First Probe of Sub-GeV Dark Matter beyond the Cosmological Expectation with the COHERENT CsI Detector at the SNS.

The COHERENT Collaboration searched for scalar dark matter particles produced at the Spallation Neutron Source with masses between 1 and 220 MeV/c^{2} using a CsI[Na] scintillation detector sensitive to nuclear recoils above 9 keV_{nr}. No evidence for dark matter is found and we thus place limits on allowed parameter space. With this low-threshold detector, we are sensitive to coherent elastic scattering between dark matter and nuclei. The cross section for this process is orders of magnitude higher than for other processes historically used for accelerator-based direct-detection searches so that our small, 14.6 kg detector significantly improves on past constraints. At peak sensitivity, we reject the flux consistent with the cosmologically observed dark-matter concentration for all coupling constants α_{D}<0.64, assuming a scalar dark-matter particle. We also calculate the sensitivity of future COHERENT detectors to dark-matter signals which will ambitiously test multiple dark-matter spin scenarios.

Measurement of Electron-Neutrino Charged-Current Cross Sections on

Using an 185-kg NaI[Tl] array, COHERENT has measured the inclusive electron-neutrino charged-current cross section on ^{127}I with pion decay-at-rest neutrinos produced by the Spallation Neutron Source at Oak Ridge National Laboratory. Iodine is one the heaviest targets for which low-energy (≤50 MeV) inelastic neutrino-nucleus processes have been measured, and this is the first measurement of its inclusive cross section. After a five-year detector exposure, COHERENT reports a flux-averaged cross section for electron neutrinos of 9.2_{-1.8}^{+2.1}×10^{-40} cm^{2}. This corresponds to a value that is ∼41% lower than predicted using the MARLEY event generator with a measured Gamow-Teller strength distribution. In addition, the observed visible spectrum from charged-current scattering on ^{127}I has been measured between 10 and 55 MeV, and the exclusive zero-neutron and one-or-more-neutron emission cross sections are measured to be 5.2_{-3.1}^{+3.4}×10^{-40} and 2.2_{-0.5}^{+0.4}×10^{-40} cm^{2}, respectively.

Measurement of the Coherent Elastic Neutrino-Nucleus Scattering Cross Section on CsI by COHERENT.

We measured the cross section of coherent elastic neutrino-nucleus scattering (CEvNS) using a CsI[Na] scintillating crystal in a high flux of neutrinos produced at the Spallation Neutron Source at Oak Ridge National Laboratory. New data collected before detector decommissioning have more than doubled the dataset since the first observation of CEvNS, achieved with this detector. Systematic uncertainties have also been reduced with an updated quenching model, allowing for improved precision. With these analysis improvements, the COHERENT Collaboration determined the cross section to be (165_{-25}^{+30})×10^{-40} cm^{2}, consistent with the standard model, giving the most precise measurement of CEvNS yet. The timing structure of the neutrino beam has been exploited to compare the CEvNS cross section from scattering of different neutrino flavors. This result places leading constraints on neutrino nonstandard interactions while testing lepton flavor universality and measures the weak mixing angle as sin^{2}θ_{W}=0.220_{-0.026}^{+0.028} at Q^{2}≈(50 MeV)^{2}.

First Measurement of Coherent Elastic Neutrino-Nucleus Scattering on Argon.

We report the first measurement of coherent elastic neutrino-nucleus scattering (CEvNS) on argon using a liquid argon detector at the Oak Ridge National Laboratory Spallation Neutron Source. Two independent analyses prefer CEvNS over the background-only null hypothesis with greater than 3σ significance. The measured cross section, averaged over the incident neutrino flux, is (2.2±0.7)×10^{-39} cm^{2}-consistent with the standard model prediction. The neutron-number dependence of this result, together with that from our previous measurement on CsI, confirms the existence of the CEvNS process and provides improved constraints on nonstandard neutrino interactions.

2-[C-11]thymidine imaging of malignant brain tumors.

Malignant brain tumors pose diagnostic and therapeutic problems. Despite the advent of new brain imaging modalities, including magnetic resonance imaging (MRI) and [F-18]fluorodeoxyglucose (FDG) positron emission tomography (PET), determination of tumor viability and response to treatment is often difficult. Blood-brain barrier disruption can be caused by tumor or nonspecific reactions to treatment, making MRI interpretation ambiguous. The high metabolic background of the normal brain and its regional variability makes it difficult to identify small or less active tumors by FDG imaging of cellular energetics. We have investigated 2-[C-11]thymidine (dThd) and PET to image the rate of brain tumor cellular proliferation. A series of 13 patients underwent closely spaced dThd PET, FDG PET, and MRI procedures, and the image results were compared by standardized visual analysis. The resulting dThd scans were qualitatively different from the other two scans in approximately 50% of the cases, which suggests that dThd provided information distinct from FDG PET and MRI. In two cases, recurrent tumor was more apparent on the dThd study than on FDG; in two other patients, tumor dThd uptake was less than FDG uptake, and these patients had slower tumor progression than the three patients with both high dThd and FDG uptake. To better characterize tumor proliferation, kinetic modeling was applied to dynamic dThd PET uptake data and metabolite-analyzed blood data in a subset of patients. Kinetic analysis was able to remove the confounding influence of [C-11]CO2, the principal labeled metabolite of 2-[C-11]dThd, and to estimate the flux of dThd incorporation into DNA. Sequential, same-day [C-11]CO2 and [C-11]dThd imaging demonstrated the ability of kinetic analysis to model both dThd and CO2 simultaneously. Images of dThd flux obtained using the model along with the mixture analysis method for pixel-by-pixel parametric imaging significantly enhanced the contrast of tumor compared with normal brain. Comparison of model estimates of dThd transport versus dThd flux was able to discern increased dThd uptake simply on the basis of blood-brain barrier disruption retention on the basis of increased cellular proliferation. This preliminary study demonstrates the potential for imaging brain tumor cellular proliferation to provide unique information for guiding patient treatment.

Applications of PET imaging with the proliferation marker [18F]-FLT.

[18F]-3'-fluoro-3'-deoxythymidine (FLT) is a nucleoside-analog imaging agent for quantifying cellular proliferation that was first reported in 1998. It accumulates during the S-phase of the cell cycle through the action of cytosolic thymidine kinase, TK1. Since TK1 is primarily expressed in dividing cells, FLT uptake is essentially limited to dividing cells. Thus FLT is an effective measure of cell proliferation. FLT uptake has been shown to correlate with the more classic proliferation marker, the monoclonal antibody to Ki-67. Increased cellular proliferation is known to correlate with worse outcome in many cancers. However, the Ki-67 binding assay is performed on a sampled preparation, ex vivo, whereas FLT can be quantitatively measured in vivo using positron emission tomography (PET). FLT is an effective and quantitative marker of cell proliferation, and therefore a useful prognostic predictor in the setting of neoplastic disease. This review summarizes clinical studies from 2011 forward that used FLT-PET to assess tumor response to therapy. The paper focuses on our recommendations for a standardized clinical trial protocol and components of a report so multi center studies can be effectively conducted, and different studies can be compared. For example, since FLT is glucuronidated by the liver, and the metabolite is not transported into the cell, the plasma fraction of FLT can be significantly changed by treatment with particular drugs that deplete this enzyme, including some chemotherapy agents and pain medications. Therefore, the plasma level of metabolites should be measured to assure FLT uptake kinetics can be accurately calculated. This is important because the flux constant (KFLT) is a more accurate measure of proliferation and, by inference, a better discriminator of tumor recurrence than standardized uptake value (SUVFLT). This will allow FLT imaging to be a specific and clinically relevant prognostic predictor in the treatment of neoplastic disease.

A radiosynthesis of fluorine-18 fluoromisonidazole.

A new preparation of [18F]fluoromisonidazole [1H-1-(3-[18F] fluoro-2-hydroxypropyl)-2-nitroimidazole] is presented as a two-step, two-pot reaction sequence. The method is useful for the production of 20-30 mCi quantities of this compound from [18F]fluoride, available in 40% radiochemical yield at end of bombardment (EOB) with a specific activity (nca) of greater than 650 Ci/mmol (EOB) and a synthesis time of approximately 140 min. The key feature of the reaction scheme is the preparation of a new fluoroalkylating agent, [18F]epifluorohydrin.

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.

Quantitation of presynaptic cardiac sympathetic function with carbon-11-meta-hydroxyephedrine.

UNLABELLED: The purpose of this study was to validate an axially distributed blood-tissue exchange model for the quantitation of cardiac presynaptic sympathetic nervous system function that could be applied to PET images. The model accounts for heterogeneity in myocardial blood flow, differences in transport rates of 11C-meta-hydroxyephedrine (mHED) across the capillary endothelium and/or neuronal membranes, the virtual volumes of distribution in the interstitial space and neuron and retention of mHED in the neuronal vesicles. METHODS: Multiple indicator outflow dilution and residue detection methods were used to measure the kinetics of radiolabeled intravascular space and interstitial space markers and 11C-mHED in isolated perfused rat heart at baseline and during norepinephrine neuronal transporter blockade with desipramine (DMI). The outflow dilution and residue detection data were modeled with a multiple pathway, four-region, axially distributed model of blood-tissue exchange describing flow in the capillary and exchange between regions using permeability-surface area products with units of clearance of milliliters per minute per gram. Meta-hydroxyephedrine may enter the nerve terminal via membrane transport, where it may be sequestered by first-order unidirectional uptake within vesicles. Release of mHED from the vesicles is modeled via exchange with the interstitial space. RESULTS: After intracoronary injection, mHED transport across the capillary endothelium and in the interstitial space closely followed that of sucrose. Subsequently, mHED was retained in the heart, whereas sucrose washed out rapidly. With DMI the outflow dilution curves more closely resembled those of sucrose. Model parameters reflecting capillary-interstitial kinetics and volumes of distribution were unchanged by DMI, whereas parameters reflecting the neuronal transporter process and volumes of distribution in the nerve terminal and vesicular sequestration were markedly decreased by DMI. Application of the model to a pilot set of canine PET images of mHED suggests the feasibility of this approach. CONCLUSION: Meta-hydroxyephedrine kinetics in the heart can be quantitated using an axially distributed, blood-tissue exchange model that accounts for heterogeneity of flow, reflects changes in neuronal function and is applicable to PET images.

Iodophenylpentadecanoic acid-myocardial blood flow relationship during maximal exercise with coronary occlusion.

Imaging 123I-labeled iodophenylpentadecanoic acid (IPPA) uptake and clearance from the myocardium following exercise has been advocated as a means of detecting myocardial ischemia because fatty acid deposition is enhanced and clearance prolonged in regions of low flow. However, normal regional myocardial blood flows are markedly heterogeneous, and it is not known how this heterogeneity affects regional metabolism or substrate uptake and thus image interpretation. In five instrumented dogs running at near maximal workload on a treadmill, 131I-labeled IPPA and 15-micron 46Sc microspheres were injected into the left atrium after 30 sec of circumflex coronary artery occlusion. Microsphere and IPPA activity were determined in 250 mapped pieces of myocardium of approximately 400 mg. Myocardial blood flows (from microspheres) ranged from 0.05 to 7.6 ml/min/g. Deposition of IPPA was proportional to regional flows (r = 0.83) with an average retention of 25%. The mean endocardial-epicardial ratio for IPPA (0.90 +/- 0.43) was similar to that for microspheres (0.94 +/- 0.47; p = 0.08). Thus, initial IPPA deposition during treadmill exercise increases in proportion to regional myocardial blood flow over a range of flows from very low to five times normal.

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.

Kinetic analysis of 2-[11C]thymidine PET imaging studies: validation studies.

UNLABELLED: 2-[11C]thymidine has been tested as a PET tracer of cellular proliferation. We have previously described a model of thymidine and labeled metabolite kinetics for use in quantifying the flux of thymidine into DNA as a measure of tumor proliferation. We describe here the results of studies to validate some of the model's assumptions and to test the model's ability to predict the time course of tracer incorporation into DNA in tumors. METHODS: Three sets of studies were conducted: (a) The uptake of tracers in proliferative tissues of normal mice was measured early after injection to assess the relative delivery of thymidine and metabolites of thymidine catabolism (thymine and CO2) and calculate relative blood-tissue transfer rates (relative K1s). (b) By using sequential injections of [11C]thymidine and [11C]thymine in normal human volunteers, the kinetics of the first labeled metabolite were measured to determine whether it was trapped in proliferating tissue such as the bone marrow. (c) In a multitumor rat model, 2-[14C]thymidine injection, tumor sampling and quantitative DNA extraction were performed to measure the time course of label uptake into DNA for comparison with model predictions. RESULTS: Studies in mice showed consistent relative delivery of thymidine and metabolites in somatic tissue but, as expected, showed reduced delivery of thymidine and thymine in the normal brain compared to CO2. Thymine studies in volunteers showed only minimal trapping of label in bone marrow in comparison to thymidine. This quantity of trapping could be explained by a small amount of fixation of labeled CO2 in tissue, a process that is included as part of the model. Uptake experiments in rats showed early incorporation of label into DNA, and the model was able to fit the time course of uptake. CONCLUSION: These initial studies support the assumptions of the compartmental model and demonstrate its ability to quantify thymidine flux into DNA by using 2-[11C]thymidine and PET. Results suggest that further work will be necessary to investigate the effects of tumor heterogeneity and to compare PET measures of tumor proliferation to in vitro measures of proliferation and to clinical tumor behavior in patients undergoing therapy.

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.

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.

[18F]fluoroestradiol radiation dosimetry in human PET studies.

UNLABELLED: [18F]16alpha-fluoroestradiol (FES) is a PET imaging agent useful for the study of estrogen receptors in breast cancer. We estimated the radiation dosimetry for this tracer using data obtained in patient studies. METHODS: Time-dependent tissue concentrations of radioactivity were determined from blood samples and PET images in 49 patients (52 studies) after intravenous injection of FES. Radiation absorbed doses were calculated using the procedures of the MIRD committee, taking into account the variation in dose based on the distribution of activities observed in the individual patients. Effective dose equivalent was calculated using International Commission on Radiological Protection Publication 60 weights for the standard woman. RESULTS: The effective dose equivalent was 0.022 mSv/MBq (80 mrem/mCi). The organ that received the highest dose was the liver (0.13 mGy/MBq [470 mrad/mCi]), followed by the gallbladder (0.10 mGy/MBq [380 mrad/mCi]) and the urinary bladder (0.05 mGy/MBq [190 mrad/mCi]). CONCLUSION: The organ doses are comparable to those associated with other commonly performed nuclear medicine tests. FES is a useful estrogen receptor-imaging agent, and the potential radiation risks associated with this study are well within accepted limits.

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.

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.

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.

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.

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.