title: 18F-FDG and 18F-FLT-PET imaging for monitoring everolimus effect on tumor-growth in neuroendocrine tumors: studies in human tumor xenografts in mice.
abstract: BACKGROUND
  The mTOR inhibitor everolimus has shown promising results in some but not all neuroendocrine tumors. Therefore, early assessment of treatment response would be beneficial. In this study, we investigated the in vivo and in vitro treatment effect of everolimus in neuroendocrine tumors and evaluated the performance of 18F-FDG and the proliferation tracer 18F-FLT for treatment response assessment by PET imaging.
  
  
  METHODS
  The effect of everolimus on the human carcinoid cell line H727 was examined in vitro with the MTT assay and in vivo on H727 xenograft tumors. The mice were scanned at baseline with 18F-FDG or 18F-FLT and then treated with either placebo or everolimus (5 mg/kg daily) for 10 days. PET/CT scans were repeated at day 1,3 and 10.
  
  
  RESULTS
  Everolimus showed significant inhibition of H727 cell proliferation in vitro at concentrations above 1 nM. In vivo tumor volumes measured relative to baseline were significantly lower in the everolimus group compared to the control group at day 3 (126±6% vs. 152±6%; p = 0.016), day 7 (164±7% vs. 226±13%; p<0.001) and at day 10 (194±10% vs. 281±18%; p<0.001). Uptake of 18F-FDG and 18F-FLT showed little differences between control and treatment groups, but individual mean uptake of 18F-FDG at day 3 correlated with tumor growth day 10 (r2 = 0.45; P = 0.034), 18F-FLT mean uptake at day 1 correlated with tumor growth day 7 (r2 = 0.63; P = 0.019) and at day 3 18F-FLT correlated with tumor growth day 7 (r2 = 0.87; P<0.001) and day 10 (r2 = 0.58; P = 0.027).
  
  
  CONCLUSIONS
  Everolimus was effective in vitro and in vivo in human xenografts lung carcinoid NETs and especially early 18F-FLT uptake predicted subsequent tumor growth. We suggest that 18F-FLT PET can be used for tailoring therapy for neuroendocrine tumor patients through early identification of responders and non-responders.
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Faculty of Health Sciences, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.
authors.forename: Camilla Bardram
authors.initials: CB
authors.lastname: Johnbeck
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Faculty of Health Sciences, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Munk Jensen
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Faculty of Health Sciences, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.
authors.forename: Carsten
authors.initials: C
authors.lastname: Haagen Nielsen
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Faculty of Health Sciences, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anne Mette
authors.initials: AM
authors.lastname: Fisker Hag
authors.affiliation: Department of Surgical Gastroenterology C and Department of Endocrinology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Knigge
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Faculty of Health Sciences, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kjaer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015224:Dideoxynucleosides; D016903:Drug Monitoring / Q000379:methods*; D000068338:Everolimus / Q000627:therapeutic use*; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D051379:Mice; D064847:Multimodal Imaging; D018358:Neuroendocrine Tumors / Q000188:drug therapy*; D049268:Positron-Emission Tomography; D014057:Tomography, X-Ray Computed; D055114:X-Ray Microtomography; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015224:Dideoxynucleosides; D019788:Fluorodeoxyglucose F18; D000068338:Everolimus; C002854:alovudine