The development of fatigue after treatment for pediatric brain tumors does not differ between tumor locations.

BACKGROUND: Children and adolescents treated for a brain tumor suffer from more fatigue than survivors of other types of childhood cancer. As tumor location might be predictive of fatigue, our aim was to investigate the longitudinal development of fatigue in children with brain tumors and risk factors for fatigue separately for different tumor locations. METHODS: Fatigue was assessed 1235 times for 425 participants. Self-report versions of PedsQL Multidimensional Fatigue Scale were used to repeatedly assess fatigue from the end of treatment up to 8 years later. Mixed models were used to analyze fatigue over time and determinants separately for infratentorial (N = 205), supratentorial hemispheric (N = 91), and supratentorial midline tumors (N = 129). RESULTS: Cognitive fatigue worsened with time, while sleep-rest and general fatigue first decreased and then increased. There was no difference in fatigue between the tumor locations, but the risk factors differed when stratified by location. Radiotherapy was associated with more fatigue for infratentorial tumors, and centralization of care was associated with less fatigue for the supratentorial midline tumors. For supratentorial hemispheric tumors, female sex was associated with more fatigue. Higher parental education was associated with less fatigue regardless of tumor location. CONCLUSIONS: The development of fatigue seems to be more related to sociodemographic and treatment variables than to tumor location. Healthcare providers need to be aware that fatigue may develop in the years following end of treatment, and that patients with a low/middle educational family background might be more vulnerable and in need of targeted support.

A Dutch paediatric palliative care guideline: a systematic review and evidence-based recommendations for symptom treatment.

BACKGROUND: Children with life-threatening and life-limiting conditions can experience high levels of suffering due to multiple distressing symptoms that result in poor quality of life and increase risk of long-term distress in their family members. High quality symptom treatment is needed for all these children and their families, even more so at the end-of-life. In this paper, we provide evidence-based recommendations for symptom treatment in paediatric palliative patients to optimize care. METHODS: A multidisciplinary panel of 56 experts in paediatric palliative care and nine (bereaved) parents was established to develop recommendations on symptom treatment in paediatric palliative care including anxiety and depression, delirium, dyspnoea, haematological symptoms, coughing, skin complaints, nausea and vomiting, neurological symptoms, pain, death rattle, fatigue, paediatric palliative sedation and forgoing hydration and nutrition. Recommendations were based on evidence from a systematic literature search, additional literature sources (such as guidelines), clinical expertise, and patient and family values. We used the GRADE methodology for appraisal of evidence. Parents were included in the guideline panel to ensure the representation of patient and family values. RESULTS: We included a total of 18 studies that reported on the effects of specific (non) pharmacological interventions to treat symptoms in paediatric palliative care. A few of these interventions showed significant improvement in symptom relief. This evidence could only (partly) answer eight out of 27 clinical questions. We included 29 guidelines and two textbooks as additional literature to deal with lack of evidence. In total, we formulated 221 recommendations on symptom treatment in paediatric palliative care based on evidence, additional literature, clinical expertise, and patient and family values. CONCLUSION: Even though available evidence on symptom-related paediatric palliative care interventions has increased, there still is a paucity of evidence in paediatric palliative care. We urge for international multidisciplinary multi-institutional collaboration to perform high-quality research and contribute to the optimization of symptom relief in palliative care for all children worldwide.

Safety of Growth Hormone Replacement Therapy in Childhood-Onset Craniopharyngioma: A Systematic Review and Cohort Study.

INTRODUCTION: Survival of childhood-onset craniopharyngioma (cCP) is excellent; however, many survivors suffer from hypothalamic-pituitary dysfunction. Growth hormone replacement therapy (GHRT) is of high importance for linear growth and metabolic outcome. Optimal timing for initiation of GHRT in cCP is on debate because of concerns regarding tumor progression or recurrence. METHODS: A systematic review and cohort studys were performed for the effect and timing of GHRT on overall mortality, tumor progression/recurrence, and secondary tumors in cCP. Within the cohort, cCP receiving GHRT ≤1 year after diagnosis were compared to those receiving GHRT >1 year after diagnosis. RESULTS: Evidence of 18 included studies, reporting on 6,603 cCP with GHRT, suggests that GHRT does not increase the risk for overall mortality, progression, or recurrent disease. One study evaluated timing of GHRT and progression/recurrence-free survival and found no increased risk with earlier initiation. One study reported a higher than expected prevalence of secondary intracranial tumors compared to a healthy population, possibly confounded by radiotherapy. In our cohort, 75 of 87 cCP (86.2%) received GHRT for median of 4.9 years [0.0-17.1]. No effect of timing of GHRT was found on mortality, progression/recurrence-free survival, or secondary tumors. CONCLUSION: Although the quality of the evidence is low, the available evidence suggests no effect of GHRT or its timing on mortality, tumor progression/recurrence, or secondary neoplasms in cCP. These results support early initiation of GHRT in cCP aiming to optimize linear growth and metabolic outcome. Prospective studies are needed to increase the level of evidence upon the optimal timing to start GHRT in cCP patients.

Distinct DNA Methylation Patterns of Subependymal Giant Cell Astrocytomas in Tuberous Sclerosis Complex.

Tuberous sclerosis complex (TSC) is a monogenic disorder caused by mutations in either the TSC1 or TSC2 gene, two key regulators of the mechanistic target of the rapamycin complex pathway. Phenotypically, this leads to growth and formation of hamartomas in several organs, including the brain. Subependymal giant cell astrocytomas (SEGAs) are low-grade brain tumors commonly associated with TSC. Recently, gene expression studies provided evidence that the immune system, the MAPK pathway and extracellular matrix organization play an important role in SEGA development. However, the precise mechanisms behind the gene expression changes in SEGA are still largely unknown, providing a potential role for DNA methylation. We investigated the methylation profile of SEGAs using the Illumina Infinium HumanMethylation450 BeadChip (SEGAs n = 42, periventricular control n = 8). The SEGA methylation profile was enriched for the adaptive immune system, T cell activation, leukocyte mediated immunity, extracellular structure organization and the ERK1 & ERK2 cascade. More interestingly, we identified two subgroups in the SEGA methylation data and show that the differentially expressed genes between the two subgroups are related to the MAPK cascade and adaptive immune response. Overall, this study shows that the immune system, the MAPK pathway and extracellular matrix organization are also affected on DNA methylation level, suggesting that therapeutic intervention on DNA level could be useful for these specific pathways in SEGA. Moreover, we identified two subgroups in SEGA that seem to be driven by changes in the adaptive immune response and MAPK pathway and could potentially hold predictive information on target treatment response.

Ophthalmological Evaluation in Children Presenting With a Primary Brain Tumor.

BACKGROUND: Children with a brain tumor are prone to develop visual impairment, which to date is often underestimated and unrecognized. Our aim was to assess the prevalence of ophthalmological evaluation and abnormal ophthalmological findings, and investigate whether demographic and tumor-related characteristics are associated with abnormal ophthalmological findings in children presenting with a primary brain tumor. METHODS: Medical records of all 90 children diagnosed with a primary brain tumor between June 2018 and May 2019 and treated at the Princess Máxima Center for Pediatric Oncology, a tertiary referral center in the Netherlands, were retrospectively reviewed. Univariate regression analysis was used to investigate associations between demographic, tumor-related and clinical characteristics, and abnormal ophthalmological findings. RESULTS: Sixty children (34 male [56.7%]; median [range] age, 9.3 [0-16.9] years) underwent ophthalmological evaluation within 6 weeks before or after diagnosis, 11 children (5 male [45.5%]; median [range] age, 5.7 [0.1-17.2] years) were seen more than 6 weeks before or after diagnosis, and 19 children (7 male [36.8%]; median [range] age, 7.2 [1.9-16.6] years) did not receive ophthalmological evaluation within at least 6 months from diagnosis. A total of 19 children (21.1%) presented with visual symptoms as first sign leading to the diagnosis of a brain tumor. Children who presented with visual symptoms (odds ratio [OR], 22.52; 95% confidence interval [CI], 4.90-103.60) and/or hydrocephalus (OR, 3.60; 95% CI, 1.38-9.36) at diagnosis were more often seen for ophthalmological evaluation. The most common abnormal ophthalmological findings were eye movement disorders (66.0%), papilledema (44.1%), and visual field defects (58.1%). Eye movement disorders occurred more frequently in patients with an infratentorial tumor (OR, 4.71; 95% CI, 1.03-21.65). The risk of papilledema was associated with older age (OR, 1.19; 95% CI, 1.05-1.34), hydrocephalus (OR, 9.63; 95% CI, 2.68-34.61), and infratentorial (OR, 9.11; 95% CI, 1.77-46.78) and supratentorial (OR, 13.13; 95% CI, 1.92-89.52) tumors. CONCLUSIONS: In this study, most children with a primary brain tumor underwent ophthalmological evaluation around diagnosis, 21% of the children were not evaluated. The high prevalence of abnormal ophthalmological findings stresses the importance of early standardized ophthalmological evaluation to detect visual impairment and provide timely treatment to potentially prevent permanent visual loss.

No increase in psychosocial stress of Dutch children with cancer and their caregivers during the first months of the COVID-19 pandemic.

We studied the psychosocial impact of the start of the COVID-19 pandemic on Dutch children with cancer in outpatient care and their caregivers (n = 799) using regular monitoring and screening outcomes. No differences were observed between the pre-COVID-19 and early-COVID-19 periods in health-related quality of life and fatigue of children. Fewer caregivers were distressed during the COVID-19 period than pre-COVID-19. In conclusion, the additional stress of COVID-19 did not deteriorate psychosocial functioning of children with cancer and their caregivers. Results may be explained by alleviating daily life changes, experience in coping with medical traumatic stress, and appropriate care and support.

The coding and non-coding transcriptional landscape of subependymal giant cell astrocytomas.

Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited neurocutaneous disorder caused by inactivating mutations in TSC1 or TSC2, key regulators of the mechanistic target of rapamycin complex 1 (mTORC1) pathway. In the CNS, TSC is characterized by cortical tubers, subependymal nodules and subependymal giant cell astrocytomas (SEGAs). SEGAs may lead to impaired circulation of CSF resulting in hydrocephalus and raised intracranial pressure in patients with TSC. Currently, surgical resection and mTORC1 inhibitors are the recommended treatment options for patients with SEGA. In the present study, high-throughput RNA-sequencing (SEGAs n = 19, periventricular control n = 8) was used in combination with computational approaches to unravel the complexity of SEGA development. We identified 9400 mRNAs and 94 microRNAs differentially expressed in SEGAs compared to control tissue. The SEGA transcriptome profile was enriched for the mitogen-activated protein kinase (MAPK) pathway, a major regulator of cell proliferation and survival. Analysis at the protein level confirmed that extracellular signal-regulated kinase (ERK) is activated in SEGAs. Subsequently, the inhibition of ERK independently of mTORC1 blockade decreased efficiently the proliferation of primary patient-derived SEGA cultures. Furthermore, we found that LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5 were overexpressed at both gene and protein levels in SEGA compared to control tissue. Taken together LAMTOR1-5 can form a complex, known as the 'Ragulator' complex, which is known to activate both mTORC1 and MAPK/ERK pathways. Overall, this study shows that the MAPK/ERK pathway could be used as a target for treatment independent of, or in combination with mTORC1 inhibitors for TSC patients. Moreover, our study provides initial evidence of a possible link between the constitutive activated mTORC1 pathway and a secondary driver pathway of tumour growth.

Anticipating the future of the child and family in pediatric palliative care: a qualitative study into the perspectives of parents and healthcare professionals.

Preparing for future scenarios in pediatric palliative care is perceived as complex and challenging by both families and healthcare professionals. This interpretative qualitative study using thematic analysis aims to explore how parents and healthcare professionals anticipate the future of the child and family in pediatric palliative care. Single and repeated interviews were undertaken with 42 parents and 35 healthcare professionals of 24 children, receiving palliative care. Anticipating the future was seen in three forms: goal-directed conversations, anticipated care, and guidance on the job. Goal-directed conversations were initiated by either parents or healthcare professionals to ensure others could align with their perspective regarding the future. Anticipated care meant healthcare professionals or parents organized practical care arrangements for future scenarios with or without informing each other. Guidance on the job was a form of short-term anticipation, whereby healthcare professionals guide parents ad hoc through difficult situations.Conclusion: Anticipating the future of the child and family is mainly focused on achievement of individual care goals of both families and healthcare professionals, practical arrangements in advance, and short-term anticipation when a child deteriorates. A more open approach early in disease trajectories exploring perspectives on the future could allow parents to anticipate more gradually and to integrate their preferences into the care of their child. What is Known: • Anticipating the future in pediatric palliative care occurs infrequently and too late. What is New: • Healthcare professionals and parents use different strategies to anticipate the future of children receiving palliative care, both intentionally and unwittingly. Strategies to anticipate the future are goal-directed conversations, anticipated care, and guidance on the job. • Parents and healthcare professionals are engaged to a limited extent in ongoing explorative conversations that support shared decision-making regarding future care and treatment.

Parental experiences and coping strategies when caring for a child receiving paediatric palliative care: a qualitative study.

Parenting and providing extensive care to a child with a life-limiting or life-threatening disease while being aware of the future loss of the child are among the most stressful parental experiences. Due to technical and medical improvements, children are living longer and are increasingly cared for at home. To align healthcare professionals' support with the needs of parents, a clear understanding of prominent experiences and main coping strategies of parents caring for a child in need of palliative care is needed. An interpretative qualitative study using thematic analysis was performed. Single or repeated interviews were undertaken with 42 parents of 24 children with malignant or non-malignant diseases receiving palliative care. Prominent reported parental experiences were daily anxiety of child loss, confrontation with loss and related grief, ambiguity towards uncertainty, preservation of a meaningful relationship with their child, tension regarding end-of-life decisions and engagement with professionals. Four closely related coping strategies were identified: suppressing emotions by keeping the loss of their child at bay, seeking support, taking control to arrange optimal childcare and adapting to and accepting the ongoing change(s).Conclusion: Parents need healthcare professionals who understand and carefully handle their worries, losses, parent-child relationship and coping strategies. What is Known: • In paediatric palliative care, parents have a daunting task in fulfilling all caregiving tasks while striving for control of their child's symptoms, a life worth living and a family balance. What is New: • Prominent experiences were: continuous management of anxiety of child loss, feelings of uncertainty, tension with end-of-life decision making and engagement with professionals. Parents experienced unique significance to their child, reinforcing a meaningful parent-child relationship. • Relevant coping strategies were: suppressing emotions, seeking support, taking control to arrange optimal care and adapting to the ongoing changes. • To provide tailored support, professionals need to understand parents' perceptions, relationship with their child and coping strategies.

Biological material collection to advance translational research and treatment of children with CNS tumours: position paper from the SIOPE Brain Tumour Group.

Paediatric CNS tumours are the most common cause of childhood cancer-related morbidity and mortality, and improvements in their diagnosis and treatment are needed. New genetic and epigenetic information about paediatric CNS tumours is transforming the field dramatically. For most paediatric CNS tumour entities, subgroups with distinct biological characteristics have been identified, and these characteristics are increasingly used to facilitate accurate diagnoses and therapeutic recommendations. Future treatments will be further tailored to specific molecular subtypes of disease, specific tumour predisposition syndromes, and other biological criteria. Successful biomaterial collection is a key requirement for the application of contemporary methodologies for the validation of candidate prognostic factors, the discovery of new biomarkers, the establishment of appropriate preclinical research models for targeted agents, a quicker clinical implementation of precision medicine, and for other therapeutic uses (eg, for immunotherapies). However, deficits in organisational structures and interdisciplinary cooperation are impeding the collection of high-quality biomaterial from CNS tumours in most centres. Practical, legal, and ethical guidelines for consent, storage, material transfer, biobanking, data sharing, and funding should be established by research consortia and local institutions to allow optimal collection of primary and subsequent tumour tissue, body fluids, and normal tissue. Procedures for the collection and storage of biomaterials and related data should be implemented according to the individual and organisational structures of the local institutions.

Current and emerging treatment strategies for children with progressive chiasmatic-hypothalamic glioma diagnosed as infants: a web-based survey.

Treatment of infant hypothalamic chiasmatic glioma (iCHG) is challenging, about 30% of the children progress during chemotherapy. Despite subsequent treatments the 5 year overall-survival rate is only 70%. This study investigates treatment strategies currently applied for progressive iCHG. A web-based questionnaire was sent out to the members of the SIOPE Brain Tumour Group asking for current second and third line strategies at progression during and after the end of first line therapy. The questionnaire was answered by 47 paediatric oncologists from 15 countries. iCHG progressing during first line therapy with carboplatin-vincristine would be considered for treatment with alternative chemotherapy by 17 (36%) and with surgery plus chemotherapy by 27 respondents (58%). Components suggested for second line were vinblastine (62%), cisplatin (34%) and cyclophosphamide (26%). For third line therapy bevacizumab (BVZ) was considered as suitable by respondents in 53% (often with irinotecan 40%) and vinblastine by 34% respectively. Experience with BVZ in CHG is shown by 53% of respondents regarding at least 95 patients (median treated 1-5 patients per respondent at any age) with a median BVZ administration over 12 months. Effectiveness was reported varying between stable disease and regression while complications were rarely stated (proteinuria, hypertension, bleeding). BVZ would be available to 85% of respondents as therapeutic option for iCHG patients. Multiple anti-neoplastic drug regimens are applied for progressive iCHG, partly considered in combination with surgery if safely feasible. BVZ is commonly used at a satisfactory level in third line, mainly combined with irinotecan.

The development of hypothalamic obesity in craniopharyngioma patients: A risk factor analysis in a well-defined cohort.

BACKGROUND: Hypothalamic obesity (HO) is a major concern in patients treated for craniopharyngioma (CP). The influence of degree of resection on development of HO, event-free survival (EFS), and neuroendocrine sequelae is an issue of debate. PROCEDURE: A retrospective cohort consisting of all CP patients treated between 2002 and 2012 in two university hospitals was identified. Multivariable logistic regression was used to study the associations between preoperative BMI, age at diagnosis, tumor volume, performed surgical resection, and presence of HO at follow-up. RESULTS: Thirty-five patients (21 children and 14 adults) were included. Median follow-up time was 35.6 months (4.1-114.7). Four patients were obese at diagnosis. HO was present in 19 (54.3%) patients at last follow-up of whom eight were morbidly obese. Thirteen (37.1%) patients underwent partial resection (PR) and 22 (62.9%) gross total resection (GTR). GTR was related to HO (OR 9.19, 95% CI 1.43-59.01), but for morbid HO, obesity at diagnosis was the only risk factor (OR 12.92, 95% CI 1.05-158.73). EFS in patients after GTR was 86%, compared to 42% after PR (log-rank 9.2, P = 0.003). Adjuvant radiotherapy after PR improved EFS (log-rank 8.2, P = 0.004). Panhypopituitarism, present in 15 patients, was mainly seen after GTR. CONCLUSIONS: HO is less frequent after PR than after GTR, but PR cannot always prevent the development of morbid obesity in patients with obesity at diagnosis. PR reduces the occurrence of panhypopituitarism. When developing a treatment algorithm, all these factors should be considered.

Barriers and facilitators to the implementation of a paediatric palliative care team.

BACKGROUND: Over the last decade, paediatric palliative care teams (PPCTs) have been introduced to support children with life-limiting diseases and their families and to ensure continuity, coordination and quality of paediatric palliative care (PPC). However, implementing a PPCT into an organisation is a challenge. The objective of this study was to identify barriers and facilitators reported by healthcare professionals (HCPs) in primary, secondary or tertiary care for implementing a newly initiated multidisciplinary PPCT to bridge the gap between hospital and home. METHODS: The Measurement Instrument for Determinants of Innovations (MIDI) was used to assess responses of 71 HCPs providing PPC to one or more of the 129 children included in a pilot study of a PPCT based at a university children's hospital. The MIDI (29 items) assessed barriers and facilitators to implementing the PPCT by using a 5-point scale (completely disagree to completely agree) and additional open-ended questions. Items to which ≥20% of participants responded with 'totally disagree/disagree' and ≥80% responded with 'agree/totally agree' were considered as barriers and facilitators, respectively. A general inductive approach was used for open-ended questions. RESULTS: Reported barriers to implementing a PPCT were related to the HCP's own organisation (e.g., no working arrangements related to use of the intervention [PPCT] registered, other organisational changes such as merger going on). Reported facilitators were mainly related to the intervention (correctness, simplicity, observability and relevancy) and the user scale (positive outcome expectations, patient satisfaction) and only once to the organisation scale (information accessibility). Additionally, HCPs expressed the need for clarity about tasks of the PPCT and reported having made a transition from feeling threatened by the PPCT to satisfaction about the PPCT. CONCLUSION: Positive experiences with the PPCT are a major facilitator for implementing a PPCT. Tailored organisational strategies such as working arrangements by management, concrete information about the PPCT itself and the type of support provided by the PPCT should be clearly communicated to involved HCPs to increase awareness about benefits of the PPCT and ensure a successful implementation. New PPCTs need protection and resources in their initial year to develop into experienced and qualified PPCTs.

Real-world implementation of electronic patient-reported outcomes in outpatient pediatric cancer care.

OBJECTIVE: The KLIK method is an online tool that monitors and discusses electronic patient-reported outcomes (ePROs), which has been shown to enhance outcomes. This study aimed (1) to determine the fidelity (ie, extent to which used as intended) of the KLIK method as implemented in outpatient pediatric cancer care and (2) to study health care professional (HCP)-reported barriers and facilitators for implementation. METHODS: Two hundred five children with newly diagnosed cancer (enrollment rate 85%) participated. At 1 (T1), 3 (T2), and 6 (T3) months after diagnosis, patients (8-18 years) or parents (of patients 0-7 years) completed health-related quality of life (HRQoL) questionnaires, which were transformed into an ePROfile and discussed by their HCP during consultations. Fidelity was determined by the following: percentage of website registrations, HRQoL questionnaires completed, and ePROfiles discussed. Implementation determinants were assessed with HCPs after the final T3 with the Measurement Instrument for Determinants of Innovations. RESULTS: Depending on the time point (T1-T3), fidelity was 86% to 89% for website registration, 66-85% for completed HRQoL questionnaires, and 56% to 62% for ePROfile discussion. Barriers were mainly related to organizational issues (eg, organizational change) and less frequently to users (eg, motivation to comply) or the intervention (compatibility). Facilitators were related to the user (eg, positive outcome expectations) and intervention (simplicity) but not to the organization. CONCLUSIONS: When implementing ePROs in outpatient pediatric oncology practice, HCPs report determinants that influence ePRO integration. To improve implementation and outcomes, tailored organizational (eg, formal ratification by management and time) and specific local (eg, individualized assessments) strategies should be developed to achieve optimal ePRO discussion.

Aims and tasks in parental caregiving for children receiving palliative care at home: a qualitative study.

In paediatric palliative care (PPC), parents are confronted with increasing caregiving demands. More children are cared for at home, and the need for PPC of children is lengthened due to technical and medical improvements. Therefore, a clear understanding of the content of parental caregiving in PPC becomes increasingly important. The objective is to gain insight into parental caregiving based on the lived experience of parents with a child with a life-limiting disease. An interpretative qualitative study using thematic analysis was performed. Single or repeated interviews were undertaken with 42 parents of 24 children with a malignant or non-malignant disease, receiving PPC. Based on their ambition to be a 'good parent', parents caring for a child with a life-limiting disease strived for three aims: controlled symptoms and controlled disease, a life worth living for their ill child and family balance. These aims resulted in four tasks that parents performed: providing basic and complex care, organising good quality care and treatment, making sound decisions while managing risks and organising a good family life. CONCLUSION: Parents need early explanation from professionals about balancing between their aims and the related tasks to get a grip on their situation and to prevent becoming overburdened. What is Known: • In paediatric palliative care, parents are confronted with increasing caregiving demands. • Parenting is often approached from the perspective of stress. What is New: • Parents strive for three aims: controlled symptoms and controlled disease, a life worth living for their child and family balance. • Parents perform four tasks: providing basic and complex care, organising good quality care, making decisions while managing risks and organising a good family life. • Professionals need insight into the parents' aims and tasks from the parental perspective to strengthen parents' resilience.

A prospective study on the characteristics and subjects of pediatric palliative care case management provided by a hospital based palliative care team.

BACKGROUND: Case management is a subject of interest within pediatric palliative care. Detailed descriptions of the content of this type of case management are lacking. We aim to describe the contents of care provided, utilization of different disciplines, and times of usage of a pediatric palliative care case management program compared for patients with malignant disease (MD) and non-malignant disease (NMD). METHODS: A three-month prospective study, with questionnaires filled in by members of a pediatric palliative care team (PPCT) for each contact with parents. RESULTS: Four hundred fifty-five contacts took place with parents of 70 patients (27MD, 43NMD). Sixty-two percent of all contacts were with the specialized nurse. The child life specialists, psychologist and social worker were also regularly consulted, the chaplain was not consulted. Ninety-five percent of all contacts took place between 8 am and 6 pm during weekdays, a limited number between 6 pm and 9 pm. Twenty-five percent of all contacts were proactively initiated by the PPCT, 25 % were initiated by parents. In these care characteristics, no differences were seen for MD and NMD patients. Psychosocial topics were addressed most frequently. MD patients consulted the PPCT more often about school and NMD patients about socio-economic issues. CONCLUSIONS: All different disciplines of the PPCT were regularly consulted, except for the chaplain. With an easy accessible team with a highly pro-active approach, availability from 8 am to 9 pm seems sufficient to accommodate patient's and parent's needs. More anticipation seems required for socio-economic topics. This insight in pediatric palliative case management can provide guidance in the development of a new PPCT.

Chemotherapy for children with medulloblastoma.

BACKGROUND: Post-surgical radiotherapy (RT) in combination with chemotherapy is considered as standard of care for medulloblastoma in children. Chemotherapy has been introduced to improve survival and to reduce RT-induced adverse effects. Reduction of RT-induced adverse effects was achieved by deleting (craniospinal) RT in very young children and by diminishing the dose and field to the craniospinal axis and reducing the boost volume to the tumour bed in older children. PRIMARY OBJECTIVES: 1. to determine the event-free survival/disease-free survival (EFS/DFS) and overall survival (OS) in children with medulloblastoma receiving chemotherapy as a part of their primary treatment, as compared with children not receiving chemotherapy as part of their primary treatment; 2. to determine EFS/DFS and OS in children with medulloblastoma receiving standard-dose RT without chemotherapy, as compared with children receiving reduced-dose RT with chemotherapy as their primary treatment. SECONDARY OBJECTIVES: to determine possible adverse effects of chemotherapy and RT, including long-term adverse effects and effects on quality of life. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2013, Issue 7), MEDLINE/PubMed (1966 to August 2013) and EMBASE/Ovid (1980 to August 2013). In addition, we searched reference lists of relevant articles, conference proceedings and ongoing trial databases (August 2013). SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating the above treatments in children (aged 0 to 21 years) with medulloblastoma. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, data extraction and risk of bias assessment. We performed analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. Where possible, we pooled results. MAIN RESULTS: The search identified seven RCTs, including 1080 children, evaluating treatment including chemotherapy and treatment not including chemotherapy. The meta-analysis of EFS/DFS not including disease progression during therapy as an event in the definition showed a difference in favour of treatment including chemotherapy (hazard ratio (HR) 0.70; 95% confidence interval (CI) 0.54 to 0.91; P value = 0.007; 2 studies; 465 children). However, not including disease progression as an event might not be optimal and the finding was not confirmed in the meta-analysis of EFS/DFS including disease progression during therapy as an event in the definition (HR 1.02; 95% CI 0.70 to 1.47; P value = 0.93; 2 studies; 300 children). Two individual studies using unclear or other definitions of EFS/DFS also showed no clear evidence of difference between treatment arms (one study with unclear definition of DFS: HR 1.67; 95% CI 0.59 to 4.71; P value = 0.34; 48 children; one study with other definition of EFS: HR 0.84; 95% CI 0.58 to 1.21; P value = 0.34; 233 children). In addition, it should be noted that in one of the studies not including disease progression as an event, the difference in DFS only reached statistical significance while the study was running, but due to late relapses in the chemotherapy arm, this significance was no longer evident with longer follow-up. There was no clear evidence of difference in OS between treatment arms (HR 1.06; 95% CI 0.67 to 1.67; P value = 0.80; 4 studies; 332 children). Out of eight reported adverse effects, of which seven were reported in one study, two (severe infections and fever/neutropenia) showed a difference in favour of treatment not including chemotherapy (severe infections: risk ratio (RR) 5.64; 95% CI 1.28 to 24.91; P value = 0.02; fever/neutropenia: RR not calculable; Fisher's exact P value = 0.01). There was no clear evidence of a difference between treatment arms for other adverse effects (acute alopecia: RR 1.00; 95% CI 0.92 to 1.08; P value = 1.00; reduction in intelligence quotient: RR 0.78; 95% CI 0.46 to 1.30; P value = 0.34; secondary malignancies: Fisher's exact P value = 0.5; haematological toxicity: RR 0.54; 95% CI 0.20 to 1.45; P value = 0.22; hepatotoxicity: Fisher's exact P value = 1.00; treatment-related mortality: RR 2.37; 95% CI 0.43 to 12.98; P value = 0.32; 3 studies). Quality of life was not evaluated. In individual studies, the results in subgroups (i.e. younger/older children and high-risk/non-high-risk children) were not univocal.The search found one RCT comparing standard-dose RT with reduced-dose RT plus chemotherapy. There was no clear evidence of a difference in EFS/DFS between groups (HR 1.54; 95% CI 0.81 to 2.94; P value = 0.19; 76 children). The RCT did not evaluate other outcomes and subgroups.The presence of bias could not be ruled out in any of the studies. AUTHORS' CONCLUSIONS: Based on the evidence identified in this systematic review, a benefit of chemotherapy cannot be excluded, but at this moment we are unable to draw a definitive conclusion regarding treatment with or without chemotherapy. Treatment results must be viewed in the context of the complete therapy (e.g. the effect of surgery and craniospinal RT), and the different chemotherapy protocols used. This systematic review only allowed a conclusion on the concept of treatment, not on the best strategy regarding specific chemotherapeutic agents and radiation dose. Several factors complicated the interpretation of results including the long time span between studies with important changes in treatment in the meantime. 'No evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. The fact that no significant differences between treatment arms were identified could, besides the earlier mentioned reasons, also be the result of low power or too short a follow-up period. Even though RCTs are the highest level of evidence, it should be recognised that data from non-randomised studies are available, for example on the use of chemotherapy only in very young children with promising results for children without metastatic disease. We found only one RCT addressing standard-dose RT without chemotherapy versus reduced-dose RT with chemotherapy, so no definitive conclusions can be made. More high-quality research is needed.

Impact of a multifaceted education program on implementing a pediatric palliative care guideline: a pilot study.

BACKGROUND: A national clinical practice guideline for pediatric palliative care was published in 2013. So far there are only few reports available on whether an educational program fosters compliance with such a guideline implementation. We aimed to test the effect of the education program on actual compliance as well as documentation of compliance to the guideline. METHODS: We performed a prospective study with pre- and post-intervention evaluation on compliance to the guideline of the nurse specialists of a pediatric palliative care team for case management at a children's university hospital. Eleven quality indicators were selected from 192 recommendations from the pediatric palliative care guideline, based on frequency, measurability and relevance. The multifaceted education program included e-learning and an interactive educational meeting. Four e-learning modules addressed 19 patient cases on symptoms, diagnostics and treatment, and a chart-documentation exercise. During the interactive educational meeting patient cases were discussed on how to use the guideline. Documentation of compliance to the guideline in the web-based patient-charts as well as actual compliance to the guideline through weekly web-based parent reports was measured before and after completion of the e-learning. RESULTS: Eleven quality indicators were selected. The educational program did not result in significant improvement in compliance for any of these indicators. The indicators "treatment of nausea", "pain medications two steps ahead" and "pain medication for 48 h present", measured through parent reports, scored a compliance beyond 80 % before and after e-learning. The remaining indicators measuring compliance, as well as six indicators measuring documentation by chart review, showed a compliance below 80 % before and after e-learning. CONCLUSIONS: The multifaceted education program did not lead to improvement in documentation of compliance to the guideline. Parent reported outcome revealed better performance and might be the more adequate assessment tool for future studies.

Severe skin toxicity in pediatric oncology patients treated with voriconazole and concomitant methotrexate.

We report the occurrence of skin toxicities in pediatric oncology patients on concomitant treatment with voriconazole and methotrexate (MTX). Of 23 patients who received this combination, 11 patients suffered from cheilitis and/or photosensitivity. In contrast, only in 1 of 9 patients who received voriconazole without MTX was photosensitivity observed. A mechanism of action was not able to be identified. We describe two cases with severe skin toxicities. Caution is warranted when using voriconazole and concomitant MTX.

Neurocognitive consequences of a paediatric brain tumour and its treatment: a meta-analysis.

AIM: This meta-analysis provides a systematic review of studies into intellectual and attentional functioning of paediatric brain tumour survivors (PBTS) as assessed by two widely used measures: the Wechsler Intelligence Scale for Children (3rd edition; WISC-III) and the Conners' Continuous Performance Test (CPT). METHOD: Studies were located that reported on performance of PBTS (age range 6-16y). Meta-analytic effect sizes were calculated for Full-scale IQ, Performance IQ, and Verbal IQ as measured by the WISC-III, and mean hit reaction time, errors of omission, and errors of commission as measured by the CPT. Exploratory analyses investigated the possible impacts of treatment mode, tumour location, age at diagnosis, and time since diagnosis on intelligence. RESULTS: Twenty-nine studies were included: 22 reported on the WISC-III in 710 PBTS and seven on CPT results in 372 PBTS. PBTS performed below average (p(s) <0.001) on Full-scale IQ (Cohen's d=-0.79), Performance IQ (d=-0.90), and Verbal IQ (d=-0.54). PBTS committed more errors of omission than the norm (d=0.82, p<0.001); no differences were found for mean hit reaction time and errors of commission. Cranial radiotherapy, chemotherapy, and longer time since diagnosis were associated with lower WISC-III scores (p(s) <0.05). INTERPRETATION: PBTS have seriously impaired intellectual functioning and attentiveness. Being treated with cranial radiotherapy and/or chemotherapy as well as longer time since diagnosis leads to worse intellectual functioning.