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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., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Support for relatives is highly important in the intensive care unit (ICU). During the first COVID-19 wave  support for relatives had to be changed considerably. The alternative support could have decreased the quality and sense of support. We aimed to evaluate how support for relatives in Dutch ICUs was organised during the first COVID-19 wave and how this was experienced by these relatives in comparison to relatives from pre-COVID-19 and the second wave. Additionally, we aimed to investigate which elements of support are associated with positive experiences., Methods: We performed a cross-sectional multicentre cohort study in six Dutch ICUs in the Netherlands. Written questionnaires were distributed among relatives of ICU patients from pre-COVID-19, the first wave and the second wave. The questionnaire included questions on demographics, the organisation of support, and the experiences and satisfaction of relatives with the support., Results: A total of 329 relatives completed the questionnaire (52% partner, 72% woman and 63% ICU stay of 11 days or longer). Support for relatives of ICU patients during the first COVID-19 wave differed significantly from pre-COVID-19 and the second wave. Differences were found in all categories of elements of support: who, when, how and what. Overall, relatives from the three time periods were very positive about the support. The only difference in satisfaction between the three time periods, was the higher proportion of relatives indicating that healthcare professionals had enough time for them during the first wave. Elements of support which were associated with many positive experiences and satisfaction were: fixed timeslot, receiving information (e.g. leaflets) on ≥ 2 topics, discussing > 5 topics with healthcare professionals, and being offered emotional support., Conclusions: Although, support for relatives in the ICU changed considerably during the COVID-19 pandemic, relatives were still positive about this support. The altered support gave insight into avenues for improvement for future comparable situations as well as for normal daily ICU practice: e.g. daily contact at a fixed timeslot, offering video calling between patients and relatives, and offering emotional support. ICUs should consider which elements need improvement in their practice., (© 2023. The Author(s).)

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.

Renal function-based carboplatin dosing using measured glomerular filtration rate (GFR) results in more consistent drug exposure than anthropometric dosing. We aimed to validate the Newell dosing equation using estimated GFR (eGFR) and study which equation most accurately predicts carboplatin clearance in children with retinoblastoma. In 13 children with retinoblastoma 38 carboplatin clearance values were obtained from individual fits using MWPharm++. Carboplatin exposure (AUC) was calculated from administered dose and observed carboplatin clearance and compared to predicted AUC calculated with a carboplatin dosing equation (Newell) using different GFR estimates. Different dosing regimens were compared in terms of accuracy, bias and precision. All patients had normal eGFR. Carboplatin exposure using cystatin C-based eGFR equations tended to be more accurate compared to creatinine-based eGFR (30% accuracy 76.3-89.5% versus 76.3-78.9%, respectively), which led to significant overexposure, especially in younger (aged ≤ 2 years) children. Of all equations, the Schwartz cystatin C-based equation had the highest accuracy and lowest bias. Although anthropometric dosing performed comparably to many of the eGFR equations overall, we observed a weight-dependent change in bias leading to underdosing in the smallest patients. Using cystatin C-based eGFR equations for carboplatin dosing in children leads to more accurate carboplatin-exposure in patients with normal renal function compared to anthropometric dosing. In children with impaired kidney function, this trend might be more pronounced. Anthropometric dosing is hampered by a weight-dependent bias.

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., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: During the first peak of the COVID-19 pandemic in the Netherlands, relatives of patients with COVID-19 admitted to Intensive Care Units (ICUs) were severely restricted in visiting their relatives and in communicating with treating physicians. Family communication is a core element of critical care, however, this pandemic forced medical ICU staff to arrange alternative family support for instance by Family Support Teams (FSTs), consisting of non-ICU affiliated staff who telephonically contacted relatives. This study aims to examine relatives' experiences with FSTs on two ICUs of a Dutch university medical centre, and to evaluate its working strategies. ., Methods: In a semi-structured interview study, relatives of patients with COVID-19 admitted to ICU's, who had been supported by the FSTs, were sampled purposively. Twenty-one interviews were conducted telephonically by three researchers. All interviews were topic list guided and audio-recorded. Data was analysed thematically., Results: All participants indicated they went through a rough time. Almost all evaluated the FSTs positively. Four major themes were identified. First, three important pillars of the FSTs were providing relatives with transparency about the patients' situation, providing attention to relatives' well-being, and providing predictability and certainty by calling on a daily basis in a period characterised by insecurity. Second, relatives appeared to fulfil their information needs by calls of the FSTs, but also by calling the attending ICU nurse. Information provided by the FSTs was associated with details and reliability, information provided by nurses was associated with the patient's daily care. Third, being a primary family contact was generally experienced as both valuable and as an emotional burden. Last, participants missed proper aftercare. Family support often stopped directly after the patient died or had left the ICU. Relatives expressed a need for extended support after that moment since they had strong emotions after discharge or death of the patient., Conclusions: Family support in times of the extreme COVID-19 situation is important, as relatives are restricted in communication and have a strong need for information and support. Relatives feel encouraged by structure, frequency, support and understanding by FSTs. However, remote family support should be tailored to the needs of relatives. A fixed contact person on de ICU and video calling might be good extra options for family support, also in future post COVID-19 care, but cannot replace physical visits., (© 2021. The Author(s).)

Introduction: Advanced intraocular retinoblastoma can be cured by enucleation, but spread of retinoblastoma cells beyond the natural limits of the eye is related to a high mortality. Adjuvant therapy after enucleation has been shown to prevent metastasis in children with risk factors for extraocular retinoblastoma. However, histological criteria and adjuvant treatment regimens vary and there is no unifying consensus on the optimal choice of treatment., Method: Data on guidelines for adjuvant treatment in European retinoblastoma referral centres were collected in an online survey among all members of the European Retinoblastoma Group (EURbG) network. Extended information was gathered via personal email communication., Results: Data were collected from 26 centres in 17 countries. Guidelines for adjuvant treatment were in place at 92.3% of retinoblastoma centres. There was a consensus on indication for and intensity of adjuvant treatment among more than 80% of all centres. The majority of centres use no adjuvant treatment for isolated focal choroidal invasion or prelaminar optic nerve invasion. Patients with massive choroidal invasion or postlaminar optic nerve invasion receive adjuvant chemotherapy, while microscopic invasion of the resection margin of the optic nerve or extension through the sclera are treated with combined chemo- and radiotherapy., Conclusion: Indications and adjuvant treatment regimens in European retinoblastoma referral centres are similar but not uniform. Further biomarkers in addition to histopathological risk factors could improve treatment stratification. The high consensus in European centres is an excellent foundation for a common European study with prospective validation of new biomarkers., (© 2021 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

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 VCR push injections in pediatric oncology patients. However, one-hour infusions lead to less severe VIPN compared to push-injections when azole therapy is administered concurrently with VCR. These results indicate that in children treated with VCR and requiring concurrent azole therapy, one-hour infusions might be beneficial over push injections, although larger trials are needed to confirm this association.

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 (C max ) 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 (V 2 ), and C max 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, V 2 , and C max , 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.

Purpose: The aims were to evaluate the construct validity and reliability of the Dutch version of the pediatric-modified Total Neuropathy Score (ped-mTNS) for assessing vincristine-induced peripheral neuropathy (VIPN) in Dutch pediatric oncology patients aged 5-18 years., Methods: Construct validity (primary aim) of the ped-mTNS was determined by testing hypotheses about expected correlation between scores of the ped-mTNS (range: 0-32) and the Common Terminology Criteria for Adverse Events (CTCAE) (range: 0-18) for patients and healthy controls and by comparing patients and controls regarding their total ped-mTNS scores and the proportion of children identified with VIPN. Inter-rater and intra-rater reliability and measurement error (secondary aims) were assessed in a subgroup of study participants., Results: Among the 112 children (56 patients and 56 age- and gender-matched healthy controls) evaluated, correlation between CTCAE and ped-mTNS scores was as expected (moderate (r = 0.60)). Moreover, as expected, patients had significantly higher ped-mTNS scores and more frequent symptoms of VIPN compared with controls (both p < .001). Reliability as measured within the intra-rater group (n = 10) (intra-class correlation coefficient (ICC agreement ) = 0.64, standard error of measurement (SEM agreement ) = 2.92, and smallest detectable change (SDC agreement ) = 8.1) and within the inter-rater subgroup (n = 10) (ICC agreement = 0.63, SEM agreement = 3.7, and SDC agreement = 10.26) indicates insufficient reliability., Conclusion: The Dutch version of the ped-mTNS appears to have good construct validity for assessing VIPN in a Dutch pediatric oncology population, whereas reliability appears to be insufficient and measurement error high. To improve standardization of VIPN assessment in children, future research aimed at evaluating and further optimizing the psychometric characteristics of the ped-mTNS is needed.

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., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Venous thromboembolism (VTE) is a common and severe complication during treatment of acute lymphoblastic leukemia (ALL). An important cause is the intensive use of asparaginase. Prospective cohort studies in which prophylactic low-molecular-weight heparin (LMWH) was used to prevent VTE showed lower VTE risk than in historic control cohorts, with a negligible bleeding risk. However, the efficacy of thromboprophylaxis with LMWH during ALL treatment has never been investigated in a randomized design. Here, we present the protocol of a randomized controlled trial in which the efficacy and safety of thromboprophylaxis with high prophylactic dose LMWH versus no thromboprophylaxis will be assessed in children treated for primary ALL with asparaginase., Methods/design: Thromboprophylaxis in Children treated for Acute Lymphoblastic Leukemia with Low-molecular-weight heparin (TropicALL) is a multicenter, randomized controlled open-label trial conducted in the Netherlands. Patients between 1 and 19 years of age with primary ALL, who are treated within the Dutch Childhood Oncology Group (DCOG) ALL-11 or 12 study will be randomized to thromboprophylaxis with LMWH once daily, (dose of 85 IU/kg (intervention arm A)), or to no thromboprophylaxis (arm B, standard of care) during asparaginase courses of ALL treatment. Primary efficacy endpoint is symptomatic objectified VTE during ALL treatment; secondary efficacy endpoints are overall survival and the composite of symptomatic and asymptomatic objectified VTE. Primary safety endpoints are major bleeding, clinically relevant non-major bleeding and minor bleeding. A total of 324 patients will be included to obtain a relative risk reduction of 75% with a power of 80%, using a two-sided test with significance level α = 0.05., Discussion: This trial will be the first to assess efficacy and safety of thromboprophylaxis with LMWH during asparaginase treatment for ALL in children in a randomized design., Trail Registration: Nederlands Trial Register NTR4707 . Registered 30 July 2014.