Development of the Dutch Structure for Integrated Children's Palliative Care

Children’s palliative care (CPC) is gaining attention worldwide, facilitated by the exchange of knowledge during regular specialised congresses. This article describes the developments in the Netherlands over the past 15 years. The Foundation for Children’s Palliative Expertise (PAL) was established as a nationwide initiative committed to improving palliative care for children countrywide. This led to the development of the first hospital-based CPC team in 2012, which expanded to a total of seven teams adjacent to children’s university hospitals. Regional networks for CPC were developed in parallel to these teams from 2014 onwards. The networks are a collaboration of professionals from different disciplines and organisations, from hospital to homecare, and have covered the aspects of CPC nationally from 2019 onwards. They are connected through the Dutch Knowledge Centre for CPC. This centre was established in 2018 by the PAL Foundation in collaboration with the Dutch Association for Pediatrics. In 2013, the first evidence-based guideline, ‘palliative care for children’, provided access to knowledge for parents and healthcare providers, and in 2017, a format for an individual palliative care plan was established. Within the Knowledge Centre for CPC, a physician’s support centre for dilemma’s regarding the end of life of children was set up. The efforts to have children’s palliative care embedded in the regular Dutch health care insurance are ongoing

Tocilizumab for the fifth progression of cystic childhood craniopharyngioma-a case report

We present the case of a 15-year-old girl, with a fifth cystic progression of an adamantinomatous craniopharyngioma after multiple surgeries and previous local radiotherapy. She had severe visual impairment, panhypopituitarism including diabetes insipidus, and several components of hypothalamic damage, including morbid obesity and severe fatigue. To prevent further late effects hampering her quality of survival, she was treated biweekly with intravenous tocilizumab, an anti-interleukin-6 agent, which stabilized the cyst for a prolonged time. Based on the biology of adamantinomatous craniopharyngioma, this immune-modulating treatment seems promising for the treatment of this cystic tumor in order to reduce surgery and delay or omit radiotherapy

Treatment and outcome of the Dutch Childhood Craniopharyngioma Cohort study; first results after centralization of care

BACKGROUND: Childhood craniopharyngioma (cCP) has excellent survival, but quality of life may be severely hampered by hypothalamic dysfunction. We aimed to evaluate treatment and hypothalamic outcomes of a Dutch cCP cohort, and evaluate the effect of centralization of care. METHODS: A retrospective cohort study was performed, including cCP patients diagnosed between 2004 and 2021. Treatment characteristics and hypothalamic outcomes were evaluated and compared before and since centralization of care in May 2018. RESULTS: We included 87 cCP patients. Cyst drainage/fenestration was performed in 29.9%, limited resection in 27.6%, near-total resection in 16.1%, and gross total resection (GTR) in 25.4%. Radiotherapy was given in 46.0%. After a median follow-up of 6.5 years, hypothalamic obesity (HO) was present in 24.7% and panhypopituitarism with diabetes insipidus in 71.3%. Higher body mass index (BMI) SDS at diagnosis and Muller grade II at last magnetic resonance imaging of follow-up were associated with overweight/obesity. No association was found between extensiveness of resection and overweight/obesity at last follow-up. When comparing before and after centralization of care, rates of GTR remained similar, but BMI outcomes changed; mean ΔBMI SDS 1 year after diagnosis from 1.12 (SD 1.15) to 0.81 (SD 1.24), and HO after 1 year decreased from 33.3% to 12.0% (P = .067), and after 2 years from 28.6% to 6.7% (P = NS). CONCLUSIONS: In our nationwide cohort, GTR was performed in a relatively low percentage of patients and extensiveness of resection was no longer associated with HO at follow-up. A trend toward improvement of BMI is observed since centralization of care, which needs further exploration

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

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

The MOBI-Kids Study Protocol: Challenges in Assessing Childhood and Adolescent Exposure to Electromagnetic Fields from Wireless Telecommunication Technologies and Possible Association with Brain Tumor Risk

The rapid increase in mobile phone use in young people has generated concern about possible health effects of exposure to radiofrequency (RF) and extremely low frequency (ELF) electromagnetic fields (EMF). MOBI-Kids, a multinational case-control study, investigates the potential effects of childhood and adolescent exposure to EMF from mobile communications technologies on brain tumor risk in 14 countries. The study, which aims to include approximately 1,000 brain tumor cases aged 10-24 years and two individually matched controls for each case, follows a common protocol and builds upon the methodological experience of the INTERPHONE study. The design and conduct of a study on EMF exposure and brain tumor risk in young people in a large number of countries is complex and poses methodological challenges. This manuscript discusses the design of MOBI-Kids and describes the challenges and approaches chosen to address them, including: (1) the choice of controls operated for suspected appendicitis, to reduce potential selection bias related to low response rates among population controls; (2) investigating a young study population spanning a relatively wide age range; (3) conducting a large, multinational epidemiological study, while adhering to increasingly stricter ethics requirements; (4) investigating a rare and potentially fatal disease; and (5) assessing exposure to EMF from communication technologies. Our experience in thus far developing and implementing the study protocol indicates that MOBI-Kids is feasible and will generate results that will contribute to the understanding of potential brain tumor risks associated with use of mobile phones and other wireless communications technologies among young people

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 15 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.(VLID)357262

Stage of presentation and visual outcome of patients screened for familial retinoblastoma: nationwide registration in the Netherlands

BACKGROUND: In the Netherlands a comprehensive programme for screening just after birth for familial retinoblastoma is taking place. In this report the stage of the disease at the time of detection, by way of screening, and the long term visual outcome in these patients was evaluated. METHODS: A nationwide, retrospective study. From January 1992–July 2004, patients at risk for familial retinoblastoma were screened 1–2 weeks after birth, and investigated for laterality, Reese‐Ellsworth classification/International Classification of Retinoblastoma, macular involvement, age of primary retinoblastoma , initial therapy, and visual outcome. RESULTS: 17 patients were diagnosed with familial retinoblastoma. 88.3% developed bilateral, 11.7% unilateral retinoblastoma. Of the 34 eyes, 56% were R‐E group I, 16% were group II A‐B, 16% were group III A‐B, 9% were group IV, 3% were group V. Using the International Classification of Retinoblastoma, 72% were group A, 19% were group B, 6% were group C, 3% were group E. The visual outcome revealed 73.5% of eyes with 20/20–20/40, 26.5% eyes with ⩽20/100–no light perception; 5.9% of eyes were enucleated, all other eyes were treated with local or conservative treatment methods. Of all eyes, 59% had extramacular retinoblastoma, 98% of patients had at least one eye with extramacular retinoblastoma. CONCLUSION: Most familial retinoblastoma patients present as a R‐E group I or group A when screened within 2 weeks after birth. Nearly 90% of patients had a long term visual acuity of 20/20–20/40. Despite the common occurrence of macula involvement, bilateral macula involvement was infrequent, and since most eyes were salvaged, good vision was obtained in the majority of patients

Towards culturally competent paediatric oncology care. A qualitative study from the perspective of care providers

In order to gain more insight on the influence of ethnic diversity in paediatric cancer care, the perspectives of care providers were explored. Semi-structured interviews were conducted among 12 paediatric oncologists and 13 nurses of two different paediatric oncology wards and were analysed using a framework method. We found that care providers described the contact with Turkish and Moroccan parents as more difficult. They offered two reasons for this: (1) language barriers between care provider and parents hindered the exchange of information; (2) cultural barriers between care provider and parents about sharing the diagnosis and palliative perspective hindered communication. Care providers reported different solutions to deal with these barriers, such as using an interpreter and improving their cultural knowledge about their patients. They, however, were not using interpreters sufficiently and were unaware of the importance of eliciting parents' perspectives. Communication techniques to overcome dilemmas between parents and care providers were not used and care providers were unaware of stereotypes and prejudice. Care providers should be offered insight in cultural barriers they are unaware of. Training in cultural competence might be a possibility to overcome manifest barrier