Altundag et al.  provide an interesting interpretation of our findings on neuropsychological function in high-risk breast cancer survivors after different treatment regimens . The authors propose that the slightly better global cognitive outcome in breast cancer patients 5 years after stem-cell supported high-dose therapy compared with standard-dose treatment might be partly explained by enhanced neurogenesis in this patient group. However, we advise caution in drawing conclusions too early as both plasticity of adult stem cells and long-term cognitive outcome in cancer patients following high-dose therapy with stem-cell rescue are ongoing research topics with several questions left open.
To date, the underlying mechanisms of adult stem-cell plasticity are not completely understood. While several reviews on this topic discuss recent findings suggesting that this phenomenon might be rather a result of cell fusion with mature tissue-specific cells than hematopoietic differentiation [3, 4], other authors provide evidence for the capacity of human hematopoietic stem cells to transdifferentiate into neural cells without fusion . Next to the pertinence of understanding plasticity for developing advanced therapeutic strategies in patients with CNS diseases, future investigations have to show whether new neurons are capable of integrating into the neuronal network and compensating for neuronal loss, for example, induced by cancer treatments. Although recent autopsy studies in female patients who had received bone marrow transplants from male donors found Y chromosome-positive cells in the host brains [5–7], there are some limitations in interpretation due to small sample sizes and a diversity in several variables (e.g. age, survival times after transplantation). In addition, observed frequencies of neurons among cells containing Y chromosomes were only modest.
Another important issue that has to be considered is the result of the Dutch study conducted by Schagen et al. . In their follow-up study on long-term cognitive outcome in breast cancer patients 4 years, on average, after stem-cell supported high-dose versus standard-dose chemotherapy, the authors reported a mild higher prevalence rate for cognitive impairment in high-dose patients, although this difference was not statistically significant.
As we mentioned in our article, we assume that the tendentially lower outcome in our standard-dose patients is based on a neurotoxic side-effect of the anticancer agent methotrexate (MTX) primarily known as causing CNS neurotoxicity .
Although research indicates hematopoietic stem-cell transplantation as a promising approach in neuronal cell replacement therapies after CNS disease, further studies on the potential of adult stem cells for functional brain repair and neuropsychological recovery are needed.