Biomedical subjects

M M Graham

Publications and source records attributed to M M Graham.

At least 37 records · Page 2Linked to original sources

PubMed1998

Imaging of oncologic patients: benefit of combined CT and FDG PET in the diagnosis of malignancy.

OBJECTIVE: The purpose of this study was to assess the benefit of combined CT and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in diagnosing malignancy. MATERIALS AND METHODS: The records of 26 patients with intraabdominal and intrathoracic neoplasms who underwent CT and FDG PET between January 1995 and September 1996 were retrospectively reviewed. Most of these patients had inconclusive findings on prior CT for the diagnosis of malignancy. Only sites of potential malignant disease were included in the data analysis. Presence or absence of malignancy was confirmed by histopathology or follow-up CT. Three observers experienced in abdominal imaging used CT findings alone to estimate level of suspicion (1 = definitely not malignant to 5 = definitely malignant) for primary or recurrent neoplasms (n = 21), distant metastases (n = 25), and neoplastic nodal involvement (n = 18). Six weeks later the three observers reviewed the same CT examinations supplemented with FDG PET and reestimated suspicion of malignancy. Receiver operating characteristic methodology was used to analyze the results. Sensitivity, specificity, positive and negative predictive values, and accuracy in diagnosis of malignant disease were calculated using level 4 (probable malignancy) as the cutoff for the presence of disease. RESULTS: The mean area under the receiver operating characteristic curve, indicating successful diagnosis of malignancy, was .82 for CT alone and .92 for CT with FDG PET (p < .05). The accuracies for diagnosis of primary or recurrent neoplasms, distant metastases, and neoplastic nodal involvement were 62%, 68%, and 83%, respectively, for CT alone and 81% (p = .06), 88% (p = .03), and 89% (p > .25), respectively, for CT with FDG PET. Also, supplemental FDG PET imaging improved observer confidence and accuracy in diagnosing recurrent neoplasm in four (36%) of 11 patients who had undergone surgery or chemoradiation and in diagnosing four (29%) of 14 extrahepatic sites that had potential metastases. CONCLUSION: Diagnosis of malignancy in oncologic patients is significantly improved when CT is supplemented with FDG PET. Combined imaging is particularly helpful in the evaluation of potential recurrence in previously treated patients and for diagnosing extrahepatic lesions that may be distant metastases.

Abdominal Neoplasms↗

PubMed1998

Glucose metabolism in human malignant gliomas measured quantitatively with PET, 1-[C-11]glucose and FDG: analysis of the FDG lumped constant.

UNLABELLED: Calculation of the glucose metabolic rate (MRGlc) in brain with PET and 2-[18F]fluoro-2-deoxy-D-glucose (FDG) requires knowing the rate of uptake of FDG relative to glucose from plasma into metabolite pools in the tissue. The proportionality factor for this is the FDG lumped constant (LC[FDG]), the ratio of the volumes of distribution of FDG and glucose multiplied by the hexokinase phosphorylation ratio for the two hexoses, Km(Glc) x Vm(FDG)/Km(FDG) x Vm(Glc) x MRGlc equals the FDG metabolic rate (MRFDG) divided by the LC(FDG), i.e., MRGlc = MRFDG/LC(FDG) and LC(FDG) = MRFDG/MRGlc. This investigation tested the hypothesis that LC(FDG) is significantly higher in gliomas than it is in brain uninvolved with tumor. METHODS: We imaged 40 patients with malignant gliomas with 1-[11C]glucose followed by FDG. The metabolic rates MRGlc and MRFDG were estimated for glioma and contralateral brain regions of interest by an optimization program based on three-compartment, four-rate constant models for the two hexoses. RESULTS: The LC(FDG), estimated as MRFDG/MRGlc, in gliomas was 1.40 +/- 0.46 (mean +/- s.d.; range = 0.72-3.10), whereas in non-tumor-bearing contralateral brain, it was 0.86 +/- 0.14 (range = 0.61-1.21) (p < 0.001, glioma versus contralateral brain). CONCLUSION: These data strongly suggest that the glioma LC(FDG) exceeds that of contralateral brain, that quantitation of the glioma MRGlc with FDG requires knowing the LC(FDG) specific for the glioma and that the LC(FDG) of normal brain is higher than previously reported estimates of about 0.50. 2-Fluoro-2-deoxy-D-glucose/PET studies in which glioma glucose metabolism is calculated by the autoradiographic approach with normal brain rate constants and LC(FDG) will overestimate glioma MRGlc, to the extent that the glioma LC(FDG) exceeds the normal brain LC(FDG). "Hot spots" visualized in FDG/PET studies of gliomas represent regions where MRGlc, LC(FDG) or their product is higher in glioma than it is in uninvolved brain tissue.

Autoradiography↗

PubMed1998

Kinetic analysis of 2-[carbon-11]thymidine PET imaging studies: compartmental model and mathematical analysis.

UNLABELLED: Carbon-11-thymidine is a PET tracer of DNA synthesis and cellular proliferation. Quantitative analysis of [11C]thymidine images is complicated by the presence of significant quantities of labeled metabolites. Estimation of the rate of thymidine incorporation into DNA using [11C]thymidine requires a kinetic model that is capable of describing the behavior of thymidine and labeled metabolites. METHODS: Based on previous studies with labeled thymidine, we constructed a five-compartment model describing the kinetic behavior of 2-[11C]thymidine and its labeled metabolites. In addition, we have performed a series of calculations and simulations to calculate the sensitivity and identifiability of model parameters to estimate the extent to which individual parameters can be estimated; to determine appropriate model constraints necessary for reproducible estimates of the constant describing flux of thymidine from the blood into DNA, i.e., thymidine flux constant; and to determine the potential accuracy of model parameter and thymidine flux constant estimates from PET imaging data. RESULTS: The underlying assumptions in the thymidine compartmental model lead to a description of the thymidine flux constant for DNA incorporation in terms of model parameters. Sensitivity and identifiability analyses suggest that the model parameters pertaining to labeled metabolites will be difficult to estimate independently of the thymidine parameters. Exact evaluation of the kinetic parameters of the labeled metabolites is not the principal goal of this model. Simulations were performed that suggest that it is preferable to tightly constrain these parameters to preset values near the center of their expected ranges. Although it is difficult to estimate individual thymidine model parameters, the flux constant for incorporation into DNA can be accurately estimated (r > 0.9 for estimated versus true simulated flux constant). Flux constant estimates are not affected by modest levels of local degradation of thymidine that may occur in proliferating tissue. CONCLUSION: By using a kinetic model for thymidine and labeled metabolites, it is possible to estimate the flux of thymidine uptake and incorporation into DNA and, thereby, noninvasively estimate regional cellular proliferation using [11C]thymidine and PET.

Carbon Radioisotopes↗

PubMed1998

Carbon-11-thymidine and FDG to measure therapy response.

UNLABELLED: This study was performed to determine if PET imaging with 11C-thymidine could measure tumor response to chemotherapy early after the initiation of treatment. Imaging of deoxyriboneucleic acid biosynthesis, quantitated with 11C-thymidine, was compared with measurements of tumor energetics, obtained by imaging with 18F-fluorodeoxyglucose (FDG). METHODS: We imaged four patients with small cell lung cancer and two with high-grade sarcoma both before and approximately 1 wk after the start of chemotherapy. Thymidine and FDG studies were done on the same day. Tumor uptake was quantified by standardized uptake values (SUVs) for both tracers by the metabolic rate of FDG and thymidine flux constant (K(TdR)) using regions of interest placed on the most active part of the tumor. RESULTS: In the four patients with clinical response to treatment, both thymidine and FDG uptake markedly declined 1 wk after therapy. Thymidine measurements of SUV and K(TdR) declined by 64% +/- 15% and 84% +/- 33%, respectively. FDG SUV and the metabolic rate of FDG declined by 51% +/- 9% and 63% +/- 23%, respectively. In the patient with metastatic small cell lung cancer who had disease progression, the thymidine SUV decreased by only 8% (FDG not done). In a patient with abdominal sarcoma and progressive disease, thymidine SUV was essentially unchanged (declined by 3%), whereas FDG SUV increased by 69%. CONCLUSION: Images show a decline in both cellular energetics and proliferative rate after successful chemotherapy. In the two patients with progressive disease, thymidine uptake was unchanged 1 wk after therapy. In our limited series, K(TdR) measurements showed a complete shutdown in tumor proliferation in patients in whom FDG showed a more limited decrease in glucose metabolism.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1998

1-[Carbon-11]-glucose radiation dosimetry and distribution in human imaging studies.

UNLABELLED: 1-[Carbon-11]-D-glucose ([11C]-glucose) is an important imaging agent for PET studies that have been used to study the normal brain, encephalitis, epilepsy, manic-depressive disorder, schizophrenia and brain tumors. METHODS: Dosimetry estimates were calculated in subjects undergoing imaging studies to help define the radiation risk of [11C]-glucose PET imaging. Time-dependent radioactivity concentrations in normal tissues in 33 subjects after intravenous injection of [11C]-glucose were obtained by PET imaging. Radiation absorbed doses were calculated according to the procedures of the Medical Internal Radiation Dose (MIRD) committee along with the variation in dose based on the calculated standard deviation of activity distribution seen in the individual patients. RESULTS: Total body exposure was a median of 3.0 microGy/MBq in men and 3.8 microGy/MBq in women. The effective dose equivalent was 3.8 microGy/ MBq in men and 4.8 microGy/MBq in women. The critical organs were those that typically take up the most glucose (brain, heart wall and liver). CONCLUSION: The organ doses reported here are small and comparable to those associated with other commonly performed nuclear medicine tests and indicate that potential radiation risks associated with this radiotracer are within generally accepted limits.

Carbon Radioisotopes↗

PubMed1997

Feasibility of imaging pentose cycle glucose metabolism in gliomas with PET: studies in rat brain tumor models.

UNLABELLED: The feasibility of imaging pentose cycle (PC) glucose utilization in human gliomas with PET was explored in two rat glioma models by means of glucose radiolabeled in either the carbon-1 (C-1) or carbon-6 (C-6) position. METHODS: In vitro, monolayers of T-36B-10 glioma, tissue slices of intracerebral glioma grafts or slices of normal brain were fed [1-14C]glucose or [6-14C]glucose, and the generated [14C]CO2 was trapped to quantitate the ratio of [14C]CO2 from 14C-1 versus 14C-6. In vivo, rats bearing grafts of either T-36B-10 or T-C6 rat gliomas at six subcutaneous sites received simultaneous intravenous injections of either [1-11C]glucose and [6-14C]glucose, or [1-14C]glucose and [6-11C]glucose. Tumors were excised between 5 and 55 min postinjection to quantify tracer uptake while arterial plasma was collected to derive time-activity input curves. RESULTS: In vitro, the C-1/C-6 ratio for CO2 production from T-36B-10 monolayers was 8.8 +/- 0.4 (s.d.), in glioma slices it was 6.1 +/- 2.1 and in normal brain slices it was 1.1 +/- 0.7. PC metabolism in T-36B-10 was 1.8% +/- 0.5 of total glucose utilization. In vivo, tumor radioactivity levels normalized by plasma isotopic glucose levels showed that retained C-1 relative to C-6 radiolabeled glucose was significantly lower in both gliomas, 4.9% lower in T-36B-10 (p < 0.01) and 4.7% lower in T-C6 (p < 0.01). In an additional group of rats bearing T-36B-10 gliomas and exposed to 10 Gy of 137Cs irradiation 4 hr before isotope injection, the C-1 level was 5.6% lower than that for C-6 (p < 0.05). These results were analyzed with a model of glucose metabolism that simultaneously optimized parameters for C-1 and C-6 glucose kinetics by simulating the C-1 and C-6 tumor time-activity curves. The rate constant for loss of radiolabeled carbon from the tumors, k4, was higher for C-1 than for C-6 in all groups of rats (19% higher for T-36B-10 unirradiated, 32% for T-36B-10 irradiated and 32% for T-C6 unirradiated). CONCLUSION: Mathematical modeling, Monte Carlo simulations and construction of receiver-operator-characteristic curves show that if human gliomas have a similar fractional use of the PC, it should be measurable with PET using sequential studies with [1-11C]glucose and [6-11C]glucose.

Animals↗

PubMed1997

Physiologic smoothing of blood time-activity curves for PET data analysis.

UNLABELLED: Blood or plasma time-activity curves (TACs) are used as the input function for mathematical models of tracer kinetics in several applications including PET. Uncertainty associated with both the blood data and the PET tissue data can result in uncertainty in the estimates of metabolic rates, blood flow, etc. METHODS: This article presents an approach to reduce the uncertainty in the blood TAC by fitting a model to the curve. The model includes a choice of bolus or infusion input and has three compartments (plasma, interstitial fluid and tissue fluid) with exchange between them. There is a parameter for loss from the plasma compartment. To test the utility of smoothing blood TACs with this approach, a program was set up, using the fluorodeoxyglucose (FDG) model, with simulated noisy blood and tissue TACs. The smoothed blood TAC was compared to a linearly interpolated TAC as the input function with a compartmental model parameter estimation program and with graphical analysis. RESULTS: With a well sampled blood TAC (19 points), the model approach is somewhat more accurate than linear interpolation if the s.d. of noise added to the data exceeded 10%. With sparsely sampled blood TACs (five points) or with a large gap in the blood TAC, the modeled approach was markedly better. For graphical analysis, the model smoothed TAC was also more accurate, although, in general, the results were not as sensitive to the input function. CONCLUSION: This approach, using a physiologically reasonable model to smooth the blood TAC, is a useful aid in PET data analysis, particularly when the data are quite noisy or when there are large gaps in the data.

Computer Simulation↗

PubMed1997

Fluorine-18-fluoromisonidazole radiation dosimetry in imaging studies.

UNLABELLED: Fluoromisonidazole (FMISO), labeled with the positron emitter 18F, is a useful hypoxia imaging agent for PET studies, with potential applications in patients with tumors, cardiovascular disease and stroke. METHODS: Radiation doses were calculated in patients undergoing imaging studies to help define the radiation risk of FMISO-PET imaging. Time-dependent concentrations of radioactivity were determined in blood samples and PET images of patients following intravenous injection of [18F]FMISO. Radiation absorbed doses were calculated using the procedures of the Medical Internal Radiation Dose (MIRD) committee, taking into account the variation in dose based on the distribution of activities observed in the individual patients. As part of this study we also calculated an S value for brain to eye. Effective dose equivalent was calculated using ICRP 60 weights. RESULTS: Effective dose equivalent was 0.013 mSv/MBq in men and 0.014 mSv/MBq in women. Individual organ doses for women were not different from men. Assuming bladder voiding at 2- or 4-hr intervals, the critical organ that received the highest dose was the urinary bladder wall (0.021 mGy/MBq with 2-hr voiding intervals or 0.029 mGy/MBq with 4-hr voiding intervals). CONCLUSION: The organ doses for [18F]FMISO are comparable to those associated with other commonly performed nuclear medicine tests and indicate that potential radiation risks associated with this study are within generally accepted limits.

Female↗

PubMed1996

Quantifying regional hypoxia in human tumors with positron emission tomography of [18F]fluoromisonidazole: a pretherapy study of 37 patients.

PURPOSE: To assess pretreatment hypoxia in a variety of tumors using positron emission tomography (PET) after injection of the hypoxia-binding radiopharmaceutical [18F]fluoromisonidazole ([18F]FMISO). METHODS AND MATERIALS: Tumor fractional hypoxic volume (FHV) was determined in 21 nonsmall cell lung cancer patients, 7 head and neck cancer patients, 4 prostate cancer patients, and 5 patients with other malignancies by quantitative PET imaging after injection of [18F]FMISO (0.1 mCi/kg). The FHV was defined as the proportion of pixels in the imaged tumor volume with a tissue:blood [18F] activity ratio > or = 1.4 at 120-160 min postinjection. A FHV > 0 was taken as evidence for tumor hypoxia. RESULTS: Hypoxia was observed in 36 of 37 tumors studied with FMISO PET imaging; FHVs ranged from 0 to 94.7%. In nonsmall cell lung cancers (n = 21), the median FHV was 47.6% and the range, 1.3 to 94.7%. There was no correlation between tumor size and FHV. In the seven head and neck carcinomas, the median FHV was 8.8%, with a range from 0.2 to 18.9%. In the group of four prostate cancers, the median and range were 18.2% and 0 to 93.9%, while in a group of five tumors of different types the median FHV was 55.2% (range: 21.4 to 85.8%). CONCLUSIONS: Hypoxia was present in 97% of the tumors studied and the extent of hypoxia varied markedly between tumors in the same site or of the same histology. Hypoxia also was distributed heterogeneously between regions within a single tumor. These results are consistent with O2 electrode measures with other types of human tumors. The intra- and intertumor variability indicate the importance of making oxygenation measures in individual tumors and the necessity to sample as much of the tumor volume as possible.

Carcinoma, Non-Small-Cell Lung↗

PubMed1996

Effect of glucose on uptake of radiolabeled glucose, 2-DG, and 3-O-MG by the perfused rat liver.

In the transition from the fasting to the fed state, plasma glucose levels rise, and the liver converts from an organ producing glucose to one of storage. To determine the effect of glucose on hepatic glucose uptake, radiolabeled glucose, 2-deoxyglucose, and 3-O-methylglucose were injected into perfused rat livers during different nontracer glucose levels, and the concentrations in the outflow were measured. A mathematical model was developed that described the behavior of the injected compounds as they traveled through the liver and was used to simulate and fit the experimental results. The rates of membrane transport, glucokinase, glucose-6-phosphatase, and the consumption of glucose 6-phosphate were estimated. Membrane transport for all of the tracers decreased as nontracer glucose increased, demonstrating competitive inhibition of the glucose transporter. In contrast, the consumption of injected [2-14C]glucose increased when glucose was elevated, demonstrating that glucose caused an activation of enzyme activity that overcame the competitive inhibition of transport and phosphorylation. When glucose was elevated, the rate coefficient of glucokinase did not decrease, indicating that glucokinase was stimulated by glucose. Both changes would lead to the increased glycogen synthesis and decreased glucose production rate observed in vivo during the fasted-to-fed transition.

3-O-Methylglucose↗

PubMed1996

Collaboration using Internet for the development of case-based teaching files: report of the Computer and Instrumentation Council Internet Focus Group.

UNLABELLED: The Internet and particularly the World-Wide-Web is becoming a useful tool for the nuclear medicine community. METHODS: The Computer and Instrumentation Council of the Society of Nuclear Medicine convened an Internet Focus group to discuss collaboration using the Internet. The prototype application considered was development of case-based teaching files using the World-Wide-Web. Teaching file cases (clinical history, images, description of findings and discussion) on World-Wide-Web servers at different institutions are integrated using the Internet. The user can navigate from case to case using point-and-click hypertext linking. RESULTS: The initial experience with collaboration has been encouraging. An etiquette to help foster collaboration has been proposed. Development of quality control mechanisms and introduction of peer review were identified as issues needing further work. CONCLUSION: The World-Wide-Web offers great potential for new forms of collaboration. There is, however, a need to learn how to make best use of this new resource.

Computer Communication Networks↗

PubMed1996

Analysis of 2-carbon-11-thymidine blood metabolites in PET imaging.

UNLABELLED: Carbon-11-thymidine labeled in the ring-2 position was used with PET to image tumor and tissue proliferation. Since thymidine is rapidly degraded in the body, one must consider the generation of metabolites to fully interpret the PET data. METHODS: We have measured the blood time-activity curves of thymidine and its metabolites in arterial blood samples. Blood was processed to obtain three input curves, including the total activity, the activity with CO2 removed and the fraction of CO2-free activity in intact thymidine (% Tdr). RESULTS: We found that CO2 reached a plateau of 65% (+/- 12%) of total blood activity by 11 min after injection. When a 1-min infusion of labeled thymidine is used, the time to 50% degradation to thymine and metabolites other than CO2 (measured in acidified samples by HPLC) was 2.9 +/- 0.6 min. We fit the results of the blood metabolism with a compartmental model. We found that we could accurately determine the % Tdr curve with as few as three measured points with an root mean square (RMS) error of 2% in the integrated curve, compared to the curve using all blood samples (mean of seven samples per patient). The integral of thymidine blood activity serves as the input to thymidine models, so similar errors could be expected in calculations of DNA synthetic rates. We found that the determination of CO2 could be accomplished with as few as five samples, with an RMS error of 4% in plateau %CO2 value. CONCLUSION: While it is essential to take metabolites into account when interpreting results obtained with 11C-thymidine, the reproducibility of these degradation curves may allow the use of a limited number of samples to measure the catabolic products of thymidine. These data from the blood, along with tissue kinetic models, are needed to calculate DNA synthetic rates.

Carbon Dioxide↗

PubMed1996

A graphical analysis method to estimate blood-to-tissue transfer constants for tracers with labeled metabolites.

UNLABELLED: The Patlak graphical analysis technique is a popular tool for estimating blood-to-tissue transfer constants from multiple-time uptake data. Our objective was to extend this technique to tracers with labeled metabolites, the presence of which can cause errors in the standard Patlak analysis. METHODS: Based on previously described formulations, we generalized the graphical technique for use under specific conditions. To test the extended graphical approach, we applied the method to both simulated and patient data using a preliminary compartmental model for the PET tumor proliferation marker, 2-[11C]-thymidine. RESULTS: When given conditions are met, a linear relationship exists between the normalized tissue activity (tissue activity/blood activity) and a new set of graphical analysis basis functions, including a new definition of normalized time, which takes the presence of labeled metabolites into account. Graphical estimations of the tumor thymidine incorporation rate for simulated data were accurate and showed close agreement to the results of detailed compartmental analysis. In patient studies, the graphical and compartmental estimates showed good agreement but a somewhat poorer correlation than in the simulations. CONCLUSION: The extended graphical analysis approach provides an efficient method for estimating blood-tissue transfer constants for tracers with labeled metabolites.

Carbon Radioisotopes↗

PubMed1995

Evaluation of oxygenation status during fractionated radiotherapy in human nonsmall cell lung cancers using [F-18]fluoromisonidazole positron emission tomography.

PURPOSE: Recent clinical investigations have shown a strong correlation between pretreatment tumor hypoxia and poor response to radiotherapy. These observations raise questions about standard assumptions of tumor reoxygenation during radiotherapy, which has been poorly studied in human cancers. Positron emission tomography (PET) imaging of [F-18]fluoromisonidazole (FMISO) uptake allows noninvasive assessment of tumor hypoxia, and is amenable for repeated studies during fractionated radiotherapy to systematically evaluate changes in tumor oxygenation. METHODS AND MATERIALS: Seven patients with locally advanced nonsmall cell lung cancers underwent sequential [F-18]FMISO PET imaging while receiving primary radiotherapy. Computed tomograms were used to calculate tumor volumes, define tumor extent for PET image analysis, and assist in PET image registration between serial studies. Fractional hypoxic volume (FHV) was calculated for each study as the percentage of pixels within the analyzed imaged tumor volume with a tumor:blood [F-18]FMISO ratio > or = 1.4 by 120 min after injection. Serial FHVs were compared for each patient. RESULTS: Pretreatment FHVs ranged from 20-84% (median 58%). Subsequent FHVs varied from 8-79% (median 29%) at midtreatment, and ranged from 3-65% (median 22%) by the end of radiotherapy. One patient had essentially no detectable residual tumor hypoxia by the end of radiation, while two others showed no apparent decrease in serial FHVs. There was no correlation between tumor size and pretreatment FHV. CONCLUSIONS: Although there is a general tendency toward improved oxygenation in human tumors during fractionated radiotherapy, these changes are unpredictable and may be insufficient in extent and timing to overcome the negative effects of existing pretreatment hypoxia. Selection of patients for clinical trials addressing radioresistant hypoxic cancers can be appropriately achieved through single pretreatment evaluations of tumor hypoxia.

Aged↗

PubMed1995

Induction of DNA single-strand breaks in human lymphocytes by low doses of gamma-rays.

We hypothesized that very low doses of gamma-rays have a genotoxic effect as measured by DNA single-strand breaks (ssbs). To test our hypothesis we used a newly developed alkaline microgel electrophoretic technique to quantitate DNA ssbs in freshly isolated human lymphocytes. An enhanced sensitivity to detect low levels of DNA damage was made possible by this method due to an additional step of DNA precipitation by ethanol in agarose microgels. We exposed lymphocytes from three subjects for 1 h at 4 degrees C to 740 MBq of technetium 99-m at a distance of 20 cm (0.25 mGy), 10 cm (1.02 mGy), and 5 cm (4.08 mGy) from the source vial. Doses of 1.02 and 4.08 mGy induced a significant dose-dependent increase in DNA ssbs in human lymphocytes from three subjects, each examined on three different days.

DNA Damage↗

PubMed1995

A modeling approach for quantifying tumor hypoxia with [F-18]fluoromisonidazole PET time-activity data.

[F-18]fluoromisonidazole (FMISO), a positron-emitting nitroimidazole, binds preferentially to hypoxic cells. It has been used to image hypoxia in human tumors with positron emission tomography (PET). In order to quantify tumor oxygenation status from these PET data, a kinetic model of FMISO cellular bioreduction has been developed to relate cellular oxygen concentration to the cellular FMISO reaction rate constant, kappa A. Also, a compartmental model of FMISO transport and metabolism has been developed to compute the volume average kappa A in tissue regions from [F-18]FMISO PET time-activity data. This compartmental model was characterized using Monte Carlo simulations and [F-18]FMISO PET time-activity data. The model performed well in Monte Carlo simulations; performance was enhanced by fixing three of the seven model parameters at physiologically reasonable values. The four parameters optimized were blood flow rate, kappa A for two partial volume/spillover correction factors. The model was able to accurately determine kappa A for a variety of computer-generated time-activity curv including those for hypothetical heterogeneous tissue regions and poorly perfused tissue regions. The model was also able to fit [H-3]FMISO time-activity data from 36B-10 rat tumors as well as [F-18]FMISO PET time-activity data from a human patient with a base of the tongue squamous cell carcinoma. The kappa A values in muscles ROIs were comparable to those in well-oxygenated cell monolayers while kappa A values in tumor ROIs were greater, suggesting the presence of hypoxic cells in the tumor.

Animals↗

PubMed1995

Acetazolamide slows VA/Q matching after changes in regional blood flow.

Inhibition of carbonic anhydrase (CA) by acetazolamide increases ventilation-perfusion (VA/Q) heterogeneity (E. R. Swenson, H. T. Robertson, and M. P. Hlastala. J. Clin. Invest. 92: 702-709, 1993), possibly because of slowing of CO2/H(+)-dependent mechanisms of VA/Q matching with temporal fluctuations of regional ventilation and perfusion. To study this concept, we imposed abrupt changes in regional perfusion by lobar or left main pulmonary artery occlusions (PAOs) in anesthetized mechanically ventilated dogs before and after CA inhibition (20 mg/kg iv acetazolamide). The rate of ventilation redistribution and change in VA/Q distributions with changes in perfusion were measured by planar gamma imaging of the lungs during continuous inhalation of 81mKr gas ventilation scanning and the multiple inert-gas elimination technique. PAO for 5 min caused regional Kr activity to fall by 30 +/- 5% (SD) with a half time (t1/2) of 75 +/- 10 s. With release of the occlusion, counts returned to baseline with t1/2 of 79 +/- 12 s. Acetazolamide increased these respective t1/2 values (161 +/- 16 and 180 +/- 17 s). Consistent with these kinetics, VA/Q mismatch was greater with lobar PAO at 2 min but not at 10 min with CA inhibition compared with that caused by lobar PAO alone. Cyclical lobar PAO and release (10 cycles of 1-min occlusion and 1-min release) caused more VA/Q heterogeneity during CA inhibition. The arterial-to-alveolar inert-gas area difference rose minimally from 0.18 to 0.23 (P < 0.05) with cyclical PAO and from 0.24 to 0.48 (P < 0.01) after CA inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetazolamide↗

PubMed1994

Mechanism by which the prone position improves oxygenation in acute lung injury.

The mechanism by which oxygenation improves when patients with ARDS are turned from supine to prone position is not known. From results of our previous studies we reasoned that (1) when supine, in the setting of lung injury, transpulmonary pressure will be less than airway opening pressure and (2) atelectasis will develop preferentially in dorsal lung areas, and (3) both ventilation and ventilation/perfusion ratios would improve in these regions on turning prone. To study this directly, we measured regional ventilation and perfusion using 81mKr and 99mTc-MAA, respectively, and single photon emission computed tomography, both prone and supine, in four control animals and four given oleic acid. After oleic acid, the prone position improved (1) oxygenation (mean +/- SD PaO2 = 140 +/- 112 versus 453 +/- 54 mm Hg), (2) median ventilation/perfusion ratios (0.77 versus 0.95), (3) ventilation/perfusion heterogeneity (coefficient of variation 86 +/- 15 versus 61 +/- 6), and (4) the gravitational ventilation/perfusion gradient (dependent to non-dependent slopes of 0.22 versus -0.02, all p < 0.05). The prone position generates a transpulmonary pressure sufficient to exceed airway opening pressure in dorsal lung regions, i.e., in regions where atelectasis, shunt, and ventilation/perfusion heterogeneity are most severe, without adversely affecting ventral lung regions.

Animals↗