title: 18F-FDG PET increases visibility of bone lesions in relapsed multiple myeloma: is this hypoxia-driven?
abstract: BACKGROUND
  Whole-body x-ray (WBX) is used for detecting skeleton abnormalities in patients with multiple myeloma (MM). An alternative might be 18F-FDG PET, which makes use of metabolic changes of malignant cells. The aims of this study were to evaluate whether 18F-FDG PET detects more lesions compared with WBX in patients with relapsing MM and to define its prognostic value. In addition 1-α-D-(5-deoxy-5-[F]-fluoroarabinofuranosyl)-2-nitroimidazole (18F-FAZA) scan and immunohistochemical staining on bone marrow were performed to define whether FDG uptake coincides with angiogenesis-related tumor hypoxia.
  
  
  METHODS
  18F-FDG PET (n = 44) and 18F-FAZA-PET (n = 5) were performed in patients with relapsed MM. Bone marrow biopsies (n = 20) were evaluated for hypoxia inducible factors (HIF) 1α and 2α, vascular endothelial growth factor, glucose transport proteins 1 and 3, and the microvessel density.
  
  
  RESULTS
  New lesions were more frequently demonstrated on 18F-FDG PET than on WBX (P = 0.000001). 18F-FDG PET was not predictive for progression-free survival and overall survival. Immunohistochemical staining on bone marrow biopsies demonstrated a significant increase in microvessel density and elevated expression of vascular endothelial growth factor, HIF-2α, and glucose transport protein 3 by the malignant plasma cells. However, HIF-1α expression and 18F-FAZA scan results were negative.
  
  
  CONCLUSIONS
  Our results demonstrate that 18F-FDG PET is relevant for diagnostic purposes compared with WBX in relapsing MM. The enhanced uptake of 18F-FDG PET is likely related to the activation of the HIF-2α signaling pathway but probably independent of hypoxia-induced signaling in view of the negative findings on both 18F-FAZA-PET and HIF-1α expression.
authors.affiliation: From the Departments of *Hematology, †Nuclear Medicine and Molecular Imaging, and ‡Pathology, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Esther G M
authors.initials: EG
authors.lastname: de Waal
authors.forename: Riemer H J A
authors.initials: RH
authors.lastname: Slart
authors.forename: Marnix J
authors.initials: MJ
authors.lastname: Leene
authors.forename: Philip M
authors.initials: PM
authors.lastname: Kluin
authors.forename: Edo
authors.initials: E
authors.lastname: Vellenga
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D001859:Bone Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000556:secondary; D015687:Cell Hypoxia; D005260:Female; D019788:Fluorodeoxyglucose F18; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051274:Glucose Transporter Type 3 / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D009593:Nitroimidazoles; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019788:Fluorodeoxyglucose F18; D051272:Glucose Transporter Type 1; D051274:Glucose Transporter Type 3; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009593:Nitroimidazoles; D019275:Radiopharmaceuticals; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C495677:SLC2A1 protein, human; C495687:SLC2A3 protein, human; C498052:fluoroazomycin arabinoside