Intrathecal administration of anticancer drugs is an effective dosage strategy, but the elimination of intraventricular drugs is not uniform in all patients. For safety, a system to evaluate local pharmacokinetics in the ventricles after administration is desired. In this study, we developed a simple and reproducible method to measure topotecan concentration in the cerebrospinal fluid (CSF) and confirmed its clinical applicability. High-performance liquid chromatography (HPLC) analysis was performed using a C18 column to measure the total topotecan concentration in the CSF. Clinical CSF samples were obtained from a 1-year old child with poor CSF absorption and stagnation. The patient received topotecan via an intraventricular subcutaneous reservoir. The HPLC method complied with the validation criteria. The lower limit of quantitation of this method was 0.04 µM. Using the developed method, we could determine the difference in topotecan CSF concentrations at 24 and 48 h after administration. The patient’s topotecan elimination rate was extremely low, and signs of adverse effects were observed at high CSF concentration of topotecan. The developed method could detect the delay in topotecan elimination after intrathecal injection. The findings of this study are valuable for the development of personalized treatments for the intrathecal administration of anticancer drugs.

Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT). Previous reports in the United States have suggested that TA-TMA is caused by complement-related genetic variants. However, these findings need to be validated in other countries and ethnic populations. Methods: We performed targeted sequencing of 40 complement-and coagulopathy-related genes in 44 Japanese pediatric patients who underwent HSCT, including 20 patients with TA-TMA and 24 patients without TA-TMA. Seventeen genes reported to be related to TA-TMA were included. Additionally, 23 genes that are thought to be associated with complement system activation and coagulopathy were investigated. CFHR 1 /CFHR 3 deletions were also examined using multiplex ligation-dependent probe amplification. Results: There was no significant difference in the percentage of patients bearing genetic variants between patients with and without TA-TMA. Furthermore, no marked differences in the percentage of patients or the average number of rare variants per patient were found between the two groups. Although we identified several rare non-synonymous variants in TA-TMA patients, we did not find any known pathogenic variants causing TA-TMA. Interestingly, a novel rare genetic variant in the C 1 r-like protein (C 1 RL) gene was identified in a patient with neuroblastoma who had undergone autologous HSCT, potentially associated with TA-TMA. Conclusion: In this limited number of Japanese pediatric cohort with TA-TMA, we could not find an enrichment of rare variants among 40 complement- and coagulopathy-related genes. A novel, rare variant of C 1 RL was identified in a single patient with TA-TMA. Further studies with larger cohorts are necessary to clarify the genetic association in Japanese patients with TA-TMA.