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MicroRNAs (miRNAs) are short, non-protein-coding genes that regulate the expression of numerous protein-coding genes. Their expression is dysregulated in cancer, where they may function as oncogenes or tumour suppressor genes. As miRNAs are highly resistant to degradation, they are ideal biomarker candidates to improve the diagnosis and clinical management of cancer, including prognostication. Furthermore, miRNAs dysregulated in malignancy represent potential therapeutic targets. The use of miRNAs for these purposes is a particularly attractive option to explore for paediatric malignancies, where the mutational burden is typically low, in contrast to cancers affecting adult patients. As childhood cancers are rare, it has taken time to accumulate the necessary body of evidence showing the potential for miRNAs to improve clinical management across this group of tumours. Here, we review the current literature regarding the potential clinical utility of miRNAs in paediatric solid tumours, which is now both timely and justified. Exploring such avenues is warranted to improve the management and outcomes of children affected by cancer.

Testicular germ cell tumours (GCTs) are the most common malignancy among young men. Management of GCTs relies on the serum tumour markers α-fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase, among other parameters. However, these tumour markers can only be detected at elevated levels in half of GCT patients. Circulating miR-371a-3p has emerged as a blood-based biomarker that can reliably detect macroscopic GCTs, aside from teratoma. Here we review the literature, describe the methodologies currently used to measure circulating miR-371a-3p, and discuss the following clinical scenarios in which miR-371a-3p may impact practice in the future: (1) men with an inconclusive small testicular mass; (2) response monitoring during chemotherapy; (3) postchemotherapy residual masses; and (4) follow-up after treatment with curative intent. PATIENT SUMMARY: We discuss the potential uses and promise, as well as current limitations, of a novel blood test that may improve care for men with testicular cancer.

Homogeneous and common objective disease assessments and standardised response criteria are important for better international clinical trials for CNS germ cell tumours. Currently, European protocols differ from those of North America (the USA and Canada) in terms of criteria to assess radiological disease response. An international working group of the European Society for Paediatric Oncology Brain Tumour Group and North American Children's Oncology Group was therefore established to review existing literature and current practices, identify major challenges regarding imaging assessment, and develop consensus recommendations for imaging response assessment for patients with CNS germ cell tumours. New clinical imaging standards were defined for the most common sites of CNS germ cell tumour and for the definition of locoregional extension. These new standards will allow the evaluation of response to therapy in patients with CNS germ cell tumours to be more consistent, and facilitate direct comparison of treatment outcomes across international studies.

Objective : Circulating microRNAs have clear potential for improving malignant germ-cell-tumor (MGCT) diagnosis. Here, we address the central issue of whether measurement of a single microRNA is sufficient for detecting testicular MGCTs, or whether there is added benefit in quantifying other members of the four-microRNA panel previously identified (miR-371a-3p/miR-372-3p/miR-373-3p and miR-367-3p). Patients/Methods : We performed a pooled analysis of available published data where all four panel miRNAs had been assessed using pre-amplification PCR technology (four studies; total 329 patients). Two studies using identical methodology (and identical normalization using endogenous miR-30b-5p) were used in the discovery phase (n=51 patients: 17 MGCT, 34 controls). The two other studies (n=278 patients: 140 MGCT, 138 controls), which assessed the same test panel but with different normalization approaches (endogenous miR-93-5p, exogenous cel-miR-39-3p), were used for the validation phase. We derived sensitivity, specificity, positive- and negative-predictive-values (PPV/NPV) for the detection thresholds that maximised the Youden Index (YI). Results : In the discovery-phase, the YI was 0.97 for miR-371a-3p (sensitivity=1, specificity=0.97), 0.71 (miR-367-3p), 0.68 (miR-372-3p), and 0.50 (miR-373-3p). These findings were confirmed in the validation-phase, with YI of 0.75 for miR-371a-3p (sensitivity=0.90, specificity 0.85), 0.55 (miR-367-3p), 0.47 (miR-372-3p), and 0.51 (miR-373-3p). Importantly, no combination of markers added additional diagnostic benefit to miR-371a-3p alone, in either the discovery or the validation phase. Conclusion : Quantifying circulating miR-371a-3p alone is sufficient for testicular MGCT diagnosis. PCR measurement of this single miRNA marker will be more cost-effective and easier to interpret, facilitating future incorporation into routine clinical practice. MicroAbstract Circulating microRNA testing is likely to transform future management for testicular cancer patients. Here, we undertook a pooled analysis (329 patients) to test whether measurement of a single microRNA is sufficient for detecting testicular cancer, or whether it is necessary to quantify other members of the four microRNA panel previously identified (miR-371a-3p/miR-372-3p/miR-373-3p/miR-367-3p). We show that quantifying circulating miR-371a-3p alone is sufficient for testicular cancer diagnosis.

Immature teratomas (IT) are rare and recurrences uncommon. A 12-year-old female with grade 3 (high-grade) ovarian IT underwent surgical resection but experienced early recurrences; the first was treated with surgery but the second was metastatic and managed with chemotherapy, resulting in growing-teratoma-syndrome and need for further surgery. She now remains well in uneventful clinical follow-up. We believe chemotherapy could be reserved for very carefully selected recurrent IT cases, which may alter the natural history of disease.

Purpose: To compare the outcomes of paediatric and adolescent extracranial malignant germ cell tumour (GCT) patients treated with either carboplatin or cisplatin on clinical trials conducted by the Children's Oncology Group (COG) and the Children's Cancer and Leukaemia Group (CCLG).\ud \ud \ud \ud Methods: The Malignant Germ Cell International Consortium (MaGIC) has created a database of the GCT clinical trials conducted since 1983 by COG (United States, Canada and Australia), which used cisplatin-based regimens, and by CCLG (United Kingdom), which used carboplatin-based regimens. Using the parametric cure model, this study compared the overall 4-year event-free survival (EFS), stratified by age, stage, site and the a-priori defined MaGIC ‘risk’ groups: standard risk ((SR) 1 (EFS >80%; age 80%, age ≥ 11y) and poor risk (PR) (EFS ≤ 70%, age ≥ 11y).\ud \ud \ud \ud Results: Cisplatin-based therapy was used in 620 patients; carboplatin was used in 163 patients. In the overall multivariate cure model, the two regimens did not differ significantly (cisplatin: 4-year EFS 86%; 95% confidence interval (CI) 83–89% versus carboplatin 4-year EFS 86%; 95% CI 79–90%; p = 0.87). No significant differences were noted in stratified analyses by site, stage, age and MaGIC risk groups: SR1 (p = 0.20), SR2 (p = 0.55) or PR (p = 0.72) patients.\ud \ud \ud \ud Conclusions: In these trials conducted contemporaneously, there is no significant difference in outcome observed overall, or any subset of patients, who were treated with regimens containing cisplatin versus carboplatin These results suggested sufficient equipoise to justify a randomised trial to evaluate the effectiveness of carboplatin versus cisplatin in the treatment of children, adolescents and young adults with standard risk GCT, which is currently underway.

Intracranial germ cell tumours (icGCTs) are uncommon tumours occurring in children and young adults. They are usually segregated into germinomas and non-germinomatous tumours (NGGCTs) in most classifications. Germinomas are highly curable tumours with multimodality treatment, but NGGCTs are associated with poorer survival outcomes. There are some differences in the approach to the management of icGCTs globally. Current research generally focuses on reducing treatment intensity, particularly the dose and volume of radiotherapy, in order to minimise the risks of late sequelae while maintaining high cure rates in icGCTs.

High-resolution transient IR absorption spectroscopy was used to measure (0001− 0000) R-branch transition frequencies for N2O molecules in extreme rotational states, with quantum number up to J = 205 and energies as high as Erot=17,000 cm−1. A population inversion of rotationally excited N2O states was prepared with an optical centrifuge and probed in a multi-pass IR cell using a quantum cascade laser. The optical centrifuge is based on 800-nm ultrafast, chirped laser pulses that optically trap molecules and accelerate them angularly to extreme rotational states. This work substantially increases the range of observed transitions for this band beyond the J = 100 transitions previously reported and provides benchmark measurements for theoretical predictions based on an effective Hamiltonian using a polyad model. Transient Doppler-broadened IR line profiles of N2O show that optical excitation of the sample is selectively partitioned into rotation, prior to Doppler broadening from rotation-to-translation collisional energy transfer. These results demonstrate how high-J transitions can be measured without thermal heating by coupling optical centrifuge excitation with high-resolution transient IR absorption probing.

The management of intracranial germ-cell tumours is complex because of varied clinical presentations, tumour sites, treatments and outcomes, and the need for multidisciplinary input. Participants of the 2013 Third International CNS Germ Cell Tumour Symposium (Cambridge, UK) agreed to undertake a multidisciplinary Delphi process to identify consensus in the clinical management of intracranial germ-cell tumours. 77 delegates from the symposium were selected as suitable experts in the field and were invited to participate in the Delphi survey, of which 64 (83%) responded to the invitation. Invited participants represented multiple disciplines from Asia, Australasia, Europe, and the Americas. 38 consensus statements encompassing aspects of intracranial germ-cell tumour work-up, staging, treatment, and follow-up were prepared. To achieve consensus, statements required at least 70% agreement from at least 60% of respondents. Overall, 34 (89%) of 38 statements met consensus criteria. This international Delphi approach has defined key areas of consensus that will help guide and streamline clinical management of patients with intracranial germ-cell tumours. Additionally, the Delphi approach identified areas of different understanding and clinical practice internationally in the management of these tumours, areas which should be the focus of future collaborative studies. Such efforts should translate into improved patient outcomes.

Management of paediatric extracranial germ-cell tumours carries a unique set of challenges. Germ-cell tumours are a heterogeneous group of neoplasms that present across a wide age range and vary in site, histology, and clinical behaviour. Patients with germ-cell tumours are managed by a diverse array of specialists. Thus, staging, risk stratification, and treatment approaches for germ-cell tumours have evolved disparately along several trajectories. Paediatric germ-cell tumours differ from the adolescent and adult disease in many ways, leading to complexities in applying age-appropriate, evidence-based care. Suboptimal outcomes remain for several groups of patients, including adolescents, and patients with extragonadal tumours, high tumour markers at diagnosis, or platinum-resistant disease. Survivors have significant long-term toxicities. The challenge moving forward will be to translate new insights from molecular studies and collaborative clinical data into improved patient outcomes. Future trials will be characterised by improved risk-stratification systems, biomarkers for response and toxic effects, rational reduction of therapy for low-risk patients and novel approaches for poor-risk patients, and improved international collaboration across paediatric and adult cooperative research groups.

Introduction Rhabdomyosarcomas (RMS) are the most prevalent form of paediatric soft tissue sarcomas. They arise from skeletal muscle progenitor cells and are divided predominantly into two subtypes, embryonic and alveolar, with relatively poor prognosis. The alveolar subtype appears to be driven by an oncogenic fusion gene protein, typically but not exclusively FOXO1-PAX3 or FOXO1-PAX7. Fusion negative tumours better define the embryonal subtype, with occasional RMS cases where both subtypes histologically appear to coincide. Previously published work on somatic RMS variants associate embryonal RMS with hits in the RAS/AKT pathway (KRAS, NRAS, HRAS, NF1, PIK3CA, PTEN) alongside other cancer-related genes (TP53, FGFR4, FBXW7, BCOR). In this study we generate new whole exome sequencing data and integrate with previously published datasets to study germline predisposition to RMS. Material and methods The study includes 3 published datasets (Shern 2014 – 120 samples; Seki 2015 – 16 samples and Zhang 2015 – 30 samples) in addition to our in-house set (36 tumour-normal pairs of both RMS subtypes, collected in collaboration with the Children’s Cancer and Leukaemia Group tissue bank). Our primary samples were processed using Illumina’s Nextera Rapid Capture kit and sequenced on HiSeq NGS machines. The combined analysis cohort consists of 202 cases of paediatric RMS. Results and discussions A customised bioinformatics pipeline was used for integration of the studied datasets: from raw fastqs through BWA-MEM alignment and GATK-HC joint variant calling. Germline variants passing several quality control filters were pruned for a MAF Conclusion We explored the potential for germline predisposition to RMS as genetic inheritance is common in a number of paediatric cancers. The relative rarity of paediatric RMS prevents sufficiently powered single-centre studies and requires the consolidation of all available data to make meaningful conclusions. We employ this approach to identify new candidate predisposition genes. Expanding our understanding of genes predisposing to rhabdomyosarcomas, could assist earlier diagnosis and therapy for these children, ultimately improving their survival.

This project aimed to assess the accuracy of Tempa-DOT and FeverScan for measuring children's temperatures. Tempa-DOT is a small flat chemical thermometer with 50 dots that change colour at specific temperatures. FeverScan is a liquid crystal strip thermometer with temperature sensitive colour bars that change colour when held against the forehead. Two medical students undertook this study in a hospital in Zambia. They saw most children presented to the hospital over a six-week period and on the children's ward. A mercury thermometer was placed in one axilla, a Tempa-DOT thermometer in the other, and the FeverScan was held on the child's forehead. Data were obtained from 1090 children with a median age of two years. The sensitivity of FeverScan to correctly identify febrile children was 89% and the positive predictive value to detect a fever was 57%. The sensitivity of Tempa-DOT to correctly identify febrile children was 92% and the positive predictive value for detecting febrile children was 86%. Tempa-DOT has a much better predictive value than FeverScan for detecting fever.

Background Making hypothesis-led interrogations of whole-genome transcriptomic datasets is a challenge. Transcriptional modules define specific biological processes, but multiple modules have now been published with overlapping annotations. In this study we aimed to generate and validate the modular discrimination index (MDI) score, ranking the accuracy and resolution of any cell type specific module to assess cellular enrichment in tissues from transcriptional datasets. Methods We made use of publicly available transcriptomic datasets of purified immune cell types to compare the expression of modules annotated to reflect the expression of different immune cells. MDI scores were derived from the relative expression of each module in its annotated cell type, relative to all other cells. Independent datasets from human tissue and blood samples were then used to validate the MDI score in relation to the relative enrichment of different modules' gene expression. Findings We found that 26 T-cell modules varied both in their composition and in their gene expression in a tuberculin skin test, a prototypical T cell driven cell inflammatory process. To address this heterogeneity, we assessed the accuracy of cell-type modules, by calculating MDI scores for all published T cell, B cell, natural killer cell and neutrophil modules. MDI scores strongly predicted each module's ability to show histologically proven cellular enrichment in a variety of independent tissue samples: T cells in psoriatic skin, B cells in lung fibrosis, and neutrophils in erythema nodosum leprosum skin lesions. In addition, MDI scores were also validated in relation to changes in cell frequency in blood: modules with the greatest MDI score were most predictive of each module's association with cell numbers for both high frequency cells (neutrophils r 2 =0·545, p=0·01) and low frequency cells (B cells r 2 =0·865, p=0·01) in blood. Finally, we showed that modules with the highest MDI score elicited the T cell enrichment seen in the tuberculin skin test, whereas this was most often not detected by low MDI scoring modules. Interpretation This study shows that MDI scoring provides a robust and reproducible assessment of a transcriptional module's accuracy and resolution, and should be determined before using modular deconvolution of tissue samples. The MDI scoring framework can be extended and applied across a range of disciplines for which annotated modules could be used to interrogate transcriptional datasets. Funding Wellcome Trust.