Reply

We thank Vassilakopoulos et al. for their comments and their interest in HD¹ and topoisomerase IIα expression. It is a pleasure to respond to their remarks. They communicate a series of HD patients in which topoisomerase IIα expression did not offer prognostic significance.

There are several important differences between our series and that reported by Vassilakopoulos et al. We studied patients with advanced disease and at least two risk factors (1), whereas Vassilakopoulos et al. included few patients with advanced stages and consequently with fewer risk factors than in our series: for example, B symptoms (62 versus 24%), bulky disease (36 versus 22%), or high presence of nodular sclerosis. This is concordant with the low proportion of relapses observed in their series (only 8 patients), which is insufficient to justify consistent conclusions. Vassilakopoulos et al. did not document the median follow-up of this subgroup of patients, but in any case, it was lower than the follow-up in our study, which was long enough to detect late relapses. In conclusion, we believe that our study was based on a series of advanced HD patients, uniformly treated and with a long follow-up. These characteristics contrast strongly with those of the series reported by Vassilakopoulos et al., but we believe that such a long follow up was necessary to identify new prognostic factors in HD.

Regarding topoisomerase IIα expression, we took the 30% level as a cutoff in the prognostic study because it was the median of the expression in our series. Vassilakopoulos et al. observed a median expression of topoisomerase IIα of 60% in their series, but they used a level of 30% in their prognostic analysis. We believe that in the study of Vassilakopoulos et al., it would be interesting to calculate the median topoisomerase IIα expression of this small number of patients with advanced disease and use this level in the prognostic analysis. Moreover, in immunohistochemical studies, there are variations depending on the observer, and so it is important that several qualified specialists should analyze the samples. In our study, the immunohistochemical expression analysis was performed by three pathologists independently.

Topoisomerase IIα is the molecular target for a variety of clinically useful chemotherapy agents. Experimental results showed that the intracellular level of topoisomerase IIα is a molecular target that determines specific chemotherapy sensitivity. Thus, a high level of topoisomerase IIα expression is correlated with increased sensitivity to the agent (2,3 4), which is likely to have repercussions for survival, as was indeed observed in our results.

Because topoisomerase IIα expression is practically constant in HD, we suggest that this parameter could be incorporated in larger studies to determine its value as a predictor of chemotherapy response in HD.