75 results on '"Evelhoch, J. L."'
Search Results
2. Effect of Bicarbonate and Inhibitors on the 113Cadmium NMR Signals in Zinc-Replaced Human Carbonic Anhydrase
- Author
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Sudmeier, J. L., primary, Evelhoch, J. L., additional, and Carlsson, U., additional
- Published
- 1979
- Full Text
- View/download PDF
3. Proton magnetic resonance spectroscopy in patients with glial tumors : a multicenter study
- Author
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Negendank, W. G., Sauter, R., Brown, T. R., Evelhoch, J. L., Falini, A., Gotsis, E. D., Heerschap, A., Kamada, K., Lee, B. C. P., Mengeot, M. M., Ewald Moser, Padavic-Shaller, K. A., Sanders, J. A., Spraggins, T. A., Stillman, A. E., Terwey, B., Vogl, T. J., Wicklow, K., and Zimmerman, R. A.
- Subjects
GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries) - Abstract
Contains fulltext : 22812___.PDF (Publisher’s version ) (Open Access)
- Published
- 1996
4. The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations
- Author
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Leach, M O, primary, Brindle, K M, additional, Evelhoch, J L, additional, Griffiths, J R, additional, Horsman, M R, additional, Jackson, A, additional, Jayson, G C, additional, Judson, I R, additional, Knopp, M V, additional, Maxwell, R J, additional, McIntyre, D, additional, Padhani, A R, additional, Price, P, additional, Rathbone, R, additional, Rustin, G J, additional, Tofts, P S, additional, Tozer, G M, additional, Vennart, W, additional, Waterton, J C, additional, Williams, S R, additional, and Workman, P, additional
- Published
- 2005
- Full Text
- View/download PDF
5. Therapeutic efficacy as predicted by quantitative assessment of murine RIF-1 tumour pH and phosphorous metabolite response during hyperthermia: anin vivo31P NMR study
- Author
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Bezabeh, T., primary, Evelhoch, J. L., additional, Thompson, P., additional, Sloop, D. J., additional, and Ackerman, J. J. H., additional
- Published
- 2004
- Full Text
- View/download PDF
6. Assessment of antiangiogenic and antivascular therapeutics using MRI: recommendations for appropriate methodology for clinical trials
- Author
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Leach, M O, primary, Brindle, K M, additional, Evelhoch, J L, additional, Griffiths, J R, additional, Horsman, M R, additional, Jackson, A, additional, Jayson, G, additional, Judson, I R, additional, Knopp, M V, additional, Maxwell, R J, additional, McIntyre, D, additional, Padhani, A R, additional, Price, P, additional, Rathbone, R, additional, Rustin, G, additional, Tofts, P S, additional, Tozer, G M, additional, Vennart, W, additional, Waterton, J C, additional, Williams, S R, additional, and Workman, P, additional
- Published
- 2003
- Full Text
- View/download PDF
7. Pulse waveform analysis of arterial compliance: relation to other techniques, age, and metabolic variables
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Resnick, L. M., primary, Militianu, D., additional, Cunnings, A. J., additional, Pipe, J. G., additional, Evelhoch, J. L., additional, Soulen, R. L., additional, and Lester, M. A., additional
- Published
- 2000
- Full Text
- View/download PDF
8. Proceedings of a National Cancer Institute workshop: MR spectroscopy and tumor cell biology.
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Negendank, W G, primary, Brown, T R, additional, Evelhoch, J L, additional, Griffiths, J R, additional, Liotta, L A, additional, Margulis, A R, additional, Morrisett, J D, additional, Ross, B D, additional, and Shtern, F, additional
- Published
- 1992
- Full Text
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9. In vivo 31P MR spectral patterns and reproducibility in cancer patients studied in a multi-institutional trial.
- Author
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Arias-Mendoza, F., Payne, G. S., Zakian, K. L., Schwarz, A. J., Stubbs, M., Stoyanova, R., Ballon, D., Howe, F. A., Koutcher, J. A., Leach, M. O., Griffiths, J. R., Heerschap, A., Glickson, J. D., Nelson, S. J., Evelhoch, J. L., Charles, H. C., and Brown, T. R.
- Abstract
The standardization and reproducibility of techniques required to acquire anatomically localized
31 P MR spectra non-invasively while studying tumors in cancer patients in a multi-institutional group at 1.5 T are reported. This initial group of patients was studied from 1995 to 2000 to test the feasibility of acquiring in vivo localized31 P MRS in clinical MR spectrometers. The cancers tested were non-Hodgkin's lymphomas, sarcomas of soft tissue and bone, breast carcinomas and head and neck carcinomas. The best accrual and spectral quality were achieved with the non-Hodgkin's lymphomas. The initial analysis of the spectral values of the sum of phosphoethanolamine plus phosphocholine normalized by the content of nucleotide triphosphates in a homogeneous sample of 32 NHL patients studied by in vivo31 P MRS showed good reproducibility among different institutions. No statistical differences were found between the institution with the largest number of cases accrued and the rest of the multi-institutional NHL data (2.28 ± 0.64, mean ± standard error; n = 17, vs 2.08 ± 0.14, n = 15). The preliminary data reported demonstrate that the institutions involved in this trial are obtaining reproducible31 P MR spectroscopic data non-invasively from human tumors. This is a fundamental prerequisite for the international cooperative group to be able to demonstrate the clinical value of the normalized determination of phosphoethanolamine plus phosphocholine by31 P MRS as predictor for treatment response in cancer patients. Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]- Published
- 2006
- Full Text
- View/download PDF
10. Methodological standardization for a multi-institutional in vivo trial of localized 31P MR spectroscopy in human cancer research. In vitro and normal volunteer studies.
- Author
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Arias-Mendoza, F., Zakian, K., Schwartz, A., Howe, F. A., Koutcher, J. A., Leach, M. O., Griffiths, J. R., Heerschap, A., Glickson, J. D., Nelson, S. J., Evelhoch, J. L., Charles, H. C., and Brown, T. R.
- Abstract
A multi-institutional group has been created to demonstrate the utility of in vivo
31 P magnetic resonance spectroscopy (31 P-MRS) to study human cancers in vivo. This review is concerned with the novel problems concerning quality control in this large multinational trial of31 P MRS. Our results show that the careful and systematic performance of the quality control tests depicted here (standardized dual1 H/31 P tuned radiofrequency probe, quality control procedures, routine use of1 H irradiation while acquiring31 P MR signals) has ensured comparable results between the different institutions. In studies made in vitro, the root-mean-square error was 3.6 %, and in muscle of healthy volunteers in vivo the coefficients of variance for the ratios phosphocreatine/nucleotide-triphosphates, phosphocreatine/noise and nucleotide-triphosphate/noise were 12.2, 7.0 and 10.8 %, respectively. The standardization of the acquisition protocol for in vivo-localized31 P MR spectroscopy across the different institutions has resulted in comparable in vivo data, decreasing the possible problems related to a research study carried out under a multi-institutional setting. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]- Published
- 2004
- Full Text
- View/download PDF
11. Methodology for applied 4 MHz RF hyperthermia concomitant with 31 P NMR spectroscopic monitoring of murine tumours.
- Author
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Bezabeh, T., Evelhoch, J. L., Sloop, D. J., and Ackerman, J. J. H.
- Subjects
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METABOLITES , *MAGNETIC resonance imaging , *TUMORS , *CELL death , *METABOLISM , *DRUG therapy , *RADIOTHERAPY - Abstract
It has been generally found that solid tumours in vivo are more susceptible to destruction by heat than normal tissues. Hyperthermia has, thus, been employed in the treatment of cancer either applied alone or in combination with other modalities such as chemotherapy and radiotherapy. However, the critical mechanism(s) by which heat sensitizes and kills cells in the solid tumour remains poorly defined. Magnetic resonance spectroscopic monitoring of tumour metabolism during application of hyperthermia may provide important insight into the response to hyperthermic challenge. The implementation of dual antenna-coil methodology that provides for NMR spectroscopic monitoring (31P at 121 MHz) concomitant with applied 4 MHz RF hyperthermia in murine tumours is described herein, in some detail. This technology, which does not require advanced (and expensive) magnetic resonance imaging systems, should be readily adaptable by other laboratories with an interest in murine tumour models. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
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12. Therapeutic efficacy as predicted by quantitative assessment of murine RIF-1 tumour pH and phosphorous metabolite response during hyperthermia: an in vivo 31 P NMR study.
- Author
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Bezabeh, T., Evelhoch, J. L., Thompson, P., Sloop, D. J., and Ackerman, J. J. H.
- Subjects
- *
THERAPEUTICS , *TUMORS , *HYDROGEN-ion concentration , *PHOSPHORUS , *FEVER , *BAYESIAN analysis , *CANCER - Abstract
Described herein are the initial findings from an 'in-magnet' 31 P NMR compatible hyperthermia system capable of concurrently heating and monitoring the metabolic response of murine tumours; the murine radiation induced fibrosarcoma (RIF-1) was employed for these studies. At thermal doses sufficient to raise tumour temperature to 41.5 and 43°C for a period of 30 min, a marked and rapid decrease in nucleoside triphosphate concentration and in pH was observed during the heating period, while inorganic phosphate concentration increased significantly but more gradually. These 31 P NMR determined metabolic indices remained depressed/elevated throughout a 1.5 h post-hyperthermia monitoring period. Importantly, these metabolic indices correlated significantly with specific growth delay. This suggests a possible role for NMR spectroscopy in early assessment, and perhaps control, of therapeutic response to hyperthermia. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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13. MR imaging of tumor microcirculation: promise for the new millennium.
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Taylor, June S., Tofts, Paul S., Port, Ruediger, Evelhoch, Jeffrey L., Knopp, Michael, Reddick, Wilburn E., Runge, Val M., Mayr, Nina, Taylor, J S, Tofts, P S, Port, R, Evelhoch, J L, Knopp, M, Reddick, W E, Runge, V M, and Mayr, N
- Published
- 1999
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14. Estimating kinetic parameters from dynamic contrast-enhanced T(1)-weighted MRI of a diffusable tracer: standardized quantities and symbols.
- Author
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Tofts, Paul S., Brix, Gunnar, Buckley, David L., Evelhoch, Jeffrey L., Henderson, Elizabeth, Knopp, Michael V., Larsson, Henrik B.W., Lee, Ting-Yim, Mayr, Nina A., Parker, Geoffrey J.M., Port, Ruediger E., Taylor, June, Weisskoff, Robert M., Tofts, P S, Brix, G, Buckley, D L, Evelhoch, J L, Henderson, E, Knopp, M V, and Larsson, H B
- Published
- 1999
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15. Key factors in the acquisition of contrast kinetic data for oncology.
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Evelhoch, Jeffrey L. and Evelhoch, J L
- Published
- 1999
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16. Size Dependence of Regional Blood Flow in Murine Tumours Using Deuterium Magnetic Resonance Imaging.
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Larcombe-McDouall, J. B., Mattiello, J., McCoy, C. L., Simpson, N. E., Seyedsadr, M., and Evelhoch, J. L.
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- 1991
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17. Early detection of treatment response by diffusion-weighted 1H-NMR spectroscopy in a murine tumour in vivo.
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Zhao, M, Pipe, JG, Bonnett, J, Evelhoch, JL, Pipe, J G, and Evelhoch, J L
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- 1996
- Full Text
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18. In vivo metabolic effects of hyperglycemia in murine radiation-induced fibrosarcoma: a 31P NMR investigation.
- Author
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Evelhoch, J L, Sapareto, S A, Jick, D E, and Ackerman, J J
- Abstract
The hyperglycemia-induced in vivo metabolic changes produced in subcutaneous murine RIF-1 tumors, grown on female C3H/Anf mice, were examined with 31P surface-coil NMR. Serum glucose levels were elevated 4-fold by bolus intraperitoneal injection of 0.3 ml of an aqueous 50% glucose solution. Tumor pH was calculated from the chemical shift of Pi and relative phosphocreatine and ATP concentrations were determined by Simpson's rule integration of the peak areas. Tumor pH decreased by ca. 0.45 unit over 2 hr while phosphocreatine concentrations decreased by ca. 50% over the same time period (n = 9). Initial tumor pH correlated inversely with the initial peak intensity ratio of Pi:ATP (r = -0.77). In a significant number of tumors (n = 4), two pH populations were observed. In these tumors, one population was unaffected by hyperglycemia and the other showed a decrease in pH. In the other tumors (n = 5), the pH distribution broadened as the pH decreased. In these tumors, the observed decreased in phosphocreatine concentration correlated with that calculated from the effect of measured tumor pH on the intracellular creatine kinase equilibrium (n = 18, r = 0.91). This correlation and consideration of the Pi distribution in the tumor suggest that the pH measured by 31P NMR is weighted heavily by intracellular pH for the RIF-1 tumor. The presence of two distinct tumor pH populations or a broadened pH distribution likely reflects variations in tumor microcellular environment. Control experiments showed negligible changes in tumor pH and high energy phosphate concentrations after bolus intraperitoneal injection of 0.3 ml of isotonic saline. In addition, negligible changes in leg muscle pH and high energy phosphate concentrations were observed after glucose injection into mice with or without tumors. These results indicate that hyperglycemia induced by intraperitoneal glucose injection is effective in lowering the tumor pH of the murine RIF-1 tumor.
- Published
- 1984
- Full Text
- View/download PDF
19. Cadmium-113 NMR of carbonic anhydrases: effect of pH, bicarbonate, and cyanide.
- Author
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Jonsson, N B, Tibell, L A, Evelhoch, J L, Bell, S J, and Sudmeier, J L
- Abstract
113Cd-Substituted human and bovine erythrocyte carbonic anhydrases have been studied by 113Cd NMR as a function of pH and bicarbonate concentration. Plots of chemical shift versus pH give sigmoidal titration curves in the pH range of the study, 6.9 to 10.5. The pKa values vary from 9.2 to 9.7, which correlates well with available activity profiles for the Cd-enzymes. Because the samples contain no buffers and no anions other than hydroxide, the results point to the existence of high and low pH forms of the enzymes in rapid exchange and differing in inner sphere coordination. When bicarbonate is added to the samples, upfield shifts are produced which eventually level off. Only a single CN- binds to the metal for all three enzymes. These observations are best explained by a rapid exchange among three species in which the open coordination site of the metal ion is occupied by hydroxide, water, or bicarbonate, as in the scheme: E--OH- in equilibrium or formed from E--H2O in equilibrium or formed from E--HCO-3.
- Published
- 1980
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- View/download PDF
20. An Examination of the Specificity of in Vivo 31P MRS Adriamycin Response Markers.
- Author
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EVELHOCH, J. L., KELLER, N. A., and CORBETT, T. H.
- Published
- 1987
- Full Text
- View/download PDF
21. Assessment of anti-angiogenic and anti-vascular therapeutics using magnetic resonance imaging: Recommendations for appropriate methodology for clinical Trials
- Author
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Leach, M. O., Brindle, K. M., Evelhoch, J. L., Griffiths, J. R., Horseman, M., Jackson, A., Gordon Jayson, Judson, I. R., Knopp, M. V., Maxwell, R. J., Mcintyre, D., Padhani, A., Price, P., Rathbone, R., Rustin, G., Tofts, P., Tozer, G. M., Vennart, W., Waterton, J. C., Williams, S. R., and Workman, P.
22. Bone and soft-tissue lesions: diagnosis with combined H-1 MR imaging and P-31 MR spectroscopy.
- Author
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Negendank, W G, primary, Crowley, M G, additional, Ryan, J R, additional, Keller, N A, additional, and Evelhoch, J L, additional
- Published
- 1989
- Full Text
- View/download PDF
23. An Examination of the Specificity of in Vivo 31P MRS Adriamycin Response Markers
- Author
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EVELHOCH, J. L., primary, KELLER, N. A., additional, and CORBETT, T. H., additional
- Published
- 1987
- Full Text
- View/download PDF
24. In vivo 31P MR spectral patterns and reproducibility in cancer patients studied in a multi-institutional trial.
- Author
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Arias-Mendoza F, Payne GS, Zakian KL, Schwarz AJ, Stubbs M, Stoyanova R, Ballon D, Howe FA, Koutcher JA, Leach MO, Griffiths JR, Heerschap A, Glickson JD, Nelson SJ, Evelhoch JL, Charles HC, and Brown TR
- Subjects
- Humans, Phosphorus, Reproducibility of Results, Sensitivity and Specificity, United States, Biomarkers, Tumor analysis, Diagnosis, Computer-Assisted methods, Magnetic Resonance Spectroscopy methods, Neoplasms diagnosis, Neoplasms metabolism, Phosphorus Compounds analysis
- Abstract
The standardization and reproducibility of techniques required to acquire anatomically localized 31P MR spectra non-invasively while studying tumors in cancer patients in a multi-institutional group at 1.5 T are reported. This initial group of patients was studied from 1995 to 2000 to test the feasibility of acquiring in vivo localized 31P MRS in clinical MR spectrometers. The cancers tested were non-Hodgkin's lymphomas, sarcomas of soft tissue and bone, breast carcinomas and head and neck carcinomas. The best accrual and spectral quality were achieved with the non-Hodgkin's lymphomas. The initial analysis of the spectral values of the sum of phosphoethanolamine plus phosphocholine normalized by the content of nucleotide triphosphates in a homogeneous sample of 32 NHL patients studied by in vivo (31)P MRS showed good reproducibility among different institutions. No statistical differences were found between the institution with the largest number of cases accrued and the rest of the multi-institutional NHL data (2.28 +/- 0.64, mean +/- standard error; n = 17, vs 2.08 +/- 0.14, n = 15). The preliminary data reported demonstrate that the institutions involved in this trial are obtaining reproducible 31P MR spectroscopic data non-invasively from human tumors. This is a fundamental prerequisite for the international cooperative group to be able to demonstrate the clinical value of the normalized determination of phosphoethanolamine plus phosphocholine by 31P MRS as predictor for treatment response in cancer patients., (Copyright 2006 John Wiley & Sons, Ltd.)
- Published
- 2006
- Full Text
- View/download PDF
25. Methodological standardization for a multi-institutional in vivo trial of localized 31P MR spectroscopy in human cancer research. In vitro and normal volunteer studies.
- Author
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Arias-Mendoza F, Zakian K, Schwartz A, Howe FA, Koutcher JA, Leach MO, Griffiths JR, Heerschap A, Glickson JD, Nelson SJ, Evelhoch JL, Charles HC, and Brown TR
- Subjects
- Ethanolamines analysis, Humans, Internationality, Phosphorus Isotopes, Phosphorylcholine analysis, Quality Assurance, Health Care methods, Quality Assurance, Health Care standards, Reference Standards, Reproducibility of Results, Research standards, Research Design, Sensitivity and Specificity, Biomarkers, Tumor analysis, Magnetic Resonance Spectroscopy methods, Magnetic Resonance Spectroscopy standards, Multicenter Studies as Topic methods, Multicenter Studies as Topic standards, Muscle, Skeletal metabolism, Neoplasms diagnosis, Neoplasms metabolism
- Abstract
A multi-institutional group has been created to demonstrate the utility of in vivo 31P magnetic resonance spectroscopy (31P-MRS) to study human cancers in vivo. This review is concerned with the novel problems concerning quality control in this large multinational trial of 31P MRS. Our results show that the careful and systematic performance of the quality control tests depicted here (standardized dual 1H/31P tuned radiofrequency probe, quality control procedures, routine use of 1H irradiation while acquiring 31P MR signals) has ensured comparable results between the different institutions. In studies made in vitro, the root-mean-square error was 3.6 %, and in muscle of healthy volunteers in vivo the coefficients of variance for the ratios phosphocreatine/nucleotide-triphosphates, phosphocreatine/noise and nucleotide-triphosphate/noise were 12.2, 7.0 and 10.8 %, respectively. The standardization of the acquisition protocol for in vivo-localized 31P MR spectroscopy across the different institutions has resulted in comparable in vivo data, decreasing the possible problems related to a research study carried out under a multi-institutional setting., (Copyright (c) 2004 John Wiley & Sons, Ltd.)
- Published
- 2004
- Full Text
- View/download PDF
26. pH and therapy of human cancers.
- Author
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Evelhoch JL
- Subjects
- Humans, Magnetic Resonance Spectroscopy, Neoplasms diagnostic imaging, Neoplasms metabolism, Tomography, Emission-Computed, Hydrogen-Ion Concentration, Neoplasms therapy
- Abstract
Studies in model systems have demonstrated that tumour pH can be a determinant of treatment response. The potential that tumour pH differs from that of normal tissues may provide a basis for selective killing of tumour cells. Although the data are limited, pH measurements in humans indicate a difference between tumour and normal tissues. In general, electrode pH (generally considered to reflect primarily extracellular pH, pHe) is lower in tumour than normal tissue. However, pH measured by magnetic resonance spectroscopy (MRS) or positron emission tomography (PET; both are generally considered to reflect primarily intracellular pH, pHi) is equal to or slightly higher in tumours than normal tissues. Hence, not only may pHe and pHi differ between normal and malignant tissues, but the pH gradient (which determines the distribution of chemotherapeutic agents that are weak acids or bases) is also reduced or reversed in tumours. To date, the majority of treatment-related studies conducted have focused on hyperthermia (combined with radiotherapy) due to the recognized importance of acidic pH as a thermal sensitizer. However, the results have been somewhat surprising: patients with a better response to hyperthermia radiotherapy have higher pH (as measured by electrode or 31P MRS) prior to treatment.
- Published
- 2001
- Full Text
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27. Magnetic resonance imaging to measure therapeutic response using an orthotopic model of human pancreatic cancer.
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He Z, Evelhoch JL, Mohammad RM, Adsay NV, Pettit GR, Vaitkevicius VK, and Sarkar FH
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- Adenocarcinoma pathology, Animals, Female, Humans, Magnetic Resonance Imaging methods, Mice, Mice, SCID, Pancreas pathology, Pancreatic Neoplasms pathology, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Adenocarcinoma drug therapy, Antineoplastic Agents therapeutic use, Oligopeptides therapeutic use, Pancreatic Neoplasms drug therapy
- Abstract
Pancreatic cancer is one of the most incurable and lethal human cancers in the United States. To facilitate development of novel therapeutic agents, we previously established an orthotopic pancreatic tumor model that closely mimics the natural biological behavior of human pancreatic cancer. In this study, magnetic resonance imaging (MRI) techniques were developed to detect tumor formation noninvasively and monitor serially tumor growth kinetics in this orthotopic model used for experimental drug testing. By using an optimized T2-weighted imaging method, we were able to distinguish human pancreas cancer from normal mouse pancreas. Orthotopic tumor formation was detected as early as day 1 after tumor cell implantation with a tumor volume as small as 12 mm3. Mice with evidence of tumor were separated into four treatment groups: control, auristatin-PE, gemcitabine, and their combination. After treatment, the mice were imaged at least three times before termination of the experiment. Comparison between MRI tumor volume measurements and tumor weights made at biopsy resulted in a correlation coefficient of 0.98. The tumor growth curves constructed from serial magnetic resonance imaging (MRI) measurements clearly showed tumor growth inhibition in treated mice compared with the control group. As expected, the group treated with the combination had the highest response rate compared with either auristatin-PE or gemcitabine alone, and the data were statistically highly significant (p < 0.004). From these results, we conclude that noninvasive MRI can be used to monitor serially therapeutic response in this orthotopic human pancreatic tumor model and can be used in the future to evaluate novel antitumor agents before human studies.
- Published
- 2000
- Full Text
- View/download PDF
28. Applications of magnetic resonance in model systems: cancer therapeutics.
- Author
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Evelhoch JL, Gillies RJ, Karczmar GS, Koutcher JA, Maxwell RJ, Nalcioglu O, Raghunand N, Ronen SM, Ross BD, and Swartz HM
- Subjects
- Animals, Apoptosis, Humans, Neoplasms drug therapy, Time Factors, Magnetic Resonance Imaging methods, Neoplasms diagnosis, Neoplasms pathology
- Abstract
The lack of information regarding the metabolism and pathophysiology of individual tumors limits, in part, both the development of new anti-cancer therapies and the optimal implementation of currently available treatments. Magnetic resonance [MR, including magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and electron paramagnetic resonance (EPR)] provides a powerful tool to assess many aspects of tumor metabolism and pathophysiology. Moreover, since this information can be obtained nondestructively, pre-clinical results from cellular or animal models are often easily translated into the clinic. This review presents selected examples of how MR has been used to identify metabolic changes associated with apoptosis, detect therapeutic response prior to a change in tumor volume, optimize the combination of metabolic inhibitors with chemotherapy and/or radiation, characterize and exploit the influence of tumor pH on the effectiveness of chemotherapy, characterize tumor reoxygenation and the effects of modifiers of tumor oxygenation in individual tumors, image transgene expression and assess the efficacy of gene therapy. These examples provide an overview of several of the areas in which cellular and animal model studies using MR have contributed to our understanding of the effects of treatment on tumor metabolism and pathophysiology and the importance of tumor metabolism and pathophysiology as determinants of therapeutic response.
- Published
- 2000
- Full Text
- View/download PDF
29. Deuterium NMR tissue perfusion measurements using the tracer uptake approach: II. Comparison with microspheres in tumors.
- Author
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Simpson NE and Evelhoch JL
- Subjects
- Anesthesia, Inhalation, Animals, Deuterium, Fluorescent Dyes, Linear Models, Male, Microspheres, Neoplasm Transplantation, Rats, Rats, Inbred F344, Regional Blood Flow, Tumor Cells, Cultured, Gliosarcoma blood supply, Magnetic Resonance Spectroscopy methods
- Abstract
Whole-volume tumor perfusion measured using nuclear magnetic resonance (NMR) observation of deuterated water uptake after intravenous injection and a common arterial input function (AIF) derived from AIF estimates in a small set of animals was compared with perfusion measured by the commonly used microsphere method in rat 9L gliosarcomas. Tumor perfusion estimated with this optimized NMR technique using an appropriate common AIF (i.e., taking into account the duration of anesthesia) correlates highly (n = 13, P = 0. 001) with that measured by the microsphere method, yielding no significant differences (P = 0.5, paired Student's t-test). Thus, the optimized NMR method can be used for repeatable, non-invasive, and quantitative measurements of tumor perfusion. Magn Reson Med 42:240-247, 1999., (Copyright 1999 Wiley-Liss, Inc.)
- Published
- 1999
- Full Text
- View/download PDF
30. Deuterium NMR tissue perfusion measurements using the tracer uptake approach: I. Optimization of methods.
- Author
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Simpson NE, He Z, and Evelhoch JL
- Subjects
- Animals, Artifacts, Computer Simulation, Male, Microcirculation physiology, Rats, Rats, Inbred F344, Sensitivity and Specificity, Deuterium, Magnetic Resonance Spectroscopy, Regional Blood Flow physiology
- Abstract
This paper considers potential problems encountered when using the Kety approach to measure perfusion in small laboratory animals with nuclear magnetic resonance (NMR) tracer uptake methods: a) the need to measure the arterial input function (AIF) in each animal; b) sensitivity to perfusion heterogeneity; c) sensitivity to low signal-to-noise ratio (SNR); and d) influence of changes in the AIF. A method to estimate the AIF in rats is presented that derives an AIF from the time course of a tracer passing through a carotid chamber. The results of computer simulations indicate that a common AIF obtained in one set of animals can be used for perfusion estimations in another set of animals if the tracer is delivered as a dose and that optimal data analysis (fitting data vs. integration approach) is dictated by SNR and perfusion heterogeneity. Experimental strategies are suggested to minimize the effects of changes in the individual AIF that could distort perfusion estimates.
- Published
- 1999
- Full Text
- View/download PDF
31. Direct magnetic resonance determination of aortic distensibility in essential hypertension: relation to age, abdominal visceral fat, and in situ intracellular free magnesium.
- Author
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Resnick LM, Militianu D, Cunnings AJ, Pipe JG, Evelhoch JL, and Soulen RL
- Subjects
- Adult, Age Factors, Compliance, Female, Humans, Hypertension etiology, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Male, Middle Aged, Aorta physiopathology, Hypertension physiopathology, Magnesium analysis, Obesity complications
- Abstract
To investigate the contribution of vascular compliance to essential hypertension (EH), we developed magnetic resonance imaging (MRI) techniques to directly measure aortic distensibility (AD) in the ascending and descending thoracic and abdominal aorta of fasting normal (n= 10) and EH (n=20) subjects. These results were compared with concurrent MR-based measurements of left ventricular mass index (LVMI) and abdominal subcutaneous and visceral fat and with 31P-MR spectroscopic measurement of in situ intracellular free magnesium levels (Mgi) in brain and skeletal muscle. Aortic distensibility in EH was consistently and significantly reduced at all measured sites (2.5+/-0.4, 2.2+/-0.4, 2.3+/-0.4 versus 7.0+/-1.6, 5.1+/-0.3, 7.3+/-0.8 mm Hg(-1) x 10(-3), P<.05), as was Mgi in the brain (284+/-22 versus 383+/-34 micromol/L, P<.05) and skeletal muscle (397+/-10 versus 527+/-36 micromol/L, P<.05). For all subjects, systolic blood pressure (r=-.662, P<.0001) and LVMI (r=-.484, P<.01) were inversely related to AD. AD and brain Mgi were inversely related to age (AD, r=-.792, P<.0001; brain Mgi: r=-.673, P<.05). AD was inversely related to fasting blood glucose (r=-.413, P<.05) and to abdominal visceral fat (r=-.416, P<.05) but not to body mass index (BMI: r=-.328, P=NS) or subcutaneous fat (r=-.157, P=NS). AD was also significantly and positively related to in situ Mgi, both in the brain and skeletal muscle (brain: r=.712, P<.01; skeletal muscle: r=.632, P<.01). We conclude that (1) MR techniques can be used to coordinately and noninvasively assess cardiac, vascular, metabolic, and ionic aspects of hypertensive disease in humans; (2) increased systolic blood pressure and LVMI in EH may at least in part result from decreased AD; (3) decreased Mgi contributes to arterial stiffness in hypertension and may help to explain the characteristic age-related decreases in AD; and (4) decreased AD may be one mechanism by which abdominal visceral fat contributes to cardiovascular risk.
- Published
- 1997
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32. Musculoskeletal complications of neutron therapy for prostate cancer.
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Soulen RL, Romero JA, Chuba PJ, Evelhoch JL, Simpson RE, and Forman JD
- Subjects
- Adipose Tissue pathology, Adipose Tissue radiation effects, Antineoplastic Agents, Hormonal therapeutic use, Combined Modality Therapy, Dose-Response Relationship, Radiation, Follow-Up Studies, Hip pathology, Hip radiation effects, Hip Joint pathology, Hip Joint radiation effects, Humans, Magnetic Resonance Imaging methods, Male, Muscle, Skeletal pathology, Muscle, Skeletal radiation effects, Musculoskeletal Diseases diagnosis, Prostatic Neoplasms diagnosis, Prostatic Neoplasms drug therapy, Treatment Outcome, Musculoskeletal Diseases etiology, Neutron Capture Therapy adverse effects, Prostatic Neoplasms radiotherapy
- Abstract
The purpose of this study was to investigate the cause of hip complaints following conformal neutron therapy delivered by opposed lateral and oblique anterior ports to treat prostate cancer. Twenty-seven patients with hip complaints following neutron or mixed neutron and photon therapy for prostate cancer had 34 magnetic resonance imaging (MRI) studies 3-39 (mean 15.3) months following treatment; for comparison, 13 similarly treated patients without hip complaints were imaged 1-32 (mean 13.8) months post-treatment; 25/40 imaged patients received concurrent nonsteroidal hormone therapy. Coronal and axial images of the hips/pelvis were obtained utilizing T1 weighted spin echo and fat suppressed inversion recovery (STIR) sequences. Signal amplitude (SA) of involved muscles was measured on the STIR images and normalized to that of the psoas outside the treatment field. Hip complaints ranged from mild soreness or motion limitation to severe pain and limitation of ambulation; presence and severity of symptoms (sx) were significantly related to neutron dose (P = 0.020 and 0.0001) but not to hormone therapy (each P > 0.17). Normalized SA of the obturator muscles differed significantly with neutron dose (P = 0.013), the presence, and the severity, of sx (P = 0.0002 and 0.0007); estimated extent of abnormal muscle also differed significantly with neutron dose (P = 0.039), presence, and severity, of sx (P = 0.00004 and 0.0007); [hormone treatment had a profound effect on SA (P = 0.0001) and extent (P = 0.005) which was independent of sx (P = 0.10 and 0.14, respectively) and neutron dose (P = 0.33 and 0.32, respectively)]. Subcutaneous changes localized lateral to the greater trochanter were seen in all, and edema of the subjacent gluteus muscles in many, symptomatic hips; only 4/13 asymptomatic hips showed subcutaneous changes, 6 had mild gluteus edema. Avascular necrosis of the femoral head was seen in 5 symptomatic hips, with marked acetabular necrosis in 3 of these; small joint effusions were seen in 8 symptomatic hips; asymptomatic hips had no significant bone or joint abnormalities. Neutron therapy for prostate cancer designed to spare the rectum results in significant dose-dependent, musculoskeletal complications which are well demonstrated by MRI. SA abnormalities of irradiated muscle correlate significantly with neutron dose and both presence and severity of hip sx. Protocol modifications have been implemented to reduce these complications. MRI provides an objective means to assess both complications and the success of new protocols in ameliorating them. Concurrent hormone therapy has a profound effect on muscle changes on MRI which is independent of neutron dose and sx.
- Published
- 1997
- Full Text
- View/download PDF
33. The NMR chemical shift pH measurement revisited: analysis of error and modeling of a pH dependent reference.
- Author
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Ackerman JJ, Soto GE, Spees WM, Zhu Z, and Evelhoch JL
- Subjects
- Hydrogen-Ion Concentration, Mathematics, Models, Theoretical, Magnetic Resonance Spectroscopy
- Abstract
A standard differential calculus-based propagation of error treatment is applied to the traditional chemical-exchange Henderson-Hasselbalch NMR pH model in which the reference shift is pH independent. It is seen naturally from this analysis that (i) the error minimum in derived pH occurs in the region where pH and indicator pKa are equal and that (ii) the dynamic range, or difference between the limiting chemical shifts of acid and base forms of indicator species, determines the insensitivity of the technique to propagation of errors. To extend the useful pH range and utility of NMR pH determination methodology, a more general model is developed in which the internal reference species is also considered as having a pH-dependent chemical shift. Data from standard solution pH titrations are fitted to both models and parameters are estimated for the normally observed family of ionizable phosphorus metabolites (ATP, inorganic phosphate, phosphoethanolamine and phosphocholine) and the xenometabolite 2-deoxyglucose-6-phosphate with either phosphocreatine, the alpha-phosphate of ATP, or H2O taken as the 31P or 1H chemical shift internal reference species as well as with an external reference.
- Published
- 1996
- Full Text
- View/download PDF
34. Tumor 31P NMR pH measurements in vivo: a comparison of inorganic phosphate and intracellular 2-deoxyglucose-6-phosphate as pHnmr indicators in murine radiation-induced fibrosarcoma-1.
- Author
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Soto GE, Zhu Z, Evelhoch JL, and Ackerman JJ
- Subjects
- Animals, Female, Glucose-6-Phosphate analysis, Hydrogen-Ion Concentration, Mice, Mice, Inbred C3H, Phosphorus Isotopes, Fibrosarcoma chemistry, Glucose-6-Phosphate analogs & derivatives, Magnetic Resonance Spectroscopy, Neoplasms, Radiation-Induced chemistry, Phosphates analysis, Sarcoma, Experimental chemistry
- Abstract
Uncertainty regarding the intracellular/extracellular distribution of inorganic phosphate (P(i)) in tumors has raised concerns that pH calculated from the tumor P(i) chemical shift may not accurately represent the intracellular pH (pHin). This issue was addressed in subcutaneously transplanted murine radiation induced fibrosarcoma-1 by directly comparing pH measured via P(i) with pH measured via the in situ generated intracellular xenometabolite 2-deoxyglucose-6-phosphate (2DG6P). In 131 comparative measurements employing eight tumor-bearing mice under both control and hyperglycemic conditions (the latter to extend the range of tumor pH examined), the pH as derived from either 2DG6P or P(i) showed only a small, but statistically significant, difference (0.07 +/- 0.11 SD; P = 0.0001). Scatter in the comparative analysis over the pH range examined (ca. 5.5-7.5) was not uniform. Above pH 6.6, 2DG6P indicated a pH lower than that of P(i) by 0.088 +/- 0.105 SD (n = 107, P = 0.0001); below pH 6.6, 2DG6P indicated a pH essentially identical to and not statistically different from that of P(i) (mean difference 0.003 +/- 0.128 SD (n = 24, P = 0.92)). Evidence is presented in support of this differential arising from a systematic measurement error due to peak overlap between 2DG6P and endogenous phosphomonoester species. These results support the use of P(i) as a tumor 31P NMR pHin indicator, at least in RIF-1 tumors under control and hyperglycemic conditions.
- Published
- 1996
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- View/download PDF
35. Proton magnetic resonance spectroscopy in patients with glial tumors: a multicenter study.
- Author
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Negendank WG, Sauter R, Brown TR, Evelhoch JL, Falini A, Gotsis ED, Heerschap A, Kamada K, Lee BC, Mengeot MM, Moser E, Padavic-Shaller KA, Sanders JA, Spraggins TA, Stillman AE, Terwey B, Vogl TJ, Wicklow K, and Zimmerman RA
- Subjects
- Adolescent, Adult, Aged, Analysis of Variance, Astrocytoma metabolism, Brain metabolism, Child, Child, Preschool, Choline metabolism, Creatine metabolism, Feasibility Studies, Female, Glioblastoma metabolism, Humans, Magnetic Resonance Spectroscopy, Male, Middle Aged, Protons, Brain Neoplasms metabolism, Glioma metabolism
- Abstract
The authors represent a cooperative group of 15 institutions that examined the feasibility of using metabolic features observed in vivo with 1H-magnetic resonance (MR) spectroscopy to characterize brain tumors of the glial type. The institutions provided blinded, centralized MR spectroscopy data processing long with independent central review of MR spectroscopy voxel placement, composition and contamination by brain, histopathological typing using current World Health Organization criteria, and clinical data. Proton 1H-MR spectroscopy was performed using a spin-echo technique to obtain spectra from 8-cc voxels in the tumor and when feasible in the contralateral brain. Eighty-six cases were assessable, 41 of which had contralateral brain spectra. Glial tumors had significantly elevated intensities of choline signals, decreased intensities of creatine signals, and decreased intensities of N-acetylaspartate compared to brain. Choline signal intensities were highest in astrocytomas and anaplastic astrocytomas, and creatine signal intensities were lowest in glioblastomas. However, whether expressed relative to brain or as intratumoral ratios, these metabolic characteristics exhibited large variations within each subtype of glial tumor. The resulting overlaps precluded diagnostic accuracy in the distinction of low-and high-grade tumors. Although the extent of contamination of the 1H-MR spectroscopy voxel by brain had a marked effect on metabolite concentrations and ratios, selection of cases with minimal contamination did not reduce these overlaps. Thus, each type and grade of tumor is a metabolically hetero-geneous group. Lactate occurred infrequently and in all grades. Mobile lipids, on the other hand, occurred in 41% of high-grade tumors with higher mean amounts found in glioblastomas. This result, coupled with the recent demonstration that intratumoral mobile lipids correlate with microscopic tumor cell necrosis, leads to the hypothesis that mobile lipids observed in vivo in 1H-MR spectroscopy may correlate independently with prognosis of individual patients.
- Published
- 1996
- Full Text
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36. The effects of isoflurane and halothane on blood flow and 31P NMR spectra in murine RIF-1 tumors.
- Author
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Zhao M, Fortan LG, and Evelhoch JL
- Subjects
- Animals, Female, Hydrogen-Ion Concentration, Liver drug effects, Liver metabolism, Magnetic Resonance Spectroscopy, Mice, Mice, Inbred C3H, Neoplasms, Experimental metabolism, Phosphorus, Regional Blood Flow drug effects, Halothane pharmacology, Isoflurane pharmacology, Neoplasms, Experimental blood supply
- Abstract
The principal aim of these studies was to evaluate the utility of isoflurane and halothane for NMR investigations of tumor physiology. In vivo 31P and 2H NMR were used to examine RIF-1 tumors before, during, and (for 31P) after anesthesia. In tumors, halothane decreases blood flow, [PCR]:[NTP], and pH indicated by the Pi chemical shift (pHnmr), while it increases [Pi]:[NTP]; effects consistent with well-established cardiovascular effects of halothane. Isoflurane does not affect tumor blood flow or [PCr]:[NTP], but increases tumor [Pi]:[NTP] and decreases tumor pHnmr. In vivo 31P NMR measurements of normal mouse liver (upper abdomen) indicate that isoflurane has a similar effect in the liver. Although the mechanism for these effects is unknown, observation of a split Pi peak during isoflurane anesthesia suggests that a pool of Pi in a lower pH environment may become evident under isoflurane anesthesia. Regardless of the cause for increased [Pi]:[NTP] and decreased pHnmr, the utility of isoflurane anesthesia for 31P NMR studies of energy metabolism is limited.
- Published
- 1995
- Full Text
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37. International workshop on standardization in clinical MRS measurements: proceedings and recommendations.
- Author
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Leach MO, Arnold D, Brown TR, Charles HC, de Certaines JD, Evelhoch JL, Margulis AR, Negendank WG, Nelson SJ, and Podo F
- Subjects
- Europe, Humans, International Cooperation, Quality Control, Reference Standards, United States, Magnetic Resonance Spectroscopy instrumentation, Magnetic Resonance Spectroscopy methods, Signal Processing, Computer-Assisted instrumentation
- Published
- 1994
38. International Workshop on Standardization in Clinical Magnetic Resonance Spectroscopy Measurements: proceedings and recommendations.
- Author
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Leach MO, Arnold D, Brown TR, Charles HC, de Certaines JD, Evelhoch JL, Margulis AR, Negendank WG, Nelson SJ, and Podo F
- Subjects
- Calibration, Humans, Multicenter Studies as Topic, Quality Control, Sensitivity and Specificity, Magnetic Resonance Spectroscopy instrumentation, Magnetic Resonance Spectroscopy methods
- Published
- 1994
- Full Text
- View/download PDF
39. Measurement of tumor blood flow by deuterium NMR and the effects of modifiers.
- Author
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Evelhoch JL
- Subjects
- Animals, Deuterium, Humans, Neoplasms metabolism, Neoplasms, Experimental metabolism, Regional Blood Flow drug effects, Magnetic Resonance Spectroscopy, Neoplasms blood supply, Neoplasms, Experimental blood supply
- Abstract
Tumor metabolism is directly coupled to tumor blood flow (TBF) and both metabolism and blood flow may be determinants of tumor response to treatment. Since NMR has been used extensively to monitor tumor metabolism noninvasively, development of NMR-based methods for TBF measurement was motivated by the desire to examine the roles tumor metabolism and blood flow may play as determinants of therapeutic response. The concept of using deuterated water as an NMR-detectable, flow-limited tracer for the measurement of tissue blood flow (or capillary perfusion) was introduced in 1987 by Ackerman and coworkers (Proc. Natl., Acad. Sci., USA 84, 4099-4102 (1987)). Since that time, methods have been devised using both spectroscopic and imaging detection for TBF measurement based on either clearance or uptake of deuterated water. In general, the clearance methods are more straightforward to implement, while the uptake methods are less invasive to the tumor. When used with appropriate caution, both approaches yield reliable results. To date, these methods have been applied in a relatively limited number of animal tumors. However, their use is increasing and some of these methods ultimately should be applicable in human tumors.
- Published
- 1992
- Full Text
- View/download PDF
40. Nonglycolytic acidification of murine radiation-induced fibrosarcoma 1 tumor via 3-O-methyl-D-glucose monitored by 1H, 2H, 13C, and 31P nuclear magnetic resonance spectroscopy.
- Author
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Hwang YY, Kim SG, Evelhoch JL, and Ackerman JJ
- Subjects
- 3-O-Methylglucose, Animals, Carbon Radioisotopes, Deuterium, Female, Fibrosarcoma blood supply, Glucose pharmacology, Hematocrit, Hydrogen-Ion Concentration, Lactic Acid, Magnetic Resonance Spectroscopy, Mannitol pharmacology, Mice, Mice, Inbred C3H, Neoplasms, Radiation-Induced blood supply, Nucleosides metabolism, Phosphates, Phosphocreatine metabolism, Blood Glucose metabolism, Fibrosarcoma metabolism, Lactates metabolism, Methylglucosides pharmacology, Neoplasms, Radiation-Induced metabolism
- Abstract
The effects of 3-O-methyl-D-glucose (3-OMG) on subcutaneously implanted murine radiation-induced fibrosarcoma 1 tumor were examined with 2H, 13C, and 31P nuclear magnetic resonance (NMR) in situ. Using 31P NMR, changes in tumor high-energy phosphate metabolism were monitored for 2.5 h after i.p. administration of 3-OMG (8.1 g/kg body weight); tumor pH decreased by a mean maximum of 0.52 +/- 0.05 (SE) (n = 10), [PCr] decreased by 54%, [NTP] decreased by 35%, and [Pi] increased by 36%. Tumor blood flow, as measured by 2H NMR monitoring of D2O washout kinetics, decreased by 40% at 1 h and by 47% at 2 h after 3-OMG injection (n = 4). This substantial tumor acidification (pH decrease much greater than 0.1), expected to require a glycolytic substrate (Hwang et al., Cancer Res., 51: 3108-3118, 1991), is surprising in light of the previously documented metabolically inert nature of 3-OMG. In situ 13C NMR spectroscopy, following [6-13C]3-OMG i.p. injection, examined the possibility of the glycolytic metabolism of 3-OMG. However, only the C-6 resonance of 3-OMG was detected (n = 6); no resonances from [6-13C]3-OMG-6-phosphate or [3-13C]lactate were observed. These results confirmed that 3-OMG was not metabolized in radiation-induced fibrosarcoma 1 tumor. At the completion of the in situ 13C NMR experiments, tumors were freeze clamped, and perchloric acid extraction was performed. High-resolution 1H NMR measurement of lactate concentrations showed no statistically significant difference in control tumor extracts (from mice not receiving i.p. injection; n = 5) and in tumor extracts from mice administered i.p. [6-13C]3-OMG (n = 5), indicating that there was no significant increase in lactate level in the tumor extracts from mice administered i.p. 3-OMG due to increased plasma glucose concentration. The results of these 1H and 13C NMR studies indicated that the radiation-induced fibrosarcoma 1 tumor acidification caused by i.p. administration of 3-OMG was not due to a direct (3-OMG----lactate) or an indirect (systemic glucose----lactate) increase in tumor lactic acid levels.
- Published
- 1992
41. Measurement of relative regional tumor blood flow in mice by deuterium NMR imaging.
- Author
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Evelhoch JL, McDouall JB, Mattiello J, and Simpson NE
- Subjects
- Animals, Deuterium, Dihematoporphyrin Ether, Female, Hematoporphyrins therapeutic use, Image Enhancement methods, Mice, Mice, Inbred C3H, Mice, Inbred Strains, Neoplasms, Experimental drug therapy, Photochemotherapy, Regional Blood Flow drug effects, Magnetic Resonance Spectroscopy instrumentation, Magnetic Resonance Spectroscopy methods, Neoplasms, Experimental blood supply
- Abstract
A noninvasive method to measure relative regional tumor blood flow (rTBF) throughout murine tumors which uses deuterium NMR imaging to observe regional uptake of HOD after bolus iv injection of D2O is introduced. HOD uptake images are formed by subtraction of a background (preinjection) image from 94-s gradient-refocused deuterium NMR images acquired starting 30 s and 10 min after D2O injection. The pixel intensity in the HOD uptake image acquired starting 30 s after injection is directly related to rTBF with a limit of detection estimated at 7 ml/(100 g-min). The image acquired 10 min after D2O injection extends the estimated limit of detection for rTBF to 3 ml/(100 g-min). Heterogeneity in rTBF and regional effects of photodynamic therapy within RIF-1 tumors are readily perceived. This method may provide a valuable tool to further our understanding of the relationship between blood flow and therapeutic response in tumors.
- Published
- 1992
- Full Text
- View/download PDF
42. Modulation of murine radiation-induced fibrosarcoma-1 tumor metabolism and blood flow in situ via glucose and mannitol administration monitored by 31P and 2H nuclear magnetic resonance spectroscopy.
- Author
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Hwang YC, Kim SG, Evelhoch JL, Seyedsadr M, and Ackerman JJ
- Subjects
- Animals, Blood Glucose metabolism, Carbon Dioxide blood, Deuterium, Female, Fibrosarcoma blood supply, Hematocrit, Hydrogen-Ion Concentration, Kinetics, Magnetic Resonance Spectroscopy methods, Mice, Mice, Inbred C3H, Neoplasms, Radiation-Induced blood supply, Oxygen blood, Partial Pressure, Phosphocreatine metabolism, Phosphorus, Regional Blood Flow drug effects, Ribonucleotides metabolism, Sarcoma, Experimental blood supply, Fibrosarcoma metabolism, Glucose pharmacology, Mannitol pharmacology, Neoplasms, Radiation-Induced metabolism, Sarcoma, Experimental metabolism
- Abstract
The hyperglycemia-induced in situ metabolism and blood flow changes produced in s.c. implanted murine radiation-induced fibrosarcoma-1 tumors, grown on the flanks of female C3H/HeJ mice, were examined with 31P and 2H nuclear magnetic resonance. Initial experiments verified a hyperglycemic tumor acidification similar to that reported earlier with a different substrain of mice, C3H/AnF (J.L. Evelhoch et al., Proc. Natl. Acad. Sci. USA, 81: 6496-6500, 1984). Changes in the tumor pH, phosphorus metabolites, and blood flow were then compared after administration of saline, glucose, or mannitol (a nonmetabolizable glucose analogue) using a mole-equivalent dose of the sugars (i.e., 0.8 mmol/20g mouse). Neither saline (n = 8) nor mannitol (n = 6) administration had any marked effect upon tumor pH, whereas glucose administration produced a mean maximum tumor pH reduction of 0.74 +/- 0.09 (SE; n = 9) during the 2.5 h post-glucose injection. No significant changes in high energy phosphate concentrations were observed during the same period after saline injection. After glucose injection, the [phosphocreatine] gradually decreased by 64% (P = 0.0001). After the initial 1 h post-glucose injection, the [inorganic phosphate] increased by 58% (P = 0.0001), and the [nucleoside triphosphates] decreased by 29% (P = 0.0001) during the following 1.5 h. After mannitol injection, while there was no change in [inorganic phosphate] over time (P = 0.37), the [phosphocreatine] decreased by 33% (P = 0.0001) and the [nucleoside triphosphates] decreased by 21% (P = 0.0015) within 20 min, then both the [phosphocreatine] and [nucleoside triphosphates] remained at constant levels during the following 2 h. In parallel experiments, the volumetric rate of tumor blood flow and perfusion was measured by 2H nuclear magnetic resonance monitoring of 2H2O washout kinetics (S-G. Kim and J. J. H. Ackerman, Cancer Res., 48: 3449-3453, 1988); tumor blood flow decreased by 80% (P = 0.0001, n = 11), 60% (P = 0.0031, n = 4), and 20% (P = 0.058, n = 10) at 2 h after glucose, mannitol, or saline injections, respectively. These results suggest that anaerobic glycolysis is a requirement for hyperglycemic tumor acidification. However, the decrease in tumor blood flow accompanying hyperglycemic acidification suggests that flow reduction also may be a contributing or a required cofactor for acidification via inhibition of lactic acid egress.(ABSTRACT TRUNCATED AT 400 WORDS)
- Published
- 1991
43. Relative volume-average murine tumor blood flow measurement via deuterium nuclear magnetic resonance spectroscopy.
- Author
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Mattiello J and Evelhoch JL
- Subjects
- Animals, Computer Simulation, Deuterium, Deuterium Oxide, Female, Fibrosarcoma diagnosis, Hyperthermia, Induced, Mice, Mice, Inbred C3H, Neoplasms, Radiation-Induced diagnosis, Water, Fibrosarcoma blood supply, Magnetic Resonance Spectroscopy, Neoplasms, Radiation-Induced blood supply
- Abstract
A deuterium NMR spectroscopic method to determine relative tumor blood flow (TBF) by measuring the increase in tumor HOD concentration after intravenous injection of 100 microliters D2O (0.9% NaCl) is presented. An integration approach analogous to that validated for positron emission tomographic measurement of cerebral blood flow was implemented. Computer simulations indicated that integration from 30 to 120 s minimizes the sensitivity of the uptake integral to the shape of the arterial input function, which cannot be assessed in each mouse, while maintaining both a nearly linear relationship between TBF and the integral and high NMR signal-to-noise. A strong positive linear correlation was observed between the uptake integral and TBF measured by D2O clearance in both untreated tumors (n = 19; P less than 0.001) and tumors after hyperthermia (n = 16; P less than 0.001). This method can measure relative TBF in tumors with heterogeneous blood flow and is ideally suited to concurrent or interleaved measurement of TBF and metabolism via multinuclear NMR spectroscopy.
- Published
- 1991
- Full Text
- View/download PDF
44. Effect of photodynamic therapy on RIF-1 tumor metabolism and blood flow examined by 31P and 2H NMR spectroscopy.
- Author
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Mattiello J, Evelhoch JL, Brown E, Schaap AP, and Hetzel FW
- Subjects
- Animals, Cell Line, Female, Fibrosarcoma blood supply, Fibrosarcoma metabolism, Magnetic Resonance Spectroscopy, Mice, Mice, Inbred C3H, Neoplasm Transplantation, Fibrosarcoma drug therapy, Photochemotherapy
- Abstract
Photodynamic therapy utilizes the tumor localizing drug dihematoporphyrin ether and red laser light to produce both direct tumor cell destruction via damage to mitochondrial membranes, and also indirect cell kill via destruction of the tumor vasculature. As a first step towards examining the mechanistic relationship between metabolic and vascular effects of photodynamic therapy, murine RIF-1 tumors were treated with a subcurative treatment (500 J/cm2). Tumor metabolic status was monitored using in vivo 31P NMR before, during and after the treatment. The tumor blood flow immediately before and after treatment was measured by direct intratumor injection of D2O saline and observation of the tracer signal clearance from the tumor via 2H NMR. During the photodynamic therapy treatment, significant decreases were observed for the nucleoside triphosphate concentrations, tumor pH and tumor blood flow, while inorganic phosphate concentrations increased. Animals treated with laser light alone and those not given any treatment, demonstrated no significant changes in tumor metabolic status, tumor pH or tumor blood flow. Further studies are required to determine whether tumor blood flow or metabolic status is affected first.
- Published
- 1990
- Full Text
- View/download PDF
45. Deuterium nuclear magnetic resonance imaging of tracer distribution in D2O clearance measurements of tumor blood flow in mice.
- Author
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Larcombe McDouall JB and Evelhoch JL
- Subjects
- Animals, Deuterium Oxide, Female, Magnetic Resonance Spectroscopy, Metabolic Clearance Rate, Mice, Mice, Inbred C3H, Regional Blood Flow, Deuterium, Neoplasms, Experimental blood supply, Water
- Abstract
Proper implementation of direct injection clearance techniques to measure tumor blood flow (TBF) requires knowledge of the tracer distribution because TBF distribution is often inhomogeneous. Therefore, deuterium nuclear magnetic resonance imaging was used to follow tracer (HOD) distribution after direct injection of 10-40 microliters isotonic saline/D2O into RIF-1 tumors. Within 2 to 4 min after intratumor injection, tracer clearance was imaged by obtaining deuterium images every 1.4 min. The mean volume occupied by HOD in tumors in the first image acquired after injection with 10, 20, or 40 microliters D2O was 56 +/- 37 (SD) mm3, 44 +/- 2.9 mm3, and 174 +/- 83 mm3, respectively (n = 3 for each). In these control tumors, HOD was cleared from that volume without an appreciable increase in tracer distribution. In tumors heated for 45 min at 45 degrees C to greatly reduce TBF, the mean tracer volume in the first image after 10-microliters D2O injection was 41 +/- 10 mm3 and increased to 111 +/- 24 mm3 at 30 min (n = 3). For 10 microliters D2O injected at two distinct sites, the intensity decreased at each site while the sites remained separate (n = 6). The TBF at the two sites, measured independently by fitting the integrated HOD intensity from each site to a monoexponential decay function, was significantly different in only one of the six tumors examined. The use of deuterium nuclear magnetic resonance imaging to measure TBF from two (or more in larger tumors) independent sites provides a practical approach to assess TBF heterogeneity. The direct measurement of the tissue volume labeled with tracer and its dependence on injection volume should aid in determining how best to implement direct injection tracer clearance methods.
- Published
- 1990
46. 31P spin-lattice relaxation times and resonance linewidths of rat tissue in vivo: dependence upon the static magnetic field strength.
- Author
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Evelhoch JL, Ewy CS, Siegfried BA, Ackerman JJ, Rice DW, and Briggs RW
- Subjects
- Animals, Brain metabolism, Liver metabolism, Muscles metabolism, Rats, Magnetic Resonance Spectroscopy
- Abstract
Phosphorus-31 NMR spin-lattice relaxation times and resonance linewidths of rat leg muscle, brain, and liver metabolites in vivo have been examined at 1.9-, 4.7-, and 8.5-T static magnetic field strengths. The resonance linewidths expressed in ppm that have been measured are independent of field strength. The spin-lattice relaxation times of muscle and brain phosphorus metabolites decrease linearly with increasing field strength while those of liver are constant over the range of static fields examined.
- Published
- 1985
- Full Text
- View/download PDF
47. A method for direct in vivo measurement of drug concentrations from a single 2H NMR spectrum.
- Author
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Evelhoch JL, McCoy CL, and Giri BP
- Subjects
- Animals, Deuterium, Evaluation Studies as Topic, Female, Fibrosarcoma metabolism, Mice, Mice, Inbred C3H, Misonidazole metabolism, Water metabolism, Magnetic Resonance Spectroscopy, Pharmaceutical Preparations analysis
- Abstract
The use of 2H-labeled drugs provides a measure of drug concentration in situ directly from a single 2H NMR spectrum obtained with any antenna by correcting only for differential saturation effects. The limit of detection for a drug labeled with three equivalent deuterons is roughly 0.5 mM.
- Published
- 1989
- Full Text
- View/download PDF
48. Characterization of the internal calcium(II) binding sites in dissolved insulin hexamer using europium(III) fluorescence.
- Author
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Alameda GK, Evelhoch JL, Sudmeier JL, and Birge RR
- Subjects
- Binding Sites, Calcium, Cobalt, Crystallography, Europium, Molecular Conformation, Spectrometry, Fluorescence, Zinc, Insulin
- Abstract
The fluorescence of Eu(III) is used to study the nature of the Ca(II) binding sites in the central cavity of the two-zinc(II) insulin hexamer. The dependence of the Eu(III) fluorescence lifetime upon Eu(III) stoichiometry indicates that there are three identical Eu(III) binding sites present in the two-zinc(II) insulin hexamer in solution. Addition of excess Ca(II) causes a decrease in the Eu(III) fluorescence intensity, confirming that Ca(II) competes for the observed Eu(III) sites. The solvent dependence of the Eu(III) fluorescence lifetime (H2O vs. D2O) indicates that four OH groups are coordinated to each Eu(III) in the hexamer. Substitution of Co(II) for Zn(II) causes a decrease in the Eu(III) fluorescence lifetime. Calculations based on Förster energy-transfer theory predict that the Co(II) [or Zn(II) in vivo] and Eu(III) [or Ca(II) in vivo] binding sites are separated by 9.6 +/- 0.5 A. Variation of the metal stoichiometries indicates that all three Eu(III) [or Ca(II) in vivo] sites are equidistant from the Zn(II) sites. We conclude that these sites are identical with the three central Zn(II) sites present in insulin hexamer crystals soaked in excess Zn(II) [Emdin, S. O., Dodson, G., Cutfield, J. M., & Cutfield, S. M. (1980) Diabetologia 19, 174-182] and suggest that these central sites are occupied by Ca(II) in vivo.
- Published
- 1985
- Full Text
- View/download PDF
49. In vivo 19F nuclear magnetic resonance spectroscopy: a potential monitor of 5-fluorouracil pharmacokinetics and metabolism.
- Author
-
Evelhoch JL
- Subjects
- Animals, Fluorouracil metabolism, Humans, Fluorine Radioisotopes, Fluorouracil pharmacokinetics, Magnetic Resonance Spectroscopy
- Abstract
In vivo 19F nuclear magnetic resonance (NMR) spectroscopy has the potential to non-invasively measure the concentration of 5-fluorouracil (FUra) and some of its metabolites in humans. Such a measure could be useful in predicting and optimizing the response of individual patients treated with FUra. The ability of 19F NMR to monitor FUra metabolism in situ in rodent tumors and liver and in human liver has been demonstrated. However, the potential impact of this technique as a predictor of FUra response in individual patients is limited by both the sensitivity (i.e., limit of detection) and the resolution (i.e., ability to distinguish among magnetically similar metabolites) of NMR. To date, the ability of in vivo 19F NMR spectroscopy to provide information that can distinguish FUra-sensitive from FUra-insensitive tumors has not been established. This crucial point should be addressed in the immediate future in studies using the best of experimental conditions (i.e., optimum sensitivity and resolution in well-defined rodent tumor models with NMR methodology appropriate for measurement of absolute metabolite concentrations). The information gained from such studies and any new technical developments to enhance in vivo NMR sensitivity should be directly applicable to any future application of 19F NMR spectroscopy in clinical FUra therapy.
- Published
- 1989
- Full Text
- View/download PDF
50. Evidence for direct metal-nitrogen binding in aromatic sulfonamide complexes of cadmium (II)-substituted carbonic anhydrases by cadmium-113 nuclear magnetic resonance.
- Author
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Evelhoch JL, Bocian DF, and Sudmeier JL
- Subjects
- Binding Sites, Magnetic Resonance Spectroscopy, Protein Binding, Structure-Activity Relationship, Sulfonamides pharmacology, Cadmium pharmacology, Carbonic Anhydrases metabolism
- Abstract
113Cd NMR has been used to study the nature of the metal-sulfonamide interaction in complexes of 113Cd-substituted carbonic anhydrases and the aromatic sulfonamides benzenesulfonamide and Neoprontosil. The 113Cd chemical shifts of the complexes exhibit negligible dependence on the isotopic composition of the sulfonamide nitrogen. However, benzenesulfonamide and Neoprontosil, when 90% 15N-enriched at the sulfonamide nitrogen, each split the 113Cd resonance into a doublet (J113Cd-15N approximately or equal to 200 Hz). This constitutes evidence for metal-nitrogen bonds in these complexes. The chemical shifts of the complexes (approximately 390 ppm) and their pH independence from pH 7.0 to 10.0 suggest the sulfonamides are bound in the anionic form. The resonance Raman (RR) spectra of 15N-labeled and unlabeled Neoprontosil have been obtained to clarify the report of anomalous Neoprontosil binding in the nonionized form [Petersen, R. L., Li, T.-Y., McFarland, J. T., & Watters, K. L. (1977) Biochemistry 16, 726]-a report based on the assignment of a band at approximately 900 cm-1 to a sulfonamide S-N stretching vibration. We find the frequencies of Raman bands observed in the range 800-1700 cm-1 to be virtually identical for the 15N-labeled and unlabeled molecules, indicating that none of the bands can be assigned to a S-N stretching vibration. The RR data unambiguously show the report of Petersen et al. (1977) is based on the misassignment of the band at approximately 900 cm-1.
- Published
- 1981
- Full Text
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