Wilms tumors: genotypes and phenotypes

Wilms tumor, or nephroblastoma, represents about 90% of all pediatric renal tumors and about 7% of all pediatric malignancies. Most Wilms tumors are unilateral, although in 5-10 % of the patients both kidneys are infected. Wilms tumor typically occurs between the age of 2 and 4 years, and 90% of the patients are diagnosed before the age of 7 years. Above the age of 18 years, Wilms tumor is rare, representing less than 1% of all adult renal tumors. Most pediatric Wilms tumor patients present with an asymptomatic abdominal mass, although abdominal pain, anorexia, vomiting, hematuria, fever and hypertension have frequently been described. Unusual presentations of Wils tumor in children are acquired von Willebrand disease, sudden death due to pulmanory embolism, and Cushing syndrome

Randomized controlled trial on the effect of 1-hour infusion of vincristine versus push injection on neuropathy in children with cancer (final analysis)

Introduction: Vincristine is an integral component of treatment for children with cancer. Its main dose-limiting side effect is vincristine-induced peripheral neuropathy (VIPN). The VINCA trial was a randomized controlled trial that explored the effect of 1-hour infusion compared with push injection of vincristine on the development of VIPN in children with cancer. The short-term outcomes (median follow-up 9 months) showed that there was no difference in VIPN between the randomization groups. However, 1-hour infusion was less toxic in children who also received azoles. We now report the results of the final analyses (median follow-up 20 months), which includes treatment outcome as a secondary objective (follow-up 3 years). Methods: VIPN was measured 1–7 times per participant using the Common Terminology Criteria for Adverse Events (CTCAE) and the pediatric-modified total neuropathy score. Poisson mixed model and logistic generalized estimating equation analysis for repeated measures were performed.Results: Forty-five participants per randomization group were included. There was no significant effect of 1-hour infusion compared with push injection on VIPN. In participants receiving concurrent azoles, the total CTCAE score was significantly lower in the one-hour group (rate ratio 0.52, 95% confidence interval 0.33–0.80, p = 0.003). Four patients in the one-hour group and one patient in the push group relapsed. Two patients in the one-hour group died. Conclusion:1-hour infusion of vincristine is not protective against VIPN. However, in patients receiving concurrent azoles, 1-hour infusion may be less toxic. The difference in treatment outcome is most likely the result of differences in risk profile.</p

Vincristine-induced peripheral neuropathy in pediatric oncology: A randomized controlled trial comparing push injections with one-hour infusions (the vinca trial)

Vincristine (VCR) is a frequently used chemotherapeutic agent. However, it can lead to VCR-induced peripheral neuropathy (VIPN). In this study we investigated if one-hour infusions of VCR instead of push-injections reduces VIPN in pediatric oncology patients. We conducted a multicenter randomized controlled trial in which participants received all VCR administrations through push injections or one-hour infusions. VIPN was measured at baseline and 1–5 times during treatment using Common Terminology Criteria of Adverse Events (CTCAE) and pediatric-modified Total Neuropathy Score. Moreover, data on co-medication, such as azole antifungals, were collected. Overall, results showed no effect of administration duration on total CTCAE score or ped-mTNS score. However, total CTCAE score was significantly lower in patients receiving one-hour infusions concurrently treated with azole antifungal therapy (β = −1.58; p = 0.04). In conclusion, generally VCR administration through one-hour infusions does not lead to less VIPN compared to VC

Gain of 1q Is a Marker of Poor Prognosis in Wilms' Tumors

Wilms' tumor (WT) trials aim to better tailor treatment intensity to the risk of relapse and death. Currently, stage, histology, age ( 24 months), and combined loss of heterozygosity at 1p and 16q in chemotherapy-naïve WTs are the only risk factors used for treatment stratification. However, they predict only less than one-third of all relapsing patients, implying that other factors are involved in treatment failure. Previous studies have associated 1q gain with adverse outcome. Therefore, in this study, the role of 1q gain and other common cytogenetic aberrations (CAs) in WTs was investigated and related to follow-up data from patients with WT treated in the United Kingdom; 19% (64/331) had 1q gain. Gain of 1q was significantly associated with 16q loss (P < 0.001) and 1p loss (P < 0.001). In multivariate analysis taking account of age, tumor stage, anaplasia, and common CA (e.g., 1p loss and 16q loss), 1q gain was independently associated with adverse event-free survival [EFS; hazard ratio (HR) = 2.45, P = 0.02] and overall survival (HR = 4.28, P = 0.004). Loss of 14q was independently associated with an adverse EFS (HR = 4.0, P = 0.04). Gain of 1q is a marker of poor prognosis in WTs, independent of high tumor stage and anaplasia which remain the overarching adverse prognostic factors. Confirmation in other studies is necessary before future therapeutic studies can incorporate 1q gain into new risk stratification schema

Final height and IGF1 in adult survivors of Wilms tumour

Objective: One-sided nephrectomy is followed by increased levels of IGF1, associated with linear growth during childhood. The aim was to evaluate final height and IGF1 levels in nephrectomized Wilms tumour survivors when compared with healthy Dutch references and survivors of other cancer types. Design: Cross-sectional retrospective study. Methods: Data of 575 adult childhood cancer survivors were analysed. Median follow-up time was 17.8 (range 5.0-48.8) years. Analysis of (co)variance was performed to evaluate differences between subgroups: nephrectomized Wilms survivors treated with or without abdominal irradiation (nZ41 and nZ36) and survivors of other cancer types treated with or without irradiation involving the cranium, abdomen or total body (nZ149 and nZ349). Main outcome measures were IGF1 and height, expressed as SDS. Results: After adjustment for age at diagnosis, former corticosteroid treatment and renal impairment, height SDS in non-irradiated nephrectomized Wilms survivors was significantly higher than that in non-irradiated survivors of other cancer types (estimated mean SDS K0.09 vs K0.49, PZ0.044), abdominal irradiated survivors (SDS K0.70, PZ0.015) and other irradiated survivors (SDS K1.47, P!0.001). Non-irradiated nephrectomized Wilms tumour survivors had significantly higher IGF1 SDS than other irradiated survivors (estimated mean SDS K0.05 vs K1.36, P!0.001 and 0.11 vs 1.37, P!0.001), while there was no significant difference with the other two subgroups. Conclusions: Adult survivors of Wilms tumour showed better attainment of final height and relatively higher IGF1 levels than those of other cancer types who had significantly shorter stature and lower IGF1 levels than Dutch references

Correction: Vincristine-Induced Peripheral Neuropathy in Pediatric Oncology: A Randomized Controlled Trial Comparing Push Injections with One-Hour Infusions (The VINCA Trial) (Cancers, (2020), 12, (3745), 10.3390/cancers12123745)

Error in Table In the original publication, there was a mistake in Table 1 as published [1]. The number of patients with death was swapped between the one-hour administration group and the push administration group. The corrected Table 1 appears below. The authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated

The association between vincristine-induced peripheral neuropathy and health-related quality of life in children with cancer

Purpose: Vincristine (VCR) is a chemotherapeutic agent used in the treatment of pediatric oncology patients, but its main toxicity is VCR-induced peripheral neuropathy (VIPN). However, whether VIPN has an effect on health-related quality of life (HR-QoL) in children during treatment is unknown. Therefore, the aim of our study was to investigate the association between VIPN and HR-QoL in children starting treatment for cancer. Methods: Measurements of VIPN were performed using two tools: Common Terminology Criteria for Adverse Events (CTCAE) and pediatric-modified Total Neuropathy Score (ped-mTNS). Assessment of HR-QoL was done with self- and proxy assessment of the Cancer and Generic module of the Pediatric Cancer Quality of Life Inventory™ (PedsQL). Results: In total, N = 86 children were included. HR-QoL of children with VIPN (n = 67%, 76%) was significantly lower in comparison with children without VIPN: estimated Total score of PedsQL Generic (proxy) 84.57; β = −8.96 and 95% confidence interval (CI) −14.48 to −3.43; p = 0.002, estimated PedsQL Generic Total score (self-reported): 85.16, β = −8.38 (95% CI: −13.76 to −3.00); p = 0.003. Similar results were found in the Pain and Hurt domain of the PedsQL Cancer (pain: estimated score [proxy]: 85.28, β = −9.94 [95%CI: −16.44 to −3.45], p = 0.003; hurt: estimated score [self-report] 97.57, β = −19.15 [95%CI: −26.82 to −11.48], p < 0.001). Conclusion: VIPN results in a significant reduction of HR-QoL in children under treatment for a malignancy, which means that VIPN is important for the well-being of pediatric oncology patients. Therefore, this study underlines the importance of optimizing treatment with VCR, thereby aiming to reduce VIPN while maintaining efficacy

Genetic Polymorphisms Associated with Vincristine Pharmacokinetics and Vincristine-Induced Peripheral Neuropathy in Pediatric Oncology Patients

Vincristine (VCR) is an important component of curative chemotherapy for many childhood cancers. Its main side effect is VCR-induced peripheral neuropathy (VIPN), a dose limiting toxicity. Some children are more susceptible to VIPN, which is at least partially dependent on genetic factors and pharmacokinetics (PK). In this study, we identify and replicate genetic variants associated with VCR PK and VIPN. Patient samples from a randomized clinical trial studying the effect of administration duration of VCR on VIPN in 90 patients were used. PK sampling was conducted on between one and five occasions at multiple time points. A linear two-compartment model with first-order elimination was used, and targeted next-generation DNA sequencing was performed. Genotype–trait associations were analyzed using mixed-effect models or logistic regression analysis for repeated measures, or Poisson regression analysis in which the highest VIPN score per patient was included. Nine single-nucleotide polymorphisms (SNPs) in seven genes (NDRG1, GARS, FIG4, FGD4, SEPTIN9, CEP72, and ETAA1) were associated with VIPN. Furthermore, three SNPs in three genes (MTNR1B, RAB7A and SNU13) were associated with PK of VCR. In conclusion, PK of VCR and VIPN are influenced by SNPs; upfront identification of those that lead to an altered susceptibility to VIPN or VCR exposure could help individualize VCR treatment

Somatic mutations and single-cell transcriptomes reveal the root of malignant rhabdoid tumours

Malignant rhabdoid tumour (MRT) is an often lethal childhood cancer that, like many paediatric tumours, is thought to arise from aberrant fetal development. The embryonic root and differentiation pathways underpinning MRT are not firmly established. Here, we study the origin of MRT by combining phylogenetic analyses and single-cell mRNA studies in patient-derived organoids. Comparison of somatic mutations shared between cancer and surrounding normal tissues places MRT in a lineage with neural crest-derived Schwann cells. Single-cell mRNA readouts of MRT differentiation, which we examine by reverting the genetic driver mutation underpinning MRT, SMARCB1 loss, suggest that cells are blocked en route to differentiating into mesenchyme. Quantitative transcriptional predictions indicate that combined HDAC and mTOR inhibition mimic MRT differentiation, which we confirm experimentally. Our study defines the developmental block of MRT and reveals potential differentiation therapies

Population pharmacokinetics of vincristine related to infusion duration and peripheral neuropathy in pediatric oncology patients

Vincristine (VCR) is frequently used in pediatric oncology and can be administered intravenously through push injections or 1 h infusions. The effects of administration duration on population pharmacokinetics (PK) are unknown. We described PK differences related to administration duration and the relation between PK and VCR-induced peripheral neuropathy (VIPN). PK was assessed in 1–5 occasions (1–8 samples in 24 h per occasion). Samples were analyzed using high-performance liquid chromatography/tandem mass spectrometry. Population PK of VCR and its relationship with administration duration was determined using a non-linear mixed effect. We estimated individual post-hoc parameters: area under the concentration time curve (AUC) and maximum concentration (Cmax) in the plasma and peripheral compartment. VIPN was assessed using Common Terminology Criteria for Adverse Events (CTCAE) and the pediatric-modified total neuropathy score (ped-mTNS). Overall, 70 PK assessments in 35 children were evaluated. The population estimated that the intercompartmental clearance (IC-Cl), volume of the peripheral compartment (V2), and Cmax were significantly higher in the push group. Furthermore, higher IC-Cl was significantly correlated with VIPN development. Administration of VCR by push led to increased IC-Cl, V2, and Cmax, but were similar to AUC, compared to 1 h infusions. Administration of VCR by 1 h infusions led to similar or higher exposure of VCR without increasing VIPN