Explore the vast range of titles available.

Cancer in children and adolescents is rare and biologically very different from cancer in adults. It accounts for 1·4% of all cancers worldwide, although this proportion ranges from 0·5% in Europe to 4·8% in Africa, largely because of differences in age composition and life expectancy. In high-income countries, survival from childhood cancer has reached 80% through a continuous focus on the integration of clinical research into front-line care for nearly all children affected by malignant disease. However, further improvement must entail new biology-driven approaches, since optimisation of conventional treatments has in many cases reached its limits. In many instances, such approaches can only be achieved through international collaborative research, since rare cancers are being subdivided into increasingly smaller subgroups on the basis of their molecular characteristics. The long-term effect of anticancer treatment on quality of life must also be taken into account because more than one in 1000 adults in high-income countries are thought to be survivors of cancer in childhood or adolescence. The introduction of drugs that are less toxic and more targeted than those currently used necessitates a partnership between clinical and translational researchers, the pharmaceutical industry, drug regulators, and patients and their families. This therapeutic alliance will ensure that efforts are focused on the unmet clinical needs of young people with cancer. Most children with cancer live in low-income and middle-income countries, and these countries account for 94% of all deaths from cancer in people aged 0–14 years. The immediate priority for these children is to improve access to an affordable, best standard of care in each country. Every country should have a national cancer plan that recognises the unique demographic characteristics and care needs of young people with cancer. Centralisation of the complex components of treatment of these rare diseases is essential to improve survival, accelerate research, and train the future specialist workforce. Referral routes and care pathways must take account of the large geographical distances between many patients' homes and treatment centres, and the economic, cultural, and linguistic diversity of the populations served.

Pediatric acute lymphoblastic leukemia (ALL) is a heterogeneous disease consisting of distinct clinical and biological subtypes that are characterized by specific chromosomal abnormalities or gene mutations. Mutation of genes encoding tyrosine kinases is uncommon in ALL, with the exception of Philadelphia chromosome-positive ALL, where the t(9,22)(q34;q11) translocation encodes the constitutively active BCR-ABL1 tyrosine kinase. We recently identified a poor prognostic subgroup of pediatric BCR-ABL1-negative ALL patients characterized by deletion of IKZF1 (encoding the lymphoid transcription factor IKAROS) and a gene expression signature similar to BCR-ABL1-positive ALL, raising the possibility of activated tyrosine kinase signaling within this leukemia subtype. Here, we report activating mutations in the Janus kinases JAK1 (n = 3), JAK2 (n = 16), and JAK3 (n = 1) in 20 (10.7%) of 187 BCR-ABL1-negative, high-risk pediatric ALL cases. The JAK1 and JAK2 mutations involved highly conserved residues in the kinase and pseudokinase domains and resulted in constitutive JAK-STAT activation and growth factor independence of Ba/F3-EpoR cells. The presence of JAK mutations was significantly associated with alteration of IKZF1 (70% of all JAK-mutated cases and 87.5% of cases with JAK2 mutations; P = 0.001) and deletion of CDKN2A/B (70% of all JAK-mutated cases and 68.9% of JAK2-mutated cases). The JAK-mutated cases had a gene expression signature similar to BCR-ABL1 pediatric ALL, and they had a poor outcome. These results suggest that inhibition of JAK signaling is a logical target for therapeutic intervention in JAK mutated ALL.

Mary Relling and colleagues explore the effects of ancestry on the pharmacogenomics of relapse in acute lymphoblastic leukemia. They found that Native American ancestry was associated with risk of relapse but that differences in relapse risk were abrogated by the addition of a single extra phase of chemotherapy. Although five-year survival rates for childhood acute lymphoblastic leukemia (ALL) are now over 80% in most industrialized countries 1 , not all children have benefited equally from this progress 2 . Ethnic differences in survival after childhood ALL have been reported in many clinical studies 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , with poorer survival observed among African Americans or those with Hispanic ethnicity when compared with European Americans or Asians 3 , 4 , 5 . The causes of ethnic differences remain uncertain, although both genetic and non-genetic factors are likely important 4 , 12 . Interrogating genome-wide germline SNP genotypes in an unselected large cohort of children with ALL, we observed that the component of genomic variation that co-segregated with Native American ancestry was associated with risk of relapse ( P = 0.0029) even after adjusting for known prognostic factors ( P = 0.017). Ancestry-related differences in relapse risk were abrogated by the addition of a single extra phase of chemotherapy, indicating that modifications to therapy can mitigate the ancestry-related risk of relapse.

Background Discovery that the transcriptional output of the human genome is far more complex than predicted by the current set of protein-coding annotations and that most RNAs produced do not appear to encode proteins has transformed our understanding of genome complexity and suggests new paradigms of genome regulation. However, the fraction of all cellular RNA whose function we do not understand and the fraction of the genome that is utilized to produce that RNA remain controversial. This is not simply a bookkeeping issue because the degree to which this un-annotated transcription is present has important implications with respect to its biologic function and to the general architecture of genome regulation. For example, efforts to elucidate how non-coding RNAs (ncRNAs) regulate genome function will be compromised if that class of RNAs is dismissed as simply 'transcriptional noise'. Results We show that the relative mass of RNA whose function and/or structure we do not understand (the so called 'dark matter' RNAs), as a proportion of all non-ribosomal, non-mitochondrial human RNA (mt-RNA), can be greater than that of protein-encoding transcripts. This observation is obscured in studies that focus only on polyA-selected RNA, a method that enriches for protein coding RNAs and at the same time discards the vast majority of RNA prior to analysis. We further show the presence of a large number of very long, abundantly-transcribed regions (100's of kb) in intergenic space and further show that expression of these regions is associated with neoplastic transformation. These overlap some regions found previously in normal human embryonic tissues and raises an interesting hypothesis as to the function of these ncRNAs in both early development and neoplastic transformation. Conclusions We conclude that 'dark matter' RNA can constitute the majority of non-ribosomal, non-mitochondrial-RNA and a significant fraction arises from numerous very long, intergenic transcribed regions that could be involved in neoplastic transformation.

Abstract Background Since pediatric cancer drug development is a global enterprise, we sought to provide an overview of the landscape of intercontinental clinical trials in pediatric oncology opened over the last decade. Methods ClinicalTrials.gov was systematically searched to identify all clinical therapeutic trials which opened between 2010 and 2020 and recruited pediatric patients (<18 years) with cancer. Results Over the last 10 years, 295 (8.7%) of 3383 therapeutic pediatric cancer trials were international and 182 (5.4%) were intercontinental. Most intercontinental trials were phase‐1 or 2, with 25% late‐phase, 65% were sponsored by industry, and North America was involved in 92%. Industry‐sponsored proportionally more phase‐1 trials than academia (41% vs. 25%); conversely, academia sponsored more phase‐2 and late‐phase trials (39% and 31% vs. 36% and 21%, respectively) ( p = 0.020). North America–Europe collaboration was predominantly industry sponsored as opposed to North America–Oceania and Europe–Oceania collaboration, more frequently academic ( p < 0.0001). Most late‐phase trials (18/20, 90%) focusing on pediatric malignancies were conducted by academic sponsors and 10 of these were conducted by Children's Oncology Group (COG)/National Cancer Institute in the United States and Oceania. There was no significant increase over time of intercontinental trials and a trend for a reduction in academic trials. Conclusions Despite the relative rarity of childhood malignancies, especially within molecular subtypes, only 5.4% of pediatric cancer trials were intercontinental. The number of intercontinental trials remains small, with no significant increase over the last decade. The ACCELERATE International Collaboration Working Group aims to identify existing hurdles and propose solutions to improve intercontinental collaboration in clinical research for the benefit of children and adolescents with cancer.

Purpose We explored the impact of obesity, body composition, and genetic polymorphisms on the pharmacokinetics (PK) of daunorubicin in children with cancer. Patients and methods Patients ≤21 years receiving daunorubicin as an infusion of any duration <24 h for any type of cancer were eligible. Plasma drug concentrations were measured by high-performance liquid chromatography. Body composition was measured by dual-energy X-ray absorptiometry. Obesity was defined as a BMI >95 % for age or as body fat >30 %. NONMEM was used to perform PK model fitting. The Affymetrix DMET chip was used for genotyping. The impact of genetic polymorphisms was investigated using SNP/haplotype association analysis with estimated individual PK parameters. Results A total of 107 subjects were enrolled, 98 patients had PK sampling, and 50 patients underwent DNA analysis. Population estimates for daunorubicin clearance and volume of distribution were 116 L/m 2 /h ± 14 % and 68.1 L/m 2  ± 24 %, respectively. Apparent daunorubicinol clearance and volume of distribution were 26.8 L/m 2 /h ± 5.6 % and 232 L/m 2  ± 10 %, respectively. No effect of body composition or obesity was observed on PK. Forty-four genes with variant haplotypes were tested for association with PK. FMO3-H1/H3 genotype was associated with lower daunorubicin clearance than FMO3-H1/H1, p  = 0.00829. GSTP1*B/*B genotype was also associated with lower daunorubicin clearance compared to GSTP1*A/*A, p  = 0.0347. However, neither of these associations was significant after adjusting for multiple testing by either Bonferroni or false discovery rate correction. Conclusions We did not detect an effect of body composition or obesity on daunorubicin PK. We found suggestive associations between FMO3 and GSTP1 haplotypes with daunorubicin PK that could potentially affect efficacy and toxicity.

Cisplatin is an essential chemotherapeutic agent in the treatment of many pediatric cancers. Unfortunately, cisplatin‐induced hearing loss (CIHL) is a common, clinically significant side effect with life‐long ramifications, particularly for young children. ACCL05C1 and ACCL0431 are two recently completed Children’s Oncology Group studies focused on the measurement and prevention of CIHL. The purpose of this paper was to gain insights from ACCL05C1 and ACCL0431, the first published cooperative group studies dedicated solely to CIHL, to inform the design of future pediatric otoprotection trials. Use of otoprotective agents is an attractive strategy for preventing CIHL, but their successful development must overcome a unique constellation of methodological challenges related to translating preclinical research into clinical trials that are feasible, evaluate practical interventions, and limit risk. Issues particularly important for children include use of appropriate methods for hearing assessment and CIHL severity grading, and use of trial designs that are well‐informed by preclinical models and suitable for relatively small sample sizes. Increasing interest has made available new funding opportunities for expanding this urgently needed research. Cisplatin, an essential chemotherapeutic agent in the treatment of many pediatric cancers, frequently causes hearing loss. Cisplatin‐induced hearing loss can result in long‐term disability. This paper describes issues in the design of otoprotection clinical trials in children.

Background Single patient Investigational New Drug (IND) applications are one mechanism through which experimental therapies are accessed for children with cancer. The landscape of use, outcomes, and toxicity from single patient INDs remains unknown in pediatric oncology. Methods We performed a retrospective analysis of all single patient INDs requested and prescribed at a single institution between 1/1/2007 and 5/1/2019. We report aggregate data from the US Food and Drug Administration (FDA) on single patient IND applications over the final two years of the study (2017–2019). We report an overview of all IND applications, as well as clinical descriptions of patients, treatments, outcomes, and toxicity. Results Over the 2‐year period, the FDA approved all 171 submitted single patient IND requests for pediatric oncology. We identified 56 requests from our center during the 12‐year study period, and all were approved (median time from FDA submission to approval: 1 day (range 0–12)). 71% of requests were based on disease histology. Lack of pediatric clinical trial (65%) was the most common reason for use. 48 approved requests were ultimately administered. The median duration of treatment was 84 days (range: 4–1590), with 3 patients remaining on treatment at time of analysis. Only 7% discontinued treatment due to toxicity. Three‐year overall survival was 50% (95% CI, 35–64). Conclusions Single patient INDs in pediatric oncology were universally approved in our national and single‐center analysis. In our cohort, single patient INDs were primarily utilized based on disease histology, rather than genomics, for agents that lacked a clinical trial. Single patient Investigational New Drug (IND) applications in pediatric oncology are universally approved in a timely fashion in our analysis. Single patient IND therapy is pursued for a range of reasons, with few patients discontinuing therapy due to toxicity.

Success in improving treatment outcomes in childhood cancer has been achieved almost exclusively through multicenter and multidisciplinary clinical and applied research over several decades. While biologically rational as well as empirical approaches have led to combination chemotherapy and multimodality approaches to therapy, which have given rise to evidence-based practice standards, similar scientific rigor has not always been as evidently applied to modalities utilized to assess initial disease burden and, more important, response to investigational approaches to therapy. As the empirical approach to therapeutic advances has likely maximized its benefit, future progress will require translation of biologic discovery most notably from the areas of genomics and proteomics. Hence, attempts to improve efficacy of therapy will require a parallel effort to minimize collateral damage of future therapeutic approaches, and such a parallel approach will mandate the continued dependence on advances in diagnostic imaging for improvements in staging methodologies to best define risk groups for risk-adjusted therapy. In addition, anatomic and functional assessment of response and surveillance for disease recurrence will require improved understanding of the biology as well as natural history of individual diseases, which one hopes will better inform investigators in designing trials. Clinical and research expertise is urgently needed in the selection of specific imaging studies and frequencies that best assess a response as well as to define disease-free intervals. Despite limited resources to develop sufficient infrastructure, emphasis on enabling early assessment of new technology to minimize risks associated with treatment advances and with those critical diagnostic and staging procedures must continue to be a focus of pediatric cancer clinical research.