title: Neoadjuvant sorafenib treatment of clear cell renal cell carcinoma and release of circulating tumor fragments.
abstract: BACKGROUND
  Clear cell renal cell carcinoma (ccRCC) is characterized by high constitutive vascular endothelial growth factor A (VEGF-A) production that induces a specific vascular phenotype. We previously reported that this phenotype may allow shedding of multicellular tumor fragments into the circulation, possibly contributing to the development of metastasis. Disruption of this phenotype through inhibition of VEGF signaling may therefore result in reduced shedding of tumor fragments and improved prognosis. To test this hypothesis, we investigated the effect of neoadjuvant sorafenib treatment on tumor cluster shedding.
  
  
  METHODS
  Patients with renal cancer (n = 10, of which 8 have ccRCC) received sorafenib for 4 weeks before tumor nephrectomy. The resection specimens were perfused, and the perfundate was examined for the presence of tumor clusters. Effects of the treatment on the tumor morphology and overall survival were investigated (follow-up of 2 years) and compared with a carefully matched control group.
  
  
  RESULTS
  Neoadjuvant sorafenib treatment induced extensive ischemic tumor necrosis and, as expected, destroyed the characteristic ccRCC vascular phenotype. In contrast to the expectation, vital groups of tumor cells with high proliferation indices were detected in postsurgical renal venous outflow in 75% of the cases. Overall survival of patients receiving neoadjuvant treatment was reduced compared to a control group, matched with regard to prognostic parameters.
  
  
  CONCLUSIONS
  These results suggest that neoadjuvant sorafenib therapy for ccRCC does not prevent shedding of tumor fragments. Although this is a nonrandomized study with a small patient group, our results suggest that neoadjuvant treatment may worsen survival through as yet undefined mechanisms.
authors.affiliation: Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Gursah
authors.initials: G
authors.lastname: Kats-Ugurlu
authors.affiliation: Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Egbert
authors.initials: E
authors.lastname: Oosterwijk
authors.affiliation: Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Stijn
authors.initials: S
authors.lastname: Muselaers
authors.affiliation: Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Jeannette
authors.initials: J
authors.lastname: Oosterwijk-Wakka
authors.affiliation: Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Christina
authors.initials: C
authors.lastname: Hulsbergen-van de Kaa
authors.affiliation: Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Mirjam
authors.initials: M
authors.lastname: de Weijert
authors.affiliation: Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Han
authors.initials: H
authors.lastname: van Krieken
authors.affiliation: Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Desar
authors.affiliation: Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Carla
authors.initials: C
authors.lastname: van Herpen
authors.affiliation: Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Cathy
authors.initials: C
authors.lastname: Maass
authors.affiliation: Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: de Waal
authors.affiliation: Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Mulders
authors.affiliation: Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. Electronic address: william.leenders@radboudumc.nl.
authors.forename: William
authors.initials: W
authors.lastname: Leenders
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D007668:Kidney / Q000098:blood supply / Q000187:drug effects; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009392:Nephrectomy; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D000077157:Sorafenib; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D000077157:Sorafenib
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