title: FDG small animal PET permits early detection of malignant cells in a xenograft murine model.
abstract: OBJECTIVE
  The administration of new anticancer drugs in animal models is the first step from in vitro to in vivo pre-clinical protocols. At this stage it is crucial to ensure that cells are in the logarithmic phase of growth and to avoid vascular impairment, which can cause inhomogeneous distribution of the drug within the tumour and thus lead to bias in the final analysis of efficacy. In subcutaneous xenograft murine models, positivity for cancer is visually recognisable 2-3 weeks after inoculation, when a certain amount of necrosis is usually already present. The aim of this study was to evaluate the accuracy of FDG small animal PET for the early detection of malignant masses in a xenograft murine model of human rhabdomyosarcoma. A second goal was to analyse the metabolic behaviour of this xenograft tumour over time.
  
  
  METHODS
  We studied 23 nude mice, in which 7 x 10(6) rhabdomyosarcoma cells (RH-30 cell line) were injected in the dorsal subcutaneous tissues. Each animal underwent four FDG PET scans (GE, eXplore Vista DR) under gas anaesthesia. The animals were studied 2, 5, 14 and 20 days after inoculation. We administered 20 MBq of FDG via the tail vein. Uptake time was 60 min, and acquisition time, 20 min. Images were reconstructed with OSEM 2D iterative reconstruction and the target to background ratio (TBR) was calculated for each tumour. Normal subcutaneous tissue had a TBR of 0.3. Necrosis was diagnosed when one or more cold areas were present within the mass. All the animals were sacrificed and histology was available to verify PET results. PET results were concordant with the findings of necropsy and histology in all cases.
  
  
  RESULTS
  The incidence of the tumour was 69.6% (16/23 animals); seven animals did not develop a malignant mass. Ten of the 23 animals had a positive PET scan 2 days after inoculation. Nine of these ten animals developed a tumour; the remaining animal became negative, at the third scan. The positive predictive value of the early PET scan was 90% (9/10 animals) while the negative predictive value was 46% (6/13 animals). In the whole group of animals, mean TBR increased scan by scan. There was a statistically significant difference in TBR between 2 and 20 days after inoculation. Necrosis was present at the second scan in two animals, at the third scan in six animals and at the fourth scan in 11 animals.
  
  
  CONCLUSIONS
  The high positive predictive value of FDG PET 2 days after inoculation means that an animal with a first positive scan has a very high likelihood of developing a mass and can be treated at an early stage with an experimental drug. Animals negative at this point in time will never develop a mass or will eventually do so at a late phase. As 2 of the 16 (12.5%) positive animals had necrosis at the second scan, indicating a vascular mismatch, it may be argued that animals should be treated 2 days after inoculation to guarantee homogeneous vascularisation (thereby ensuring a good drug supply within the tumour) in all subjects.
authors.affiliation: Nuclear Medicine, Azienda Ospedaliera di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Nanni
authors.affiliation: Department of Pediatrics, University of Bologna, Sant'Orsola-Malpighi Hospital, Bologna, Italy.
authors.forename: Korinne
authors.initials: K
authors.lastname: Di Leo
authors.affiliation: Department of Pediatrics, University of Bologna, Sant'Orsola-Malpighi Hospital, Bologna, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Tonelli
authors.affiliation: Physics, Azienda Ospedaliera di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Pettinato
authors.affiliation: Service of Nuclear Medicine and PET, Ospedale S. Maria della Misericordia, Viale Tre Martiri, 140, 45100, Rovigo, Italy. domenico.rubello@libero.it.
authors.forename: Domenico
authors.initials: D
authors.lastname: Rubello
authors.affiliation: Nuclear Medicine, Azienda Ospedaliera di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
authors.forename: Antonello
authors.initials: A
authors.lastname: Spinelli
authors.affiliation: Nuclear Medicine, Azienda Ospedaliera di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Trespidi
authors.affiliation: Nuclear Medicine, Azienda Ospedaliera di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Ambrosini
authors.affiliation: Nuclear Medicine, Azienda Ospedaliera di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Castellucci
authors.affiliation: Nuclear Medicine, Azienda Ospedaliera di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Farsad
authors.affiliation: Nuclear Medicine, Azienda Ospedaliera di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Franchi
authors.affiliation: Department of Pediatrics, University of Bologna, Sant'Orsola-Malpighi Hospital, Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pession
authors.affiliation: Nuclear Medicine, Azienda Ospedaliera di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fanti
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D006801:Humans; D007091:Image Processing, Computer-Assisted; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012208:Rhabdomyosarcoma / Q000175:diagnosis / Q000000981:diagnostic imaging*; D012680:Sensitivity and Specificity; D013997:Time Factors
chemical_list: D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18