title: Are metastases from metastases clinical relevant? Computer modelling of cancer spread in a case of hepatocellular carcinoma.
abstract: BACKGROUND
  Metastasis formation remains an enigmatic process and one of the main questions recently asked is whether metastases are able to generate further metastases. Different models have been proposed to answer this question; however, their clinical significance remains unclear. Therefore a computer model was developed that permits comparison of the different models quantitatively with clinical data and that additionally predicts the outcome of treatment interventions.
  
  
  METHODS
  The computer model is based on discrete events simulation approach. On the basis of a case from an untreated patient with hepatocellular carcinoma and its multiple metastases in the liver, it was evaluated whether metastases are able to metastasise and in particular if late disseminated tumour cells are still capable to form metastases. Additionally, the resection of the primary tumour was simulated. The simulation results were compared with clinical data.
  
  
  RESULTS
  The simulation results reveal that the number of metastases varies significantly between scenarios where metastases metastasise and scenarios where they do not. In contrast, the total tumour mass is nearly unaffected by the two different modes of metastasis formation. Furthermore, the results provide evidence that metastasis formation is an early event and that late disseminated tumour cells are still capable of forming metastases. Simulations also allow estimating how the resection of the primary tumour delays the patient's death.
  
  
  CONCLUSIONS
  The simulation results indicate that for this particular case of a hepatocellular carcinoma late metastases, i.e., metastases from metastases, are irrelevant in terms of total tumour mass. Hence metastases seeded from metastases are clinically irrelevant in our model system. Only the first metastases seeded from the primary tumour contribute significantly to the tumour burden and thus cause the patient's death.
authors.affiliation: Competence Center Bioinformatics, Institute for Applied Computer Science, University of Applied Sciences Stralsund, Stralsund, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Bethge
authors.forename: Udo
authors.initials: U
authors.lastname: Schumacher
authors.forename: Andreas
authors.initials: A
authors.lastname: Wree
authors.forename: Gero
authors.initials: G
authors.lastname: Wedemann
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000401:mortality / Q000473:pathology*; D002452:Cell Count; D003198:Computer Simulation; D006801:Humans; D008113:Liver Neoplasms / Q000401:mortality / Q000473:pathology*; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000166:cytology