Vincristine-induced peripheral neuropathy (VIPN) is a dose-limiting side effect of vincristine (VCR) treatment in children, leading to diminished quality of life. Much remains unknown about the underlying mechanisms of VIPN. This review systematically summarizes the available literature concerning contributing factors of VIPN development in children. Studied factors include patient characteristics, VCR dose, administration method, pharmacokinetics, and genetic factors. Furthermore, this review reports on currently available tools to assess VIPN in children. In total, twenty-eight publications were included. Results indicate that Caucasian race, higher VCR dose, older age and low clearance negatively influence VIPN, although results regarding the latter two factors were rather conflicting. Moreover, genetic pathways influencing VIPN were identified. Furthermore, the studied tools to assess VIPN seriously impairs comparability across study results. Studying the factors and their interactions that seem to influence VIPN in children, should aid in personalized VCR treatment, thereby increasing VCR effectiveness while minimizing toxicity.

Summary:Glomerular function of all long-term survivors who underwent hemopoietic stem cell transplantation (HSCT) from 1991 to 1998 (study I, n ¼ 121) was studied retrospectively. In addition, we prospectively analyzed glomerular and tubular function of all long-term surviving children who received an HSCT between 1998 and 2000 (study II, n ¼ 41). We found a lower prevalence of children with chronic renal failure (CRF) post-HSCT in our more recent cohort (study II: 10%) as compared to the older cohort (study I: 24%) 5.0 (0.7 s.d.) and 7.6 (2.4 s.d.) year's post-HSCT, respectively. Furthermore, it seems that renal function may stabilize after 1-year post-HSCT. None of the patients required dialysis or antihypertensive medication at long-term follow-up. The sole predictor of CRF in our study was high serum creatinine pre-HSCT (P ¼ 0.007), while acute renal failure within 3 months after HSCT (P ¼ 0.08) only showed a trend towards predicting CRF. We could not confirm a relation of conditioning with irradiation with CRF post-HSCT, as was shown in several other pediatric and adult studies. Proximal and distal tubular dysfunction only occurred in a minority of long-time survivors of HSCT (3-12 and 9-13%, respectively) and had no clinical consequences. Hemopoietic stem cell transplantation (HSCT) has evolved as an accepted treatment modality for a diverse spectrum of diseases in children such as hematological malignancies, bone marrow failure syndromes, immunodeficiencies and inborn errors of metabolism. The 5-year survival rates depend on the disease for which HSCT is performed and vary from 90% for immunodeficiencies to 25% for highrisk hematological malignancies. 1 As long-term survival has improved over the years, assessment of late complications becomes increasingly important. Chronic renal failure (CRF) following allogeneic HSCT is reported in children, although data on incidence and etiology in long-term survivors of HSCT are still scarce. 2,3 Understanding of the possible risk factors and the pathogenesis of acute and chronic renal failure after HSCT is required in order to reduce its incidence. We have previously shown a prevalence of 28% CRF in children 1-year post-HSCT in a retrospective study, and more recently a lower prevalence of only 11% in a prospective study. 4,5 In the current study, we investigated how renal function of these patients evolved after an extended follow-up period. Patients and methods

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Background Vincristine (VCR) is a critical part of treatment in pediatric malignancies and is associated with dose-dependent peripheral neuropathy (vincristine-induced peripheral neuropathy [VIPN]). Our previous findings show VCR metabolism is regulated by the CYP3A5 gene. Individuals who are low CYP3A5 expressers metabolize VCR slower and experience more severe VIPN as compared to high expressers. Preliminary observations suggest that Caucasians experience more severe VIPN as compared to nonCaucasians. Procedure Kenyan children with cancer who were undergoing treatment including VCR were recruited for a prospective cohort study. Patients received IV VCR 2 mg/m2/dose with a maximum dose of 2.5 mg as part of standard treatment protocols. VCR pharmacokinetics (PK) sampling was collected via dried blood spot cards and genotyping was conducted for common functional variants in CYP3A5, multi-drug resistance 1 (MDR1), and microtubule-associated protein tau (MAPT). VIPN was assessed using five neuropathy tools. Results The majority of subjects (91%) were CYP3A5 high-expresser genotype. CYP3A5 low-expresser genotype subjects had a significantly higher dose and body surface area normalized area under the curve than CYP3A5 high-expresser genotype subjects (0.28 ± 0.15 hr·m2/l vs. 0.15 ± 0.011 hr·m2/l, P = 0.027). Regardless of which assessment tool was utilized, minimal neuropathy was detected in this cohort. There was no difference in the presence or severity of neuropathy assessed between CYP3A5 high- and low-expresser genotype groups. Conclusion Genetic factors are associated with VCR PK. Due to the minimal neuropathy observed in this cohort, there was no demonstrable association between genetic factors or VCR PK with development of VIPN. Further studies are needed to determine the role of genetic factors in optimizing dosing of VCR for maximal benefit.