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Cisplatin and amphotericin B are both known to be potentially nephrotoxic. We describe acute kidney injury due to the combination of Liposomal amphotericin B and cisplatin in an adolescent with osteosarcoma. Acute kidney injury (peak creatinine 431 µmol/L) consistent with drug-induced acute tubulointerstitial nephritis was observed a few days after concomitant administration of cisplatin and amphotericin B. Kidney function nearly normalised during follow-up. The timing of the concomitant administration of amphotericin B and cisplatin led us to presume that the combination was the cause of renal failure, and we conclude that concurrent administration of cisplatin and amphotericin B should be avoided. [ABSTRACT FROM AUTHOR]

Background: Hyperthyroidism is a rare disorder which may negatively affect health and quality of life. Its occurrence in childhood cancer survivors has not previously been investigated in detail. Material and methods: In the hospital registers of the five Nordic countries, 32,944 childhood cancer survivors and 212,675 population comparisons were followed for the diagnosis of hyperthyroidism. Hospitalisation rates, standardised hospitalisation rate ratios and absolute excess risks were calculated with 95% confidence intervals (CI). Results: Hyperthyroidism was diagnosed in 131 childhood cancer survivors, yielding an overall relative risk of 1.6 (95% CI: 1.3-1.9) compared with population comparisons. The risk was greatest 1-5 years after the diagnosis of cancer and in survivors of thyroid cancers, neuroblastomas, acute lymphoblastic leukaemia and Hodgkin lymphoma. Sixty-seven percent of survivors with hyperthyroidism had tumours located in the head, neck or upper body and half of survivors with hyperthyroidism were irradiated with 77% of them in the head and neck area. Conclusion: Childhood cancer survivors are at an increased risk of hyperthyroidism, potentially resulting in non-endocrine morbidity. [ABSTRACT FROM AUTHOR]

Primary bone tumors in children and adolescents, while rare, pose significant challenges in diagnosis and management. Children treated for Ewing sarcoma and osteosarcoma are offered a 5-year follow-up program after end of treatment, including radiological surveillance of primary location of tumor and the lungs. There is no consensus regarding how often and how the children should be followed with radiological imaging. This retrospective descriptive study of 69 patients (34 with Ewing sarcoma and 35 with osteosarcoma) investigated the consequences of abnormal findings in 1279 follow-up images. Nine relapses were detected, 4 in the Ewing group (3 local and 1 pulmonary) and 5 in the osteosarcoma group (1 local and 4 pulmonary). Of these, only two patients exhibited symptomatic relapses, with the remainder identified through imaging. The positive predictive value for relapse detection was 0.44 in the Ewing group, and 0.5 in the osteosarcoma group. In the Ewing sarcoma patient image follow-up program, the probability of anomaly detection was 12% (95% CI, 10–15). For osteosarcoma patients, the likelihood was 6% (95% CI, 4–8). Our data indicates that abnormal findings on follow-up images rarely represents relapse of tumor. As the surveillance protocol differs between the patient groups, wherein Ewing sarcoma patients primarily are monitored through MRI while osteosarcoma patients are predominantly tracked via X-rays, there is an increased occurrence of incidental findings in the first group. However, it is imperative to interpret imaging data in conjunction with clinical information, avoiding isolated reliance on imaging results when making treatment decisions. [ABSTRACT FROM AUTHOR]

Summary: Prevention of infections is of obvious relevance in paediatric patients with acute myeloid leukaemia (AML). However, recommendations are often non‐specific and supported by low‐quality evidence, resulting in divergent infection preventive regimens. Using a web‐based survey, we investigated the infection prophylaxis guidelines of 22 paediatric AML study groups affiliated to the international Berlin–Frankfürt–Münster study group. In order to evaluate differences in daily practice among hospitals, representatives (n = 27) from the Nordic Society for Paediatric Haematology and Oncology‐Dutch‐Belgium‐Hong Kong ‐ AML study group participated in a slightly modified survey. Seven study groups (32%) advise gram‐negative antibiotic prophylaxis, mainly with fluoroquinolones (n = 6). Gram‐positive prophylaxis is prescribed by eight groups (36%). Over 60% of the study groups prescribe food and social restrictions, but the specific topics and strictness differ widely. According to the hospital‐based survey, sites roughly comply with common study group guidelines. However, the use of any gram‐negative antibiotic prophylaxis, the specific prophylactic antifungal agent and the strictness of the food and social restrictions differ substantially between the hospitals. Despite a long history of close collaboration, many differences are still present between the affiliated groups. The results of this survey provide an appropriate baseline measure to study the emergence and impact of future guidelines on infection prophylaxis in paediatric AML. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukemia (ALL) is the most common childhood neoplasia and may present with arthralgia and arthritis, with the risk of misdiagnosis and diagnostic delay. We describe in detail arthropathy (arthritis/arthralgia) among children with leukemia as the children’s laboratory results, misdiagnosis, and treatment before the diagnosis of ALL and the diagnostic delay. In this retrospective cohort study, we reviewed records of 286 children aged 1-15 years diagnosed with ALL from January 1992 to March 2013. We identified 26 children with arthralgia and 27 children with arthritis. The majority of the children had one or two joints involved (arthralgia 72%, arthritis 42%), and most often hips and knees. Morning stiffness was not reported. Imaging of affected joints was included in the initial workup of 77% of children with ALL and arthropathy, and 66% was abnormal. Misdiagnosis as JIA occurred in 26% and 71% of these children received treatment with intraarticular corticosteroids. The diagnostic delay was 3 weeks longer for the children with arthritis than those with arthralgia (median 54 vs 36 days), primarily as a consequence of a longer first doctor’s delay. Compared to the children with arthralgia, the children with arthritis were more often misdiagnosed and treated with intraarticular steroid before the diagnosis of ALL. They also had longer diagnostic delay, primarily as a consequence of a longer first doctor’s delay. [ABSTRACT FROM AUTHOR]

Over the last four decades the survival of paediatric patients with acute myeloid leukaemia has gradually increased to 70% in high-income countries. The therapy is very intensive and associated with many acute and long-term side effects. The early death rate has been reduced to 1-4%. The acute toxicity is a limiting factor for improving survival in low-income countries. Transplant is associated with more endocrinological late effects while cardiotoxicity is more common after relapse. Reducing the physical costs of therapy without jeopardizing survival may be accomplished by optimal supportive care, less cardiotoxic anthracyclines, less consolidation courses and strict indications for stem cell transplantation. Analysing scenarios with different frequency of transplantation in first complete remission show similar overall survival rates, indicating that almost all patients can be spared the procedure in first remission. Reducing relapse risk is an effective way of reducing toxicity and more targeted therapy and improved risk group stratifications are needed. [ABSTRACT FROM AUTHOR]

The last decades have seen parallel improvements in chemotherapy-based and haematopoietic stem cell transplantation ( HSCT) regimens for acute myeloid leukaemia ( AML) in children. There has been no consensus on indication for HSCT. Reserving HSCT for high-risk and relapsed patients spare many patients from the long-term toxicity of this treatment. The results of matched unrelated donor HSCT equal family donor transplantation and the presence of a matched sibling should no longer be a transplant indication. Minimal residual disease measured by flow cytometry may identify poor responders benefitting from HSCT in first complete remission ( CR1) and those with a favourable response to induction therapy who do not need HSCT even with adverse cytogenetic aberrations. FLT3-internal tandem duplication without NPM1 mutation has a very high relapse rate despite favourable response and HSCT is indicated in CR1 in these cases. Finding the optimal indications for HSCT is a delicate balance between risk of relapse and late effects. [ABSTRACT FROM AUTHOR]

There are no data on the role of postconsolidation therapy with gemtuzumab ozogamicin (GO; Mylotarg) in children with acute myeloid leukemia (AML). The NOPHO-AML 2004 protocol studied post-consolidation randomization to GO or no further therapy. GO was administered at 5 mg/m2 and repeated after 3 weeks. We randomized 120 patients; 59 to receive GO. Survival was analyzed on an intention-to-treat basis. The median follow-up for patients who were alive was 4.2 years. Children who received GO showed modest elevation of transaminase and bilirubin without signs of veno-occlusive disease. Severe neutropenia followed 95% and febrile neutropenia 40% of the GO courses. Only a moderate decline in platelet count and a minor decrease in hemoglobin occurred. Relapse occurred in 24 and 25 of those randomized to GO or no further therapy. The median time to relapse was 16 months versus 10 months (nonsignificant). The 5-year event-free survival and overall survival was 55% versus 51% and 74% versus 80% in those randomized to receive GO or no further therapy, respectively. Results were similar in all subgroups. In conclusion, GO therapy postconsolidation as given in this trial was well tolerated, showed a nonsignificant delay in time to relapse, but did not change the rate of relapse or survival (clinicaltrials.gov identifier NCT00476541). (Blood. 2012;120(5): 978-984) [ABSTRACT FROM AUTHOR]

Advanced myelodysplastic syndrome (MDS) in children includes refractory anaemia with excess blasts (RAEB) and RAEB in transformation (RAEB-T) according to the paediatric modification of the World Health Organization classification. Clinical features and cytogenetics are essential to make a diagnosis because blast count alone is insufficient to differentiate MDS from acute myeloid leukaemia (AML). Little is known about molecular genetics in paediatric MDS but hypermethylation seem to be frequent. Monosomy 7 is the most common cytogenetic aberration but prognostic neutral whereas those with structural complex karyotype have a very poor outcome. Haematopoietic stem cell transplantation (HSCT) is the treatment of choice and results in cure rates of around 60%. Intensive chemotherapy prior to HSCT provides no survival benefit for children with RAEB and RAEB-T and can generally not be recommended. Intensive chemotherapy before HSCT should be considered in patients with myelodysplasia-related-AML (MDR-AML). [ABSTRACT FROM AUTHOR]

The overall risk of cancer in children with Noonan (NS), cardio-facial-cutaneous, Costello or LEOPARD syndrome is high, although no precise estimates are available. There are few data on cancer in adults with NS, but the reported numbers of malignancies in adults do not seem excessive. Juvenile myelomonocytic leukemia (JMML) is a rare aggressive leukemia in young children. A JMML-like myeloproliferative disorder has been described in about 30 neonates with NS and the PTPN11 mutation. The disorder often regresses spontaneously, but fatal complications may occur. A review of the literature indicates an increased risk of acute lymphoblastic leukemia and acute myeloid leukemia in NS. Young children with Costello syndrome have an extremely high risk of rhabdomyosarcoma, and also an increased risk of neuroblastoma and bladder carcinoma. Registry-based studies of patients with NS and related disorders diagnosed with molecular genetics and a high-quality long-term follow-up are necessary to further estimate the incidence of malignancy. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Transient myeloproliferative disorder (TMD) is found in 10% of newborns with Down syndrome (DS). Myeloid leukemia develops in 25% within the following 3 years. Little is known about markers predicting leukemia occurrence. We studied expression levels of the Wilms tumor gene (WT1) by real-time quantitative PCR (RQ-PCR) in peripheral blood of five infants with TMD. WT1 levels were elevated similar to findings in AML. Longitudinal studies showed normalization of the WT1 level in all patients except one who developed GATA1 mutated myeloid leukemia at 11 months of age. The lack of normalization of WT1 level may be a predictor of leukemia development and WT1 expression may be an attractive marker for monitoring of minimal residual disease. [Copyright &y& Elsevier]

Cancer risk in children born before term has been assessed in a large number of case–control studies but very rarely in cohort studies. We carried out a cohort study of 35 178 children with the diagnosis immaturity at birth in the Hospital Discharge Register during 1977–89. The children were followed for cancer in the Danish Cancer Registry until 1994 and comparisons were made with incidence rates for all children in Denmark. The 64 observed cases of childhood cancer in the cohort corresponded closely to the expected number {standardised incidence ratio (SIR) = 1.03; [95% confidence interval (CI) 0.80, 1.32]}. The only cancer site with an observed number that deviated significantly from the expected number was central nervous system (CNS) tumours (26 cases observed; SIR = 1.57; [95% CI 1.02, 2.30]) in particular medulloblastoma (9 cases observed; SIR = 3.1; [95% CI 1.4, 5.9]). In a nested case–control study of the CNS tumours, we found that more cases than controls had been exposed to diagnostic X-rays, but the result was not significant. Surprisingly, for those born before term, the risk of CNS tumours increased with increasing gestational age in the nested case–control data. Our results are in line with previous evidence that children born before term are not at increased risk for childhood cancer in general. An explanation behind the excess of CNS tumours could not be identified, but the effect of diagnostic X-rays in newborns may deserve further attention. [ABSTRACT FROM AUTHOR]

Loss of chromosome 7 material, either as complete loss of one chromosome-monosomy 7 (-7)- or as deletion of the long arm (7q-), is the most common cytogenetic abnormality in childhood myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML), seen in approximately 30% of the cases. Only 4-5% of childhood acute myeloid leukemia (AML) cases show -7/7q-. Monosomy 7 in children has often been considered to represent a distinct hematologic disorder described as the monosomy 7 syndrome. Loss of chromosome 7 occurs in a heterogeneous group of myeloid disorders and recent data give no support to the concept of monosomy 7 as a distinct syndrome. Only patients with a diagnosis of JMML fit what previously has been referred to as the monosomy 7 syndrome. There are no major clinical differences between JMML with and without -7. Unlike what has been found in adults, monosomy 7 is not a poor prognostic factor in childhood MDS. However, -7 in AML is associated with a very poor prognosis. AML with 7q-, in contrast, has an outcome similar to AML with normal karyotype. Stem cell transplantation is the treatment of choice and should be performed as early as possible. [ABSTRACT FROM AUTHOR]

SummaryBackgroundIndividuals with Down's syndrome have a greater risk of leukaemia than the general population, but reliable estimates of the age-specific risk are lacking and little is known about the risk of solid tumours.MethodsWe identified 2814 individuals with Down's syndrome from the Danish Cytogenetic Register, and linked the data to the Danish Cancer Registry. The number of person-years at risk was 48453. Standardised incidence ratio (SIR) and 95% CI were calculated of the basis of cancer rates specific for age and sex in the general population.Findings60 cases of cancer were found, with 49.8 expected (SIR 1.20 [95% CI 0.92-1.55]). Leukaemia constituted 60% of cases of malignant disease overall and 97% of cases in children. The SIR for leukaemia varied with age, being 56 (38-81) at age 0-4 years and 10 (4-20) at 5-29 years. No cases of leukaemia were seen after the age of 29 years. The SIR for acute myeloid leukaemia was 3.8 (1.7-8.4) times higher than that for acute lymphoblastic leukaemia in children aged 0-4 years. The cumulative risk for leukaemia by the age of 5 years was 2.1% and that by 30 years was 2.7%. Only 24 solid tumours were seen, with 47.8 expected (0.50 [0.32-0.75]). No cases of breast cancer were found, with 7.3 expected (p=0.0007). Higher than expected numbers of testicular cancers, ovarian cancers, and retinoblastomas were seen but were not significant.IntrepretationThe occurrence of cancer in Down's syndrome is unique with a high risk of leukaemia in children and a decreased risk of solid tumours in all age-groups. The distinctive pattern of malignant diseases may provide clues in the search for leukaemogenic genes and tumour-suppressor genes on chromosome 21. [ABSTRACT FROM AUTHOR]

ABSTRACT Objectives Methods Results Conclusion Childhood cancer often presents with non‐specific signs and symptoms that might mimic non‐malignant disorders including musculoskeletal diseases, potentially leading to rheumatic and orthopaedic misdiagnoses. We aimed to compare clinical presentation, diagnostic interval and survival in paediatric acute myeloid leukaemia (AML) with and without initial musculoskeletal symptoms.This nationwide retrospective, cohort study reviewed medical records of 144 children below 15 years diagnosed with AML in Denmark from 1996 to 2018.Musculoskeletal symptoms occurred in 29% (42/144) of children with AML and 8% (11/144) received an initial musculoskeletal misdiagnosis, being mainly non‐specific and pain‐related. The children with and without musculoskeletal symptoms did not differ markedly up to the diagnosis of AML and blood counts were affected equally in both groups. However, the children with prior musculoskeletal symptoms were more likely to have elevated levels of LDH and ferritin. Furthermore, they revealed a tendency towards a longer total interval (median 53 days vs. 32 days, p = 0.07), but the overall survival did not differ.AML should be considered as an underlying cause in children with unexplained musculoskeletal symptoms and abnormal blood counts. Concomitant elevation of LDH and ferritin should strengthen the suspicion. [ABSTRACT FROM AUTHOR]

The treatment of childhood cancer is challenged by toxic side effects mainly due to chemotherapy-induced organ damage and infections, which are accompanied by severe systemic inflammation. Insulin-like growth factor I (IGF-I) is a key regulating factor in tissue repair. This study investigated associations between the circulating IGF-I levels and chemotherapy-related toxicity in pediatric acute lymphoblastic leukemia (ALL). In this prospective study, we included 114 patients (age: 1–17 years) with newly diagnosed ALL treated according to The Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol between 2013 and 2018. The patients' plasma levels of IGF-I, and the primary binding protein, IGFBP-3, were measured weekly during the first six weeks of treatment, including the induction therapy. The patients' systemic inflammation was monitored by their C-reactive protein (CRP) and interleukin (IL)-6 levels and their intestinal epithelial damage by their plasma citrulline levels. IGF-I and IGFBP-3 were converted into sex-and age-adjusted standard deviation scores (SDS) using 1621 healthy children as reference. At ALL diagnosis, IGF-I levels were decreased (median (quartiles): −1.2 SDS (−1.9 to −0.5), p = 0.001), but increased significantly following the initiation of chemotherapy, peaking on day 8 (0.0 SDS (from −0.8 to 0.7), p < 0.001). This increase correlated with the levels of CRP (rho = 0.37, p < 0.001) and IL-6 (rho = 0.39, p = 0.03) on day 15, when these markers reached maximum levels. A larger IGF-I increase from day 1 to 15 correlated with a slower recovery rate of the intestinal damage marker citrulline from day 15 to 29 (rho = −0.28, p = 0.01). Likewise, IGFBP-3 was reduced at diagnosis, followed by an increase after treatment initiation, and was highly correlated with same-day IGF-I levels. This study demonstrates a chemotherapy-induced increase in IGF-I, with a response that appears to reflect the severity of tissue damage and systemic inflammation, preceding CRP and IL-6 increases. IGF-I may have potential as an early reactive biomarker for acute toxicity in patients with ALL. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndrome (MDS) is considered to be very rare in children. However, the only two published population-based studies reported widely divergent incidence figures. To further explore the epidemiology of childhood MDS and to evaluate the accuracy of cancer registry and treatment trial data, we conducted a population-based study of children aged 0–14 years in British Columbia (BC), Canada, between 1982 and 1996. MDS was diagnosed in 31 cases corresponding to an annual incidence of 3.2 per million children or 6% of all leukaemias, compared with an incidence of 6.0/million for acute myeloid leukaemia (AML), and of 0.5/million for chronic myeloid leukaemia. There was a non-significant (P = 0.19) trend toward an increase in MDS incidence with time, the increase was partly explained by an increasing number of patients with Down syndrome. Associated abnormalities were found in 48% of the MDS cases with Down syndrome as the most common (seven cases). Only one third of the MDS cases were correctly registered in the Cancer Registry and less than half of the eligible MDS patients were enrolled on a cooperative group study. Data on MDS from treatment-based studies and cancer registries were inaccurate and seemed to significantly underestimate the incidence of MDS in children. [ABSTRACT FROM AUTHOR]

Autoimmune neutropenia (AIN) in early childhood is characterized by chronic neutropenia and positivity for human neutrophil antibodies (HNA), resulting in the excessive destruction of neutrophils. The association between regulatory T cells (Tregs) and AIN has been described, and in this study, we investigated three Treg‐associated genes, IL‐2, IL‐10 and FOXP3. The frequencies of three single nucleotide polymorphisms (SNPs) in IL‐2 −330T>G (rs2069762), +114G>T (rs2069763) and IVS3‐116 A>G (rs2069772), four SNPs in IL‐10 −3575T>A (rs1800890), −1082G>A (rs1800896), −819 C>T (rs1800871) and −592 C>A (rs1800872) and three SNPs in FOXP3 –3499 A>G (rs3761547), −3279 C>A (rs3761548) and −924 A>G (rs2232365) were compared between 166 Danish AIN patients and 358 healthy controls. Disease association was observed for IL‐2 IVS3‐116 GG (p = 0.0081, OR = 0.35 [0.15–0.80]), IL‐10 −3575 TT (p = 0.0078, OR = 1.71 [1.16–2.54]) and IL‐10 −1082 AA (p = 0.014, OR = 1.76 [1.14–2.72]) in all patients and FOXP3 –924 (p = 0.0005, A OR = 0.41 [0.25–0.68] and G OR = 2.42 [1.46–4.01]) in male patients. None of the associations were linked to antibody specificity. Disease‐associated haplotypes were observed in IL‐2 and FOXP3. IL‐2 −330T/+114 T/IVS3‐116A was associated with anti‐FcγRIIIb‐positive patients (p = 0.012, OR = 2.07 [1.18–3.62]). FOXP3 –3499A/–3279C/−924A was associated with anti‐HNA‐1a‐positive male patients (p = 0.016, OR = 0.41 [0.20–0.83]), and ACG was associated with female patients, both in the combined group (p = 0.006, OR = NA) and the anti‐FcγRIIIb‐positive group (p = 0.002, OR = NA). We conclude that our findings reveal a correlation between SNP in Treg‐associated genes and AIN, indicating that AIN could be driven by dysfunction of immune homeostatic‐evolving Tregs. [ABSTRACT FROM AUTHOR]

Background: Hereditary anemias are a group of genetic diseases prevalent worldwide and pose a significant health burden on patients and societies. The clinical phenotype of hereditary anemias varies from compensated hemolysis to life-threatening anemia. They can be roughly categorized into three broad categories: hemoglobinopathies, membranopathies, and enzymopathies. Traditional therapeutic approaches like blood transfusions, iron chelation, and splenectomy are witnessing a paradigm shift with the advent of targeted treatments. However, access to these treatments remains limited due to lacking or imprecise diagnoses. The primary objective of the study is to establish accurate diagnoses for patients with hereditary anemias, enabling optimal management. As a secondary objective, the study aims to enhance our diagnostic capabilities. Results: The DAHEAN study is a nationwide cohort study that collects advanced phenotypic and genotypic data from patients suspected of having hereditary anemias from all pediatric and hematological departments in Denmark. The study deliberates monthly by a multidisciplinary anemia board involving experts from across Denmark. So far, fifty-seven patients have been thoroughly evaluated, and several have been given diagnoses not before seen in Denmark. Conclusions: The DAHEAN study and infrastructure harness recent advancements in diagnostic tools to offer precise diagnoses and improved management strategies for patients with hereditary anemias. [ABSTRACT FROM AUTHOR]

HLA studies in patients with autoimmune neutropenia (AIN) have shown very consistent results for the association with HLA class II alleles at low resolution. This study aimed to examine the association of both HLA class I and class II at high resolution to clarify the contribution of risk alleles to the disease. A total of 107 AIN patients were genotyped for six loci of HLA class I (HLA‐A, ‐B and ‐C) and class II (HLA‐DRB1, ‐DQB1, and ‐DPB1) genes by a high‐resolution (3‐field, 6‐digit) analysis and compared with HLA typing of 1000 healthy controls. Compared with the controls, the allele frequencies were significantly higher in AIN patients for A*02:17:01G, C*01:02:01G, DRB1*10:01:01G, DRB1*14:01:01G, DRB1*16:01:01G, DQB1*05:02:01G, and DQB1*05:03:01G but lower significant for C*03:04:01G, DRB1*04:01:01G, DRB1*13:02:01G, DQB1*03:02:01G, and DQB1*06:04:01G. Frequently associated two‐locus haplotypes were found to be DRB1*10:01:01G‐DQB1*05:01:01G and DRB1*16:01:01G‐DQB1*05:02:01G, while the S2 (Q‐ or D‐KRAA) shared epitope (SE) was associated with lower risk. A unique association with HLA alleles was observed between patients with specific anti‐HNA‐1a antibodies and broad‐reacting anti‐FcγRIIIb. Anti‐HNA‐1a antibody‐positive patients were associated with C*01:02:01G, DRB1*01:01:01G, DRB1*16:01:01G, DQB1*05:01:01G, DQB1*05:02:01G, DQB1*06:04:01G, and DPB1*10:01:01G; the two‐locus haplotypes DRB1*01:01:01G‐DQB1*05:01:01G and DRB1*16:01:01G‐DQB1*05:02:01G; and the S3P (Q‐ or R‐RRAA) SE. Anti‐FcγRIIIb antibody‐positive patients were associated with the alleles A*02:17:01G, DRB1*10:01:01G, and DQB1*05:02:01G; the haplotypes DRB1*10:01:01G‐DQB1*05:01:01G and DRB1*11:01:02G‐DQB1*05:02:01G; and the S3D (DRRAA) SE. The different associations regarding FcγRIIIb antibody specificities could indicate disease heterogeneity. [ABSTRACT FROM AUTHOR]

Background: Survivors of childhood cancer may face difficulties at school. We investigated whether childhood cancer affects attainment of upper secondary education, in a register-based cohort study from Denmark, Finland, and Sweden, where we limit bias from selection and participation. Methods: From the national cancer registers, we identified all long-term survivors of childhood cancer diagnosed aged 0–14 years in 1971–2005 (n = 7629), compared them to matched population comparisons (n = 35,411) and siblings (n = 6114), using odds ratios (OR) and 95% confidence intervals (CI). Results: Overall, 6127 survivors (80%) had attained upper secondary education by age 25, compared to 84% among comparison groups. Elevated OR for not attaining this level were mainly confined to survivors of central nervous system (CNS) tumours (ORSurv_PopComp2.05, 95%CI: 1.83–2.29). Other risk groups were survivors who had spent more time in hospital around cancer diagnosis and those who had hospital contacts in early adulthood, particularly psychiatric. Survivors of all cancer types were less likely to have attained upper secondary education without delay. Conclusions: Although survivors of childhood cancer experienced delays in their education, many had caught up by age 25. Except for survivors of CNS tumours, survivors attained upper secondary education to almost the same extent as their peers. [ABSTRACT FROM AUTHOR]

Summary: Juvenile myelomonocytic leukaemia (JMML) is characterized by gene variants that deregulate the RAS signalling pathway. Children with neurofibromatosis type 1 (NF‐1) carry a defective NF1 allele in the germline and are predisposed to JMML, which presumably requires somatic inactivation of the NF1 wild‐type allele. Here we examined the two‐hit concept in leukaemic cells of 25 patients with JMML and NF‐1. Ten patients with JMML/NF‐1 exhibited a NF1 loss‐of‐function variant in combination with uniparental disomy of the 17q arm. Five had NF1 microdeletions combined with a pathogenic NF1 variant and nine carried two compound‐heterozygous NF1 variants. We also examined 16 patients without clinical signs of NF‐1 and no variation in the JMML‐associated driver genes PTPN11, KRAS, NRAS or CBL (JMML‐5neg) and identified eight patients with NF1 variants. Three patients had microdeletions combined with hemizygous NF1 variants, three had compound‐heterozygous NF1 variants and two had heterozygous NF1 variants. In addition, we found a high incidence of secondary ASXL1 and/or SETBP1 variants in both groups. We conclude that the clinical diagnosis of JMML/NF‐1 reliably indicates a NF1‐driven JMML subtype, and that careful NF1 analysis should be included in the genetic workup of JMML even in the absence of clinical evidence of NF‐1. [ABSTRACT FROM AUTHOR]

The article focuses on investigating pregnancy outcomes in 230 female survivors of neuroblastoma from a Nordic register-based cohort study. Topics include the similar incidence of live births before age 30 between survivors and the general population, the decreased live birth rate by age 50 among survivors, and an increased risk of abortions among survivors compared to the general population, emphasizing the need for further research on recent cases' fertility outcomes.

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. [ABSTRACT FROM AUTHOR]

Background: Exon deletions are generally considered pathogenic, particularly when they are located out of frame. Here, we describe a pediatric, female patient presenting with hypercalcemia and a small cell carcinoma of the ovary, hypercalcemic type, and carrying a germline de novoSMARCA4 exon 14 deletion. Methods: The SMARCA4 deletion was identified by whole genome sequencing, and the effect on the RNA level was examined by gel‐ and capillary electrophoresis and nanopore sequencing. Results: The deletion was in silico predicted to be truncating, but RNA analysis revealed two major transcripts with deletion of exon 14 alone or exon 14 through 15, where the latter was located in‐frame. Because the patient's phenotype matched that of other patients with pathogenic germline variants in SMARCA4, the deletion was classified as likely pathogenic. Conclusion: We propose to include RNA analysis in classification of single‐exon deletions, especially if located outside of known functional domains, as this can identify any disparate effects on the RNA and DNA level, which may have implications for variant classification using the American College of Medical Genetics and Genomics guidelines. [ABSTRACT FROM AUTHOR]

Examines the connection between childhood living conditions and myocardial infarction in Denmark. Absence of differences in essential indications of poverty; Identification of infant mortality in poor areas; Incidence of cardiovascular diseases in the lowest social class.

Simple Summary: Malignant liver tumours in children are rare and outcomes seldom published. A global collaboration has recently been initiated to ensure improved treatment, and, in this study, we report the incidence, outcomes and long-term adverse events in a Danish population during the last 35 years. We included 79 patients in the analysis, and the overall incidence was ~2.29 per 1 million children (<15 yr) per year. Hepatoblastoma was the most frequent tumour, with 61 cases. Overall survival 5 years after diagnosis was 84% and 78% for hepatoblastomas and hepatocellular carcinomas, respectively. Age ≥ 8 years was the most predominant factor associated with a poorer outcome. Adverse events included reduced renal function in 10%, reduced cardiac function in 6% and impaired hearing function in 60%, where 19% needed hearing aids. Survival after hepatoblastoma in childhood has improved during the last 35 years and is comparable with international results. Background: Malignant liver tumours in children are rare and national outcomes for this tumour entity are rarely published. This study mapped paediatric liver tumours in Denmark over 35 years and reported on the incidence, outcomes and long-term adverse events. Methods: We identified all liver tumours from the Danish Childhood Cancer Registry and reviewed the case records for patient and tumour characteristics, treatment and clinical outcome. Results: We included 79 patients in the analyses. Overall crude incidence was ~2.29 per 1 million children (<15 yr) per year, with 61 hepatoblastomas (HB), 9 hepatocellular carcinomas and 9 other hepatic tumours. Overall 5-year survival was 84%, 78% and 44%, respectively. Nine patients had underlying liver disease or predisposition syndrome. Seventeen children underwent liver transplantation, with two late complications, biliary stenosis and liver fibrosis. For HB, age ≥ 8 years and diagnosis prior to 2000 were significant predictors of a poorer outcome. Adverse events included reduced renal function in 10%, reduced cardiac function in 6% and impaired hearing function in 60% (19% needed hearing aids). Behavioural conditions requiring additional support in school were registered in 10 children. Conclusions: In Denmark, incidences of malignant liver tumours during the last four decades have been increasing, as reported in the literature. HB survival has improved since the year 2000 and is comparable with international results. Reduced hearing is the major treatment-related side effect and affects approximately 60% of patients. [ABSTRACT FROM AUTHOR]

Objective: Childhood brain tumors belong to the cancer type with the longest diagnostic delay, the highest health care utilization prior to diagnosis, and the highest burden of long-term sequelae. We aimed to clarify whether prior musculoskeletal diagnoses in childhood brain cancer were misdiagnoses and whether it affected the diagnostic delay. Study design: In this retrospective, chart-reviewed case-control study we compared 28 children with brain tumors and a prior musculoskeletal diagnosis to a sex and age-matched control group of 56 children with brain tumors and no prior musculoskeletal diagnosis. Using the Danish registries, the cases were identified from consecutive cases of childhood brain cancers in Denmark over 23 years (1996–2018). Results: Of 931 children with brain tumors, 3% (28/931) had a prior musculoskeletal diagnosis, of which 39% (11/28) were misdiagnoses. The misdiagnoses primarily included torticollis-related diagnoses which tended to a longer time interval from first hospital contact until a specialist was involved: 35 days (IQR 6–166 days) compared to 3 days (IQR 1–48 days), p = 0.07. When comparing the 28 children with a prior musculoskeletal diagnosis with a matched control group without a prior musculoskeletal diagnosis, we found no difference in the non-musculoskeletal clinical presentation, the diagnostic time interval, or survival. Infratentorial tumor location was associated with a seven-fold risk of musculoskeletal misdiagnosis compared to supratentorial tumor location. Conclusion: Musculoskeletal misdiagnoses were rare in children with brain tumors and had no significant association to the diagnostic time interval or survival. The misdiagnoses consisted primarily of torticollis- or otherwise neck-related diagnoses. [ABSTRACT FROM AUTHOR]

Background: Although neutropenic fever is frequently observed during chemotherapy, only a minor proportion is caused by blood stream infections (BSI). This study investigated measurements of neutrophil chemotaxis as risk markers for BSI in children with acute lymphoblastic leukemia (ALL). Methods: The chemokines CXCL1 and CXCL8 were measured weekly in 106 children with ALL during induction treatment. Information regarding BSI episodes was collected from the patients' medical records. Results: During induction treatment, 102 (96%) patients developed profound neutropenia and 27 (25%) were diagnosed with BSI, debuting on median day 12 (range: 4–29). Patients developing BSI had increased levels of CXCL1 on days 8 and 15 as well as increased CXCL8 on days 8, 15, 22, and 29 compared to patients without BSI (all p < 0.05). Patients with BSI < day 12 exhibited increased CXCL1 and CXCL8 levels as early as day 8 (81 vs. 4 pg/mL, p = 0.031 and 35 vs. 10 pg/mL, p < 0.0001, respectively), while CXCL1 and CXCL8 were increased on day 15 (215 vs. 57 pg/mL, p = 0.022 and 68 vs. 17 pg/mL, p = 0.0002) and after (all p < 0.01) in patients with BSI ≥ day 12. Conclusion: The markers of neutrophil chemotaxis, CXCL1, and CXCL8 may help to identify patients at increased risk of BSI during chemotherapy‐induced neutropenia. [ABSTRACT FROM AUTHOR]

Given that 30-40% of children with acute myeloid leukaemia ( AML) relapse after primary therapy it is important to define prognostic factors and identify optimal therapy. From 1993 to 2012, 543 children from the Nordic countries were treated according to two consecutive protocols: 208 children relapsed. The influence of disease characteristics, first line treatment, relapse therapy and duration of first remission on outcome was analysed. Second complete remission ( CR2) was achieved in 146 (70%) patients. Estimated 5-year overall survival ( OS5y) was 39 ± 4% for the whole group and 43 ± 4% for the 190 patients given re-induction therapy, of whom 76% received regimens that included fludarabine, cytarabine ( FLA) ± anthracyclines, 18% received Nordic Society for Paediatric Haematology and Oncology ( NOPHO) upfront blocks and 5% received other regimens. Late relapse ≥1 year from diagnosis, no allogeneic stem cell transplantation ( SCT) in first remission and core binding factor AML were independent favourable prognostic factors for survival. For the 128 children (124 in CR2) that received SCT as consolidation therapy after relapse, OS5y was 61 ± 5%. Four of 19 children (21%) survived without receiving SCT as part of relapse therapy. Our data show that intensive re-induction followed by SCT can give cure rates of 40% in children with relapsed AML. [ABSTRACT FROM AUTHOR]

Summary: A significant proportion of events in paediatric acute myeloid leukaemia (AML) are caused by resistant disease (RD). We investigated clinical and biological characteristics in 66 patients with RD from 1013 children with AML registered and treated according to the NOPHO‐AML 93, NOPHO‐AML 2004, DB AML‐01 and NOPHO‐DBH AML 2012 protocols. Risk factors for RD were age10 years or older and a white‐blood‐cell count (WBC) of 100 × 109/L or more at diagnosis. The five‐year overall survival (OS) was 38% (95% confidence interval [CI]: 28%–52%). Of the 63 children that received salvage therapy with chemotherapy, 59% (N = 37) achieved complete remission (CR) with OS 57% (95% CI: 42%–75%) compared to 12% (95% CI: 4%–35%) for children that did not achieve CR. Giving more than two salvage chemotherapy courses did not increase CR rates. OS for all 43 patients receiving allogeneic haematopoietic stem cell transplantation (HSCT) was 49% (95% CI: 36%–66%). Those achieving CR and proceeding to HSCT had an OS of 56% (95% CI: 41%–77%, N = 30). This study showed that almost 40% of children with primary resistant AML can be cured with salvage therapy followed by HSCT. Children that did not achieve CR after two salvage courses with chemotherapy did not benefit from additional chemotherapy. [ABSTRACT FROM AUTHOR]

In this retrospective cohort study, we evaluated the level of biomarkers of inflammation like phagocyte-related S100 proteins and a panel of cytokines in 128 children with pre-B ALL and 22 with T-ALL. The biomarkers were evaluated at diagnosis and during antileukemic therapy (day 29 and after six months) and we evaluated their correlation with basic laboratory values. Further, for the children with pre-B ALL, we evaluated whether the biomarkers could predict the outcome of ALL expressed as minimal residual disease (MRD), relapse, and death. The levels of S100A9, S100A12, IL-1beta, IL-12p70, IL-13, IL-17, IL-18, and MPO serum levels increased significantly as chemotherapy was initiated. The difference was most pronounced for S100A9 and S100A12, which had strong positive correlations with the neutrophil counts. In contrast, TNF-alpha, IL-6, IL-10, CCL-2, MMP-3, and CD25 serum levels decreased after chemotherapy. Although none of these biomarkers appear to be an independent predictor of outcomes, in predictive models with MRD as the outcome, AUC increased from 76% (95% CI 68–84%) when using initial risk group stratification alone to 83% (95% CI 73–91%) in a multivariate predictive model including initial risk group stratification and the biomarkers S100A12, TNF-alpha, and IL-10. [ABSTRACT FROM AUTHOR]

Background Childhood brain tumor survivors are at high risk of late effects, especially neurocognitive impairment. Limited data are available examining neurocognitive function and associations with quality of life (QoL) in childhood brain tumor survivors. Our aim was to examine neurocognitive function in childhood brain tumor survivors, and associations with QoL and symptom burden. Methods Five–year survivors of brain tumors over the age of 15 were identified in the Danish Childhood Cancer Registry (n = 423). Eligible and consenting participants completed neuropsychological tests and questionnaires assessing QoL, insomnia, fatigue, anxiety, and depression. Survivors treated with radiation (n = 59) were statistically compared with survivors not treated with radiation (n = 102). Results In total, 170 survivors participated (40.2% participation rate). Sixty-six percent of the survivors who completed neurocognitive tests (n = 161) exhibited overall neurocognitive impairment. Survivors treated with radiation, especially whole-brain irradiation, exhibited poorer neurocognitive outcomes than survivors not treated with radiation. Neurocognitive outcomes for survivors treated with surgery were below normative expectations. Furthermore, a number of survivors experienced significant fatigue (40%), anxiety (23%), insomnia (13%), and/or depression (6%). Survivors treated with radiation reported lower quality of life (QoL) and higher symptom burden scores than survivors not treated with radiation; particularly in physical functioning, and social functioning with symptoms of fatigue. Neurocognitive impairment was not associated with QoL or symptom burden. Conclusions In this study, a majority of the childhood brain tumor survivors experienced neurocognitive impairment, reduced QoL, and high symptom burden. Although not associated with each other, it is apparent that childhood brain tumor survivors experience not only neurocognitive dysfunction but may also experience QoL impairments and significant symptom burden. [ABSTRACT FROM AUTHOR]

Autoimmune neutropenia (AIN) in early childhood is caused by autoantibodies directed against antigens on the neutrophil membrane and is a frequent cause of neutropenia in children. Association of AIN with Fcγ receptor (FCGR) 3B variants is well described. In this study, we investigate genetic variations in the FCGR locus and copy number variation of FCGR3B. A total of 130 antibody‐positive AIN patients, 64 with specific anti‐HNA‐1a antibodies and 66 with broad‐reacting anti‐FcγRIIIb antibodies, were genotyped with a multiplex ligation probe assay and compared with healthy controls. Positive findings were confirmed with real‐time q‐PCR. We determined copy numbers of the FCGR2 and FCGR3 genes and the following SNPs: FCGR2A Q62W (rs201218628), FCGR2A H166R (rs1801274), FCGR2B I232T (rs1050501), FCGR3A V176F (rs396991), haplotypes for FCGR2B/C promoters (rs3219018/rs780467580), FCGR2C STOP/ORF and HNA‐1 genotypes in FCGR3B (rs447536, rs448740, rs52820103, rs428888 and rs2290834). Generally, associations were antibody specific, with all associations being representative of the anti‐HNA‐1a‐positive group, while the only association found in the anti‐FcγRIIIb group was with the HNA‐1 genotype. An increased risk of AIN was observed for patients with one copy of FCGR3B; the HNA genotypes HNA‐1a, HNA‐1aa or HNA‐1aac; the FCGR2A 166H and FCGR2B 232I variations; and no copies of FCGR2B 2B.4. A decreased risk was observed for HNA genotype HNA‐1bb; FCGR2A 166R; FCGR2B 232T; and one copy of FCGR2B promoter 2B.4. We conclude that in our Danish cohort, there was a strong association between variation in the FCGR locus and AIN. The findings of different genetic associations between autoantibody groups could indicate the presence of two different disease entities and disease heterogeneity. [ABSTRACT FROM AUTHOR]

Provides information on studies conducted on essential thrombocythemia in children. Evaluation of children at risk of acquiring the disease; Annual incidence of the disease.

Background: Survival after Wilms tumor has significantly increased and focus on late effects has become increasingly important. However, knowledge about long‐term renal function in survivors of Wilms tumor is missing. Our aim was to investigate evidence of kidney disease in 20‐ or more‐year survivors of Wilms tumor in a clinical setting, with siblings as comparisons. Methods: In this cross‐sectional study, we established a cohort of Danish 20‐plus‐year survivors of Wilms tumor and siblings as controls. Participants answered a comprehensive health questionnaire supplemented by measurements of estimated glomerular filtration rate (eGFR), urine albumin‐to‐creatinine ratio, and blood pressure and were categorized according to the chronic kidney disease classification. Multiple linear regression analysis, taking family membership into account, was used to describe the differences in eGFR. Logistic regression analysis was performed to describe risk factors for the development of kidney disease. Results: We included 99 survivors of Wilms tumor and 38 sibling controls with a median of 37 years of follow‐up. The eGFR of Wilms tumor survivors was 13 ml/min/1.73 m2 (95% CI –20; −5) lower when compared to sibling control. Evidence of kidney disease, with risk factors as hypertension and diabetes, was found in 19% of the Wilms tumor survivors and 2% developed end‐stage renal disease. Ninety‐two percent of the Wilms tumor survivors had an eGFR >60 ml/min/1.732. Conclusion: Long‐term Wilms tumor survivors have on average a significantly decreased renal function along with the increased prevalence of kidney disease and end‐stage renal disease when compared to sibling controls. Still, most survivors had kidney function within the normal range. [ABSTRACT FROM AUTHOR]

The article focuses on analysis of measurable residual disease is increasingly used for treatment allocation in patients with acute myeloid leukaemia. Topics include examines MRD methodologies differ and their results are not always concordant, resulting in difficulties in interpretation and clinical decision-making.

Since cardiotoxicity is a life threatening late effect, a reduction of cardiotoxicity in the treatment of acute myeloid leukaemia (AML) is essential. This review is a compilation of the current knowledge about cardiotoxicity after AML treatment and of how future directions in treatment may affect its incidence. A total of six studies concerning AML and cardiotoxicity were identified. The incidence of late subclinical cardiotoxicity varied between 1·3 and 15·3%, and late clinical cardiotoxicity varied between 1·3 and 9·3%. Cumulative dose of anthracyclines ( ACs) and history of relapse were the most common risk factors identified. No conclusions could be drawn about new, potentially less toxic ACs. Differences in treatment data and variations in study populations made comparisons uncertain. The echocardiographic techniques used in the majority of the studies are inferior to more modern echocardiographic methods. This decreases reproducibility and may increase the risk of overestimation of cardiotoxicity. In summary, AML cannot be cured today without ACs. However, some ACs may cause less cardiotoxicity than others. Furthermore there is currently no consensus on equipotent doses of ACs and risk factors for cardiotoxicity. Further research including randomized trials is needed to evaluate whether or not the potentially less cardiotoxic agents fulfil their promise. [ABSTRACT FROM AUTHOR]

Simple Summary: Acute myeloid leukemia is an aggressive cancer in children and novel therapeutic tools are warranted to improve outcomes and reduce late effects in these patients. In this study, we isolate and explore the protein profiles of leukemic stem cells and normal hematopoietic stem cells from hematologically healthy children. Differences in protein profiles between leukemic and normal hematopoietic stem cells were identified. These results provide an insight into the disrupted biological pathways in childhood acute myeloid leukemia. Moreover, differences in protein profiles may serve as potential targets for future therapies specifically aiming at the disease-propagating leukemic stem cells while omitting the normal hematopoietic stem cells. Novel therapeutic tools are warranted to improve outcomes for children with acute myeloid leukemia (AML). Differences in the proteome of leukemic blasts and stem cells (AML-SCs) in AML compared with normal hematopoietic stem cells (HSCs) may facilitate the identification of potential targets for future treatment strategies. In this explorative study, we used mass spectrometry to compare the proteome of AML-SCs and CLEC12A+ blasts from five pediatric AML patients with HSCs and hematopoietic progenitor cells from hematologically healthy, age-matched controls. A total of 456 shared proteins were identified in both leukemic and control samples. Varying protein expression profiles were observed in AML-SCs and leukemic blasts, none having any overall resemblance to healthy counterpart cell populations. Thirty-four proteins were differentially expressed between AML-SCs and HSCs, including the upregulation of HSPE1, SRSF1, and NUP210, and the enrichment of proteins suggestive of protein synthesis perturbations through the downregulation of EIF2 signaling was found. Among others, NUP210 and calreticulin were upregulated in CLEC12A+ blasts compared with HSCs. In conclusion, the observed differences in protein expression between pediatric patients with AML and pediatric controls, in particular when comparing stem cell subsets, encourages the extended exploration of leukemia and AML-SC-specific biomarkers of potential relevance in the development of future therapeutic options in pediatric AML. [ABSTRACT FROM AUTHOR]

Background: Autoimmune neutropenia of early childhood (AIN) is caused by autoantibodies directed against antigens on the neutrophil membrane. The ABO, secretor, and Lewis histo-blood group systems control the expression of carbohydrate antigens and have previously been linked to autoimmune diseases. We aimed to investigate the association between genotypes and the risk of AIN in Danish patients.Study Design and Methods: One hundred fifty-four antibody-positive AIN patients were included. Controls (n = 400) were healthy unrelated Danish blood donors. Molecular determination of ABO, secretor (FUT2), and Lewis (FUT3) genotypes were determined using real-time polymerase chain reaction (qPCR) or Sanger sequencing to infer the prevalence of Lewis antigens (Lea and Leb ) and secretor (SeSe or Sese) or nonsecretor (sese) phenotypes.Results: Blood type O was more common in controls (46.8%) than in AIN patients (36.4%) (OR = 0.65; p = 0.028). Secretors of H Leb antigens were less frequent among AIN patients (25.2%) than controls (35.0%) (OR = 0.62; p = 0.037).Discussion: ABO blood group antigens and the secretion of these antigens are associated with a diagnosis of AIN. The mechanism underlying the association between autoimmunity and interaction among ABO, secretor, and Lewis genotypes has not yet been elucidated, but several studies indicate a connection to the gut microbiota. [ABSTRACT FROM AUTHOR]

Summary: As treatments for second relapsed and refractory first relapsed paediatric AML transition from purely palliative to more commonly curative in nature, comparative data is necessary for evaluating the effectiveness of emerging treatment options. Furthermore, little is known about predictors of prognosis following third‐line therapy. From 2004 until 2019, 277 of the 869 patients enrolled in NOPHO‐DB SHIP consortium trials experienced a first relapse and, of these patients, 98 experienced refractory first relapse and 59 a second relapse. Data on patient and disease characteristics within this cohort of 157 patients was analysed to determine probability of overall survival (pOS) and to identify factors influencing survival. Data on early treatment response and complete remission were not available. One and 5‐year pOS were 22 ± 3% and 14 ± 3%, respectively. There was no statistically significant difference in survival between refractory first relapsed and second relapsed AML. Factors influencing prognosis included: late relapse, type of third‐line treatment, FLT3 mutational status, and original treatment protocol. These data provide a baseline for evaluating the effectiveness of emerging therapies for the treatment of children with refractory first relapsed and second relapsed paediatric AML and evidence that select patients receiving third‐line therapy can be cured. [ABSTRACT FROM AUTHOR]

In adult acute myeloid leukaemia (AML), immunophenotypic differences enable discrimination of leukaemic stem cells (LSCs) from healthy haematopoietic stem cells (HSCs). However, immunophenotypic stem cell characteristics are less explored in paediatric AML. Employing a 15‐colour flow cytometry assay, we analysed the expression of eight aberrant surface markers together with BCL‐2 on CD34+CD38− bone marrow stem cells from 38 paediatric AML patients and seven non‐leukaemic, age‐matched controls. Furthermore, clonality was investigated by genetic analyses of sorted immunophenotypically abnormal stem cells from six patients. A total of 50 aberrant marker positive (non‐HSC‐like) subsets with 41 different immunophenotypic profiles were detected. CD123, CLEC12A, and IL1RAP were the most frequently expressed markers. IL1RAP, CD93, and CD25 expression were not restricted to stem cells harbouring leukaemia‐associated mutations. Differential BCL‐2 expression was found among defined cytogenetic subgroups. Interestingly, only immunophenotypically abnormal non‐HSC‐like subsets demonstrated BCL‐2 overexpression. Collectively, we observed pronounced immunophenotypic heterogeneity within the stem cell compartment of paediatric AML patients. Additionally, certain aberrant markers used in adults seemed to be ineligible for detection of leukaemia‐representing stem cells in paediatric patients implying that inference from adult studies must be done with caution. [ABSTRACT FROM AUTHOR]

Background: Incidence rates in Denmark of central nervous system (CNS) tumors remain among the highest in the world. Survival rates, however, have improved in the past decades in high‐income countries. Methods: We analyzed incidence and survival of childhood CNS tumors in Denmark diagnosed from 1997 to 2019 based on data from the Danish Childhood Cancer Registry and information on histological types, tumor localization, and treatment from medical records. Results: From 1997 to 2019, 949 children<15 years were diagnosed with a CNS tumor. Age‐standardized incidence was 42.1 (95% CI, 39.4–44.6) per million person‐years and stable during this period. Age‐specific incidence for children aged 0–4 years was 47.7 per million. More than one‐third (n = 374, 39.4%) were treated with surgery alone. Overall survival rates 5 and 10 years after diagnosis were 77.6% (95% CI, 74.7–80.2) and 74.7% (95% CI, 71.7–77.5). Five‐year overall survival improved from 73.0% (95% CI, 68.9–76.7) in 1997–2008 to 83.2% (95% CI, 79.2–86.4) in 2009–2019 (p‐value < 0.0001) in children aged 0–4 years (p = 0.0006). Conclusion: Incidence rates are stable but remain among the highest in the world. Despite improved survival rates in recent years in younger children, some subtypes still have a poor prognosis. [ABSTRACT FROM AUTHOR]

Following induction chemotherapy for acute myeloid leukaemia (AML), sensitive determination of minimal residual disease (MRD) in patients achieving complete remission (CR) should enable the detection of early relapse and allow intervention at a more favourable stage than at overt relapse. We have determined the expression levels of the Wilms’ tumour gene ( WT1) by real-time quantitative polymerase chain reaction (RQ-PCR) in peripheral blood and bone marrow in 133 newly diagnosed AML patients and compared them with those in healthy volunteers. At diagnosis, the WT1 level exceeded normal expression in 118 of 133 (89%) patients, and was high enough to allow for detection of a WT1 decrease of least 1000-fold in 98 of 133 (74%) patients following induction therapy. Concomitant monitoring of fusion transcripts ( PML-RAR α, AML1-ETO, MLL-MLL, CBF β- MYH11, or DEK-CAN) in 38 patients identified different relationships between WT1 and fusion transcript levels, the AML1-ETO group showing remarkably low levels of WT1 compared with fusion transcript. In 32 patients analysed longitudinally there was close concordance between relapse and increased WT1 levels. Parallel longitudinal monitoring of WT1 and fusion transcript showed close correlation in 18 of 18 patients. We conclude that WT1 expression by RQ-PCR may be employed as a tool to detect MRD in the majority of fusion transcript-negative AML patients. [ABSTRACT FROM AUTHOR]

Summary: Longitudinal molecular measurable residual disease (MRD) sampling after completion of therapy serves as a refined tool for identification of imminent relapse of acute myeloid leukaemia (AML) among patients in long‐term haematological complete remission. Tracking of increasing quantitative polymerase chain reaction MRD before cytomorphological reappearance of blasts may instigate individual management decisions and has paved the way for development of pre‐emptive treatment strategies to substantially delay or perhaps even revert leukaemic regrowth. Traditionally, MRD monitoring is performed using repeated bone marrow aspirations, albeit the current European LeukemiaNet MRD recommendations acknowledge the use of peripheral blood as an alternative source for MRD assessment. Persistent MRD positivity in the bone marrow despite continuous morphological remission is frequent in both core binding factor leukaemias and nucleophosmin 1‐mutated AML. In contrast, monthly assessment of MRD in peripheral blood superiorly separates patients with imminent haematological relapse from long‐term remitters and may allow pre‐emptive therapy of AML relapse. [ABSTRACT FROM AUTHOR]

BACKGROUND: During the past 4 decades, there has been a growing focus on preserving the fertility of patients with childhood cancer; however, no large studies have been conducted of live births across treatment decades during this period. Therefore, the authors estimated the potential birth deficit in female childhood cancer survivors and the probability of live births. METHODS: In total, 8886 women were identified in the 5 Nordic cancer registries in whom a childhood cancer had been diagnosed during 1954 through 2006. A population comparison cohort of 62,903 women was randomly selected from the central population registries matched by age and country. All women were followed for live births recorded in medical birth registries. The cumulative probability and the risk ratio (RR) with 95% confidence intervals (CIs) of a live birth were calculated by maternal age across treatment decades. RESULTS: The probability of a live birth increased with treatment decade, and, at age 30 years, the rate for survivors most recently diagnosed was close to the rate among the general population (1954‐1969: RR, 0.65 [95% CI, 0.54‐0.78]; 1970s: RR, 0.67 [95% CI, 0.60‐0.74]; 1980s: RR, 0.69 [95% CI, 0.64‐0.74]; 1990s: RR, 0.91 [95% CI, 0.87‐0.95]; 2000s: RR, 0.94 [95% CI, 0.91‐0.97]). CONCLUSIONS: Female childhood cancer survivors had a lower probability of a live birth than women in the general population, although, in survivors diagnosed after 1989, the probability was close to that of the general population. Because the pattern of live births differs by cancer type, continuous efforts must be made to preserve fertility, counsel survivors, and refer them rapidly to fertility treatment if necessary. LAY SUMMARY: The purpose of this study was to compare the probability of giving birth to a liveborn child in female survivors of childhood cancer with that of women in the general population.Survivors of childhood cancer had a lower probability of live births than women in the general population, although survivors diagnosed after 1989 had a probability close to that of the general population.Continuing focus on how to preserve the potential for fertility among female patients with childhood cancer during treatment is important to increase their chances of having a child. Female childhood cancer survivors have a lower probability of live birth than women in the general population. However, female survivors treated more recently in the 1990s and 2000s have a probability close to that of the female background population. [ABSTRACT FROM AUTHOR]

PURPOSE: Historically, cancer predisposition syndromes (CPSs) were rarely established for children with cancer. This nationwide, population-based study investigated how frequently children with cancer had or were likely to have a CPS.METHODS: Children (0–17 years) in Denmark with newly diagnosed cancer were invited to participate in whole-genome sequencing of germline DNA. Suspicion of CPS was assessed according to Jongmans'/McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) criteria and familial cancer diagnoses were verified using population-based registries. RESULTS: 198 of 235 (84.3%) eligible patients participated, of whom 94/198 (47.5%) carried pathogenic variants (PVs) in a CPS gene or had clinical features indicating CPS. Twenty-nine of 198 (14.6%) patients harbored a CPS, of whom 21/198 (10.6%) harbored a childhood-onset and 9/198 (4.5%) an adult-onset CPS. In addition, 23/198 (11.6%) patients carried a PV associated with biallelic CPS. Seven of the 54 (12.9%) patients carried two or more variants in different CPS genes. Seventy of 198 (35.4%) patients fulfilled the Jongmans' and/or MIPOGG criteria indicating an underlying CPS, including two of the 9 (22.2%) patients with an adult-onset CPS versus 18 of the 21 (85.7%) patients with a childhood-onset CPS (p = 0.0022), eight of the additional 23 (34.8%) patients with a heterozygous PV associated with biallelic CPS, and 42 patients without PVs. Children with a central nervous system (CNS) tumor had family members with CNS tumors more frequently than patients with other cancers (11/44, p = 0.04), but 42 of 44 (95.5%) cases did not have a PV in a CPS gene. CONCLUSION: These results demonstrate the value of systematically screening pediatric cancer patients for CPSs and indicate that a higher proportion of childhood cancers may be linked to predisposing germline variants than previously supposed. Author summary: Traditionally cancer in childhood have been thought to be–mostly–caused by pure bad luck. In recent years, however, this notion has been challenged by novel findings as both maternal environmental exposure and genetic causes have been identified. With this study we have investigated a national cohort of childhood cancer patients in Denmark. We have mapped family pedigree, made physical examination of the patients, and sequenced their genome, to get a 360-degree understanding of these patients. This revealed that a tenth of all patients carried a genetic variant causative of their cancer development. In addition, almost half of all patients were suspected of carrying a causative genetic variant based on tools that evaluate type of cancer, physical characteristics and family history. It also showed that tools to predict which patients carried a genetic variant did not identify all patients who in fact carried a genetic variant. Overall, roughly half of all patients were suspected of carrying an underlying genetic cause of their cancer, and a tenth had a verified underlying genetic variant predisposing to cancer development in childhood. This could suggest that the amount of childhood cancer cases attributed to genetic factors may be even higher. [ABSTRACT FROM AUTHOR]

In the 1960s only 1/3 of children with soft-tissue sarcomas survived, however with improved treatments survival today has reached 70%. Given the previous poor survival and the rarity of soft-tissue sarcomas, the risk of somatic late effects in a large cohort of Nordic soft-tissue sarcoma survivors has not yet been assessed. In this population-based cohort study we identified 985 five-year soft-tissue sarcoma survivors in Nordic nationwide cancer registries and late effects in national hospital registries covering the period 1964–2012. Information on tumour site and radiotherapy was available for Danish and Finnish survivors (N = 531). Using disease-specific rates of first-time hospital contacts for somatic diseases in survivors and in 4,830 matched comparisons we calculated relative rates (RR) and rate differences (RD). Survivors had a RR of 1.5 (95% CI 1.4–1.7) and an absolute RD of 23.5 (17.7–29.2) for a first hospital contact per 1,000 person-years. The highest risks in both relative and absolute terms were of endocrine disorders (RR = 2.5; RD = 7.6), and diseases of the nervous system (RR = 1.9; RD = 6.6), digestive organs (RR = 1.7; RD = 5.4) and urinary system (RR = 1.7; RD = 5.6). By tumour site, excess risk was lower after extremity tumours. Irradiated survivors had a 2.6 (1.2–5.9) times higher risk than non-irradiated. Soft-tissue sarcoma survivors have an increased risk of somatic late effects in 5 out of 10 main diagnostic groups of diseases, and the risk remains increased up to 40 years after cancer diagnosis. Risks were slightly lower for those treated for tumours in the extremities, and radiotherapy increased the risk by more than two-fold. [ABSTRACT FROM AUTHOR]

Objective: Acute lymphoblastic leukemia (ALL) may present with arthritis implying the risk of being misdiagnosed as juvenile idiopathic arthritis (JIA). The aim of this study was to identify predictors for ALL based on clinical and laboratory information. Methods: This cross-sectional, retrospective study compared clinical presentation and laboratory results of 26 children with ALL and arthritis versus 485 children with JIA (433 non-systemic, 52 systemic JIA). Using a Bayesian score approach the findings were evaluated by calculating odds ratios (OR) and lnOR as a measure of diagnostic weight. Results: Distinction on clinical grounds was difficult, as even a high number of joints involved did not exclude ALL. One or more hematologic cell counts were low (Hb <10 g/dL, platelet count <100 x 109/L, neutrophil count < 1.0 x 109/L) in 92% with ALL, 25% with systemic JIA and 10% with non-systemic JIA. Neutropenia and thrombocytopenia had the highest ORs of 128 (95% CI 43–387) and 129 (95% CI 26–638), each giving a diagnostic weight of 4. The estimated risks of ALL were 0.2% with normal cell counts and 9%, 67% and 100% when one, two or three cell lines were affected. Conclusion: A simple count of cell lines with low counts can serve as a basic diagnostic strategy. Children with tri- or bilinear involvement should be referred to a bone marrow, and those with unilinear involvement a thorough screen for further evidence of ALL (organomegaly, ESR, LDH, uric acid, and blood smear). [ABSTRACT FROM AUTHOR]