[(18)F]FMISO and [(18)F]FDG PET imaging in soft tissue sarcomas: correlation of hypoxia, metabolism and VEGF expression.

Hypoxia imparts resistance to radiotherapy and chemotherapy and also promotes a variety of changes in tumor biology through inducible promoters. The purpose of this study was to evaluate the use of positron emission tomography (PET) imaging with fluorine-18 fluoromisonidazole (FMISO) in soft tissue sarcomas (STS) as a measure of hypoxia and to compare the results with those obtained using [(18)F]fluorodeoxyglucose (FDG) and other known biologic correlates. FDG evaluates energy metabolism in tumors while FMISO uptake is proportional to tissue hypoxia. FMISO uptake was compared with FDG uptake. Vascular endothelial growth factor (VEGF) expression was also compared with FMISO uptake. Nineteen patients with STS underwent PET scanning with quantitative determination of FMISO and FDG uptake prior to therapy (neo-adjuvant chemotherapy or surgery alone). Ten patients receiving neo-adjuvant chemotherapy were also imaged after chemotherapy but prior to surgical resection. Standardized uptake value (SUV) was used to describe FDG uptake; regional tissue to blood ratio (>or=1.2 was considered significant) was used for FMISO uptake. Significant hypoxia was found in 76% of tumors imaged prior to therapy. No correlation was identified between pretherapy hypoxic volume (HV) and tumor grade ( r=0.15) or tumor volume ( r=0.03). The correlation of HV with VEGF expression was 0.39. Individual tumors showed marked heterogeneity in regional VEGF expression. The mean pixel-by-pixel correlation between FMISO and FDG uptake was 0.49 (range 0.09-0.79) pretreatment and 0.32 (range -0.46-0.72) after treatment. Most tumors showed evidence of reduced uptake of both FMISO and FDG following chemotherapy. FMISO PET demonstrates areas of significant and heterogeneous hypoxia in soft tissue sarcomas. The significant discrepancy between FDG and FMISO uptake seen in this study indicates that regional hypoxia and glucose metabolism do not always correlate. Similarly, we did not find any relationship between the hypoxic volume and the tumor volume or VEGF expression. Identification of hypoxia and development of a more complete biologic profile of STS will serve to guide more rational, individualized cancer treatment approaches.

Evidence for the expression of radiation-induced potentially lethal damage being a p53-dependent process.

PURPOSE: To test the hypothesis that the expression of potentially lethal damage (PLD) is a p53-dependent process. MATERIALS AND METHODS: Previously reported data on radiation sensitivity, DNA double-strand break rejoining, PLD expression and repair (PLDR) were analyzed for a group of 12 human tumor cell lines and three human diploid fibroblast cell lines. Seven of these cell lines had normal p53 gene expression while the other eight were functionally p53-deficient. None of the cell lines was sensitive to radiation-induced apoptosis. RESULTS: Cell lines with a normal p53 expression were more sensitive to radiation, but only when sensitivity was measured in plateau-phase cultures under conditions where PLDR was minimized. Mutation or functional inactivation of p53 by HPV E6-transformation led to a more radioresistant phenotype under these conditions as well as a significant reduction in PLDR. PLDR was inversely proportional to the percentage of radiation-induced DNA double-strand breaks rejoined in 1 h in the p53 normal cell lines. CONCLUSIONS: These results suggest that the expression of PLD is primarily a p53-dependent process. In the absence of functional p53 gene expression, the effects of PLD are minimized. These observations help clarify the role of p53 in tumor response to radiation therapy because they suggest that the effects of alterations in p53 are highly dependent on the microenvironment of the tumor, i.e. whether conditions allow for PLDR.

Inhibition of rat smooth muscle proliferation by radiation after arterial injury: temporal characteristics in vivo and in vitro.

Although several studies have suggested that inhibition of arterial narrowing by radiation after angioplasty is dependent on both time and dose, little is known regarding the temporal aspects of this effect and the mechanisms by which radiation affects the response of smooth muscle cells to injury. To determine the time course of inhibition of intimal hyperplasia by radiation, 135 rats were given single-fraction external gamma irradiation (1-10 Gy) to one carotid artery at intervals from 5 days before to 5 days after bilateral carotid artery balloon catheter injury, and intimal cross-sectional area was determined from histological sections at 20 days after injury. There was a prominent time- and dose-dependent inhibition of intimal hyperplasia by radiation when it was administered before or after balloon injury, with the greatest effect noted within 24 h before or after injury. To investigate the effect of radiation on smooth muscle cell growth (by cell counting) and proliferation, cell cycle kinetics (by BrdU incorporation), and cell killing (by clonogenic assay), smooth muscle cell cultures derived from rat aortic explants were seeded in equine plasma to induce quiescence, and radiation (2.5-10 Gy) was administered at various intervals before or after synchronous growth stimulation by 10% whole blood serum. A similar time and dose dependence was noted in growth kinetics, BrdU incorporation and cell killing for smooth muscle cells irradiated in vitro; in each case, the effect was most prominent for radiation administered in temporal proximity to stimulation with whole blood serum. By Western blot analysis, cultured smooth muscle cells showed a rapid time-dependent increase in Cdkn1a (formerly known as p21) protein expression, followed by a delayed increase in Tp53 (formerly known as p53) expression after irradiation. Activation of intracellular caspases, manifest by proteolytic poly(ADP-ribose) polymerase (PARP) cleavage, was not detected in smooth muscle cell cultures after irradiation. These observations suggest that radiation limits intimal hyperplasia in vivo by a transient, reversible process. Although apparent cytotoxic injury occurs in vitro, apoptosis of smooth muscle cells is not apparent. Both inhibition of proliferation of smooth muscle cells and cell cycle delay may contribute to inhibition of intimal hyperplasia in vivo by radiation.

Determining hypoxic fraction in a rat glioma by uptake of radiolabeled fluoromisonidazole.

The usefulness of radiolabeled nitroimidazoles for measuring hypoxia will be clarified by defining the relationship between tracer uptake and radiobiologically hypoxic fraction. We determined the radiobiologically hypoxic fraction from radiation response data in 36B10 rat gliomas using the paired cell survival curve technique and compared the values to the radiobiologically hypoxic fraction inferred from mathematical modeling of time-activity data acquired by PET imaging of [(18)F]FMISO uptake. Rats breathed either air or 10% oxygen during imaging, and timed blood samples were taken. The uptake of [(3)H]FMISO by 36B10 cells in vitro provided cellular binding characteristics of this radiopharmaceutical as a function of oxygen concentration. The radiobiologically hypoxic fraction determined for tumors in air-breathing rats using the paired survival curve technique was 6.1% (95% CL = 4.3- 8.6%), which agreed well with that determined by modeling FMISO time-activity data (7. 4%; 95% CL = 2.5-17.3%). These results are consistent with the agreement between the two techniques for measuring radiobiologically hypoxic fraction in Chinese hamster V79 cell spheroids. In contrast, the FMISO-derived radiobiologically hypoxic fraction in rats breathing 10% oxygen was 13.1% (95% CL 7.9-8.3%), much lower than the radiobiologically hypoxic fraction of 43% determined from the radiation response data. This discrepancy may be due to the failure of FMISO to identify hypoxic cells residing at or above an oxygen level of 2-3 mmHg that will still confer substantial protection against radiation. The presence of transiently hypoxic cells in rats breathing reduced oxygen may also be under-reported by nitroimidazole binding, which is strongly dependent on time and concentration.

Principles of radioimmunotherapy for hematologists and oncologists.

Recent trials with radiolabeled monoclonal antibodies targeting lymphoid surface membrane antigens have shown high response rates and tolerable toxicity. Radiolabeled antibodies emit continuous, exponentially decreasing, low-dose-rate radiation, whereas conventional external-beam radiotherapy delivers intermittent, fractionated radiation at higher dose rates. The most common isotopes used for radioimmunotherapy (iodine 131 and yttrium 90) kill cells primarily by emission of beta particles (electrons), which are believed to induce DNA strand breaks. The beta particles of Y 90 are more energetic than those of I 131, and affect cells over a radius of 5 mm compared with 0.9 mm to 1.0 mm for I 131. In addition, I 131 emits long-range gamma rays that permit direct imaging with a gamma camera, but also deliver a whole-body radiation dose and may pose a risk to health care workers. Physical barriers to effective delivery of radioimmunotherapy include the heterogeneous tumor vasculature, slow diffusion and convection rates of large antibody molecules through the interstitial fluid, heterogeneous biodistribution of antibodies in tumor nodules, and high intratumoral pressures impeding antibody influx into tumors. Despite these obstacles, multiple trials have shown the efficacy of radioimmunotherapy, particularly for B-cell lymphomas treated with anti-CD20 antibodies, in which response rates of 60% to 90% have been reported.

Characterization of [18F]fluoroetanidazole, a new radiopharmaceutical for detecting tumor hypoxia.

UNLABELLED: Fluorinated derivatives of etanidazole are being explored as probes for tumor hypoxia. Our research group has synthesized [18F]fluoroetanidazole (FETA) and now reports the oxygen dependency of binding to cells in vitro, the biodistribution of the tracer in tumor-bearing mice and the analysis of metabolites in their plasma and urine. METHODS: Four cultured rodent cell lines (V79, 36B10, EMT6 and RIF1) were incubated with [18F]FETA for various times under graded O2 concentrations. We also compared the biodistributions of [18F]FETA and [18F]fluoromisonidazole (FMISO) at 2 and 4 h postinjection in C3H mice bearing KHTn tumors (130-430 mg). Reverse-phase high-performance liquid chromatography was used to distinguish metabolites from parent drugs in urine and plasma of mice injected with [18F]FETA or [18F]FMISO. RESULTS: In cells labeled in vitro, O2 levels of 600-1300 ppm inhibited binding by 50% relative to uptake under anoxic conditions (<10 ppm). These inhibitory values are not statistically different from those reported for [18F]FMISO in the same cell lines (700-1500 ppm). In the biodistribution studies, uptake in heart, intestine, kidney and tumor was similar for both tracers 4 h after injection, whereas retention of [18F]FETA in liver and lung was significantly lower. Less uptake of [18F]FETA in liver suggests that this nitroimidazole is metabolized less than [18F]FMISO. The brain-to-blood ratios indicate that [18F]FETA readily crosses the blood-brain barrier. High-performance liquid chromatography of urine demonstrated that 10% of [18F]FETA-derived activity was in metabolites at 2 h postinjection, with 15% in metabolites by 4 h; comparable values for [18F]FMISO were 36% and 57%, respectively. CONCLUSION: We conclude from these data that [18F]FETA holds promise as a new hypoxia tracer in patients, having oxygen dependency of binding similar to [18F]FMISO in vitro and displaying less retention in liver and fewer metabolites in vivo.

Growth of human tumor cells in macroporous microcarriers results in p53-independent, decreased cisplatin sensitivity relative to monolayers.

Multicellular contact has been shown to influence the in vitro sensitivity of cells to drug treatment. We investigated the use of macroporous gelatin microcarriers, CultiSpher-G, as a convenient laboratory system for the molecular analysis of this "contact effect". We determined that human A549 cells can be grown in CultiSphers with growth and cell cycle parameters similar to those of monolayers. In addition, cells in CultiSphers express less p27/kip1, an indicator of cell cycle arrest, than equivalent cells in monolayers. When treated with drugs, A549 cells grown in CultiSphers or monolayers accumulate equivalent amounts of platinum-DNA adducts and similar amounts of doxorubicin. Moreover, A549 and KB-3-1 cells in CultiSphers have significantly decreased sensitivity to cis-platinum(II)diammine dichloride (cisplatin), 4-hydroperoxycyclophosphamide, doxorubicin, and paclitaxel (taxol) compared with cells in monolayers when assayed by clonogenic survival. Cisplatin treatment in monolayers or CultiSphers did not result in apoptotic cell death. In contrast, paclitaxel caused a significant amount of sub-G1 DNA, an indicator of apoptosis, which was diminished when cells were grown in CultiSphers compared with monolayers. When grown in CultiSphers, cells with abrogated p53 function (A549/16E6 and NCI-H1299) were less sensitive to cisplatin than the corresponding monolayer cells, indicating that the decrease in sensitivity is p53 independent. Taken together, the data suggest that CultiSpher-G microcarriers are a useful in vitro system to examine the effects of three-dimensional cell contact on drug sensitivity of human tumor cells.

Functional inactivation of p53 by HPV-E6 transformation is associated with a reduced expression of radiation-induced potentially lethal damage.

PURPOSE: To examine the effect of functional loss of p53 on radiation sensitivity and potentially lethal damage repair (PLDR). MATERIALS AND METHODS: Radiation sensitivity and PLDR were examined in an isogenic pair of human tumour cell lines created by HPV-E6 transformation. RESULTS: Inactivation of p53 by E6 transformation resulted in a cell line that was more resistant to killing by radiation but showed little enhancement in survival (PLDR) when plateau-phase cells were held non-cycling after radiation exposure. Holding p53-normal cells in plateau-phase after radiation exposure not only led to enhanced survival, but also to a reduction in the proportion of cells that blocked in G1 subsequent to release. CONCLUSIONS: These results suggest that p53 expression influences that component of radiation sensitivity associated with PLDR.

125I brachytherapy k-edge dose enhancement with AgTPPS4.

Photon activation is a radiotherapy technique in which an element is added to the absorbing medium to raise the probability that a photoelectric interaction will occur, thus causing an increase in the absorption of ionizing radiation. Binding energies of key elements within an absorbing medium are closely matched with the incident photon energies to maximize the production of free electrons and subsequent absorption of their kinetic energies. The purpose of this research was to quantify potential dose enhancement using a silver tetraphenyl sulfonato porphyrin (AgTPPS4) in tumors as a photon activator for use with interstitial 125I brachytherapy. A three-dimensional Monte Carlo dosimetry model was developed using the EGS4 coding system. The photon source was modeled using spectral gamma emissions from models 6702 or 6711 brachytherapy seeds for comparison. Absorbed dose within the tumor volume was calculated for AgTPPS4 concentrations ranging between 0 and 20 mmol/kg tumor weight. These theoretical studies demonstrated linear increases in dose absorbed by the tumor with corresponding increases in AgTPPS4 concentration. The required AgTPPS4 concentration (RSC) to achieve at least a ten percent absorbed dose increase is approximately 6.5 mmol/kg tumor weight for model 6702 seeds. In vivo biodistribution and in vitro toxicity studies were conducted to determine if the theoretically derived RSC could be achieved biologically. Cell toxicity studies showed that TPPS4 porphyrin derivatives were cytotoxic at concentrations required to provide significant brachytherapy dose enhancement. Reverse phase HPLC confirmed that toxicity was due to intrinsic properties of the TPPS4 molecule, not the presence of free silver, drug impurities, or metabolites. Further research is necessary to develop a nontoxic molecular carrier for delivering silver to the DNA of tumor cells.

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.

The potential role of external beam radiation in preventing restenosis after coronary angioplasty.

The potential role of radiation in the prevention of coronary artery restenosis after angioplasty has generated much recent interest. Animal research and pilot clinical efforts have focused primarily on intraluminal methods of radiation delivery. This article reviews the experience to date with external beam radiation in restenosis prevention and suggests issues that should be considered from the standpoint of both external beam and intravascular radiotherapy. External beam radiation can certainly play an effective role in clinical studies of coronary artery restenosis, and a multicenter randomized trial of external beam radiation after coronary angioplasty has been initiated.

Gamma radiation effect on vascular smooth muscle cells in culture.

PURPOSE: Prior work in our laboratory demonstrated that external gamma irradiation administered within 48 h following balloon catheter carotid artery injury in rats produced a marked inhibition of intimal hyperplasia and restenosis. The current study used smooth muscle cells (SMC) in vitro to examine the radiation dose response and to investigate the cellular mechanism by which radiation inhibits SMC proliferation. METHODS AND MATERIALS: Quiescent rat aortic SMC in plasma were refed with whole blood serum to stimulate synchronous proliferation and immediately irradiated with single fraction doses of 1.25-20 Gy. RESULTS: Comparison between a micronucleus assay and a clonogenic assay indicated a dose-dependent inhibition of SMC growth, with an ED50 at 2-3 Gy. The micronucleus assay also demonstrated a dose-dependent increase in apparent chromosomal damage at 72 h after irradiation. Inhibition of SMC growth by radiation did not correlate with changes in intracellular or released mitogenic activity. Furthermore, there was no evidence of apoptosis in irradiated SMC up to 96 h after treatment. CONCLUSION: Radiation likely inhibits SMC proliferation after arterial injury by a dose-dependent mechanism of lethal and/or sublethal cellular injury leading to clonogenic cell death.

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.

Growth and radiation response of cells grown in macroporous gelatin microcarriers (CultiSpher-G).

Four cell lines have been cultured in macroporous gelatin microcarrier beads (CultiSpher-G) to test this as a new model of three-dimensional cell growth for use in experimental cancer therapy. A549, KB 3-1, KB 8-5 and V79 cells were successfully grown in CultiSphers, albeit with longer doubling times than observed for the respective cell type in monolayer cultures. MTT staining and histology demonstrated three-dimensional contact of cells in the microcarriers. A549 cells populated the microcarriers more densely than KB 3-1 cells, and with both cell types there is bead-to-bead variation in occupancy by cells. [3H]TdR autoradiography reveals labelled cells throughout A549 and KB 3-1 CultiSphers, with no proliferation gradient from edge to centre. Central necrosis has not been observed. A549 cells but not KB 3-1 cells demonstrated a radiation contact effect (i.e. resistance) when irradiated in CultiSphers, compared with monolayers. We conclude that CultiSphers may be a useful model for three-dimensional growth and cell contact when investigators want to investigate these phenomena without the microenvironmental gradients of spheroids.

Growth rate, labeling index, and radiation survival of cells grown in the Matrigel thread in vitro tumor model.

Six rodent cell lines (36B10 rat glioma cells, 9L rat gliosarcoma cells, V79 Chinese hamster lung fibroblasts, EMT6/UW and EMT6/Ro mouse mammary sarcoma cells, and RIF-1 mouse fibrosarcoma cells) were tested for growth in cylindrical threads of Matrigel. These cells grew in the threads with doubling times of 17-23 h, reaching maximum cell densities on the order of 10(8) cells/ml. Histological sections of these threads showed a heterogeneous cell distribution: cells grew to confluence at the thread surface and at somewhat lower cell densities in the thread core. [H-3]thymidine labeling index and radiation sensitivity were measured for 9L and EMT6/UW cells in Matrigel threads. For both cell types, the labeling index in Matrigel was lower than observed in cell monolayers, with higher labeling indexes at the thread periphery than in the thread core. When these threads were grown in stirred medium, lower thread diameters, higher cell yields per thread, and higher labeling indices were obtained. EMT6 cell monolayers coated with Matrigel were less radiosensitive than cells in uncoated monolayers. This protective effect was eliminated by irradiating in the presence of 1 mg/ml misonidazole. EMT6 cells consume nearly three times as much oxygen (mole/cm3-sec) as do 9L cells, which are equally radiosensitive in monolayers with or without a Matrigel coating. The radiation sensitivity of EMT6/UW cells in Matrigel threads was similar to that for monolayers of plateau phase cells, whereas for 9L cells, the response in threads was more similar to exponentially growing cells. We conclude that Matrigel threads provide an alternative in vitro model for studying the radiation response of cells in a three-dimensional geometry.

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.

Comparison of fluorine-18-fluorodeoxyglucose and tritiated fluoromisonidazole uptake during low-flow ischemia.

UNLABELLED: Fluorine-18-fluoromisonidazole (FMISO) is trapped in hypoxic but viable canine myocardium. Because of the potential for its use as a marker of myocardial viability, we compared FMISO activity to [18F]fluorodeoxyglucose (FDG) activity in the same myocardial samples from eight dogs subjected to 3 hr of moderate regional myocardial ischemia. METHODS: Tritiated FMISO was injected 15-30 min after onset of regional ischemia (40%-70% reduction in systolic wall thickening) which was maintained for 3 hr. FDG was injected after 2 hr of ischemia. Myocardial blood flow (MBF) was measured by the radiolabeled microsphere technique at the time of each radiotracer injection. At 3 hr of ischemia, the heart was excised and cut into short-axis slices. One slice encompassing both ischemic and normal tissue was cut into 64 samples. FMISO and FDG activity in each sample were normalized to the mean normal zone activity and further expressed as a function of regional MBF. RESULTS: FMISO uptake was consistently greater than FDG uptake, although this was significantly different only for MBF, between 40%-60% of normal. When analyzed relative to endocardial-epicardial location, endocardial FMISO uptake was significantly greater in all hypoperfused samples. CONCLUSION: These results suggest that FMISO is as sensitive as FDG for detecting myocardial ischemia and could be used for identification of viable myocardium.

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.