Incidence, survival, and mortality of cancer in children and young adolescents in Belgium and the Netherlands in 2004-2015: A comparative population-based study.

International comparisons of cancer surveillance measures may provide insight into inequalities in registration practices, etiological factors, and treatment strategies. This study aimed to compare incidence, survival, and mortality of cancer in children and young adolescents between Belgium and the Netherlands. All children (0-14 years) and young adolescents (15-17 years) diagnosed with cancer between 2004 and 2015 were selected from the population-based cancer registries of Belgium (N = 4739) and the Netherlands (N = 7322). Differences in incidence and mortality were expressed as standardized rate ratios (SRR; BE/NL). Five-year observed survival was calculated using the Kaplan-Meier method. During 2004-2015, the overall cancer incidence among children and young adolescents was similar in both countries. Incidence of neuroblastoma was significantly higher in Belgian children (2010-2015: SRR = 1.3, 95% CI 1.0-1.6). Five-year survival of all malignant cancers was comparable in 2010-2015, exceeding 80% in both age groups. Remarkable differences in survival existed in children for malignant central nervous system (CNS) tumors in 2004-2009 (BE = 62%, NL = 45%), for acute myeloid leukemia (BE = 68%, NL = 78%) and rhabdomyosarcomas (BE = 60%, NL = 79%) in 2010-2015, and for neuroblastoma in both periods (2004-2009: BE = 76%, NL = 64%; 2010-2015: BE = 82%, NL = 64%). Overall cancer mortality in children decreased by approximately 3 percent-points annually in both countries, but was slightly lower in Belgium in 2004-2009 (SRR = 0.9, 95% CI 0.7-1.0). Despite differences for specific cancer types, overall cancer incidence, survival, and mortality were comparable between Dutch and Belgian children and young adolescents in 2010-2015. Variability in screening, diagnosis, and registration practices probably explains the observed differences in incidence and survival of neuroblastoma and malignant CNS tumors.

Protocol for investigating data quality and reporting outcomes of pediatric gliomas in population-based cancer registry research.

Cancer registry data on pediatric gliomas come with inherent limitations as inclusion criteria and registration practices of these tumors differ between registries due to specific guidelines that are lacking. These limitations can lead to biased estimates in incidence and survival outcomes. Here, we present a protocol to investigate data quality and comparability for retrospective population-based pediatric glioma studies. We describe steps for obtaining institutional permissions, dealing with data quality issues, regrouping tumors, and reporting tumors in a clinically relevant manner. For complete details on the use and execution of this protocol, please refer to Hoogendijk et al.1.

Sex-related incidence and survival differences in pediatric high-grade glioma subtypes: A population-based cohort study.

Not much is known on sex differences in incidence, survival, and treatment characteristics for midline and hemispheric pHGGs. This population-based study confirms previously reported study results that found worse survival outcomes for malignant diffuse gliomas in girls in the age group 0-9 years. Additionally, in our study we pinpoint this difference to girls with midline pHGGs aged 0-4 years. We provide insight in the possible underlying mechanisms contributing to sex survival differences in pHGG patients. With first line treatment having no impact on the higher risk of dying for girls, but age and tumor characteristics having a neutralizing effect. The results of this population-based study serve as a basis for future pre-clinical and clinical studies to further unravel the underlying mechanisms responsible for the survival gap between sexes in midline pHGG.

TIM-3 blockade in diffuse intrinsic pontine glioma models promotes tumor regression and antitumor immune memory.

Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain stem tumor and the leading cause of pediatric cancer-related death. To date, these tumors remain incurable, underscoring the need for efficacious therapies. In this study, we demonstrate that the immune checkpoint TIM-3 (HAVCR2) is highly expressed in both tumor cells and microenvironmental cells, mainly microglia and macrophages, in DIPG. We show that inhibition of TIM-3 in syngeneic models of DIPG prolongs survival and produces long-term survivors free of disease that harbor immune memory. This antitumor effect is driven by the direct effect of TIM-3 inhibition in tumor cells, the coordinated action of several immune cell populations, and the secretion of chemokines/cytokines that create a proinflammatory tumor microenvironment favoring a potent antitumor immune response. This work uncovers TIM-3 as a bona fide target in DIPG and supports its clinical translation.

Azacitidine (Vidaza®) in Pediatric Patients with Relapsed Advanced MDS and JMML: Results of a Phase I/II Study by the ITCC Consortium and the EWOG-MDS Group (Study ITCC-015).

BACKGROUND: Advanced myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML) are rare hematological malignancies in children. A second allograft is recommended if a relapse occurs after hematopoietic stem cell transplantation, but the outcome is poor. OBJECTIVE: We conducted a phase I/II multicenter study to evaluate the safety, pharmacokinetics, and activity of azacitidine in children with relapsed MDS/JMML prior to the second hematopoietic stem cell transplantation. METHODS: Patients enrolled from June 2013 to March 2019 received azacitidine intravenously/subcutaneously once daily on days 1-7 of a 28-day cycle. The MDS and JMML cohorts followed a two-stage design separately, with a safety run-in for JMML. Response and safety data were used to evaluate efficacy and establish the recommended dose. Pharmacokinetics was also analyzed. The study closed prematurely because of low recruitment. RESULTS: Six patients with MDS and four patients with JMML received a median of three and five cycles, respectively. Azacitidine 75 mg/m2 was well tolerated and plasma concentration-time profiles were similar to observed in adults. The most prevalent grade 3-4 adverse event was myelotoxicity. No responses were seen in patients with MDS, but 83% achieved stable disease; four patients underwent an allotransplant. Overall response rate in the JMML cohort was 75% (two complete responses; one partial response) and all responders underwent hematopoietic stem cell transplantation. One-year overall survival was 67% (95% confidence interval 38-100) in MDS and 50% (95% confidence interval 19-100) in JMML. CONCLUSIONS: Azacitidine 75 mg/m2 prior to a second hematopoietic stem cell transplantation is safe in children with relapsed MDS/JMML. Although the long-term advantage remains to be assessed, this study suggests that azacitidine is an efficacious option for relapsed JMML. CLINICAL TRIAL REGISTRATION: EudraCT 2010-022235-10.

Survival rates of children and young adolescents with CNS tumors improved in the Netherlands since 1990: A population-based study.

Introduction: Survival of children with central nervous system (CNS) tumors varies largely between countries. For the Netherlands, detailed population-based estimation of incidence, survival, and mortality of pediatric CNS tumors are lacking but are needed to evaluate progress. Methods: All CNS tumors diagnosed in patients <18 years during 1990-2017 were selected from the Netherlands Cancer Registry. Other than pilocytic astrocytomas, nonmalignant tumors were included since 2000. Incidence and mortality trends were evaluated by average annual percentage change (AAPC). Changes over time in the five-year observed survival (5-year OS) were evaluated by Poisson regression models adjusted for follow-up time. Results: Between 1990 and 2017, 2057 children were diagnosed with a malignant CNS tumor and 885 with a pilocytic astrocytoma. During 2000-2017, 695 children were diagnosed with other nonmalignant CNS tumors. Incidence rates of malignant tumors remained stable, while pilocytic astrocytomas and other nonmalignant tumors increased by 2.0% and 2.4% per year, respectively. The 5-year OS rates improved for all groups; however, improvement for malignant tumors was not constant over time. The contribution of malignant tumors located at the optic nerve tumors was 1% in 2000-2009. However, shifting from pilocytic astrocytomas, increased to 6% in 2010-2017, impacting survival outcomes for malignant tumors. Conclusion: Survival rates of CNS tumors improved over time but were not accompanied by a decreasing mortality rate. The observed temporary survival deterioration for malignant tumors appears to be related to changes in diagnostics and registration practices. Whether differences in treatment regimens contribute to this temporary decline in survival needs to be verified.

Inotuzumab ozogamicin in infants and young children with relapsed or refractory acute lymphoblastic leukaemia: a case series.

No data on inotuzumab ozogamicin (InO) in infant acute lymphoblastic leukaemia (ALL) have been published to date. We collected data internationally on infants/young children (<3 years) with ALL treated with InO. Fifteen patients (median 4.4 months at diagnosis) received InO due to relapsed or refractory (R/R) disease. Median percentage of CD22+ blasts was 72% (range 40-100%, n = 9). The median dose in the first course was 1.74 mg/m2 (fractionated). Seven patients (47%) achieved complete remission; one additional minimal residual disease (MRD)-positive patient became MRD-negative. Six-month overall survival was 47% (95% confidence interval [CI] 27-80%). Two patients developed veno-occlusive disease after transplant. Further evaluation of InO in this subgroup of ALL is justified.

Plasma thymus and activation-regulated chemokine (TARC) as diagnostic marker in pediatric Hodgkin lymphoma.

Pediatric classical Hodgkin's lymphoma (cHL) is characterized by Hodgkin Reed-Sternberg cells located in an inflammatory microenvironment. Blood biomarkers result from active crosstalk between these cells. One promising biomarker in adult cHL patients is "thymus-and-activation-regulated chemokine" (TARC). The objectives of this study were to define normal TARC values in non-cHL children and to investigate and correlate pretherapy TARC as diagnostic marker in pediatric cHL. In this multicenter prospective study, plasma and serum samples were collected of newly diagnosed cHL patients before start of treatment (n = 49), and from randomly selected non-cHL patients (n = 81). TARC levels were measured by enzyme-linked immunosorbent assay. The non-cHL patients had a median plasma TARC value of 71 pg/mL (range: 18-762), compared to 14 619 pg/mL (range: 380-73 174) in cHL patients (P < .001). TARC values had a high discriminatory power (AUC = .999; 95% confidence interval, .998-1). A TARC cutoff level of 942 pg/mL maximized the sum of sensitivity (97.9%) and specificity (100%). TARC plasma levels were associated with age, treatment level, bulky disease, B-symptoms, and erythrocyte sedimentation rate. TARC was found to be a highly specific and sensitive diagnostic marker for pediatric cHL. This noninvasive marker could be of great value as screening test in the work-up for pediatric patients with lymphadenopathy.