br Efficacy In the study by

Efficacy In the study by Haahr and colleagues, in the incontinent group, 5/6 patients underwent non-nerve sparing prostatectomy while in the continent group, 7/11 patients had some degree of nerve-sparing surgery. Thus, 8/17 patients in total had some degree of nerve sparing surgery, and 9/17 patients had non-nerve sparing surgery. If we look at the efficacy data, 9/17 patients were not able to have successful intercourse, and 8/17 patients were able to have successful sexual intercourse. Is this a coincidence? Are the patients with some degree of erection recovery the 8 patients who underwent some degree of nerve sparing surgery? Without additional information about the study cohort we cannot determine if the erection recovery was an effect of regenerative cell injection versus a spontaneous recovery which is to be expected after nerve-sparing surgery (Kaye et al., 2013). One could argue against this position by stating that 4 patients who had an improvement in erectile function where excluded. Early signs of erection recovery however, in our opinion, do not exclude the possibility for later spontaneous improvement of erectile function. The mean time from surgery in the current study was 10.1months, and it is established that erectile function recovery after nerve sparing radical prostatectomy occurs up to 24months after surgery (Rabbani et al., 2010). In the absence of a control group, we simply cannot make any conclusion on the efficacy of the proposed regenerative therapy. A power analysis for efficacy data is lacking, and the incontinent group should not be considered an “internal control” for the following reasons — (1) the rate of nerve sparing surgery in the incontinent group was much lower, (2) authors have described that in their own experience, these patients historically have an impaired erectile recovery and (3) it is well established from centers of excellence that non-nerve sparing results in delayed recovery of continence (Kaye et al., 2013; Gandaglia et al., 2012). As the authors suggested, the efficacy of autologous adipose-derived regenerative meclofenoxate in patients with erectile dysfunction following radical prostatectomy needs to be studied in an adequately powered, randomized and placebo-controlled trial, before any recommendation can be made on the (future) use of this treatment. Even though the wording “potential efficacy” has been used, we believe for the above mentioned reasons that a phase 1 trial is not designed for efficacy evaluation. We have to be rigorous and critical with our conclusions so that others in academic and private centers throughout the world do not prematurely start utilizing this form of local cell-based therapy without appropriately powered studies which show true efficacy. The erectile dysfunction market is large and continues to grow. The risks of financial interests cannot be overestimated and caution is therefore warranted in disseminating and interpreting the reported preliminary efficacy data.
Ready for translation? Dosage and timing of treatment The International Society for Stem Cell Research (ISSCR) devised guidelines for clinical translation of stem cell-based therapies which include guidance on the preclinical work up of stem-cell based therapies and the processes involved in clinical translation. Some of the statements pertain to preclinical investigation of mode of action in models that closely resemble the disease state. In young rats, known for their surprising potential for regeneration after injury, we observed only a partial (but significant) recovery of erectile function following cavernous nerve injury (Albersen et al., 2010) after penile injections of high dosages (1∗106 cells in animals weighing under 300g: ±3∗106 cells/kg) of pure populations of cultured adipose tissue derived stem cells. This clinical trial involves dosages of 8.4 and 37.2 million cells in men with a mean age of 63years and a mean BMI of 30.3kg/m2. Assuming, based on their BMI, that these patients weighed at least 80kg, they received roughly between 1∗105 and 5∗105 cells/kg body weight. How does this compare to the situation in a small rodent model? Before we can translate this form of cell-based therapy, concentration response studies, as preliminary reported by Yiou et al. (2015) for bone marrow mononuclear cells, must be conducted. We need to know what minimal concentration of cells could be effective, and what maximal concentration of cells could be safe. The further these two numbers are apart, the better for translational efficacy. In our research we have observed that a critical time-point in cavernous nerve neuropraxia is the first 24 to 48h after nerve injury, when neuro-inflammation is initiated and influx of neurotoxic subpopulations of macrophages commences (unpublished data and Albersen et al., 2013a). Injected adipose derived stem cells are attracted to the injured neural tissue by the local release of chemokines and cytokines, which is also activated shortly after the initiating events. Several days later, stem cells appear to reside in reticulo-endothelial system sites such as the spleen and bone marrow (Lin et al., 2011). Due to the highly vascular character of the corpus cavernosum, cells disappear rapidly from the penis and definitive evidence of engraftment and differentiation into cell types contained with the corpora has never been established (Albersen et al., 2013b). Although secondary prevention or treatment excludes patients who might recover spontaneously from unnecessary treatment, we hypothesize that early injection, at the time of radical prostatectomy as a primary prevention of erectile dysfunction may be a more valid physiologic-based approach, and potentially more effective, which further spares the patients a separately-timed invasive procedure.