18F-FDG kinetics and gene expression in giant cell tumors.

UNLABELLED 18F-FDG kinetics were evaluated by use of compartment and noncompartment models of giant cell tumors. The kinetic data were compared with the gene expression data for a subgroup of patients. METHODS Nineteen patients with giant cell tumors were examined with PET and 18F-FDG, and tracer kinetics were assessed quantitatively. A 2-compartment model, including the transport constants k1-k4 as well as the vascular fraction (VB) for 18F-FDG, was used for evaluation of the data. A noncompartment model was used to calculate the fractal dimension of the 18F-FDG time-activity curve to assess the heterogeneity of the tracer kinetics. Furthermore, tumor specimens obtained from 5 patients were assessed with gene chip technology (U95A), and these data were compared with the quantitative 18F-FDG data. RESULTS The giant cell tumors showed generally enhanced 18F-FDG uptake 1 h after tracer application, with a mean 18F-FDG standardized uptake value (SUV) of 4.8 (range, 1.8-9.4). Quantitative evaluation of tracer kinetics showed a preferential increase for 18F-FDG transport, with a mean k1 of 0.340. The vascular fraction accounted for 35% of the tumor volume and was high compared with those for other tumors, such as soft-tissue sarcomas. 18F-FDG kinetics were heterogeneous, with a fractal dimension of 1.3. Gene chip analysis showed that the expression of 137 genes (1.1%) exceeded the median expression value of the reference gene, beta2-microglobulin. The highest expression was observed for the gene for the small, leucine-rich proteoglycan I (biglycan), which is important for bone cell differentiation and proliferative activity. Correlation analysis revealed an association of 18F-FDG data with the expression of several genes. Mainly genes related to angiogenesis were associated with the compartment parameters. The SUV at 56-60 min was correlated with the expression of vascular endothelial growth factor A (angiogenesis) and cell division cycle 2 protein (proliferation). CONCLUSION Despite their classification as benign tumors, giant cell tumors have generally enhanced 18F-FDG uptake, mainly attributable to an enhanced vascular fraction and increased 18F-FDG transport. A comparison of gene chip data and 18F-FDG kinetic data showed a close association of quantitative 18F-FDG results and the expression of genes related to angiogenesis.

[1]  F. Pilleul,et al.  Low microvessel density is an unfavorable histoprognostic factor in pancreatic endocrine tumors. , 2003, Gastroenterology.

[2]  Kyoko Arai,et al.  Significant association of Rho/ROCK pathway with invasion and metastasis of bladder cancer. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[3]  C Burger,et al.  A JAVA environment for medical image data analysis: initial application for brain PET quantitation. , 1998, Medical informatics = Medecine et informatique.

[4]  S. Ito,et al.  Coexpression of glucose transporter 1 and matrix metalloproteinase-2 in human cancers. , 2002, Journal of the National Cancer Institute.

[5]  A. Osmont,et al.  Determination of 18F-fluoro-2-deoxy-d-glucose rate constants in the anesthetized baboon brain with dynamic positron tomography , 1993, Journal of Neuroscience Methods.

[6]  Cyrill Burger,et al.  Quantitative evaluation of skeletal tumours with dynamic FDG PET: SUV in comparison to Patlak analysis , 2001, European Journal of Nuclear Medicine.

[7]  T. Greitz,et al.  The Metabolism of the Human Brain Studied With Positron Emission Tomography , 1984 .

[8]  S. Nakamura,et al.  Identification of a vascular endothelial growth factor (VEGF) antagonist, sFlt‐1, from a human hematopoietic cell line NALM‐16 , 2000, FEBS letters.

[9]  Louis Sokoloff,et al.  Basic Principles Underlying Radioisotopic Methods for Assay of Biochemical Processes in Vivo , 1983 .

[10]  C. Lewis,et al.  Hypoxia-induced gene expression in human macrophages: implications for ischemic tissues and hypoxia-regulated gene therapy. , 2003, The American journal of pathology.

[11]  J Aoki,et al.  FDG PET of primary benign and malignant bone tumors: standardized uptake value in 52 lesions. , 2001, Radiology.

[12]  C Burger,et al.  Requirements and implementation of a flexible kinetic modeling tool. , 1997, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[13]  E. Milgrom,et al.  RANK (receptor activator of nuclear factor kappa B) and RANK ligand are expressed in giant cell tumors of bone. , 2002, American journal of clinical pathology.

[14]  K. Itoh,et al.  Overexpression of small GTP-binding protein RhoA promotes invasion of tumor cells. , 1999, Cancer research.

[15]  M. Shibuya,et al.  Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[16]  K. Chayama,et al.  Expression of Vascular Endothelial Growth Factor and Angiogenesis in Gastrointestinal Stromal Tumor of the Stomach , 2003, Oncology.

[17]  S. Abe,et al.  Tumor angiogenesis of non–small cell lung cancer , 2003, Microscopy research and technique.

[18]  P. Kristjansen,et al.  Coregulation of glucose uptake and vascular endothelial growth factor (VEGF) in two small-cell lung cancer (SCLC) sublines in vivo and in vitro. , 2001, Neoplasia.

[19]  B. Lévy,et al.  Vascular Endothelial Growth Factor‐B Promotes In Vivo Angiogenesis , 2003, Circulation research.

[20]  L. Brown,et al.  Benign giant-cell tumor of bone with pulmonary metastases: clinical findings and radiologic appearance of metastases in 13 cases. , 1992, AJR. American journal of roentgenology.

[21]  D. Xie,et al.  The expression of ADAM12 (meltrin alpha) in human giant cell tumours of bone. , 2002, Molecular pathology : MP.

[22]  L G Strauss,et al.  The applications of PET in clinical oncology. , 1991, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[23]  E. Thiel,et al.  Wilms Tumor Gene (WT1) Expression as a Panleukemic Marker , 2002, International journal of hematology.

[24]  Cyrill Burger,et al.  The role of quantitative (18)F-FDG PET studies for the differentiation of malignant and benign bone lesions. , 2002, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[25]  T. Momose,et al.  Noninvasive method to obtain input function for measuring tissue glucose utilization of thoracic and abdominal organs. , 1991, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[26]  D. Present,et al.  Proliferation index and vascular density of giant cell tumors of bone: Are they prognostic markers? , 1996, Cancer.

[27]  D. Xie,et al.  The expression of ADAM12 (meltrin α) in human giant cell tumours of bone , 2002 .

[28]  S. Kumta,et al.  Gene expression of vascular endothelial growth factor in giant cell tumors of bone. , 2000, Human pathology.

[29]  B. Shmookler,et al.  Diagnosis of primary bone tumors with image-guided percutaneous biopsy: experience with 110 tumors. , 2002, Radiology.

[30]  P. Marrack,et al.  Activation changes the spectrum but not the diversity of genes expressed by T cells. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[31]  S. Kumta,et al.  Expression of VEGF and MMP-9 in giant cell tumor of bone and other osteolytic lesions. , 2003, Life sciences.

[32]  E. Schönherr,et al.  Differential roles for small leucine-rich proteoglycans in bone formation. , 2003, European cells & materials.

[33]  S. Larson,et al.  Metabolic imaging of human extremity musculoskeletal tumors by PET. , 1988, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.