Application of the National Comprehensive Cancer Network-distress thermometer in pediatric patients during autologous and allogeneic hematopoietic stem cell transplantation and relationship to blood parameters of the stress axis.

PURPOSE: Hematopoietic stem cell transplantations (HSCT) are extremely stressful procedures for pediatric patients. The activation of the hypothalamic pituitary adrenocortical axis (HPA) can influence the immune system negatively and therefore the overall outcome. The distress thermometer (DT) is an easy to use tool for the self-assessment of perceived distress. METHODS: In this prospective study, a DT with an attached problem list was used in 40 pediatric patients undergoing HSCT and in one parent of each patient. The patients were aged 10-18 years. The patients' cortisol, thyroid stimulating hormone, free triiodothyronine and thyroxine levels were measured regularly during the in-patient stay. RESULTS: After admission to the hospital, the stress levels of the pediatric patients and their parents increased and reached their maximum on the day of HSCT. The overall stress values of the parents were higher than those of their children. There was a significant difference in the parents' stress levels on the day of HSCT, as compared to their stress levels on other days. The mean cortisol values of the pediatric patients also increased after admission, reaching significant elevated levels above the upper normal limit 1 week after HSCT and on discharge day. Although the pediatric patients experienced mainly exhaustion, especially on the day of transplantation, their parents mainly felt worry and anxiety. Interestingly, the rate of worry among children increased in the post-transplant period and reached its maximum on the day of discharge. CONCLUSIONS: In summary, a significantly increased stress level is shown for both the patients and their parents. This is reflected for the patients both in the DT scores and in the increased cortisol values. For the parents, the focus is primarily on worry and anxiety, for the patients primarily on exhaustion and worry.

PolyQ-expanded ataxin-3 protein levels in peripheral blood mononuclear cells correlate with clinical parameters in SCA3: a pilot study.

In view of upcoming clinical trials, quantitative molecular markers accessible in peripheral blood are of critical importance as prognostic or pharmacodynamic markers in genetic neurodegenerative diseases such as Spinocerebellar Ataxia Type 3 (SCA3), in particular for signaling target engagement. In this pilot study, we focused on the quantification of ataxin-3, the protein altered in SCA3, in human peripheral blood mononuclear cells (PBMCs) acquired from preataxic and ataxic SCA3 mutation carriers as well as healthy controls, as a molecular marker directly related to SCA3 pathophysiology. We established two different highly sensitive TR-FRET-based immunoassays to measure the protein levels of either total full-length, non-expanded and expanded, ataxin-3 or specifically polyQ-expanded ataxin-3. In PBMCs, a clear discrimination between SCA3 mutation carrier and controls were seen measuring polyQ-expanded ataxin-3 protein level. Additionally, polyQ-expanded ataxin-3 protein levels correlated with disease progression and clinical severity as assessed by the Scale for the Assessment and Rating of Ataxia. Total full-length ataxin-3 protein levels were directly influenced by the expression levels of the polyQ-expanded ataxin-3 protein, but were not correlated with clinical parameters. Assessment of ataxin-3 levels in fibroblasts or induced pluripotent stem cells allowed to distinguish mutation carriers from controls, thus providing proof-of-principle validation of our PBMC findings across cell lines. Total full-length or polyQ-expanded ataxin-3 protein was not detectable by TR-FRET assays in other biofluids like plasma or cerebrospinal fluid, indicating the need for ultra-sensitive assays for these biofluids. Standardization studies revealed that tube systems, blood sampling, and PBMC preparation may influence ataxin-3 protein levels indicating a high demand for standardized protocols in biomarker studies. In conclusion, the polyQ-expanded ataxin-3 protein is a promising candidate as a molecular target engagement marker in SCA3 in future clinical trials, determinable even in-easily accessible-peripheral blood biomaterials. These results, however, require validation in a larger cohort and further standardization of modifying conditions.

Antiemetic Prophylaxis with Fosaprepitant and 5-HT3-Receptor Antagonists in Pediatric Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation.

BACKGROUND: High-dose myeloablative conditioning prior to autologous hematopoietic stem cell transplantation (autoHSCT) in pediatric patients is usually highly emetogenic. The antiemetic neurokinin-1 receptor antagonist fosaprepitant was safe and effective in children receiving highly emetogenic chemotherapy. Data on fosaprepitant during autoHSCT in children are currently not available. METHODS: A total of 35 consecutive pediatric patients, who received an antiemetic prophylaxis with fosaprepitant (4 mg/kg; single dose, max. 1 x 150 mg/kg BW) and ondansetron (24-hours continuous infusion; 8-32 mg/24h) or granisetron (2 x 40 µg/kg∙d-1) during highly emetogenic conditioning chemotherapy before autoHSCT were retrospectively analyzed, and their results were compared with a control group comprising 35 consecutive pediatric patients, who received granisetron or ondansetron only. The antiemetic efficacy and the safety of the two prophylaxis regimens were compared with respect to three time periods after the first chemotherapy administration (0-24h, >24-120h, >120-240h). RESULTS: Clinical adverse events and clinically relevant increases/decreases of laboratory markers were similarly low and did not significantly differ between the two study groups (p>0.05). The registered number of vomiting events was significantly higher in the control group in the time periods of 0-24h (64 vs 22 events; p<0.01), >24-120h (135 vs 78 events; p<0.0001), >120-240h (268 vs 105 events; p<0.0001), and the whole observation period 0-240h (467 vs 205 events; p<0.0001). The percentage of patients experiencing vomiting was higher in the control group during the time period of >24-120h (100% vs 74.3%) but not the other analyzed time periods (p>0.05). CONCLUSION: The fosaprepitant-based antiemetic prophylaxis was safe, well tolerated and significantly reduced vomiting in children undergoing highly emetogenic chemotherapy prior to autoHSCT. Prospective randomized trials are necessary to confirm these results.