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repp86 Expression and Outcome in Patients With Neuroblastoma

Matthias Krams, Hans-Juergen Heidebrecht, Barbara Hero, Frank Berthold, Dieter Harms, Reza Parwaresch, Pierre Rudolph

From the Department of Pathology, University of Kiel; and German Neuroblastoma Study Group, Department of Pediatrics, University of Cologne, Germany.

Address reprint requests to Pierre Rudolph, MD, PhD, Department of Pathology, University of Kiel, Michaelisstr 11, 24105 Kiel, Germany; email: prudolph{at}path.uni-kiel.de.

Purpose: Given the well-known challenges of neuroblastoma prognosis, we investigated whether the expression of restrictedly expressed proliferation-associated protein of 86 kDa theoretical molecular mass (repp86), a proliferation-associated protein expressed in S, G₂, and M phases of the cell cycle, correlates with the clinical outcome in patients with neuroblastoma.

Patients and Methods: 161 children with different stages of neuroblastoma were studied; the median follow-up time was 72.8 months. The patients were staged according to the International Neuroblastoma Staging System, and histologic grading of the tumors was performed according to the criteria of Hughes and those of the International Neuroblastoma Pathology Classification. The MYCN gene copy number was determined by Southern blot analysis or fluorescence in situ-hybridization, and repp86 expression was assessed immunohistochemically by means of monoclonal antibody Ki-S2 on paraffin sections from archival tumor samples.

Results: A repp86 labeling index (RI) of more than 10% positive tumor cells significantly predicted a shortened disease-free interval and an increased tumor mortality (both P < .0001). Moreover, the RI allowed the identification of patients with favorable and adverse prognosis in subsets defined by stage, grade, age, and MYCN status. In a multivariate analysis, the RI emerged as the most important predictor of event-free and disease-specific survival with hazard ratios of 11.7 and 10.5, respectively (both P < .0001).

Conclusion: It seems that repp86 expression is closely associated with the biologic behavior of neuroblastoma. Assessment of the RI might, therefore, considerably refine prognostic models.

Supported by grants from the Kinder Krebs Initiative, Buchholz Holm-Seppenesen, and the Else Kröner-Fresenius Stiftung, Bad Homburg, Germany.

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