Hyperacute changes in glucose metabolism of brain tumors after stereotactic radiosurgery: a PET study (original) (raw)
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Clinical cancer research : an official journal of the American Association for Cancer Research, 2002
To examine whether quantitative 1-[(11)C]glucose- or 2-[(18)F]fluoro-2-deoxyglucose (FDG)-positron emission tomography performed before and/or after radiotherapy (RT) of malignant gliomas correlates with treatment outcome. Changes in metabolism between the start and finish of RT, and immediate post-RT studies have received little attention. Adults with malignant gliomas were imaged within 2 weeks before and/or 2 weeks after RT. Four patients were imaged only before RT, 12 only after RT, and 14 both before and after RT. Each 1-[(11)C]glucose and FDG study included arterial plasma sampling. Kinetic parameters, glucose metabolic rate (MRGlc), and FDG metabolic rate (MRFDG) were estimated by an optimization program based on a three compartment, four rate constant model. Changes in MRGlc or MRFDG from pre-RT to post-RT were calculated for the 14 patients studied at both times. Overall survival was examined, and survival was computed relative to historical controls in matched prognostic c...
Asian journal of neurosurgery, 2013
malignant astrocytomas has generally increased the median survival from 4 to 10 months only. The failure of radiotherapy (RT) in cerebral gliomas is primarily due to the presence of hypoxic, repair-proficient, and radioresistant subpopulation of cells in the tumor. [3,4] Amplification in the expression of cellular oncogenes like Raf, Myc, and N-ras is known to cause radioresistance in gliomas. [5,6] An analysis of the pattern of failures after conventional therapy, i.e., surgery, RT, and chemotherapy, indicates local regrowth of the tumor, implying that the conventional treatment (1.8-2.0 Gy/ fraction, 5 fractions per week, a total of 30-35 fractions) is not as effective. [1] On the other hand, delivery of high doses of radiation has limitation of damaging the surrounding normal brain. [7] Strategies directed toward differentially enhancing radiation damage in tumor cells and reducing the damage to normal brain tissue could significantly improve the treatment efficacy of RT. [7] Glucose usage is significantly increased in tumor cells, and these cells derive a large part of their metabolic energy (ATP)
The authors investigated whether radiation treatment directly affects glucose metabolism gene expression and whether this impacts FDG-PET imaging parameters. The results show that radiation does not directly inhibit genes involved in glucose uptake and metabolism, although the protein levels of the 2 key genes, GLUT1 and HK2, did show changes after radiation. The authors conclude that changes in PET parameters would seem to reflect altered Purpose: To investigate whether radiation treatment influences the expression of glucose metabolism genes and compromises the potential use of 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) as a tool to monitor the early response of head and neck cancer xenografts to radiation therapy (RT). Methods and Materials: Low passage head and neck squamous cancer cells (UT14) were injected to the flanks of female nu/nu mice to generate xenografts. After tumors reached a size of 500 mm 3 they were treated with either sham RT or 15 Gy in 1 fraction. At different time points, days 3, 9, and 16 for controls and days 4, 7, 12, 21, 30, and 40 after irradiation, 2 to 3 mice were assessed with dynamic FDG-PET acquisition over 2 hours. Immediately after the FDG-PET the tumors were harvested for global gene expression analysis and immunohistochemical evaluation of GLUT1 and HK2. Different analytic parameters were used to process the dynamic PET data. Results: Radiation had no effect on key genes involved in FDG uptake and metabolism but did alter other genes in the HIF1a and glucose transporterelated pathways. In contrast to the lack of effect on gene expression, changes in the protein expression patterns of the key genes GLUT1/SLC2A1 and HK2 were observed after radiation treatment. The changes in GLUT1 protein expression showed some correlation with dynamic FDG-PET parameters, such as the kinetic index.
Glucose consumption and rate constants for 18F-fluorodeoxyglucose in human gliomas
Neurologia medico-chirurgica, 1990
To investigate the value of direct measurement of the rate constants by performing 18F-labeled fluorodeoxyglucose (FDG) studies of glucose consumption in human gliomas in vivo, a kinetic method with 3- and 4-parameter rate constant models for FDG uptake was used to analyze data from dynamic scans obtained by positron emission tomography after injection of FDG into 14 patients with glioma. The results were compared with those obtained by the autoradiographic method using 3- and 4-parameter rate constant models. There were no significant differences in the glucose consumption calculated by the four different methods both in the gliomas and in the contralateral intact cortex. It was found that the rate constant k4* could be neglected in calculation of glucose consumption in gliomas as well as in the contralateral intact cortex. The rate constant k3*, an index of hexokinase function, was higher in malignant gliomas than in benign gliomas and was close to that in the contralateral cortex...
Journal of Cerebral Blood Flow & Metabolism, 1985
Reevaluation of lumped and rate constants is necessary when Sokoloff's 2-deoxyglucose (DG) method is used to measure glucose utilization in pathological tissue. We describe here a modification of Sokoloff's lumped constant measurement that permits simultaneous estimation of both lumped and rate constants from a single animal experiment. A subcutaneous tumor model (AA ascites tumor) was used for measurement of these constants with a procedure similar to Sokoloff's that kept the plasma tracer concentration constant. Measured constants were as follows: lumped constant, 0.654 +/- 0.081; k1, 0.196 +/- 0.038 min-1; k2, 0.262 +/- 0.067 min-1; k3, 0.117 +/- 0.044 min-1. These constants were used to quantify glucose utilization in the implanted brain tumor. To test the validity of this method, we compared a fraction of the free DG pool calculated using the tumor constants with a fraction measured directly by chromatographic analysis of tissue samples from both subcutaneous tumor and implanted brain tumor. The values derived by chemical analysis agreed well with those predicted by the calculations. The value of k4 varied from 0.0031 +/- 0.0018 min-1 for the tumor tissue to 0.0214 +/- 0.0024 min-1 for tumors with a large necrotic center. This method would be especially useful when applied to xenograft human gliomas in nude mice for quantification of glucose utilization in human gliomas by means of positron emission tomography.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1998
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. 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...
Molecular Imaging and Biology, 2007
Objective: The uptake of 3 ¶-[ 18 F]fluoro-3 ¶-deoxythymidine (FLT), a proliferation marker, was measured before and during fractionated radiotherapy to evaluate the potential of FLT-positron emission tomography (PET) imaging as an indicator of tumor response compared to 2 ¶-deoxy-2 ¶-[ 18 F]fluoro-D-glucose (FDG). Materials and Methods: Nude mice bearing established human head and neck xenografts (HNX-OE; nu/nu mice) were locally irradiated (three fractions/week; 22 Gy) using a 150-kV p unit. Multiple FDG-and FLT-PET scans were acquired during treatment. Tumor volume was determined regularly, and tissue was analyzed for biomarkers involved in tracer uptake. Results: Both groups revealed a significant decline in tumor volume (PG0.01) compared to untreated tumors. For FDG as well as for FLT, a significant decline in retention was observed at day 4. For FLT, most significant decline in retention was observed at day 12; whereas, for FDG, this was already noted at day 4. Maximum decline in tumor-to-nontumor ratios (T/NT) for FDG and FLT was 42T18% and 49T16% (meanTSD), respectively. FLT uptake was higher then that of FDG. For FLT, statistical significant correlations were found for both tumor volume at baseline and at day 29 with T/NT and DT/NT. All tumors demonstrated expression of glucose transporter-1, thymidine kinase-1, and hexokinase II. No differences were found for amount of tumor cells and necrosis at the end of treatment. Conclusion: This new experimental in vivo model supports the promise of using FLT-PET, as with FDG-PET, to monitor response to external radiotherapy. This warrants further clinical studies to compare these two tracers especially in cancers treated with radiotherapy.
Journal of Neuro-Oncology, 1985
Coupling of regional glucose utilization (GLU) and blood flow (CBF) was examined in rats with implanted brain tumors (AA ascites tumor) by quantitative double tracer autoradiography using 18F-2-fluorodeoxyglucose and 14C-iodoantipyrine. Four to 13 days after implantation, the animals were injected with the two tracers to obtain autoradiograms from the same brain section before and after the decay of 18F. The autoradiograms were then analyzed by an image processor to obtain a metabolic coupling index (MCI = GLU/CBF). In the tumor, high GLU and low CBF were uncoupled to give a high MCI which implied anerobic glycolysis. In large tumors, the CBF was even lower. In the peri-tumoral region, GLU was reduced (especially in gray matter) and reduction was lowest around the larger tumors. CBF in the peri-tumoral region was also reduced, but this reduction became less as the distance from the tumor margin increased. These changes in the peri-tumoral region may be secondary to edema. The GLU and CBF of white matter was little influenced by the presence of tumors except for some reduction in these values in relation to the larger tumors. On a narrow margin of tumor and brain, corresponding to a zone of increased vascularity, CBF was moderately high. The MCI in the tumor was higher than in the cortex of the same as well as the opposite hemisphere. These findings indicate that the metabolism and blood flow of the tumor and surrounding brain are variable and directly related to tumor size.
Optimizing Cancer Radiotherapy with 2-Deoxy-D-Glucose
Strahlentherapie und Onkologie, 2005
Background and Purpose: Higher rates of glucose utilization and glycolysis generally correlate with poor prognosis in several types of malignant tumors. Own earlier studies on model systems demonstrated that the nonmetabolizable glucose analog 2-deoxy-D-glucose (2-DG) could enhance the efficacy of radiotherapy in a dose-dependent manner by selectively sensitizing cancer cells while protecting normal cells. Phase I/II clinical trials indicated that the combination of 2-DG, at an oral dose of 200 mg/kg body weight (BW), with large fractions of γ-radiation was well tolerated in cerebral glioma patients. Since higher 2-DG doses are expected to improve the therapeutic gain, present studies were undertaken to examine the tolerance and safety of escalating 2-DG dose during combined treatment (2-DG + radiotherapy) in glioblastoma multiforme patients. Patients and Methods: Untreated patients with histologically proven glioblastoma multiforme (WHO criteria) were included in the study. Seven weekly fractions of 60 Co γ-rays (5 Gy/fraction) were delivered to the tumor volume (presurgical CT/MRI evaluation) plus 3 cm margin. Escalating 2-DG doses (200-250-300 mg/kg BW) were administered orally 30 min before irradiation after overnight fasting. Acute toxicity and tolerance were studied by monitoring the vital parameters and side effects. Late radiation damage and treatment responses were studied radiologically and clinically in surviving patients. Results: Transient side effects similar to hypoglycemia were observed in most of the patients. Tolerance and patient compliance to the combined treatment were very good up to a 2-DG dose of 250 mg/kg BW. However, at the higher dose of 300 mg/kg BW, two out of six patients were very restless and could not complete treatment, though significant changes in the vital parameters were not observed even at this dose. No significant damage to the normal brain tissue was observed during follow-up in seven out of ten patients who received complete treatment and survived between 11 and 46 months after treatment. Conclusion: Oral administration of 2-DG combined with large fractions of radiation (5 Gy/fraction/week) is safe and could be tolerated in glioblastoma patients without any acute toxicity and late radiation damage to the normal brain. Further clinical studies to evaluate the efficacy of the combined treatment are warranted.
Clinical Cancer Research, 2004
Purpose: The aim of this study is to compare glucose metabolism and hypoxia in four different tumor types using positron emission tomography (PET). 18 F-labeled fluorodeoxyglucose (FDG) evaluates energy metabolism, whereas the uptake of 18 F-labeled fluoromisonidazole (FMISO) is proportional to tissue hypoxia. Although acute hypoxia results in accelerated glycolysis, cellular metabolism is slowed in chronic hypoxia, prompting us to look for discordance between FMISO and FDG uptake. Experimental Design: Forty-nine patients (26 with head and neck cancer, 11 with soft tissue sarcoma, 7 with breast cancer, and 5 with glioblastoma multiforme) who had both FMISO and FDG PET scans as part of research protocols through February 2003 were included in this study. The maximum standardized uptake value was used to depict FDG uptake, and hypoxic volume and maximum tissue: blood ratio were used to quantify hypoxia. Pixel-by-pixel correlation of radiotracer uptake was performed on coregistered images for each corresponding tumor plane. Results: Hypoxia was detected in all four patient groups. The mean correlation coefficients between FMISO and FDG uptake were 0.62 for head and neck cancer, 0.47 for breast cancer, 0.38 for glioblastoma multiforme, and 0.32 for soft tissue sarcoma. The correlation between the overall tumor maximum standardized uptake value for FDG and hypoxic volume was small (Spearman r ؍ 0.24), with highly significant differences among the different tumor types (P < 0.005). Conclusions: Hypoxia is a general factor affecting glucose metabolism; however, some hypoxic tumors can have modest glucose metabolism, whereas some highly metabolic tumors are not hypoxic, showing discordance in tracer uptake that can be tumor type specific.