title: Multi-institutional validation of the predictive value of Ki-67 in patients with high grade urothelial carcinoma of the upper urinary tract.
abstract: OBJECTIVE
  We validate the independent predictive value of Ki-67 in patients with high grade upper tract urothelial carcinoma.
  
  
  METHODS
  A total of 475 patients from the international Upper Tract Urothelial Carcinoma Collaboration who underwent extirpative surgery for high grade upper tract urothelial carcinoma were included in this study. Immunohistochemical staining for Ki-67 was performed on tissue microarray formed from this patient cohort. Ki-67 expression was assessed in a semiquantitative fashion and considered over expressed at a cutoff of 20%. Multivariate analyses were performed to assess independent predictors of oncologic outcomes and Harrell's C indices were calculated for predictive models.
  
  
  RESULTS
  The median age of the cohort was 69.7 years and 55.2% of patients were male. Ki-67 was over expressed in 25.9% of patients. Ki-67 over expression was significantly associated with ureteral tumor location, higher pT-stage, lymphovascular invasion, sessile tumor architecture, tumor necrosis, concomitant carcinoma in situ and regional lymph node metastases. On Kaplan-Meier analyses over expressed Ki-67 was associated with worse recurrence-free survival (HR 12.6, p <0.001) and cancer specific survival (HR 15.8, p <0.001). On multivariate analysis Ki-67 was an independent predictor of recurrence-free survival (HR 1.6, 95% CI 1.07-2.30, p=0.021) and cancer specific survival (HR 1.9, 95% CI 1.29-2.90, p=0.001). Ki-67 improved Harrell's C index from 0.66 to 0.70 (p <0.0001) for recurrence-free survival as well as cancer specific survival in our preoperative model, and from 0.81 to 0.82 (p=0.0018) for recurrence-free survival and 0.81 to 0.83 (p=0.005) for cancer specific survival in our postoperative model.
  
  
  CONCLUSIONS
  Ki-67 was validated as an independent predictor of recurrence-free survival and cancer specific survival in patients treated with extirpative surgery for high grade upper tract urothelial carcinoma in a large, multi-institutional cohort.
authors.affiliation: Department of Urology, University of Texas Medical Center, Dallas, Texas; Department of Urology, University of Muenster Medical Center, Muenster, Germany.
authors.forename: Laura-Maria
authors.initials: LM
authors.lastname: Krabbe
authors.affiliation: Department of Urology, University of Texas Medical Center, Dallas, Texas.
authors.forename: Aditya
authors.initials: A
authors.lastname: Bagrodia
authors.affiliation: Department of Urology, University of Texas Medical Center, Dallas, Texas.
authors.forename: Ahmed Q
authors.initials: AQ
authors.lastname: Haddad
authors.affiliation: Department of Urology, University of Texas Medical Center, Dallas, Texas; Department of Pathology, University of Texas Medical Center, Dallas, Texas.
authors.forename: Payal
authors.initials: P
authors.lastname: Kapur
authors.affiliation: Department of Pathology, University of Texas Medical Center, Dallas, Texas.
authors.forename: Dina
authors.initials: D
authors.lastname: Khalil
authors.affiliation: Department of Biostatistics, University of Texas Medical Center, Dallas, Texas.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Hynan
authors.affiliation: Department of Urology, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Wood
authors.affiliation: Department of Urology, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Karam
authors.affiliation: Department of Urology, University of Michigan Cancer Center, Ann Arbor, Michigan.
authors.forename: Alon Z
authors.initials: AZ
authors.lastname: Weizer
authors.affiliation: Division of Urology, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania.
authors.forename: Jay D
authors.initials: JD
authors.lastname: Raman
authors.affiliation: Department of Urology, Medical University Vienna, Vienna, Austria.
authors.forename: Mesut
authors.initials: M
authors.lastname: Remzi
authors.affiliation: Department of Pathology, Centre Hospitalier Universitaire de Rennes, Rennes, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rioux-Leclercq
authors.affiliation: Department of Pathology, Medical University Vienna, Vienna, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Haitel
authors.affiliation: Department of Urology, Ospedali Riuniti di Bergamo, Bergamo, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Roscigno
authors.affiliation: Department of Urology, Mannheim Medical Center, University of Heidelberg, Mannheim, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Bolenz
authors.affiliation: Department of Urology, Centre Hospitalier Universitaire de Rennes, Rennes, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Bensalah
authors.affiliation: Department of Urology, University of Texas Medical Center, Dallas, Texas.
authors.forename: Arthur I
authors.initials: AI
authors.lastname: Sagalowsky
authors.affiliation: Department of Urology, Medical University Vienna, Vienna, Austria.
authors.forename: Shahrokh F
authors.initials: SF
authors.lastname: Shariat
authors.affiliation: Department of Urology, University of Texas Medical Center, Dallas, Texas.
authors.forename: Yair
authors.initials: Y
authors.lastname: Lotan
authors.affiliation: Department of Urology, University of Texas Medical Center, Dallas, Texas. Electronic address: Vitaly.margulis@utsouthwestern.edu.
authors.forename: Vitaly
authors.initials: V
authors.lastname: Margulis
mesh_terms: D000368:Aged; D002295:Carcinoma, Transitional Cell / Q000737:chemistry* / Q000473:pathology / Q000601:surgery; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis*; D007680:Kidney Neoplasms / Q000737:chemistry* / Q000473:pathology / Q000601:surgery; D007682:Kidney Pelvis; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D060787:Neoplasm Grading; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D014516:Ureteral Neoplasms / Q000737:chemistry* / Q000473:pathology / Q000601:surgery
chemical_list: D019394:Ki-67 Antigen
keywords: Ki-67 antigen; biological markers; carcinoma; transitional cell; urinary tract