title: Association of angiogenic factors with prognosis in esophageal cancer.
abstract: BACKGROUND
  Despite multimodal therapy esophageal cancer often presents with poor prognosis. To improve outcome, tumor angiogenesis and anti-angiogenic therapeutic agents have recently gained importance. However, patient subgroups who benefit from anti-angiogenic therapy are not yet defined. In this retrospective exploratory study we investigated 9 angiogenic factors in patients' serum and tissue samples with regard to their association with clinicopathological parameters, prognosis and response in patients with locally advanced preoperatively treated esophageal cancer.
  
  
  METHODS
  From 2007 to 2012 preoperative serum and corresponding tumor tissue (n = 54), only serum (n = 20) or only tumor tissue (n = 4) were collected from esophageal squamous cell carcinoma (SCC) (n = 34) and adenocarcinoma of the esophagogastric junction (AEG) (n = 44) staged cT3/4NanyM0/x after preoperative chemo(radio)therapy. Angiogenic cytokine levels in both tissue and serum were measured by multiplex immunoassay.
  
  
  RESULTS
  Median survival in all patients was 28.49 months. No significant difference was found in survival between SCC and AEG (p = 0.90). 26 patients were histopathological responders. Histopathological response was associated with prognosis (p = 0.05). Angiogenic factors were associated with the following clinicopathological factors: tumor tissue expression of Angiopoietin-2 and Follistatin was higher in SCC compared to AEG (p = 0.022 and p = 0.001). High HGF and Follistatin expression in the tumor tissue was associated with poor prognosis in all patients (p = 0.037 and p = 0.036). No association with prognosis was found in the patients' serum. Neither patients' serum nor tumor tissue showed an association between angiogenic factors and response to neoadjuvant therapy.
  
  
  CONCLUSIONS
  Two angiogenic factors (HGF and Follistatin) in posttherapeutic tumor tissue are associated with prognosis in esophageal cancer patients. Biological differences of AEG and SCC with respect to angiogenesis were evident by the different expression of 2 angiogenic factors. Results are promising and should be pursued prospectively, optimally sequentially pre- and posttherapeutically.
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. lena.dreikhausen@tesionmail.de.
authors.forename: Lena
authors.initials: L
authors.lastname: Dreikhausen
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. susanne.blank@med.uni-heidelberg.de.
authors.forename: Susanne
authors.initials: S
authors.lastname: Blank
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. leila.sisic@med.uni-heidelberg.de.
authors.forename: Leila
authors.initials: L
authors.lastname: Sisic
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. ulrike.heger@med.uni-heidelberg.de.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Heger
authors.affiliation: Department of Pathology, University of Heidelberg, 69120, Heidelberg, Germany. wilko.weichert@med.uni-heidelberg.de.
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.affiliation: National Center of Tumor Diseases, University of Heidelberg, 69120, Heidelberg, Germany. dirk.jaeger@nct-heidelberg.de.
authors.forename: Dirk
authors.initials: D
authors.lastname: Jäger
authors.affiliation: Institute of Medical Biometry, University of Heidelberg, Heidelberg, Germany. bruckner@imbi.uni-heidelberg.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bruckner
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. natalia.giese@med.uni-heidelberg.de.
authors.forename: Natalia
authors.initials: N
authors.lastname: Giese
authors.affiliation: Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany. lars.grenacher@med.uni-heidelberg.de.
authors.forename: Lars
authors.initials: L
authors.lastname: Grenacher
authors.affiliation: Institute for Transplant Immunology, Hannover Medical School, Hannover, Germany. falk.christine@mh-hannover.de.
authors.forename: Christine
authors.initials: C
authors.lastname: Falk
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. katja.ott@med.uni-heidelberg.de.
authors.forename: Katja
authors.initials: K
authors.lastname: Ott
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. thomas1.schmidt@med.uni-heidelberg.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmidt
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000175:diagnosis / Q000378:metabolism*; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D038681:Follistatin / Q000096:biosynthesis*; D005500:Follow-Up Studies; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; C503233:FST protein, human; D038681:Follistatin; C066855:HGF protein, human; D017228:Hepatocyte Growth Factor