Adjuvant Wilms' tumour 1-specific dendritic cell immunotherapy complementing conventional therapy for paediatric patients with high-grade glioma and diffuse intrinsic pontine glioma: protocol of a monocentric phase I/II clinical trial in Belgium.

INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) and paediatric high-grade glioma (pHGG) are aggressive glial tumours, for which conventional treatment modalities fall short. Dendritic cell (DC)-based immunotherapy is being investigated as a promising and safe adjuvant therapy. The Wilms' tumour protein (WT1) is a potent target for this type of antigen-specific immunotherapy and is overexpressed in DIPG and pHGG. Based on this, we designed a non-randomised phase I/II trial, assessing the feasibility and safety of WT1 mRNA-loaded DC (WT1/DC) immunotherapy in combination with conventional treatment in pHGG and DIPG. METHODS AND ANALYSIS: 10 paediatric patients with newly diagnosed or pretreated HGG or DIPG were treated according to the trial protocol. The trial protocol consists of leukapheresis of mononuclear cells, the manufacturing of autologous WT1/DC vaccines and the combination of WT1/DC-vaccine immunotherapy with conventional antiglioma treatment. In newly diagnosed patients, this comprises chemoradiation (oral temozolomide 90 mg/m2 daily+radiotherapy 54 Gy in 1.8 Gy fractions) followed by three induction WT1/DC vaccines (8-10×106 cells/vaccine) given on a weekly basis and a chemoimmunotherapy booster phase consisting of six 28-day cycles of oral temozolomide (150-200 mg/m2 on days 1-5) and a WT1/DC vaccine on day 21. In pretreated patients, the induction and booster phase are combined with best possible antiglioma treatment at hand. Primary objectives are to assess the feasibility of the production of mRNA-electroporated WT1/DC vaccines in this patient population and to assess the safety and feasibility of combining conventional antiglioma treatment with the proposed immunotherapy. Secondary objectives are to investigate in vivo immunogenicity of WT1/DC vaccination and to assess disease-specific and general quality of life. ETHICS AND DISSEMINATION: The ethics committee of the Antwerp University Hospital and the University of Antwerp granted ethics approval. Results of the clinical trial will be shared through publication in a peer-reviewed journal and presentations at conferences. TRIAL REGISTRATION NUMBER: NCT04911621.

Dilemmas in the Management of an Infant with Neuroblastoma Metastasized to the Muscles.

The risk stratification of infants with metastatic neuroblastoma (NB) has evolved over time from stage 4/M or IVs/4S/MS/Ms according to various staging systems. Despite these developments for some genetic aberrations, the prognostic value and the impact of soft tissue metastases in infants are not fully understood, nor well described in the different classification systems, hampering the definitions to uniformly treat patients and predict prognosis. A literature review on staging of infants with M/MS disease was performed at the occasion of the diagnosis of NB in an 8-month-old boy who presented with atypical metastatic sites in soft tissue and an aberrant tumor biology. The definitions of stage 4/4S/4s/M/MS/Ms were evaluated and compared to enable tumor risk stratification and inform management. International NB groups use different criteria for defining stage of infants with metastasized NB, resulting in differences in management. Limited literature is available on soft tissue metastases, especially muscular metastases, and is poorly incorporated into management guidelines mainly due to the lack of data. The uncertain prognosis of rare genetic aberrancies may add to the difficulties in treatment decisions. In some rare cases of NB in infants, the international treatment classification is not sufficient for staging and treatment decisions. Based on tumor progression, biology of unknown significance and a lack of evidence to classify a child under 12 months with NB and multiple muscular metastases, the patient was treated as stage 4/M and intermediate-risk protocols with a favorable outcome.

Effectiveness of nitrous oxide sedation for otolaryngologic examination in the outpatient clinic in uncooperative children.

OBJECTIVES: The aim of this study is to investigate the efficacy of equimolar mixture of 50% nitrous oxide and oxygen (EMONO) to obtain conscious sedation for otolaryngologic examinations and minor Ear-Nose-Throat (ENT) procedures in children with or without comorbidities. METHODS: Retrospective analysis of patient records from all children who were uncooperative during routine ENT examination, and therefore underwent otomicroscopic examinations and/or minor ENT procedures sedated with EMONO in the outpatient ENT clinic. The following data were collected: patients characteristics, sedative effect, analgesic effect and adverse effects. Patients were divided into three subgroups: 1) no relevant comorbidities, 2) Down Syndrome and 3) other causes of behavioural problems or developmental delay. RESULTS: Data were analyzed for 99 patients (170 procedures). Seven procedures failed. A good to excellent sedative and analgesic effect was obtained in most patients without a difference between subgroups. Minor and transient side effects were encountered in one third (34%) of the patients. CONCLUSIONS: EMONO is an effective agent to achieve conscious sedation and to perform ENT examinations or minor procedures in otherwise uncooperative children with or without developmental delay.

The Challenges of Crizotinib Treatment in a Child With Anaplastic Large Cell Lymphoma.

Survival in cases involving childhood malignancy is reaching nearly 80% in high-income countries, yet cancer remains one of the leading disease-related causes of death in children. In adult oncology the role of targeted therapies is established, but information regarding the use of these therapies in children is limited, largely because targeted therapies were developed in the context of adult pathologies. The few pediatric reports regarding crizotinib, an anaplastic lymphoma kinase (ALK) inhibitor, seem promising. This case of an 8-year-old male with an ALK-positive anaplastic large cell lymphoma highlights the challenges of treating children with crizotinib. Our experience with crizotinib was more challenging than described in the limited pediatric reports. Not only was the tumor response poorer than described in the reports, but a substantial amount of side-effects and practical difficulties, such as the method of administration and dosing, made management challenging. Many challenges for the use of targeted therapy in pediatric care currently persist. The limited research in pediatric populations leaves uncertainty regarding efficacy and short- and long-term side effects as well as practical difficulties. Despite a clear underlying biological rationale for certain targeted therapies, their contribution toward improving the outcome of childhood cancer remains largely unclear.

Retrospective study of diffuse intrinsic pontine glioma in the Belgian population: a 25 year experience.

INTRODUCTION: Diffuse intrinsic pontine glioma is a rare disease with a high mortality. Our primary aim was to determine the incidence of this disease in Belgium. Secondly, we wanted to compare the treatment approach of Belgian pediatric oncology centres, to investigate possibilities for improvement. METHODS: We retrospectively collected and analysed data on DIPG-patients diagnosed between 1994 and 2018 and recorded in the Belgian Cancer Registry. We included patients ≤ 18 years who were followed in one of the eight Belgian pediatric oncology centres. RESULTS: We included 100 patients. Files were complete in 87 patients. We observed an increase in diagnoses with an incidence of 3.1 per 1,000,000 persons (aged 0-≤ 18) per year over the last 5 years compared to an overall incidence of 1.8. Biopsy was performed at diagnosis in 51.7% of patients. In one fifth this was study-related. Mutation analysis was known in eight patients, of which six showed the H3 K27M-mutation. 58.8% of patients received chemotherapy, without a significant survival benefit. 12.6% of patients were included in a clinical trial. Biopsy rate and the use of chemotherapy differed widely between centres. Mean OS and PFS were 10.49 and 4.87 months respectively. We observed an improved survival over time. CONCLUSIONS: Over the past 25 years, we observed an increase of new DIPG-diagnoses. Outcome in our cohort is comparable with literature findings. We demonstrate an important heterogeneity in treatment approach between different centres and limited inclusion in clinical trials. Therefore, collaboration between centres and inclusion of patients in clinical trials is much needed.

Dendritic Cell-Based and Other Vaccination Strategies for Pediatric Cancer.

Dendritic cell-based and other vaccination strategies that use the patient's own immune system for the treatment of cancer are gaining momentum. Most studies of therapeutic cancer vaccination have been performed in adults. However, since cancer is one of the leading causes of death among children past infancy in the Western world, the hope is that this form of active specific immunotherapy can play an important role in the pediatric population as well. Since children have more vigorous and adaptable immune systems than adults, therapeutic cancer vaccines are expected to have a better chance of creating protective immunity and preventing cancer recurrence in pediatric patients. Moreover, in contrast to conventional cancer treatments such as chemotherapy, therapeutic cancer vaccines are designed to specifically target tumor cells and not healthy cells or tissues. This reduces the likelihood of side effects, which is an important asset in this vulnerable patient population. In this review, we present an overview of the different therapeutic cancer vaccines that have been studied in the pediatric population, with a main focus on dendritic cell-based strategies. In addition, new approaches that are currently being investigated in clinical trials are discussed to provide guidance for further improvement and optimization of pediatric cancer vaccines.

Spontaneous resolution of unifocal Langerhans cell histiocytosis of the skull: potential role of ultrasound in detection and imaging follow-up.

Langerhans cell histiocytosis is a tumor-like condition characterized by idiopathic proliferation of Langerhans cells. The disease may involve the skeleton as well as other organs systems. Bone involvement may be solitary or multifocal. Unifocal osseous Langerhans cell histiocytosis may involve virtually any bone, with the calvarium being most frequently involved. Plain radiography, computed tomography and magnetic resonance imaging are the most used techniques for detection and characterization of the lesion. The use of ultrasound is less known, although it may be a valuable technique in detection and follow-up of superficially located lesions such as calvarial lesions. This case report describes an 8-year-old girl, in whom the lesion was initially detected by ultrasound. Furthermore, ultrasound was used to evaluate spontaneous resolution of the lesion. The knowledge of ultrasound characteristics may be important to avoid unnecessary radiation and gadolinium administration, particularly in a pediatric population.

Personal Distress and Sympathy Differentially Influence Health Care Professional and Parents' Estimation of Child Procedure-Related Pain.

Objective: Caregivers' pain estimations may have important implications for pediatric pain management decisions. Affective responses elicited by facing the child in pain are considered key in understanding caregivers' estimations of pediatric pain experiences. Theory suggests differential influences of sympathy versus personal distress on pain estimations; yet empirical evidence on the impact of caregivers' feelings of sympathy versus distress upon estimations of pediatric pain experiences is lacking. The current study explored the role of caregiver distress versus sympathy in understanding caregivers' pain estimates of the child's pain experience. Design, Setting, Subjects and Methods: Using a prospective design in 31 children undergoing consecutive lumbar punctures and/or bone marrow aspirations at Ghent University Hospital, caregivers' (i.e., parents, physicians, nurses, and child life specialists) distress and sympathy were assessed before each procedure; estimates of child pain were obtained immediately following each procedure. Results: Results indicated that the child's level of pain behavior in anticipation of the procedure had a strong influence on all caregivers' pain estimations. Beyond the impact of child pain behavior, personal distress explained parental and physician's estimates of child pain, but not pain estimates of nurses and child life specialists. Specifically, higher level of parental and physician's distress was related to higher child pain estimates. Caregiver sympathy was not associated with pain estimations. Conclusions: The current findings highlight the important role of caregivers' felt personal distress when faced with child pain, rather than sympathy, in influencing their pain estimates. Potential implications for pain management are discussed.

The relationship between parental catastrophizing about child pain and distress in response to medical procedures in the context of childhood cancer treatment: a longitudinal analysis.

OBJECTIVE: Children with leukemia frequently undergo invasive medical procedures, such as lumbar punctures (LPs) and bone marrow aspirations (BMAs). To date, cross-sectional evidence indicates that LP/BMA procedures continue to elicit distress over the course of treatment in children and parents. METHOD: The current study used prospective analyses investigating in 28 children diagnosed with leukemia, the course of parental and child distress when confronted with consecutive LP/BMA procedures and potential moderation by catastrophic thinking. Parents' level of catastrophic thoughts was assessed before the first treatment-related LP/BMA, while child and parent distress was reported on after each LP/BMA procedure. RESULTS: Whereas parental distress decreased over time among low catastrophizing parents, LP/BMA procedures remained highly distressing for high catastrophizing parents. Child distress during LP/BMA procedures increased over time and was positively related with parental distress. CONCLUSION: These findings stress the importance of targeting child and parent distress as early as possible in treatment.

Parental distress and catastrophic thoughts about child pain: implications for parental protective behavior in the context of child leukemia-related medical procedures.

OBJECTIVES: Treatment for childhood leukemia requires frequent lumbar punctures (LP) and bone marrow aspirations (BMA), often described by children and parents as more distressing than the disease itself. Findings in schoolchildren and chronic pain samples indicate that increased parental distress may increase parental protective, pain-attending behavior, which is associated with more child pain and distress. However, in the context of invasive medical procedures, it is unknown which parents are likely to become most distressed and engage in pain-attending behavior, and how this impacts the children's experiences. The present study investigated the impact of parental catastrophic thoughts upon parental distress and pain-attending behavior (verbal and nonverbal). Furthermore, the association between parental responses and the children's pain behavior, pain, and distress was examined. MATERIALS AND METHODS: A total of 46 parents of children with leukemia (range, 0.6 to 15 y) who underwent a LP/BMA procedure participated in this study. Parental catastrophizing was assessed before and parental and child distress was assessed after the LP/BMA procedure. Parental pain-attending behavior and the child's pain behavior were observed before and after the LP/BMA procedure. RESULTS: Findings indicated that heightened parental catastrophic thinking contributed to increased parental distress during LP/BMA and less pain-attending behavior before the LP/BMA procedure, especially in young children. In contrast, heightened distress in parents with high levels of catastrophizing contributed to increased engagement in postprocedural pain-attending behavior. For young children, increased preprocedural pain-attending behavior was related to more child distress, pain, and pain behavior. DISCUSSION: The findings demonstrate the importance of parental catastrophic thinking in understanding their caregiving responses and preparing parents and children for painful invasive medical procedures.

Emesis control by aprepitant in children and adolescents with chemotherapy.

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) is a feared adverse reaction during cancer treatment. Aprepitant has shown to be effective for CINV in adults, but little is known on its effect in pediatrics. So far, the drug is not licensed in this population. OBJECTIVE: To investigate efficacy of aprepitant in children and young adolescents with high or moderate emetogenic courses, with uncontrollable emesis in previous cycles. METHOD: Retrospective, observational study in children and adolescents treated with aprepitant at Ghent University Hospital, Belgium. Antiemetic regimens and emesis control were analyzed. RESULTS: Twenty patient charts representing 104 chemotherapy cycles were reviewed. Complete vomiting control was observed in 10 patients (50 %), representing 89/104 (85.6 %) episodes. Incomplete vomiting control was observed in 10 patients (50 %), representing only 15 episodes (14.4 %). Of these episodes with incomplete vomiting control, 6 were in acute phase (40 %), 7 in delayed phase (46.7 %) and 2 in both acute and delayed phase (13.3 %). CONCLUSION: Aprepitant might be effective in preventing or reducing vomiting in children. When combined with standard antiemetics, aprepitant was well tolerated. In attendance of results of on-going international clinical trials, our results encourage us to continue the use of aprepitant after failure of emesis control in previous cycles.

Phase II study of irinotecan in combination with temozolomide (TEMIRI) in children with recurrent or refractory medulloblastoma: a joint ITCC and SIOPE brain tumor study.

BACKGROUND: This multicenter phase II study investigated temozolomide + irinotecan (TEMIRI) treatment in children with relapsed or refractory medulloblastoma. METHODS: Patients received temozolomide 100-125 mg/m(2)/day (days 1-5) and irinotecan 10 mg/m(2)/day (days 1-5 and 8-12) every 3 weeks. The primary endpoint was tumor response within the first 4 cycles confirmed ≥4 weeks and assessed by an external response review committee (ERRC). In a 2-stage Optimum Simon design, ≥6 responses in the first 15 evaluable patients were required within the first 4 cycles for continued enrollment; a total of 19 responses from the first 46 evaluable patients was considered successful. RESULTS: Sixty-six patients were treated. Seven responses were recorded during stage 1 and 15 in the first 46 ERRC evaluated patients (2 complete responses and 13 partial responses). The objective response rate during the first 4 cycles was 32.6% (95% confidence interval [CI], 19.5%-48.0%). Median duration of response was 27.0 weeks (7.7-44.1 wk). In 63 patients evaluated by local investigators, the objective response rate was 33.3% (95% CI, 22.0%-46.3%), and 68.3% (95% CI, 55.3%-79.4%) experienced clinical benefit. Median survival was 16.7 months (95% CI, 13.3-19.8). The most common grade 3 treatment-related nonhematologic adverse event was diarrhea (7.6%). Grade 3/4 treatment-related hematologic adverse events included neutropenia (16.7%), thrombocytopenia (12.1%), anemia (9.1%), and lymphopenia (9%). CONCLUSIONS: The planned study primary endpoint was not met. However, its tolerability makes TEMIRI a suitable candidate chemotherapy backbone for molecularly targeted agents in future trials in this setting.

What's in a drop? Optimizing strategies for administration of drugs in pediatrics.

Accurate administration of drugs is an essential part of pharmacotherapy in children. Small differences in the amount of drugs administered, might evoke different clinical effects. This is especially of concern in drugs with a narrow therapeutic index. Guided by a case that was observed in pediatrics, some practical recommendations for the administration of oral drops in children are described.

Time-dependent changes in 18F-FDG activity in the thymus and bone marrow following combination chemotherapy in paediatric patients with lymphoma.

PURPOSE: To investigate the time-dependent changes in (18)F-FDG uptake by the thymus and marrow following combination chemotherapy for lymphoma in a paediatric study population. METHODS: Included in the study were 27 paediatric patients who were in complete metabolic remission after chemotherapy and who underwent off-therapy follow-up with serial whole-body PET-CT scans. A total of 142 PET-CT scans were recorded. (18)F-FDG uptake by the thymus and marrow was assessed both visually and semiquantitatively. Visual uptake was scored on the three-dimensional maximum intensity projection of the whole-body PET image according to a three-point scale. For the semiquantitative assessment, standard uptake values were measured. To find a pattern in the (18)F-FDG uptake by the thymus and marrow a moving average technique was applied. RESULTS: Our time series analysis indicated that the marrow activity was highest at cessation of chemotherapy and declined thereafter. During an off-chemotherapy period of on average 6 months, marrow activity decreased quickly. From 6 months onward, the activity declined more slowly. The posttherapy changes in (18)F-FDG uptake by the thymus were quite different from the changes in uptake by the marrow. The lowest thymic FDG uptake was found at cessation of chemotherapy. Thereafter, thymic activity steadily increased, reached a peak on average 10 months after therapy, and then slowly decreased. CONCLUSION: Knowledge of the time-dependent changes in metabolic activity in the thymus and marrow is important to avoid misinterpretation of increased (18)F-FDG uptake as disease in the off-therapy setting.

Hemifacial paralysis in a child treated for leukemia: unusual side effect of omeprazole?

We report a hemifacial paralysis as an adverse drug reaction possibly related to the use of omeprazole in a patient with acute lymphoblastic leukemia. We believe that this case, although very rare, is clinically significant and worth mentioning, owing to the frequent use of omeprazole in the oncology setting.

Attitudes of adolescent cancer survivors toward end-of-life decisions for minors.

OBJECTIVES: The present study aimed to investigate the attitudes of adolescent cancer survivors toward end-of-life decisions with life-shortening effects, including nontreatment decisions (NTDs), intensified alleviation of pain and symptoms (APS), and euthanasia, and the influence of illness experience on these attitudes. METHODS: Adolescent cancer survivors were interviewed with a structured questionnaire using hypothetical case descriptions. The results were compared with a study of 1769 adolescents without experience of chronic illness. RESULTS: Eighty-three adolescents, 11 to 18 years of age, were interviewed. In terminal situations, 70% to 90% found requests for NTDs acceptable, 84% requests for APS, and 57% to 64% requests for euthanasia. Requests for end-of-life decisions were less acceptable in nonterminal situations, where 28% found requests for NTDs acceptable, 39% to 47% requests for APS, and 11% to 21% requests for euthanasia. Frequently cited reasons for holding back physicians from administering a lethal drug to a child were the child not being well informed about his or her condition (92%) and the parents' opinion not being asked (92%). Compared with adolescents without experience with chronic illness, cancer survivors were more accepting toward requests for NTDs and APS in terminal situations. CONCLUSIONS: Adolescent cancer survivors, like other adolescents, want to be involved in medical decision-making at the end of life. They value autonomous decision-making, without excluding parents from the process. The experience of living through a life-threatening illness can alter adolescents' attitudes toward requests for NTDs and APS.

Prevention of wrong route errors in a pediatric hemato-oncology ward.

Three consecutive wrong route administration errors are described in detail and the ease by which enteral preparations can be given by the wrong route is discussed. By introducing the use of purple oral liquid dispensers in our pediatric department, we hope to prevent and reduce the risk of similar medications errors in the future and to improve patients safety.

Interaction between methotrexate and omeprazole in an adolescent with leukemia: a case report.

We present a case of severe mucositis due to a drug-drug interaction between methotrexate (MTX) and omeprazole in an adolescent with Acute Lymphatic Leukemia (ALL). In view of the prevalence of MTX in many cytotoxic protocols, and the frequent use of omeprazole in the (ambulatory) oncology setting, we believe that this case-report is worth mentioning.