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M M Graham

Publications and source records attributed to M M Graham.

At least 19 recordsLinked to original sources
PubMed1992

Imaging of hypoxia in human tumors with [F-18]fluoromisonidazole.

Fluoromisonidazole (FMISO) has been shown to bind selectively to hypoxic cells in vitro and in vivo at radiobiologically significant oxygen levels. When labeled with the positron emitter fluorine-18 (F-18), its uptake in tissue can be detected quantitatively with high precision by positron emission transaxial tomography (PETT). This paper presents the first experiences with PETT imaging of [F-18]FMISO uptake in human malignancies, and describes the development of this technique as a tool for the non-invasive assessment of tumor hypoxia. Eight patients with selected cancers were imaged prior to primary radiotherapy, and 3 returned for follow-up scans, for a total of 11 imaging studies. Six of eight pre-radiotherapy studies revealed retention of [F-18]FMISO in tumors that significantly exceeded plasma concentrations by 2 hr after drug injection; all five patients with head and neck primaries had such "positive" scans. An analytic method for the interpretation of [F-18] FMISO PETT images is presented, defining hypoxic elements within a tumor volume as regions with a threshold regional tumor:plasma [F-18]FMISO ratio of greater than or equal to 1.4 by 2 or more hours after injection. Toward the end of a course of fractionated radiotherapy, three repeat studies in patients with initially positive scans showed no tumor accumulation of drug above the threshold ratio of 1.4, suggesting reoxygenation had occurred. Pharmacokinetic and dosimetry data support continued use of [F-18]FMISO as a safe hypoxia probe. Two imaging protocols have been developed for human studies; a long protocol allows for more complete biodistribution and dosimetry information, and a shorter protocol facilitates increased patient accrual by applying a simple, clinically expedient imaging procedure. When correlated with tumor outcome, [F-18]FMISO PETT imaging may be developed as a predictor of tumor response to conventional radiotherapy. The implications of this technique in addressing persistent questions of tumor hypoxia in human oncology is discussed.

Cell Hypoxia↗
PubMed1992

Vascular response to fractionated irradiation in the rat lung.

The effects of fractionated hemithorax irradiation on normal lung tissue were examined by measuring changes in the vascular permeability surface area product (PS) and relative lung blood flow in Sprague-Dawley rats. The rats received five daily fractions per week of either 3.0 or 4.0 Gy for 4 weeks to the left lung. Between 3 and 5 weeks after the start of irradiation, the average PS was approximately 50% above normal for the group of rats that received 3.0 Gy/day and 200-300% above normal in the group of rats that received 4.0 Gy/day. Treatment with cyproheptadine, indomethacin, or theophylline had no effect, but treatment with dexamethasone significantly reduced PS to near normal levels. Left-to-right blood flow ratios in the group of rats that received 3.0 Gy/day decreased to 66% of normal levels by 4 weeks. In the group of rats that received 4.0 Gy/day, blood flow decreased to 46% of normal levels by 4 weeks. Treatment with dexamethasone maintained normal blood flow until the drug dose was reduced. These results agree with earlier studies using single-dose irradiation and indicate that the methods used to measure PS and blood flow are sensitive at low doses.

Animals↗
PubMed1992

Noninvasive detection of hypoxic myocardium using fluorine-18-fluoromisonidazole and positron emission tomography.

Fluoromisonidazole (FMISO) is metabolically trapped in viable cells as a function of reduced cellular pO2. Therefore [18F]-FMISO is potentially useful for evaluating patients with hypoxic but viable myocardium. The goal of this study was to investigate [18F]FMISO uptake in ischemic myocardium non-invasively using positron emission tomography (PET). Studies were performed in 10 open-chest dogs subjected to either complete (Group 1, n = 5) or partial (Group 2, n = 5) occlusion of the left anterior descending coronary artery. The tracer was administered by intravenous bolus following the onset of ischemia and serial PET images were acquired for the next 4 hr. In Group 1, viability was assessed using histochemical staining (nitroblue tetrazolium, NBT) and 99mTc-pyrophosphate (Tc-PYP). In Group 2, viability was assessed using measurements of regional wall motion, histochemical staining and histology (two animals). In each study, PET images obtained at times between 2 and 4 hr postinjection showed specific enhancement of tracer activity in the distal anterior wall and apex of the left ventricle. At 4 hr, the tissue-to-blood pool count ratio was significantly higher in ischemic regions; 1.8 +/- 0.4 for Group 1 and 1.6 +/- 0.2 for Group 2 versus 1.0 +/- 0.1 in nonischemic regions. Postmortem tissue sampling of Group 1 hearts showed significant FMISO retention in samples without evidence for infarction, either by NBT or Tc-PYP deposition, as well as in more severely ischemic regions. In Group 2 animals, FMISO was retained in myocardial regions with reduced blood flow (microspheres), which exhibited improved contraction following reperfusion. We conclude that PET imaging of [18F]FMISO is a promising technique for the noninvasive identification of viable hypoxic myocardium.

Animals↗
PubMed1992

Contribution of labeled carbon dioxide to PET imaging of carbon-11-labeled compounds.

11CO2 is one of the major metabolites of many [11C]-labeled radiopharmaceuticals, including glucose, thymidine, acetate, amino acids, and fatty acids. Our data contradict the notion that the contribution of labeled CO2 to PET images can be disregarded because of its rapid elimination through the lungs. We have measured the retention and excretion of 11CO2 in dogs after the intravenous injection of labeled CO2/HCO3-, which had been equilibrated ex vivo with blood. Only 58% of the label was exhaled as CO2 over the first 60 min after injection, with the rest retained in the body. The injection of [11C]thymidine labeled in the ring-2 position or [11C]acetate labeled in the carboxylate position resulted in the production of large amounts of labeled CO2 with the exhalation of about 47% and 23%, respectively, of the injected label over 60 min. At 10 min after injection of either [11C]thymidine and [11C] acetate, approximately 60% to 70% of total blood activity was in labeled CO2 or bicarbonate. On the other hand, the use of [1-11C]glucose only resulted in exhalation of 5% of the injected dose and CO2/HCO3- made up less than 10% of blood activity at 10 min. Our results indicate that retention and distribution of labeled CO2 needs to be considered when interpreting PET data obtained from 11C-labeled compounds.

Acetates↗
PubMed1992

Vascular response to radiation injury in the rat lung.

Changes in relative left-to-right lung blood flow ratios were followed as an index of vascular radiation injury in left-hemithorax-irradiated Sprague-Dawley rats. Single doses of 11 to 21 Gy gamma radiation resulted in a dose-dependent decrease in relative blood flow to the irradiated lung from 3 to 5 weeks after exposure during the development of pneumonitis. Blood flow returned to near normal by 5 weeks after lower doses (11-13.5 Gy). After a single dose of 15 Gy the left-to-right blood flow ratio recovered to 75% of normal at 12 weeks and leveled off. Following 18 Gy irradiation a second period of reduced flow began 16 weeks after exposure. After 21 Gy irradiation flow to the irradiated side remained low for 1 year after exposure. Rats that received a single dose of 18 Gy to the left hemithorax were also treated with one or two of the following drugs: captopril, cyproheptadine, dexamethasone, diethylcarbamazine, penicillamine, or theophylline. Dexamethasone was most effective at preventing the decrease in blood flow to the irradiated lung when treatment was continued through the pneumonitis period and dose was not tapered until 8 weeks after radiation exposure. All other drugs and drug combinations were, for the most part, virtually ineffective after the pneumonitis period. There was a relatively poor correlation with earlier vascular permeability surface area product studies. This suggests that endothelial damage, as well as damage to other cell types, contributes to the development of post-irradiation fibrosis in the lung.

Animals↗
PubMed1991

31P magnetic resonance spectroscopy is sensitive to tumor hypoxia: perfusion and oxygenation of rat 9L gliosarcoma after treatment with BCNU.

The mechanism behind the relative increase in high-energy phosphates observed by MRS in many tumors following chemotherapy is poorly understood. To test the hypothesis that this metabolic activation is associated with a decrease in tumor hypoxia, tumor blood flow and oxygenation were measured in tumors that were also analyzed by MRS. 31P MR spectra were acquired with a GE 2T CSI spectrometer from subcutaneous 9L tumors in rats 4 days following treatment with BCNU (10 mg/kg) and from age-matched sham-treated control tumors. BCNU-treated tumors (n = 13) underwent a significant improvement in bioenergetic state compared to control tumors (n = 14), showing a relative increase in high-energy phosphate (Pi/phosphocreatine) (p less than 0.01), and a relative decrease in Pi (Pi/alpha nucleoside biphosphate) (p less than 0.01). Gamma camera imaging of 133Xe washout, following injection of 133Xe in saline into control and treated 9L tumors 4 days after treatment, was used to measure tumor perfusion. Sham-treated control tumors (n = 21) were perfused at a rate of 35.4 (+/- 6.4 SE) mL/100 g/min, while BCNU-treated tumors (n = 20) were perfused at a rate of 55.1 (+/- 7.5 SE) mL/100 g/min (T = 1.96; p less than 0.05). The partial pressure of oxygen (pO2), measured with a polarographic electrode was found to be significantly higher in treated 9L than in sham-treated controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

A simple, dual tracer method for the measurement of transvascular flux of albumin into the lung.

A simple, first-order model of albumin kinetics in the rat lung is presented and validated with a more sophisticated model. The simple model assumes that intravascular concentration of tracer albumin is constant over 30 min after injection and transvascular flux of tracer albumin is unidirectional and proportional to the permeability-surface area product (PS). 125I-albumin is injected initially and 131I-albumin at 20 min. At 30 min the rat is sacrificed and plasma and tissue samples are obtained for gamma counting. Simultaneous equations are set up for the two tracers and solved for PS and plasma volume. The accuracy of this approach is examined with data generated from a more complete model. This model uses the concepts of hydraulic conductivity, solvent drag, reflection coefficients, hydrostatic and osmotic pressures, exclusion volumes, and lymph flow, as well as PS. Based on known PS and clearance rates from the complex model, the simple model estimates tracer albumin leakage rate with less than 5% error over the range of PS encountered in rat studies.

Albumins↗
PubMed1991

Left ventricular ejection fraction: single-plane and multiplanar transesophageal echocardiography versus equilibrium gated-pool scintigraphy.

The relative accuracy and precision of estimating left ventricular ejection fraction (EF) in dogs were assessed by two-dimensional transesophageal echocardiography (2D-TEE) and by three-dimensional transesophageal echocardiographic (3D-TEE) imaging and reconstruction. This assessment was accomplished by comparing each echocardiographic method to a gated equilibrium blood pool radionuclide (RN) standard. By using both correlation and regression analysis, 2D-TEE performed reasonably well in estimating RNEF (correlation coefficient [r] = 0.80, slope = 1.01, intercept = 6.37, standard error of the estimate [SEE], 8.98), but not as well as 3D-TEE (r = 0.86, slope = 0.83, intercept = 3.38, SEE, 5.74). Using Altman and Bland's methods of comparison analysis, it was found that 2D-TEE overestimated RNEF by 7% (standard deviation [SD], 8.8). This degree of overestimation was not consistent across the range of measurement. In contrast, 3D-TEE slightly underestimated RNEF by less than 3% and showed less variability (SD, 6.0). The accuracy of the 3D-TEE determinations was not dependent on the magnitude of EF. Additionally, a significantly higher proportion of the 2D-TEE measurements (0.30) compared with the 3D-TEE measurements (0.10) differed from RN values by more than 10% (P = 0.009, McNemar's test). At the clinically important low end of the EF range (RNEF less than or equal to 35%), 2D-TEE may be expected (with 95% confidence) to be within -15% to +28% EF of reference values, whereas 3D-TEE can be expected to be within -8% to +5% EF relative to RN.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Benefit of tomography in the scintigraphic localization of cerebrospinal fluid leak.

A CSF leak was demonstrated by tomography after planar acquisition failed to localize it. The rotatogram was more definitive than the reconstructed images in showing the leak. Tomography should be considered when the leak may be in an unusual location and the patient does not have rhinorrhea or otorrhea. Tomography allows a complete 360 degrees survey to examine for the best angle for inspection of the leak, whereas the empirically oriented planar study can sample only limited projections, particularly if given time limitations for acquisition.

Adult↗
PubMed1991

Combined technetium radioisotope penile plethysmography and xenon washout: a technique for evaluating corpora cavernosal inflow and outflow during early tumescence.

Combined technetium radioisotope penile plethysmography and xenon washout is a new technique that measures both corporal arterial inflow and venous sinusoidal outflow during early tumescence in patients with erectile dysfunction. Fourteen patients were studied using 99mTc-RBCs to measure inflow and 133Xe or 127Xe in saline to measure outflow. Tumescence was induced by injecting papaverine intracorporally. Peak corporal rates corrected for outflow (r = 0.88) and uncorrected for outflow (r = 0.91) and change in volume over 2 min centered around peak flow [corrected] (r = 0.96) all correlated with angiography. Outflow measurements did not correlate with intracorporal resistance. Thus, outflow rates alone could not be used to predict venous sinusoidal competence. Normal inflow rate is greater than 20 ml/min; probable normal 12-20; indeterminate inflow 7-12; and abnormal inflow less than 7 ml/min. Technetium-99m radioisotope penile plethysmography and xenon washout can be performed together and both provide a method for simultaneously evaluating the relationship between corporal inflow and outflow rates in patients with erectile dysfunction.

Adult↗
PubMed1991

Effect of bicarbonate on stability of the gallium-transferrin complex.

When gallium citrate is injected intravenously the gallium is rapidly transchelated to transferrin. If the stability of the gallium-transferrin association is sufficiently strong it should be a good macromolecular tracer suitable for quantitative measurements of vascular permeability. Studies of the stability of the gallium transferrin complex in human plasma and serum were done using ultrafiltration and dialysis. It was found that the stability was sensitive to bicarbonate level. Above 13 mM of bicarbonate, 97%-99% of the gallium is bound to molecules greater than 10,000 MW by ultrafiltration. However, at 10 mM binding is 95% and at 7 mM 83%. Similar results were obtained with dialysis. This suggests the gallium-transferrin complex may not be sufficiently stable for quantitative measures of vascular permeability, particularly if the bicarbonate concentration is low.

Bicarbonates↗
PubMed1990

The drainage routes of the bronchial blood flow in anesthetized dogs.

It is generally accepted that the bronchial blood flow from extrapulmonary airways drains to the systemic veins through the bronchial veins, while that from the intrapulmonary airways drains into the pulmonary vasculature and eventually the left heart. This concept has not been confirmed by physiologic studies in live animals. We measured the routes taken by radionuclide-labeled Diethylenetriamine pentaacetate (DTPA) deposited in the extrapulmonary and the intrapulmonary airways in dogs. In living, anesthetized open chest animals, the pulmonary circulation of the left lower lobe was isolated and perfused with autologous heparinized blood. 99mTc DTPA was deposited on the mucosa of the extrapulmonary left mainstem bronchus just beyond the main carina (extrapulmonary deposition) and 111In DTPA on that of an intrapulmonary left lower lobe segmental bronchus (intrapulmonary deposition). Sequential blood samples from the right heart and from the isolated left lower lobe pulmonary circuit were counted for radioactivity, corrected for the volume in which they were distributed and for the bronchial blood that flowed into the isolated left lower lobe circuit, and expressed as the ratio of systemic to pulmonary drainage from each deposition site. The extrapulmonary tracer drained mostly to the systemic veins (84% of total) but also into the pulmonary circulation (16% of total). The intrapulmonary tracer drained mostly into the pulmonary circulation (70% of total) but also into the right heart (30% of total). Since tracers from both deposition sites drained to both circulations, the bronchial vasculature is continuous between the systemic (right heart) and the pulmonary circulation. Thus, it may provide a pathway for blood flow between the right and left heart.

Anesthesia↗
PubMed1990

Pharmacological alteration of the lung vascular response to radiation.

The role of endothelial cell damage in the development of radiation injury in the lung was investigated in rats. Vascular permeability-surface area product (PS) was measured as an indicator of the degree of endothelial cell damage in lungs of rats exposed to single dose hemithorax irradiation. Hemithorax irradiation was chosen to simulate clinical radiotherapy, in which only a portion of the lung is irradiated. In addition, it provided a control lung to compare to the irradiated lung. Radiation is postulated to lead to activation of several different biochemical pathways that result in lung injury and fibrosis. Many of these pathways can be specifically blocked with drugs. Thirteen different drugs were studied. Dexamethasone, indomethacin, cromolyn, cyproheptadine, Vitamin D3, theophylline, and diethylcarbamazine were all effective at reducing lung PS on the irradiated side. Dexamethasone, Vitamin D3, and indomethacin also significantly reduced lung PS in the unirradiated lungs and in sham-irradiated rats. Captopril, cobra venom factor, penicillamine, trapidil, epsilon-amino caproic acid, and dapsone had no significant effect on lung PS after hemithorax irradiation. We conclude that the major pathways involved in early post-radiation lung injury involve prostaglandin, leukotriene, and histamine release from macrophages and mast cells. Complement activation, proteolytic enzymes, and neutrophil migration do not seem to be important mediators of early post-radiation lung injury.

Animals↗
PubMed1990

Deoxyglucose lumped constant estimated in a transplanted rat astrocytic glioma by the hexose utilization index.

The lumped constant (LC) for calculating the regional glucose (glc) metabolic rate by the deoxyglucose (DG) method was estimated in a transplanted rat glioma and normal rat brain. First, the hexose utilization index (HUI) was measured at 1.5, 3.0, and 4.5 min in right hemisphere glioma implants and uninvolved contralateral hemisphere following bolus intravenous injections of [3H]DG and [14C]glucose. At these times, the glioma HUI values were 0.639, 0.732, and 0.712, respectively, and the coordinate left hemisphere values were 0.432, 0.449, and 0.418. Second, the volumes of distribution of DG and glucose were determined to be 0.436 and 0.235 in glioma implants and 0.402 and 0.237 in left hemisphere, respectively. Third, following simultaneous intracarotid injections of [3H]DG and [14C]glucose, the ratio K1/K1 was 1.1 in glioma grafts and 1.3 in left hemisphere. With these values for HUI, volume of distribution, and K1 ratio, the LC in this rat glioma was estimated to be 2.1 times higher than the left hemisphere LC (p less than 0.02). These results suggest that measurement of brain tumor CMRglc using a normal brain LC may significantly overestimate the true tumor CMRglc.

Animals↗
PubMed1990

Localization of inflammation with 111In IgG and 99Tcm albumin colloid labelled leukocytes in a rabbit model.

Localization of inflammation with two recently described radiotracers, 111In-labelled polyclonal IgG and 99Tcm albumin colloid labelled leukocytes (Tc-WBC), was studied. Accumulation of activity was compared with 111In-labelled leukocytes (In-WBC) using 131I human serum albumin as a control. Ratios of activity in a chemically induced abscess in the thigh of rabbits compared with normal muscle tissue were measured. The results showed that all agents localize in inflammation but Tc-WBC consistently localizes to a greater degree than the other agents. At 2 h the inflammed-to-normal ratios for Tc-WBC were 4, IgG 2.1, albumin 1.9 and In-WBC 1.7. The pattern of the ratios remained similar over the 18 h period of the study. The short time in which leukocytes can be labelled and the quality of the images obtained suggest that Tc-WBC imaging is the method of choice for this model.

Animals↗
PubMed1990

A multi-center study: clinical practices of HIV infected patients on CAPD/CCPD.

Our statistics reveal the average patient in our study to be a young black male with a history of IVDA with CAPD as the initial dialysis modality. He was most often trained on a mechanical assist device, but he still developed frequent peritonitis episodes, predominantly gram positive. His survival rate was less than 2 years, but he was able to remain independent until he died. Our fears about caring for the HIV infected individual cannot be denied. Even though we may never be truly comfortable when caring for someone with this disease, it is possible to train them to perform home peritoneal dialysis safely and effectively. By doing this, we can preserve the patients' independence and maintain their dignity while they cope with this overwhelming illness.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Measurement of left ventricular ejection fraction and volumes with three-dimensional reconstructed transesophageal ultrasound scans: comparison to radionuclide and thermal dilution measurements.

A transesophageal, ultrasonic cardiac imaging probe was built that incorporated a mechanism for changing the angle of the imaging plane of a conventional phased array in a precise and known manner. This probe was used to acquire an angular spatial sequence of two-dimensional images of the left ventricular cavity over a series of cardiac cycles by sweeping the imaging plane through it stepwise. The endocardial borders of these images were manually outlined off-line and the application of a three-dimensional reconstruction algorithm was then used to compute the left ventricular end-diastolic and end-systolic volumes and ejection fraction. A study was conducted with seven anesthesized dogs to compare ultrasonic determinations by this method with determinations and measurements made using radionuclide and thermal dilution methods. Comparison of 33 ejection fractions, measured by the ultrasonic volume method and by the gated blood pool radionuclide approach, yielded a correlation coefficient of 0.87 and a standard error of the estimate of 5.7% measured over a range of 10% to 58% (average, 40%). Comparison of the ultrasonically measured volumes with those calculated from stroke volume (derived from thermal dilution cardiac output measurement) and ejection fraction (measured by radionuclide technique) produced a correlation coefficient of 0.92 and a standard error of the estimate of 10.3 mL over a range of 18 to 130 mL (average, 56 mL). The accuracy of volume and ejection fraction measurements with this new ultrasonic method seems comparable to that of other currently used clinical approaches such as radionuclide and angiography.

Animals↗