title: The survivin:Fas ratio is predictive of recurrent disease in neuroblastoma.
abstract: OBJECTIVE
  Several clinical and biologic features of neuroblastoma (NB) are used to predict the risk of recurrent disease. The balance between antiapoptotic and proapoptotic factors within a tumor may affect its ability to survive. Survivin is an antiapoptotic factor expressed in highly proliferative NB, whereas Fas is a proapoptotic factor that portends a favorable prognosis. The authors determined whether the ratio of survivin to Fas (S:F ratio) is predictive of recurrent disease in patients with NB. The authors previously have shown the S:F ratio is predictive of recurrent disease in pediatric renal tumors.
  
  
  METHODS
  The authors quantified the levels of 9 different apoptotic mRNA species using Rnase Protection assay (RPA, Riboquant, PharMingen, San Diego, CA). Twenty-eight primary tumor specimens were evaluated from patients with ganglioneuroma (n = 3), ganglioneuroblastoma (n = 2), and neuroblastoma (n = 23) from tumors of all clinical stages obtained at the time of diagnosis. mRNA levels were calculated as a percentage of L32 for each specimen assayed, and positive expression was assumed to be greater than 10% of L32.
  
  
  RESULTS
  Survivin was expressed in 90% of tumors that went on to recur and only in 27.7% of those that were cured. The S:F ratio was significantly greater in tumors that went on to recur (n = 10) compared with those from patients that were cured (n = 18) (median S:F ratio, 3.3 v 0.75; P =.0002, Wilcoxon rank-sum test). A cutoff ratio of 2.3 was highly predictive of tumor recurrence irrespective of clinical stage of disease (area under ROC curve = 0.906). Sensitivity was 80% (CI, 44.4% to 97.5%), specificity was 94.4% (CI, 72.7% to 99.9%), positive predictive value was 88.9% (CI, 51.8% to 99.7%), and negative predictive value was 89.5% (66.9% to 98.7%). Twenty-five of 28 (89.3%) tumor ratios were correct in predicting outcome.
  
  
  CONCLUSIONS
  The survivin:Fas ratio in primary tumors may be used to predict the risk for recurrent disease in patients with NB. The S:F ratio appears to be a more sensitive predictor of recurrent disease than survivin expression alone. Determining this ratio may not only be helpful in guiding follow-up of patients with NB, but also may aid in stratifying patients for more aggressive therapeutic strategies.
authors.affiliation: Department of Surgery, Department of Pediatrics, The University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Sandler
authors.forename: David
authors.initials: D
authors.lastname: Scott
authors.forename: Takeo
authors.initials: T
authors.lastname: Azuhata
authors.forename: Shigeru
authors.initials: S
authors.lastname: Takamizawa
authors.forename: Sue
authors.initials: S
authors.lastname: O'Dorisio
mesh_terms: D002648:Child; D002868:Chromosomal Proteins, Non-Histone / Q000032:analysis*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D009364:Neoplasm Recurrence, Local / Q000378:metabolism* / Q000473:pathology; D009367:Neoplasm Staging; D009380:Neoplasms, Nerve Tissue / Q000737:chemistry / Q000473:pathology; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D011237:Predictive Value of Tests; D012680:Sensitivity and Specificity; D000077022:Survivin; D019014:fas Receptor / Q000032:analysis*
chemical_list: C107489:BIRC5 protein, human; D002868:Chromosomal Proteins, Non-Histone; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D019014:fas Receptor