are frequently observed following this therapy and this appearance is termed as 'pseudo-progression'. Since conventional imaging is unable to differentiate pseudo-progression from tumour recurrence, we evaluated the utility of MR spectroscopy (MRS) to differentiate these two pathological entities. Longitudinal MRI and MRS studies prior to and within four months post chemo-radiation therapy including diffusion-weighted imaging and single voxel spectroscopy (short and intermediate echo) were performed in 62 glioblastoma (GBM) patients undergoing chemo-radiation therapy. Clinical follow-up demonstrated four cases of pseudo-progression. In this study, results from these four cases and a known case of tumour recurrence are reported. Metabolite ratios and presence or absence of lipids at 1.3 ppm were used to differentiate between pseudo-progression and tumour recurrence. All four cases of pseudo-progression demonstrated elevated lipid signals on MRS. Additionally, an absence of choline or a low choline/NAA ratio was also observed. In comparison, the patient with tumour recurrence showed lower lipid signals and a high choline/NAA ratio. The presence of elevated lipid signals along with low choline/NAA ratios can aid in differentiation of pseudo-progression from tumour recurrence.

Differentiation between glioblastomas, solitary brain metastases, and primary cerebral lymphomas using diffusion tensor and dynamic susceptibility contrast-enhanced MR imaging.

BACKGROUND AND PURPOSE: Glioblastomas, brain metastases, and PCLs may have similar enhancement patterns on MR imaging, making the differential diagnosis difficult or even impossible. The purpose of this study was to determine whether a combination of DTI and DSC can assist in the differentiation of glioblastomas, solitary brain metastases, and PCLs. MATERIALS AND METHODS: Twenty-six glioblastomas, 25 brain metastases, and 16 PCLs were retrospectively identified. DTI metrics, including FA, ADC, CL, CP, CS, and rCBV were measured from the enhancing, immediate peritumoral and distant peritumoral regions. A 2-level decision tree was designed, and a multivariate logistic regression analysis was used at each level to determine the best model for classification. RESULTS: From the enhancing region, significantly elevated FA, CL, and CP and decreased CS values were observed in glioblastomas compared with brain metastases and PCLs (P < .001), whereas ADC, rCBV, and rCBV(max) values of glioblastomas were significantly higher than those of PCLs (P < .01). The best model to distinguish glioblastomas from nonglioblastomas consisted of ADC, CS (or FA) from the enhancing region, and rCBV from the immediate peritumoral region, resulting in AUC = 0.938. The best predictor to differentiate PCLs from brain metastases comprised ADC from the enhancing region and CP from the immediate peritumoral region with AUC = 0.909. CONCLUSIONS: The combination of DTI metrics and rCBV measurement can help in the differentiation of glioblastomas from brain metastases and PCLs.

Prediction of disease-free survival in patients with squamous cell carcinomas of the head and neck using dynamic contrast-enhanced MR imaging.

BACKGROUND AND PURPOSE: Patients with HNSCC have a poor prognosis and development of imaging biomarkers that predict long-term outcome might aid in planning optimal treatment strategies. Therefore, the purpose of the present study was to predict disease-free survival in patients with HNSCC by using pretreatment K(trans) measured from dynamic contrast-enhanced MR imaging. MATERIALS AND METHODS: Sixty-six patients with HNSCC were recruited from January 2005 to October 2008. Three patients were excluded because they underwent upfront neck dissection, and 6 patients were excluded due to suboptimal MR imaging data or being lost to follow-up. Disease-free survival was measured in the remaining 57 patients from the end date of chemoradiation therapy. In patients who died, the end point was the date of death, while in surviving patients the date of last clinical follow-up was used as the end point. Pretreatment K(trans) and nodal volume were computed from the largest metastatic node, and median pretreatment K(trans) and volume were used to divide patients into 2 groups (at or above the threshold value [group I] and below the threshold value [group II]. Disease-free survival was analyzed by the Kaplan-Meier method, and the results were compared by using a logrank test with K(trans) and nodal volume as predictors. A P value <.05 was considered significant. RESULTS: Thirteen of 57 patients had died of HNSCC by the last follow-up period (March 31, 2009). Patients with higher pretreatment K(trans) values had prolonged disease-free survival compared with patients with lower K(trans) values (P=.029). However, there was no significant difference in disease-free survival when nodal volume was used as a predictor (P=.599). CONCLUSIONS: Pretreatment K(trans) may be a useful prognostic marker in HNSCC.

Prediction of response to chemoradiation therapy in squamous cell carcinomas of the head and neck using dynamic contrast-enhanced MR imaging.

BACKGROUND AND PURPOSE: Tumor microenvironment, including blood flow and permeability, may provide crucial information regarding response to chemoradiation therapy. Thus, the objective of this study was to investigate the efficacy of pretreatment DCE-MR imaging for prediction of response to chemoradiation therapy in HNSCC. MATERIALS AND METHODS: DCE-MR imaging studies were performed on 33 patients with newly diagnosed HNSCC before neoadjuvant chemoradiation therapy by using a 1.5T (n = 24) or a 3T (n = 9) magnet. The data were analyzed by using SSM for estimation of K(trans), v(e), and tau(i). Response to treatment was determined on completion of chemoradiation as CR, with no evidence of disease (clinically or pathologically), or PR, with pathologically proved residual tumor. RESULTS: The average pretreatment K(trans) value of the CR group (0.64 +/- 0.11 minutes(-1), n = 24) was significantly higher (P = .001) than that of the PR (0.21 +/- 0.05 minutes(-1), n = 9) group. No significant difference was found in other pharmacokinetic model parameters: v(e) and tau(i), between the 2 groups. Although the PR group had larger metastatic nodal volume than the CR group, it was not significantly different (P = .276). CONCLUSIONS: These results indicate that pretreatment DCE-MR imaging can be potentially used for prediction of response to chemoradiation therapy of HNSCC.

Apparent diffusion coefficient reveals gray and white matter disease, and T2 mapping detects white matter disease in the brain in feline alpha-mannosidosis.

BACKGROUND AND PURPOSE: Methods to locate and identify brain pathology are critical for monitoring disease progression and for evaluating the efficacy of therapeutic intervention. The purpose of this study was to detect cell swelling, abnormal myelin, and astrogliosis in the feline model of the lysosomal storage disease alpha-mannosidosis (AMD) by using diffusion and T2 mapping. MATERIALS AND METHODS: Average apparent diffusion coefficient (ADC(av)) and T2 were measured by imaging the brains of five 16-week-old cats with feline AMD on a 4.7T magnet. ADC(av) and T2 data from affected cats were compared with data from age-matched normal cats. Brains were collected from both affected and normal cats following imaging, and histology was compared with quantitative imaging data. RESULTS: Gray matter from AMD cats demonstrated a 13%-15% decrease in ADC(av) compared with that in normal cats. White matter from AMD cats exhibited an 11%-16% decrease in ADC(av) and a 5%-12% increase in T2 values compared with those in normal control cats. Histologic evidence of neuronal and glial swelling, abnormal myelin, and astrogliosis was consistent with changes in ADC(av) and T2. CONCLUSION: ADC(av) and T2 data can be used to quantify differences in the gray and white matter in the feline AMD brain and may serve as surrogate markers of neuronal swelling, abnormal myelin, and astrogliosis associated with this disease. These studies may be helpful in assessing the efficacy of experimental therapies for central nervous system disease associated with lysosomal storage diseases.

Arterial spin-labeling and MR spectroscopy in the differentiation of gliomas.

BACKGROUND AND PURPOSE: Noninvasive grading of gliomas remains a challenge despite its important role in the prognosis and management of patients with intracranial neoplasms. In this study, we evaluated the ability of cerebral blood flow (CBF)-guided voxel-by-voxel analysis of multivoxel proton MR spectroscopic imaging ((1)H-MRSI) to differentiate low-grade from high-grade gliomas. MATERIALS AND METHODS: A total of 35 patients with primary gliomas (22 high grade and 13 low grade) underwent continuous arterial spin-labeling perfusion-weighted imaging (PWI) and (1)H-MRSI. Different regions of the gliomas were categorized as "hypoperfused," "isoperfused," and "hyperperfused" on the basis of the average CBF obtained from contralateral healthy white matter. (1)H-MRSI indices were computed from these regions and compared between low- and high-grade gliomas. Using a similar approach, we applied a subgroup analysis to differentiate low- from high-grade oligodendrogliomas because they show different physiologic and genetic characteristics. RESULTS: Cho(glioma (G)/white matter (WM)), Glx(G/WM), and Lip+Lac(G)/Cr(WM) were significantly higher in the "hyperperfused" regions of high-grade gliomas compared with low-grade gliomas. Cho(G/WM) and Lip+Lac(G)/Cr(WM) were also significantly higher in the "hyperperfused" regions of high-grade oligodendrogliomas. However, metabolite ratios from the "hypoperfused" or "isoperfused" regions did not exhibit any significant differences between high-grade and low-grade gliomas. CONCLUSION: The results suggest that (1)H-MRSI indices from the "hyperperfused" regions of gliomas, on the basis of PWI, may be helpful in distinguishing high-grade from low-grade gliomas including oligodendrogliomas.

Magnetic resonance imaging as a tool for monitoring stem cell migration.

Noninvasive monitoring of stem cells is an important step in developing stem-cell-based therapies. Among several imaging techniques available, magnetic resonance imaging (MRI) provides an effective way to detect implanted stem cells in live animals. In this mini-review, we discuss the available MRI contrast agents and different cell-labeling strategies used for detection of stem cell migration in the brain. The potential effects of MRI contrast agents on stem cell viability and differentiation are also discussed.

Diffusion tensor imaging in amyotrophic lateral sclerosis: volumetric analysis of the corticospinal tract.

BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) allows direct visualization and volumetric analysis of the corticospinal tract (CST). The purpose of this study was to determine whether color maps and fiber tracking derived from DTI data are valuable in detecting and quantifying CST degeneration in patients with amyotrophic lateral sclerosis (ALS). METHODS: Sixteen patients with ALS with clinical signs of upper motor neuron (UMN) involvement and 17 healthy subjects were studied with the use of DTI. Disease severity was determined by means of the ALS Functional Rating Scale-Revised (ALSFRS-R) and an UMN involvement score. DTI was acquired with a 12-direction, single-shot, spin-echo echo-planar sequence. The CST from the lower pons to the corona radiata at the level of the corpus callosum on 4 contiguous coronal sections was manually segmented by using color maps generated from the DTI data. The left and right CST volumes were measured separately and normalized to the total intracranial volume. Normalized CST volumes were compared between patients with ALS and healthy subjects. RESULTS: The CST volumes of patients with ALS were significantly reduced (P < .01, unpaired t test) compared with healthy subjects, in both affected and nonaffected hemispheres. No significant correlation was found between CST volumes and any of the clinical parameters, including disease duration, ALSFRS-R, or UMN involvement score. CONCLUSION: This study shows that volumetric analysis by using DTI-based color maps is valuable in detecting and monitoring structural degeneration of the CST. This will lead to objective and quantitative assessment of axonal degeneration in ALS.

In vivo and ex vivo MRI detection of localized and disseminated neural stem cell grafts in the mouse brain.

The application of stem cells as delivery vehicles opens up the opportunity for targeting therapeutic proteins to the damaged or degenerating central nervous system. Neural stem cell (NSC) lines have been shown to engraft, differentiate and correct certain central nervous system diseases. The present study was performed to test the ability of magnetic resonance imaging (MRI) in detecting transplanted NSCs under conditions of limited migration in the normal adult mouse brain versus widespread migration when the cells are transplanted neonatally. The C17.2 NSC line was labeled in vitro with superparamagnetic iron oxide (SPIO) particles and the labeled cells were implanted intracranially. Serial in vivo gradient echo MR imaging was performed using a 4.7 T horizontal bore magnet. High resolution ex vivo images of the isolated brains were performed at 9.4 T, and the presence of iron was correlated with Prussian blue staining in histological sections. Adult animals injected with SPIO-labeled stem cells exhibited hypointense regions near the injection site that were observed up to 32 days after injection. In neonatally transplanted animals, MR signal intensity from transplanted NSCs was not apparent in in vivo imaging but ex vivo MR images revealed small hypointense regions throughout the brain including the olfactory bulbs, cortex and the cerebellum, reflecting the wide distribution of the engrafted cells. These regions were correlated with Prussian blue staining, which confirmed the presence of SPIO particles inside the engrafted cells. We have shown that MRI is capable of differentiating localized and widespread engraftment of C17.2 stem cells in the central nervous system.

Effects of hyperglycemia on oxygenation, radiosensitivity and bioenergetic status of subcutaneous RIF-1 tumors.

Since tissue oxygen tension is a balance between delivery and consumption of oxygen, considerable effort has been directed at increasing the former and/or decreasing the latter. Techniques to decrease the rate of cellular oxygen consumption (increasing the distance oxygen can diffuse into tissues) include increasing glycolysis by administering supra-physiologic levels of glucose. We have examined the effect of hyperglycemia produced by intravenous glucose infusion on the tissue oxygenation and radiation response of subcutaneously implanted murine radiation induced fibrosarcomas (RIF-1). A 0.3 M glucose solution was delivered via tail vein injection according to a protocol that maintained glucose at a plasma concentration of 17+/-1 mM. The effect of this treatment on radiation response (clonogenic and growth delay studies), tumor oxygenation (needle electrode pO2 and 2-[2-nitro-1H-imidazol-1-yl]-N-(2,2,3,3,3-pentafluoropropyl) acetamide (EF5) binding), and tumor bioenergetics and pH (31P NMR spectroscopy) was examined. Systemic measurements included hematocrit and blood glucose and lactate concentrations. The results of these studies suggest that these subcutaneously implanted RIF-1 tumors are both radiobiologically and metabolically hypoxic and that intravenous glucose infusion is not an effective method of modifying this metabolic state.

Non-invasive magnetic resonance thermometry using thulium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (TmDOTA(-)).

Non-invasive thermometry is pivotal to the future advances of regional hyperthermia as a cancer treatment modality. Current magnetic resonance (MR) thermometry methods suffer from poor thermal resolution due to relatively weak dependence of chemical shift of the (1)H water signal on temperature. This study evaluated the feasibility of using thulium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (TmDOTA(-)) for MR thermometry. TmDOTA(-) is non-toxic and the gadolinium complex of DOTA(4-) is widely used as a MR contrast agent. The results demonstrate that the temperature dependence of the TmDOTA(-) proton shifts are about two orders of magnitudes higher than the water proton and, thus, provide excellent accuracy and resolution. In addition, TmDOTA(-) proton shifts are insensitive to the paramagnetic complex concentration, pH, Ca(2+) or presence of plasma macromolecules and ions. Because hyperthermia is known to produce changes in tissue pH and other physiological parameters, these properties of TmDOTA(-) greatly simplify the procedures for using the lanthanide complex for MR thermometry. Application of TmDOTA(-) for measurement of temperature in a subcutaneously implanted human melanoma xenograft is demonstrated. Finally, the feasibility of imaging one of the (1)H resonances of the lanthanide complex is demonstrated in phantom experiments. Overall, TmDOTA(-) appears to be a promising probe for MR thermometry in vivo.

Quantitative T1rho magnetic resonance imaging of RIF-1 tumors in vivo: detection of early response to cyclophosphamide therapy.

This study compares two potential magnetic resonance imaging (MRI) indices for noninvasive early detection of tumor response to chemotherapy: the spin-lattice relaxation in the rotating frame (T1rho) and the transverse relaxation time (T2). Measurements of these relaxation parameters were performed on a s.c. murine radiation-induced fibrosarcoma (RIF-1) model before and after cyclophosphamide treatment. The number of pixels exhibiting T1rho values longer than controls in viable regions of the tumor increased significantly as early as 18 h after drug administration and remained elevated up to 36 h after treatment (P < 0.005). Although a trend of increasing T2s relative to controls was noted in viable regions of the tumor 36 h after treatment, the changes were not statistically significant. Histological examination indicated a decrease in mitotic index that paralleled the changes in T1rho. We conclude that T1rho measurements may be useful for noninvasive monitoring of early response of tumors to chemotherapy.

Effects of chemotherapy by 1,3-bis(2-chloroethyl)-1-nitrosourea on single-quantum- and triple-quantum-filtered 23Na and 31P nuclear magnetic resonance of the subcutaneously implanted 9L glioma.

The effects of chemotherapy [25 mg/kg 1,3-bis(2-chloroethyl)-1-nitrosourea administered with a single i.p. injection] on cellular energetics by 31P nuclear magnetic resonance (NMR) spectroscopy, total tissue sodium by single-quantum (SQ) 23Na NMR spectroscopy, and intracellular sodium by triple-quantum-filtered (TQF) 23Na NMR spectroscopy were studied in the s.c. 9L glioma. Animals were studied by NMR 2 days before therapy and 1 and 5 days after therapy. Destructive chemical analysis was also performed 5 days after therapy to validate the origin of changes in SQ and TQF 23Na signals. One day after treatment, there was no significant difference between control and treated tumors in terms of tumor size or 23Na and 31P spectral data. Five days after therapy, treated tumors had 28 +/- 16% (P < 0.1) lower SQ 23Na signal intensity, 46 +/- 20% (P < 0.05) lower TQF 23Na signal intensity, 125 +/- 51% (P < 0.05) higher ATP:Pi ratio, 186 +/- 69% (P < 0.05) higher phosphocreatine:Pi ratio, and 0.17 +/- 0.06 pH units (P < 0.05) higher intracellular pH compared with control tumors. No significant differences in TQF 23Na relaxation times were seen between control and treated tumors at any time point. Destructive chemical analysis showed that the relative extracellular space of control and treated tumors was identical, but the treated tumors had 21 +/- 8% (P < 0.05) lower total tissue Na+ concentration and 60 +/- 24% (P < 0.05) lower intracellular Na+ concentration compared with the controls. The higher phosphocreatine:Pi and ATP:Pi ratios after 1,3-bis(2-chloroethyl)-1-nitrosourea treatment indicate improved bioenergetic status in the surviving tumor cells. The decrease in SQ and multiple-quantum-filtered 23Na signal intensity was largely attributable to a decrease in Na(i)+ because the treatment did not change the relative extracellular space. The improved energy metabolism could decrease the intracellular concentration of Na+ by increasing the activity of Na+-K+-ATPase and decreasing the activity of Na+/H+. Although both 23Na and 31P spectra were consistent with improved cellular metabolism in treated tumors, the 23Na methods may be better suited for monitoring response to therapy because of higher signal:noise ratio and ease of imaging the single 23Na resonance.