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Introduction: Regulatory decisions on paediatric investigation plans (PIPs) aim at making effective and safe medicines timely available for children with high unmet medical need. At the same time, scientific knowledge progresses continuously leading frequently to the identification of new molecular targets in the therapeutic area of oncology. This, together with further efforts to optimise next generation medicines, results in novel innovative products in development pipelines. In the context of global regulatory development requirements for these growing pipelines of innovative products (e.g. US RACE for children Act), it is an increasing challenge to complete development efforts in paediatric oncology, a therapeutic area of rare and life-threatening diseases with high unmet needs.Objective: Regulators recognise feasibility challenges of the regulatory obligations in this context. Here, we explain the EU regulatory decision making strategy applied to paediatric oncology, which aims fostering evidence generation to support developments based on needs and robust science. Because there is a plethora of products under development within given classes of or within cancer types, priorities need to be identified and updated as evidence evolves. This also includes identifying the need for third or fourth generation products to secure focused and accelerated drug development.Conclusion: An agreed PIP, as a plan, is a living document which can be modified in light of new evidence. For this to be successful, input from the various relevant stakeholders, i.e. pa-tients/parents, clinicians and investigators is required. To efficiently obtain this input, the EMA is co-organising with ACCELERATE oncology stakeholder engagement platform meet-ings.(c) 2022 Elsevier Ltd. All rights reserved.

Background: Paediatric palliative care (PPC) aims to improve children’s quality of life, but this outcome is rarely measured in clinical care. PPC is provided in Belgium through six transmural paediatric liaison teams (PLTs) ensuring continuity of care for children with life-limiting or life-threatening conditions (LLC/LTC). This study aims to measure the quality of life (QoL) of children with LLC/LTC followed-up by PLTs and the QoL of their parents. Methods: During interviews, an original socio demographic questionnaire, the Children palliative outcome scale—version 2 (CPOS-2), the Fragebogen für Kinder und Jugendliche zur Erfassung der gesundheitsbezogenen Lebensqualität (KINDL) and the Quality of life in life-threatening Illness-Family caregiver (QOLLTI-F) were filled in by PLT members. Statistics were used to investigate significant differences between scores. Results were discussed and interpreted with six PLTs. Results: 73 children aged 1–18 were included in the study. Especially for items focusing on emotional items, children reported their QoL as higher than their parents did. The QoL scores were not significantly associated with the child’s condition’s severity. Conclusions: This study provides, for the first time, an overview of the QoL of children and parents followed-up by PLTs in Belgium.

detailed information about the patients in this study

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Purpose: Activating mutations of the anaplastic lymphoma kinase (ALK) were recently described in neuroblastoma. We carried out a meta-analysis of 709 neuroblastoma tumors to determine their frequency and mutation spectrum in relation to genomic and clinical parameters, and studied the prognostic significance of ALK copy number and expression.Experimental Design: The frequency and type of ALK mutations, copy number gain, and expression were analyzed in a new series of 254 neuroblastoma tumors. Data from 455 published cases were used for further in-depth analysis.Results: ALK mutations were present in 6.9% of 709 investigated tumors, and mutations were found in similar frequencies in favorable [International Neuroblastoma Staging System (INSS) 1, 2, and 4S; 5.7%] and unfavorable (INSS 3 and 4; 7.5%) neuroblastomas (P = 0.087). Two hotspot mutations, at positions R1275 and F1174, were observed (49% and 34.7% of the mutated cases, respectively). Interestingly, the F1174 mutations occurred in a high proportion of MYCN-amplified cases (P = 0.001), and this combined occurrence was associated with a particular poor outcome, suggesting a positive cooperative effect between both aberrations. Furthermore, the F1174L mutant was characterized by a higher degree of autophosphorylation and a more potent transforming capacity as compared with the R1275Q mutant. Chromosome 2p gains, including the ALK locus (91.8%), were associated with a significantly increased ALK expression, which was also correlated with poor survival.Conclusions: ALK mutations occur in equal frequencies across all genomic subtypes, but F1174L mutants are observed in a higher frequency of MYCN-amplified tumors and show increased transforming capacity as compared with the R1275Q mutants. Clin Cancer Res; 16(17); 4353–62. ©2010 AACR.

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Supplemental figure 1: Comparison of the copy number profiles of 4 cases generated with sWGS on cfDNA (at 100 kb binsize), sWGS on tumor DNA (at 100 kb binsize), sWGS on tumor DNA (at 15 kb binsize) and arrayCGH on tumor DNA (at 180k resolution). Supplemental figure 2 : Heatmap describing the concordance between arrayCGH data on tumor DNA vs sWGS of cfDNA. Numbers on the right reflect the case numbers, followed by a 1 for aCGH data on the tumor, and 2 for sWGS data on the cfDNA; the numbers on the top and bottom indicate the chromosome numbers. Red=copy number gain, blue=copy number loss. Supplemental figure 3: Validation of LIN28B amplification by Q-PCR.Y-axis represents the haploid copy number, X-axis represents the samples. NGP is a NB cell line that was used as a positive control, since this cell line showed gain of LIN28B in arrayCGH, gDNA:genomic DNA, NTC: no template control

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Purpose: Neuroblastoma (NB) is a heterogeneous disease characterized by distinct clinical features and by the presence of typical copy-number alterations (CNAs). Given the strong association of these CNA profiles with prognosis, analysis of the CNA profile at diagnosis is mandatory. Therefore, we tested whether the analysis of circulating cell-free DNA (cfDNA) present in plasma samples of patients with NB could offer a valuable alternative to primary tumor DNA for CNA profiling.Experimental Design: In 37 patients with NB, cfDNA analysis using shallow whole genome sequencing (sWGS) was compared with arrayCGH analysis of primary tumor tissue.Results: Comparison of CNA profiles on cfDNA showed highly concordant patterns, particularly in high-stage patients. Numerical chromosome imbalances as well as large and focal structural aberrations including MYCN and LIN28B amplification and ATRX deletion could be readily detected with sWGS using a low input of cfDNA.Conclusions: In conclusion, sWGS analysis on cfDNA offers a cost-effective, noninvasive, rapid, robust and sensitive alternative for tumor DNA copy-number profiling in most patients with NB. Clin Cancer Res; 23(20); 6305–14. ©2017 AACR.

International audience; Background: Chemotherapy for non-seminomatous germ cell tumours (NSGCT) exposes to dose-dependent toxicities. The TGM13-NS protocol (EudraCT 2013-004039-60) aimed to decrease the chemotherapy burden compared to the previous TGM95 protocol while maintaining the 5-year event-free survival (EFS) at 80% or more. Procedure: Patients less than 19 years of age with disseminated NSGCT were enrolled (May 2014 to May 2019) and stratified into four groups: two intermediate-risk (IR: localised tumour with low tumour markers [TM]) groups treated with VBP (vinblastine–bleomycin–cisplatin): three courses for IR1 (ovarian tumour any age/testis tumour less than or equal to 10 years) and four courses for IR2 (extragonadal tumour 10 years or less) groups, and two high-risk (HR: metastatic and/or high TM) groups treated with etoposide–cisplatin and either ifosfamide (VIP) or bleomycin (BEP): three courses for HR1 (ovarian tumour any age/testis tumour less than or equal to 10 years and low TM/testis tumour more than 10 years and very low TM) groups and four courses for HR2 (remainder) groups. Results: One hundred fifteen patients were included: median age of 12.8 years (0.4–18.9); tumour sites: 44 ovaries, 37 testes and 34 extragonadal. The 5-year EFS and overall survival (OS) were 87% (95% CI: 80–92) and 95% (89–98), respectively (median follow-up: 3.5 years, range: 0.2–5.9), similar to those of the TGM95 protocol (5-year EFS 89% (84–93), 5-year OS 93% (89–95), p =.561). The 5-year EFS were 93% (95% CI: 80–98), 88% (71–95) and 79% (62–90) for ovarian, testicular and extragonadal tumours, respectively. The 5-year EFS varied (p =.02) according to the risk groups: 90% (66–97), 64% (30–85), 95% (72–99) and 87% (74–94) for IR1, IR2, HR1 and HR2, respectively. TM decline adjusted to tumour site, and alpha-fetoprotein (AFP) level revealed a prognostic impact of time to normalisation on EFS: HR = 1.03 (1.003–1.007). Conclusion: Risk-adapted and globally decreased chemotherapy burden maintains excellent outcomes, exclusive of the IR2 group, which warrants more intensive chemotherapy.

Introduction: Long-term survival after childhood cancer often comes at the expense of late, adverse health conditions. However, survivorship care is frequently not available for adult survivors in Europe. The PanCareFollowUp Consortium therefore developed the PanCareFollowUp Care Intervention, an innovative person-centred survivorship care model based on experiences in the Netherlands. This paper describes the protocol of the prospective cohort study (Care Study) to evaluate the feasibility and the health economic, clinical and patient-reported outcomes of implementing PanCareFollowUp Care as usual care in four European countries.Methods and analysis In this prospective, longitudinal cohort study with at least 6 months of follow-up, 800 childhood cancer survivors will receive the PanCareFollowUp Care Intervention across four study sites in Belgium, Czech Republic, Italy and Sweden, representing different healthcare systems. The PanCareFollowUp Care Intervention will be evaluated according to the Reach, Effectiveness, Adoption, Implementation and Maintenance framework. Clinical and research data are collected through questionnaires, a clinic visit for multiple medical assessments and a follow-up call. The primary outcome is empowerment, assessed with the Health Education Impact Questionnaire. A central data centre will perform quality checks, data cleaning and data validation, and provide support in data analysis. Multilevel models will be used for repeated outcome measures, with subgroup analysis, for example, by study site, attained age, sex or diagnosis.Ethics and dissemination This study will be conducted in accordance with the guidelines of Good Clinical Practice and the Declaration of Helsinki. The study protocol has been reviewed and approved by all relevant ethics committees. The evidence and insights gained by this study will be summarised in a Replication Manual, also including the tools required to implement the PanCareFollowUp Care Intervention in other countries. This Replication Manual will become freely available through PanCare and will be disseminated through policy and press releases.Trial registration number Netherlands Trial Register (NL8918; https://www.trialregister.nl/trial/8918)., + ID der Publikation: unilu_61784 + Sprache: Englisch + Letzte Aktualisierung: 2022-11-30 17:16:31

BACKGROUND: Long-term follow-up (LTFU) care for childhood, adolescent, and young adult (CAYA) cancer survivors is essential to preserve health and quality of life (QoL). Evidence-based guidelines are needed to inform optimal surveillance strategies, but many topics are yet to be addressed by the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG). Therefore, the PanCareFollowUp Recommendations Working Group collaborated with stakeholders to develop European harmonised recommendations in anticipation of evidence-based IGHG guidelines. METHODS: The PanCareFollowUp Recommendations Working Group, consisting of 23 late effects specialists, researchers, and survivor representatives from nine countries, collaborated in the first Europe-wide effort to provide unified recommendations in anticipation of evidence-based guidelines. A pragmatic methodology was used to define recommendations for topics where no evidence-based IGHG recommendations exist. The objective was to describe the surveillance requirements for high-quality care while balancing the different infrastructures and resources across European health care systems. The process included two face-to-face meetings and an external consultation round involving 18 experts from 14 countries. RESULTS: Twenty-five harmonised recommendations for LTFU care were developed collaboratively and address topics requiring awareness only (n = 6), awareness, history and/or physical examination (n = 9), or additional surveillance tests (n = 10). CONCLUSIONS: The PanCareFollowUp Recommendations, representing a unique agreement across European stakeholders, emphasise awareness among survivors and health care providers in addition to tailored clinical evaluation and/or surveillance tests. They include existing IGHG guidelines and additional recommendations developed by a pragmatic methodology and will be used in the Horizon 2020-funded PanCareFollowUp project to improve health and QoL of CAYA cancer survivors. ispartof: EUROPEAN JOURNAL OF CANCER vol:154 pages:316-328 ispartof: location:England status: published

Purpose: Childhood cancer is rare, and treatment is frequently associated with long-term morbidity. Disparities in survival and long-term side effects encourage the establishment of networks to increase access to complex organ-conservative strategies, such as brachytherapy. We report our experience of an international cooperation model in childhood cancers. Methods and Materials: We examined the outcome of all children referred to our center from national or international networks to be treated according to a multimodal organ-conservative approach, including brachytherapy. Results: We identified 305 patients whose median age at diagnosis was 2.2 years (range, 1.4 months to 17.2 years). Among these patients, 99 (32.4%) were treated between 2015 and 2020; 172 (56.4%) were referred from national centers; and 133 (43.6%) were international patients from 31 countries (mainly Europe). Also, 263 patients were referred for primary treatment and 42 patients were referred for salvage treatment. Genitourinary tumors were the most frequent sites, with 56.4% bladder/prostate rhabdomyosarcoma and 28.5% gynecologic tumors. In addition to brachytherapy, local treatment consisted of partial tumor resection in 207 patients (67.9%), and 39 patients (13%) had additional external radiation therapy. Median follow-up was 58 months (range, 1 month to 48 years), 93 months for national patients, and 37 months for international patients (P < .0001). Five-year local control, disease-free survival, and overall survival rates were 90.8% (95% confidence interval [CI], 87.3%-94.4%), 84.4% (95% CI, 80.1%-89.0%), and 93.3% (95% CI, 90.1%-96.5%), respectively. Patients referred for salvage treatment had poorer disease-free survival (P < .01). Implementation of image guided pulse-dose-rate brachytherapy was associated with better local control among patients with rhabdomyosarcoma referred for primary treatment (hazard ratio, 9.72; 95% CI, 1.24-71.0). At last follow-up, 16.7% patients had long-term severe treatment-related complications, and 2 patients (0.7%) had developed second malignancy. Conclusions: This retrospective series shows the feasibility of a multinational referral network for brachytherapy allowing high patient numbers in rare pediatric cancers. High local control probability and acceptable late severe complication probability could be achieved despite very challenging situations. This cooperation model could serve as a basis for generating international reference networks for high-tech radiation such as brachytherapy to increase treatment care opportunities and cure probability.

OBJECTIVE: Amikacin pharmacokinetics (PK) in children display large variability due to maturational and disease-related covariates. The objective was to explore amikacin PK in a large pediatric oncology cohort, taking into account within-patient changes. MATERIALS AND METHODS: Clinical data and amikacin therapeutic drug monitoring (TDM) observations were collected retrospectively from children with an oncology diagnosis receiving amikacin during febrile neutropenia. Individual amikacin PK parameters were calculated using a 1-compartment model with instantaneous input and first-order output. This approach was selected based on a pragmatic study design using TDM from routine clinical care, with availability of 2 TDM samples per treatment episode. To explore covariates of clearance (Cl) and volume of distribution (Vd), linear mixed models were used, modelling a random effect for patient to account for clustering due to repeated measurements. RESULTS: Based on 188 amikacin treatment episodes in 114 patients, median (interquartile range) amikacin Cl was 1.37 (1.05; 2.46) L/h and Vd 7.98 (5.66; 12.73) L. Height and creatinemia were significant covariates for Cl (marginal R2 71.1%), while weight, height, and creatinemia determined Vd (marginal R2 59.5%). CONCLUSION: We described extensive variability of amikacin PK in a large cohort of pediatric oncology patients, including within-patient changes across treatment episodes. Maturational covariates and creatinemia determined amikacin Cl and Vd, while primary non-maturational covariates were not significant. Our observations, based on combined clinical and PK data in children with oncology diagnoses, can be useful to feed dosing software programs to improve drug exposure in special populations. ispartof: INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS vol:59 issue:1 pages:31-41 ispartof: location:Germany status: published

Background: Paediatric palliative care (PPC) aims to improve the quality of life of children, however, this objective is rarely measured in clinical care. PPC is provided in Belgium through 6 transmural paediatric liaison teams (PLTs) ensuring continuity of care for children with life-limiting or life-threatening conditions (LLC/LTC). This study aims to measure the quality of life (QoL) of children with LLC/LTC monitored by PLT and the QoL of their parents.Methods: During interviews with children and parents, an original sociodemographic questionnaire, the Children Palliative Outcome Scale – version 2 (CPOS-2), the Fragebogen für Kinder und Jugendliche zur Erfassung der gesundheitsbezogenen Lebensqualität (KINDL) and the Quality of Life in Life-threatening Illness-Family Caregivers (QOLLTI-F) were completed by PLT members. Descriptive statistics were conducted on the sociodemographic data and the CPOS-2 and QOLLTI-F scores. The association between clinicians’ judgement of QoL and the scores on the QOLLTI-F and CPOS-2 was explored using Spearman’s correlation coefficients and boxplots. Pearson’s chi square test and Fisher’s exact test were used to investigate significant differences between scores. The results were discussed and interpreted with 6 PLTs.Results: Seventy-three children aged 1-18 years were included in the study. For items focused on emotional well-being, children reported that their QoL was higher than that of their parents. The QoL scores were not significantly associated with the severity of the child’s condition. Discrepancies were not found between health care professionals’ perceptions and parents’ perceptions of their QoL, as measured by the CPOS-2.Conclusion: This study provides, for the first time, an overview of the QoL of children and parents followed-up by PLT in Belgium.

PURPOSE Ewing 2008R3 was conducted in 12 countries and evaluated the effect of treosulfan and melphalan high-dose chemotherapy (TreoMel-HDT) followed by reinfusion of autologous hematopoietic stem cells on event-free survival (EFS) and overall survival in high-risk Ewing sarcoma (EWS). METHODS Phase III, open-label, prospective, multicenter, randomized controlled clinical trial. Eligible patients had disseminated EWS with metastases to bone and/or other sites, excluding patients with only pulmonary metastases. Patients received six cycles of vincristine, ifosfamide, doxorubicin, and etoposide induction and eight cycles of vincristine, actinomycin D, and cyclophosphamide consolidation therapy. Patients were randomly assigned to receive additional TreoMel-HDT or no further treatment (control). The random assignment was stratified by number of bone metastases (1, 2-5, and > 5). The one-sided adaptive-inverse-normal-4-stage-design was changed after the first interim analysis via Müller-Schäfer method. RESULTS Between 2009 and 2018, 109 patients were randomly assigned, and 55 received TreoMel-HDT. With a median follow-up of 3.3 years, there was no significant difference in EFS between TreoMel-HDT and control in the adaptive design (hazard ratio [HR] 0.85; 95% CI, 0.55 to 1.32, intention-to-treat). Three-year EFS was 20.9% (95% CI, 11.5 to 37.9) in TreoMel-HDT and 19.2% (95% CI, 10.8 to 34.4) in control patients. The results were similar in the per-protocol collective. Males treated with TreoMel-HDT had better EFS compared with controls: median 1.0 years (95% CI, 0.8 to 2.2) versus 0.6 years (95% CI, 0.5 to 0.9); P = .035; HR 0.52 (0.28 to 0.97). Patients age < 14 years benefited from TreoMel-HDT with a 3-years EFS of 39.3% (95% CI, 20.4 to 75.8%) versus 9% (95% CI, 2.4 to 34); P = .016; HR 0.40 (0.19 to 0.87). These effects were similar in the per-protocol collective. This observation is supported by comparable results from the nonrandomized trial EE99R3. CONCLUSION In patients with very high-risk EWS, additional TreoMel-HDT was of no benefit for the entire cohort of patients. TreoMel-HDT may be of benefit for children age < 14 years.

For the detection of bone marrow (BM) metastases in patients with neuroblastoma, microscopic BM examination and [Fifty-five patients with stage 4 or stage 4S disease were included, and 37 of them received an autologous hematopoietic stem cell transplantation (AHSCT). The concordance rate was measured and paired binary data were analysed by the McNemar test to look for a systematic difference between diagnostic tests.At diagnosis and before ASCC, we found acceptable concordance rates for [For patients with neuroblastoma, a [

Background The majority of childhood cancer survivors are at risk of treatment-related adverse health outcomes. Survivorship care to mitigate these late effects is endorsed, but it is not available for many adult survivors of childhood cancer in Europe. The PanCareFollowUp project was initiated to improve their health and quality of life (QoL) by facilitating person-centred survivorship care. Methods The PanCareFollowUp consortium was established in 2018, consisting of 14 project partners from ten European countries, including survivor representatives. The consortium will develop two PanCareFollowUp Interventions, including a person-centred guideline–based model of care (Care Intervention) and eHealth lifestyle coaching (Lifestyle Intervention). Their development will be informed by several qualitative studies and systematic reviews on barriers and facilitators for implementation and needs and preferences of healthcare providers (HCPs) and survivors. Implementation of the PanCareFollowUp Care Intervention as usual care will be evaluated prospectively among 800 survivors from Belgium, Czech Republic, Italy and Sweden for survivor empowerment, detection of adverse health conditions, satisfaction among survivors and HCPs, cost-effectiveness and feasibility. The feasibility of the PanCareFollowUp Lifestyle Intervention will be evaluated in the Netherlands among 60 survivors. Results Replication manuals, allowing for replication of the PanCareFollowUp Care and Lifestyle Intervention, will be published and made freely available after the project. Moreover, results of the corresponding studies are expected within the next five years. Conclusions The PanCareFollowUp project is a novel European collaboration aiming to improve the health and QoL of all survivors across Europe by developing and prospectively evaluating the person-centred PanCareFollowUp Care and Lifestyle Interventions.

VGLL2-rearranged rhabdomyosarcomas (RMS) are rare low-grade tumors with only favorable outcomes reported to date. We describe 4 patients with VGLL2-rearranged RMS confirmed by molecular studies, who experienced local progression and distant metastases, including 2 with fatal outcomes. Tumors were diagnosed at birth (n=3) or at 12 months of age (n=1), and were all localized at initial diagnosis, but unresectable and therefore managed with chemotherapy and surveillance. Metastatic progression occurred from 1 to 8 years from diagnosis (median, 3.5 y). Three patients experienced multimetastatic spread and one showed an isolated adrenal metastasis. At initial diagnosis, 3 tumors displaying bland morphology were misdiagnosed as fibromatosis or infantile fibrosarcoma and initially managed as such, while 1 was a high-grade sarcoma. At relapse, 3 tumors showed high-grade morphology, while 1 retained a low-grade phenotype. Low-grade primary tumors showed only very focal positivity for desmin, myogenin, and/or MyoD1, while high-grade tumors were heterogenously or diffusely positive. Whole-exome sequencing, performed on primary and relapse samples for 3 patients, showed increased genomic instability and additional genomic alterations (eg, TP53, CDKN2A/B, FGFR4) at relapse, but no recurrent events. RNA sequencing confirmed that high-grade tumors retained VGLL2 fusion transcripts and transcriptomic profiles consistent with VGLL2-rearranged RMS. High-grade samples showed a high expression of genes encoding cell cycle proteins, desmin, and some developmental factors. These 4 cases with distinct medical history imply the importance of complete surgical resection, and suggest that RMS-type chemotherapy should be considered in unresectable cases, given the risk of high-grade transformation. They also emphasize the importance of correct initial diagnosis.

For the detection of bone marrow (BM) metastases in patients with neuroblastoma, microscopic BM examination and [123I]MIBG scintigraphy are advised. The aims of this study were to assess the concordance of [123I]MIBG and microscopic BM examination (aspirate and biopsy) in detecting BM involvement and to compare invasive disease in BM biopsies and aspirates, both at diagnosis and before autologous stem cell collection (ASCC). Fifty-five patients with stage 4 or stage 4S disease were included, and 37 of them received an autologous hematopoietic stem cell transplantation (AHSCT). The concordance rate was measured and paired binary data were analysed by the McNemar test to look for a systematic difference between diagnostic tests. At diagnosis and before ASCC, we found acceptable concordance rates for [123I]MIBG versus microscopic BM examination (77.1% and 85.3% respectively). Discordant results were found in both directions and at both time points. The concordance rate for biopsy versus aspirate at diagnosis was 80.6%, however, before ASCC a much higher concordance rate between both microscopic examinations was found (94.1%). While none of the aspirates showed neuroblastoma cells before ASCC, two biopsies still showed tumor invasion. For patients with neuroblastoma, a [123I]MIBG scintigraphy and a microscopic examination of BM aspirate and its biopsy should be used as complementary tools in the evaluation of BM involvement, and this both at diagnosis and during treatment (before ASCC).

BACKGROUND: Amikacin is widely used to treat severe Gram-negative bacterial infections. Its peak concentration in plasma is associated with treatment efficacy. Amikacin pharmacokinetics (PK) is influenced by disease conditions, in addition to other patient characteristics. In this retrospective study, we evaluated the impact of clinical characteristics and disease condition on amikacin PK in children with burn injuries and those with cancer. METHODS: Amikacin PK data from 66 children with burn injuries and 112 children with cancer were analyzed. A population PK model was developed using the nonlinear mixed-effects modeling approach. Models were developed using NONMEM 7.3 (ICON Development Solutions, LLC, Ellicott City, MD). Data processing and visualization was performed using R packages. RESULTS: The amikacin PK data were best described by a 2-compartment model. The parameters were estimated with mean values (95% confidence intervals) as follows: central volume of distribution (V1), 5.70 L (4.64-6.76 L); central clearance, 2.12 L/h (1.79-2.46 L/h); peripheral volume of distribution (V2), 4.79 L (2.36-7.22 L); and distribution clearance (Q), 0.71 L/h (0.25-1.16 L/h). The final model identified the disease condition as a significant covariate and indicated 55% (28%-82%) higher central clearance and 17% (1%-34%) higher V1 in burn patients compared with cancer patients. Volume of distribution was significantly influenced by age and body weight. Clearance was significantly influenced by age, body weight, and creatinine clearance. Using the final PK model, we developed a workflow for selecting optimal dosing strategies for 3 representative pediatric patient profiles. CONCLUSIONS: Disease condition was significant in influencing amikacin PK in children. To reach the same target concentrations (64 mg/L peak concentration) with a daily-dose plan, burn patients need higher doses than cancer patients. Future investigations are needed to explore the impact of other diseases on amikacin disposition in children, and to prospectively validate the proposed dosing strategy. ispartof: THERAPEUTIC DRUG MONITORING vol:41 issue:1 pages:44-52 ispartof: location:United States status: published

Cystinosis is an autosomal recessive lysosomal storage disorder characterized by the defective transport of the amino acid cystine out of the lysosome due to a deficiency of cystinosin, the lysosomal cystine transporter. Patients have lysosomal cystine accumulation in various tissues, leading to cellular stress and damage, particularly in the kidney, cornea, and other extrarenal tissues. Cysteamine, a cystine-depleting agent, improves survival and delays the progression of disease, but it does not prevent the development of either renal failure or extrarenal complications. Furthermore, the drug has severe adverse effects that significantly reduce patient compliance. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently established as a therapeutic option for many inborn errors of metabolism, where the main pathologic driving factor is an enzyme deficiency. Recent studies in the cystinosis mouse-model suggested that HSCT could be a curative treatment alternative to cysteamine therapy. We treated a 16-year-old boy who had infantile cystinosis and side effects of cysteamine therapy with HSCT. We were able to demonstrate successful transfer of the wild-type cystinosin protein and CTNS mRNA to nonhematological epithelial cells in the recipient, as well as a decrease in the tissue cystine-crystal burden. This is the first report of allogeneic HSCT in a patient with cystinosis, the prototype of lysosomal membrane-transporter disorders. ispartof: AMERICAN JOURNAL OF TRANSPLANTATION vol:18 issue:11 pages:2823-2828 ispartof: location:United States status: published

Vitamin A intoxication is a rare cause of liver disease, but the risk increases in patients with underlying liver dysfunction. We present a patient with Shwachman-Diamond Syndrome who developed liver fibrosis, portal hypertension and very severe hepatopulmonary syndrome as a consequence of chronic vitamin A intoxication. She underwent successful liver transplantation with complete resolution of the pulmonary shunting. ispartof: ORPHANET JOURNAL OF RARE DISEASES vol:13 issue:1 ispartof: location:England status: published

Purpose: Neuroblastoma (NB) is a heterogeneous disease characterized by distinct clinical features and by the presence of typical copy-number alterations (CNAs). Given the strong association of these CNA profiles with prognosis, analysis of the CNA profile at diagnosis is mandatory. Therefore, we tested whether the analysis of circulating cell-free DNA (cfDNA) present in plasma samples of patients with NB could offer a valuable alternative to primary tumor DNA for CNA profiling. Experimental Design: In 37 patients with NB, cfDNA analysis using shallow whole genome sequencing (sWGS) was compared with arrayCGH analysis of primary tumor tissue. Results: Comparison of CNA profiles on cfDNA showed highly concordant patterns, particularly in high-stage patients. Numerical chromosome imbalances as well as large and focal structural aberrations including MYCN and LIN28B amplification and ATRX deletion could be readily detected with sWGS using a low input of cfDNA. Conclusions: In conclusion, sWGS analysis on cfDNA offers a cost-effective, noninvasive, rapid, robust and sensitive alternative for tumor DNA copy-number profiling in most patients with NB. Clin Cancer Res; 23(20); 6305–14. ©2017 AACR.

Aim: Osteosarcoma patients receive high doses of methotrexate (MTX). However, pharmacogenetic information remains limited and has mainly been investigated in leukemia so far. Patients & methods: We investigated the link between the MTHFR C677T genotype, toxicity levels (mucositis, MTX plasma level, hematological toxicity and hepatotoxicity) and survival of 48 pediatric osteosarcoma patients. Results: The TT genotype did not show more toxicity compared with the CC/CT genotype. However, plasma MTX levels were related with mucositis, but not with hematological toxicity, nor hepatotoxicity. Survival rates did not differ between homozygous and non-homozygous patients. Yet, homozygous patients had higher relapse risk. Conclusion: The MTHFR C667T polymorphism is not predictive for toxicity or overall survival, but could be used for relapse risk stratification.

Infantile myofibromatosis is one of the most prevalent soft tissue tumors of infancy and childhood. Multifocal nodules with visceral lesions are associated with a poor prognosis. A few familial cases have been linked to mutations in various genes including PDGFRB. In this study, we sequenced PDGFRB, which encodes a receptor tyrosine kinase, in 16 cases of myofibromatosis or solitary myofibroma. Mutations in the coding sequence of PDGFRB were identified in 6 out of 8 patients with the sporadic multicentric form of the disease and in 1 out of 8 patients with isolated myofibroma. Two patients had the same mutation in multiple separated lesions. By contrast, a third patient had three different PDGFRB mutations in the three nodules analyzed. Mutations were located in the transmembrane, juxtamembrane and kinase domains of the receptor. We showed that these mutations activated receptor signaling in the absence of ligand and transformed fibroblasts. In one case, a weakly-activating germline variant was associated with a stronger somatic mutation, suggesting a two-hit model for familial myofibromatosis. Furthermore, the mutant receptors were sensitive to the tyrosine kinase inhibitor imatinib, except D850V, which was inhibited by dasatinib and ponatinib, suggesting a targeted therapy for severe myofibromatosis. In conclusion, we identified gain-of-function PDGFRB mutations in the majority of multifocal infantile myofibromatosis cases, shedding light on the mechanism of disease development, which is reminiscent of multifocal venous malformations induced by TIE2 mutations. Our results provide a genetic test to facilitate diagnosis, and preclinical data for development of molecular therapies. ispartof: Human Molecular Genetics vol:26 issue:10 pages:1801-1810 ispartof: location:England status: published

Dear Editors, We have read with interest the article by Dombrecht et al. (2019) published in your journal in its edition of March 2019. The authors address a sensitive topic, namely the reported attitudes of neonatologists and neonatal nurses in the Flanders region of Belgium regarding complex issues around active end-of-live (EOL) practices for foetuses and neonates facing life-limiting conditions. As the authors correctly state in the abstract and full text, the survey was conducted among 8 centres located in the Flemish Community and did not include the 11 centres of the French Community of Belgium. This means that the title which presents the study as “a nationwide survey” is not correct. Furthermore, another representative study conducted collaboratively by those 11 French speaking neonatal intensive care units, with a very high response rate, was not taken into account (Aujoulat et al. 2018). Yet, this study led to quite different results and conclusions which could have broadened the discussion and nuanced the ethical and legal implications as well as the conclusions drawn by Dombrecht et al. (2019). Based on our clinical experience, we do acknowledge that EOL decisions in the perinatal period are complex, but that international guidelines and best practices regarding breaking bad news, involving parents in the decision-making process, dealing with uncertainty about prognosis, ensuring continuity of care by bereavement support, and offering supervision to teams might be helpful. In this respect, the absence of formal training in neonatal palliative care currently offered in Belgium is unfortunate (Arias et al., 2019). However, since 2014, despite some cultural or linguistic differences, the Belgian Paediatric Palliative Care group (www.bppc.be) brings together nurses, physicians, psychologists and social workers from all regions in Belgium, to discuss and elaborate national guidelines regarding paediatric palliative care. This may pave the way for future, hoped for, fruitful collaborations also in the field of neonatology, not only across Belgian teams but also at international level, where the complex psychosocial, medical, ethical and legal issues surrounding decisions and practices around EOL care to neonates are the object of much debate and controversies. Marie Friedel, paediatric nurse; Dr Marleen Renard, paediatrician, Prof. Hugo Devlieger neonatologist; Prof. Gaston Verellen, neonatologist. References: Arias N, Garralda E, Rhee JY. et al. EAPC Atlas of Palliative Care in Europe 2019. Vilvoorde: EAPC Press, 2019. Aujoulat I, Henrard S, Charon A, Johansson AB, Langhendries JP, Mostaert A, Vermeylen D, Verellen G; 11 neonatal intensive care units in the Wallonia-Brussels Federation. End-of-life decisions and practices for very preterm infants in the Wallonia-Brussels Federation of Belgium. BMC Pediatr. 2018; 26;18(1):206. doi: 10.1186/s12887-018-1168-x. Dombrecht L, Deliens L, Chambaere K, Baes S, Cools F, Goossens L, Naulaers G, Roets E, Piette V, Cohen J, Beernaert K; NICU consortium. Neonatologists and neonatal nurses have positive attitudes towards perinatal end-of-life decisions, a nationwide survey. Acta Paediatr. 2019. doi: 10.1111/apa.14797. Page

PURPOSE Knowledge is limited regarding the prevalence and persistence of chemotherapy-induced leukoencephalopathy in childhood sarcoma patients. This study explored the presence, clinical relevance, and potential risk factors of leukoencephalopathy in childhood bone and soft tissue sarcoma survivors, treated with intravenous chemotherapy. METHODS We acquired cross-sectional neurocognitive data in adult survivors (n = 34) (median age at diagnosis [AaD] = 13.32 years, age range = 16-35 years) and healthy age-matched controls (n = 34). Additionally, magnetic resonance imaging included T2-weighted FLAIR (leukoencephalopathy Fazekas rating), multiexponential T2 relaxation (MET2), and multishell diffusion MRI to estimate myelin integrity-related metrics and fluid movement restrictions. Finally, chemotherapy subgroups (methotrexate, alkylating agents, or combination), AaD, and Apoe and MTHFRC677T polymorphisms were explored as potential risk factors for leukoencephalopathy. RESULTS At the group level, quality of life, working memory, processing speed, and visual memory were significantly lower in patients compared to controls. Furthermore, long-term leukoencephalopathy was observed in 27.2% of the childhood sarcoma survivors, which was related to attentional processing speed. Lesions were related to diffusion-derived, but not to myelin-sensitive metrics. A significant interaction effect between AaD and chemotherapy group demonstrated more lesions in case of high-dose methotrexate (HD-MTX) (F = 3.434, P = .047). However, patients treated with alkylating agents (without HD-MTX) also showed lesions in younger patients. Genetic predictors were nonsignificant. CONCLUSION AND IMPLICATION This study suggests long-term leukoencephalopathy with possibly underlying changes in vasculature, inflammation, or axonal injury, but not necessarily long-term demyelination. Such lesions could affect processing speed, and as such long-term daily life functioning of these patients.

Background In childhood acute lymphoblastic leukemia (ALL), radiotherapy for CNS prophylaxis is not used in frontline therapy anymore. Standard treatment for ALL nowadays consists of polychemotherapy. Therefore, assessment of potential chemotherapy-induced cognitive side effects becomes important. Although neurotoxicity was demonstrated in cross-sectional studies, longitudinal studies remain scarce. Procedure We evaluated intellectual development of 94 pediatric ALL patients between 1990 and 1997, diagnosed before the age of 12 years, treated according to the European Organisation for Research and Treatment of Cancer Children's Leukemia Group 58881 protocol. Three assessments of the Wechsler Intelligence Scale for Children Revised were performed since diagnosis, according to age. Using repeated measures regression analysis, we investigated the effect of gender (low versus increased) risk group, parents' education, age at diagnosis, intelligence quotient (IQ) subscale (verbal (VIQ) versus performance (PIQ) intelligence), and test session. Results PIQ scores were lower than VIQ at baseline (−5.3 points on average, p = 0.0032), yet PIQ increased more strongly (PIQ: +3.9 points per test session; VIQ: +0.8, p = 0.0079), so this baseline difference disappeared (p = 0.0079). There were no clear effects of gender (girls: +0.6 points; p = 0.78) or risk group (low risk: +1.5 points; p = 0.49), but IQ scores were higher when one parent had followed higher education (+9.5 points, p

This commentary describes the effect of the Belgian euthanasia law extended to children law on the practices of two paediatric liaison care teams in Belgium (one in Flanders, one in Wallonia). Ethical challenges are discussed based on clinical experiences of those teams, who affirm that in 25 years of practice, they were never confronted with a child requesting euthanasia.

Over 14 000 patients aged 15-24 are estimated to be diagnosed with cancer in the European Union (EU) each year. Teenagers and young adults (TYA) often fall down gaps between children's and adults cancer services. The specific challenges of providing optimal care to them are described, but we present a summary of recent progress. Progress to overcome these challenges is happening at different rates across Europe. We summarise the European national projects in this field but more recently we have seen the beginnings of European coordination. Within the EU 7th Funding Programme (FP7) European Network for Cancer Research in Children and Adolescents programme (ENCCA), a specific European Network for Teenagers and Young Adults with Cancer has held a series of scientific meetings, including professionals, patients and caregivers. This group has proposed unanswered research questions and agreed key features of a high-quality service that can improve outcomes for TYA with cancer, including the primacy of collaboration between adult and paediatric services to eliminate the gap in the management of TYA with cancer.

Background: Although continuity of care in paediatric palliative care (PPC) is considered to be an essential element of quality of care, it's implementation is challenging. In Belgium, five paediatric liaison teams (PLTs) deliver palliative care. A Royal Decree issued in 2010 provides the legal framework that defines the PLTs' missions, as ensuring continuity of curative and palliative care between the hospital and home for children diagnosed with life-limiting conditions. This national study describes how PLTs ensure continuity of care by describing their activities and the characteristics of the children they cared for from 2010 to 2014. Methods: Thematic analysis of open-ended questions was performed and descriptive statistics of aggregated data issued from annual reports, collected by the Belgian Ministry of Public Health through the Cancer Plan was used. A review panel of PLT members discussed the results and contributed to their interpretation. Results: Between 2010 and 2014, 3607 children and young adults (0-21 years) were cared for by the 5 Belgian PLTs (mean of 721/per year). Of these children, 50% were diagnosed with an oncological disease, 27% with a neurological or metabolic disease. Four hundred and twenty eight (428) children had died. For 51% of them, death took place at home. PLT activities include coordination; communication; curative and palliative care; education; research and fundraising. Different perceptions of what constitutes a palliative stage, heterogeneity in reporting diagnosis and the current lack of specific valid indicators to report PPC activities were found. Conclusion: PLTs are offering highly individualised, flexible and integrated care from diagnosis to bereavement in all care settings. Improvements in data registration and implementation of outcome measures are foreseen., SCOPUS: ar.j, info:eu-repo/semantics/published

Hurler syndrome (HS) is a lysosomal storage disease characterized by multisystem morbidity and death in early childhood. Hematopoietic stem cell transplantation (HSCT) results in long-term survival, although with significant residual disease burden. How this residual disease affects the health-related quality of life is unknown. Therefore, we conducted a multicenter cohort study on functional and psychosocial health and compared the outcomes to normative data using the Child Health Questionnaire and Pediatric Outcomes Data Collection Instrument. Perception of carewas evaluated by the Measure of Processes of Care questionnaire. Sixty-threeHS patients receiving HSCT with at least 3 years of follow-up after HSCT were included. The influence of potential predictors was analyzed using linear regression analysis, and correlation analysis was performed using Spearman rank correlation. Functional health of transplanted HS patients was significantly diminished compared with normative data (median physical summary z score, -2.4 [range, -3.5 to -1.6]; median global functioning z score, -3.2 [range, -4.8 to -1.8]). Psychosocial health was comparable or only slightly reduced compared with healthy peers (median psychosocial summary z score, 0.15 [range, -0.7 to 0.8]). A higher obtained lysosomal enzyme level post-HSCT predicted for superior functional health. Overall, parents were satisfied with the care received. Functional health of transplanted HS patients appeared significantly more affected than psychosocial health. To improve functional health, the use of only noncarrier donors and striving to achieve full-donor chimerism, both resulting in higher enzyme levels, is advised. Assessing the health-related quality of life could play an important role in evaluating outcomes of HS patients receiving novel (cell) therapies, including autologous gene-transduced HSCT.

Summary Background Neurofibromatosis type 1 is a common genetic disorder characterised by neurocutaneous manifestations and cognitive and behavioural problems. Statins were shown to reduce analogous learning deficits in a mouse model of the disease, but a short-term trial in humans was inconclusive. We aimed to assess the use of simvastatin for the improvement of cognitive and behavioural deficits in children with neurofibromatosis type 1 for 12 months. Methods In this randomised, double-masked, placebo-controlled trial, we recruited children with genetically confirmed neurofibromatosis type 1 aged 8–16 years from two national referral centres in the Netherlands and Belgium. Those with symptomatic CNS abnormalities or on neurotropic medication, including stimulants, were excluded. Eligible patients were randomly assigned (1:1) via a computer-generated, permuted-block list to simvastatin (10 mg per day in month 1, 20 mg per day in month 2, and 20–40 mg per day in months 3–12) or placebo for 12 months. Investigators, participants, and parents were masked to treatment assignment. Primary outcome measures were full-scale intelligence (Wechsler intelligence scale for children), attention problems (child behaviour checklist, parent-rated [CBCL]), and internalising behavioural problems (CBCL). We did intention-to-treat analyses (of all patients who had outcome data) using linear regression of the 12 month outcome scores, adjusted for baseline performance. This trial is registered with the Netherlands Trial Register, number NTR2150. Findings We randomly assigned 84 children to a treatment group (43 to simvastatin, 41 to placebo) between March 9, 2010, and March 6, 2012. We did not assess outcomes in two patients in the placebo group because they needed additional drug therapy. Simvastatin for 12 months had no effect on full-scale intelligence (treatment effect compared with placebo −1·3 IQ points [95% CI −3·8 to 1·3]; p=0·33), attention problems (–1·6 T -score points [–4·3 to 1·0]; p=0·23), and internalising behavioural problems (–0·1 T -score points [–3·3 to 3·1]; p=0·96). 38 (88%) of 43 patients on simvastatin and 39 (95%) of 41 patients on placebo reported adverse events, which were serious in two and four patients, respectively. Interpretation 12 month simvastatin treatment did not ameliorate cognitive deficits or behavioural problems in children with neurofibromatosis type 1. The use of 20–40 mg simvastatin per day for cognitive enhancement in children with neurofibromatosis type 1 is not recommended. Funding The Netherlands Organization for Health Research and Development (ZonMw), Research Foundation Flanders (FWO-Vlaanderen), Marguerite-Marie Delacroix Foundation, and the Dutch Neurofibromatosis Association (NFVN).

Hematopoietic stem cell and solid organ transplant recipients diagnosed with biopsy-confirmed posttransplant lymphoproliferative disorder (PTLD) at our institution from 1989 to 2010 were identified. Patient-, transplant- and disease-related characteristics, prognostic factors and outcome were collected and analyzed. One hundred and forty biopsy-proven cases of PTLD were included. Overall incidence in the transplant population was 2.12%, with heart transplant recipients carrying the highest risk. Most PTLDs were monomorphic (82%), with diffuse large B-cell lymphoma being the most frequent subtype. The majority of cases (70.7%) occurred > 1 year posttransplant, and 66% were Epstein-Barr virus positive. Following initial therapy the overall response rate was 68.5%. Three-year relapse-free and overall survivals were 59% and 49%, respectively. At last follow-up, 44% of the patients were alive. Multivariable analysis identified several classical lymphoma-specific poor prognostic factors for the different outcome measures. The value of the International Prognostic Index was confirmed in our analysis. ispartof: LEUKEMIA & LYMPHOMA vol:54 issue:11 pages:2433-2440 ispartof: location:United States status: published

This study aimed to improve understanding and treatment of psychiatric symptoms in antiphospholipid syndrome (APS) and to present an approach to the medical management of patients presenting with obsessive-compulsive disorder (OCD) with suspected neurovascular pathology.A 15-year-old boy presented with severe OCD of recent onset. An infarct of the caudate nucleus was identified as the initial presentation of primary APS. This case report includes a selective literature review of the neuropsychiatric correlates of APS.The patient had OCD for 3 months with increasing symptoms resulting in admission for psychiatric reasons. After referral to the emergency department 3 weeks later, an infarct of the caudate nucleus was documented using magnetic resonance images of the brain, and APS was diagnosed based on additional laboratory findings. Anticoagulant treatment (enoxaparin and phenprocoumon) in this patient was effective in reducing obsessive-compulsive symptom severity.OCD may present as a neuropsychiatric manifestation of APS. The present observations are consistent with a thrombotic mechanism for neurologic or psychiatric symptoms in APS. In general, routine medical workup for childhood OCD is not indicated, but a comprehensive psychiatric, medical, and family history taking and physical examination are essential, particularly if OCD is of recent onset. The role of anticoagulant therapy in neuropsychiatric manifestations of APS without the presence of a cerebral infarct requires further research.

To describe dental and dentofacial characteristics observed in patients diagnosed with osteopetrosis and to advise a dental care approach in these patients. Four patients were clinically diagnosed with osteopetrosis, characterised by increased bone density, bone marrow failure, blindness and deafness due to compression of cranial nerves. All patients were dentally screened at different ages (2.5–31 years) and three of them were treated with a haematopoietic stem cell transplantation (HSCT) at the age of 6 months, 1 and 3.1 years. All patients showed similar dental characteristics but varying severity and extent. Dental pits, abnormalities in form, agenesis and enamel deformations are seen. The eruption of the permanent dentition occurs at a slow rate, primary teeth can persist, have no successor, and aberrant form of the primary/permanent teeth can delay eruption. Uneven surfaces and atypical dental crowns combined with visual impairment make brushing of the teeth and plaque removal more difficult to manage. Dental problems such as delay in tooth eruption, crown anomalies and agenesis are seen in the patients diagnosed with osteopetrosis, although the severity and extensiveness of the symptoms differ and possibly depend on the age of the patient at HSCT. Treatment management: Frequent dental follow-up examinations are necessary for guiding the eruption and professional dental cleanings. Aid in the eruption can be helpful. In the case of surgical interventions, an antibiotic prophylaxis is advised. A fluoride treatment can be added to prevent caries. The role of HSCT in dental findings needs further research.

Sacrococcygeal teratoma (SCT) is one of the most common tumors in newborns with a birth prevalence of up to 1 in 21,700 births. Routine fetal anomaly screening programs allow for prenatal diagnosis in many cases. Fetal ultrasound with Doppler evaluation and more recently magnetic resonance imaging may be used to document the extent of the tumor as well as identifying the population at risk for serious fetal complications. Rapidly growing SCT and highly vascularized tumors are more likely to have hemodynamic repercussions. Fetal hydrops is usually considered as a poor prognostic marker and a potential indicator for fetal intervention. Newborns with SCT require stabilization prior to early surgical resection. In case of malignancy additional chemotherapy may be required. SCT may result in significant morbidity, either directly or as a consequence of surgical therapy. Careful postnatal follow-up is required for timely identification and treatment of complications as well as recurrence. This paper aims to review the perinatal management of this condition.

Background Intensive chemotherapy has markedly improved the survival of children with acute lymphoblastic leukaemia (ALL) or lymphoblastic lymphoma (LL). Evaluation of late effects and analysis of factors contributing to their occurrence has become of major importance. Second neoplasm (SN) belongs to the most severe late events. Procedure We report the incidence of SN which occurred in patients recruited in EORTC trial 58881 for children with ALL or LL. The front-line treatment regimen was adapted from the BFM protocol, but did not include cranial radiotherapy, even in patients with initial involvement of the central nervous system. A total of 2,216 patients were recruited, of whom 2,136 achieved complete remission (CR). Results At a median follow-up of 7.5 years, 22 (1%) patients developed a SN: 20 during or after completion of front-line therapy and 2 in second CR, after relapse treatment including haematopoietic stem cell transplantation (HSCT). Ten patients developed acute myeloblastic leukaemia. Only one SN, a glioblastoma, was a brain tumour. Other SN were: two Hodgkin lymphomas, one non-Hodgkin lymphoma, two thyroid cancers, one osteosarcoma, two soft tissue sarcomas, one Ewing sarcoma, one cutaneous histiocytosis and one peritoneal carcinomatosis. The cumulative incidences of SN at 5, 8 and 13 years after registration were 0.8% (SE 0.2%), 1.0% (SE 0.2%) and 3.0% (SE 1.9%), respectively. Conclusion The overall incidence rate of SN is comparable to that reported previously. In spite of short follow-up time, the low incidence of brain tumours might be related to the omission of cranial radiotherapy. Pediatr Blood Cancer 2011;57:119–125. © 2011 Wiley-Liss, Inc.

IntroductionVoriconazole is widely used as first-line agent to treatinvasive aspergillosis in immunocompromised adults. Alsoin children, its use is increasing [1]. During the last decade,several studies in adults demonstrated a pharmacodynamicrelationship between low voriconazole levels and lack ofresponse, and high voriconazole levels and toxicity [2, 3].However, voriconazole has very complex pharmacokineticsresulting in highly variable plasma levels. As a result, it isrecommended to monitor voriconazole plasma levels inadult patients with uncontrolled infection, gastro-intestinaldysfunction, severe hepatic dysfunction, and unexplainedneurological symptoms. Target trough levels should behigher than 1 or 2 mg/L to guarantee efficacy and lowerthan 6 mg/L to avoid toxicity [2, 3].The relationship between voriconazole plasma concen-trations and outcome has only been studied in adult patients[3]. To our knowledge, until recently, only two studies wereavailable on voriconazole pharmacokinetics in childrenunder 12 years of age [4, 5]. Some recent data suggest thatthe recommended dosages for pediatric patients are insuf-ficient to achieve adequate exposure [6, 7]. We thereforemeasured voriconazole trough levels measured in ourtertiary care children’s hospital and discuss them in thelight of recent literature.Materials and methodsAll patients (aged 0–18 years) admitted to the pediatricward in a 2,000-bed tertiary care hospital between January2008 and December 2009 with at least one measuredplasma trough level of voriconazole were included in thisretrospective observational study. Patients were scheduledfor voriconazole plasma concentration monitoring if theywere already treated for a long period, or if long-termtreatment was expected. The study was approved by theInstitutional Ethics Committee. Data were collected fromthe medical, laboratory and pharmacy records. Age, sex andweight, underlying disease and infectious diagnosis, vor-iconazole treatment regimen (dose, route of administration,formulation), voriconazole plasma levels and sampling