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Purpose: Germline testing in pediatric cancer presents opportunities and challenges. Understanding family perspectives, experiences, and preferences will optimize integration into routine care., Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched 4 databases for studies exploring perspectives, experiences, and preferences of parents/caregivers and/or patients regarding germline testing of children with cancer. Qualitative and quantitative data were extracted, organized, and summarized by research question and themes., Results: We identified 2286 unique articles, of which 24 were included. Interest in and uptake of testing was high. Families were motivated by altruism and a desire for inheritance/causation information. Testing barriers included psychological concerns, timing of the testing approach if offered at diagnosis or in a high-risk cancer setting and privacy/discrimination. Testing experiences highlighted challenges yet also positive impacts, with results providing psychological relief and informing proactive decision making. Timing preferences varied; however, allowing time to adjust to a new diagnosis was a common theme. Most wanted to receive as many germline sequencing-related results as possible., Conclusion: Findings underscore the importance of integrating germline analyses into pediatric cancer care with flexibility and support for families facing challenges. Where possible, consent should be provided at a time that suits each family's situation with access to information aligning with their needs and preferences., Prospero: CRD42023444890., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Background: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD., Methods: In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions., Findings: We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions., Interpretation: The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD., Funding: The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center., Competing Interests: Declaration of interests ALa reports payment from Alexion, support from Servier and stock from Gilead, outside of the submitted work. AV is co-lead role of the Consortium for Childhood Cancer Predisposition, outside of the submitted work. BH reports payment and stock from Invitae, outside of the submitted work. BC reports participation as data safety and monitoring board member in ReRad Study, participation in the chapter advisory board for Make a Wish Canada Nova Scotia, and participation in the medical advisory committee for Make a Wish Canada, outside of the submitted work. CCP reports grants from St Baldrick's Foundation, outside of the submitted work. DSZ reports consulting fees for Bayer, AstraZeneca, Accendatech, Novartis, Day One, FivePhusion, Alexion, Amgen, and Norgine, outside of the submitted work. DTB reports grants from MSD and Novocure, consulting fees from Nanocarry Therapeutics and Servier, and payment from Servier, outside of the submitted work. EO reports payment and support from Alexion for educational event, outside of the submitted work. EB reports grants from Roche and board participation for Novartis, Alexion and Gilead, outside of the submitted work. FC reports grants from Hall Hunter Foundation (UK), outside of the submitted work. HBF reports payments from Illumina and Sanofi Genzyme, support from Illumina, participation as scientific advisory committee for Sanofi Genzyme, International Gaucher Alliance and Igentify, stock from Igentify, and receipt of materials from Illumina, outside of the submitted work. IW reports grants from Chimerix and payment from COG Partners, outside of the submitted work. IS reports grants from Fondation Saint-Luc and FNRS-CDR, outside of the submitted work. JK reports other financial interests at Servier and PRA Health Sciences, outside of the submitted work. JRG-S reports participation on the board of the Philippine Society of Pediatric Oncology and Philippine Board of Pediatric Oncology, and stock in Macrogenics, Moderna, Mirati Therapeutics, CRISPR Therapeutics, Repligen, Quidelortho, and Shockwave Medical, outside of the submitted work. KJB reports consulting fees from US WorldMeds, Springworks Therapeutics, Alexion, and YmAbs, and payment from Alexion, outside of the submitted work. MS reports grants and support from the Swedish Childhood Cancer Fund, participation as a data safety and monitoring board member for clinical trial NCT05230758, and participation in the Swedish Pediatric CNS tumour group, outside of the submitted work. MAC reports financial support from SUNY Upstate Department of Pediatrics and board participation for Paige's Butterfly Run, outside of the submitted work. MO reports payment from Aptitude Health and participation on a data safety monitoring board or advisory board for Ultragenyx and Abeona, outside of the submitted works. MZ reports payment and support from and board participation for AstraZeneca. NW reports grants from CANSEARCH Foundation, Childhood Cancer Research Switzerland, and the Foundation for Children and Adolescents with Cancer; payment, support, and advisory board participation for Swedish Orphan Biovitrum; and board participation for Childhood Cancer Switzerland, outside of the submitted work. NH reports grants from the National Institutes of Health (NIH) and board participation for Incyte and Pfizer, outside of the submitted work. PCN reports grants from the Canadian Institutes for Health Research (CIHR) Foundation, US Department of Defense, and Garron Family Cancer Centre, outside of the submitted work. RP reports participation in the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer, outside of the submitted work. RT reports consulting fees from Fennec Pharmaceuticals and Day One Biopharmaceuticals and payment from Fennec Pharmaceuticals, outside of the submitted work. SS reports payments from Sanofi Pharmaceuticals and Mylan Pharmaceutical, and board participation for Sanofi Pharmaceuticals, outside of the submitted work. SB reports consulting fees from Hoffmann-La Roche, YmAbs, MAP Biopharma and SERB SAS, and payment from Zschimmer & Schwarz Mohsdorf, outside of the submitted work. UI reports board participation in Pakistan Society of Pediatric Oncology, outside of the submitted work., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: A non-contrast CT head scan (NCCTH) is the most common cross-sectional imaging investigation requested in the emergency department. Advances in computer vision have led to development of several artificial intelligence (AI) tools to detect abnormalities on NCCTH. These tools are intended to provide clinical decision support for clinicians, rather than stand-alone diagnostic devices. However, validation studies mostly compare AI performance against radiologists, and there is relative paucity of evidence on the impact of AI assistance on other healthcare staff who review NCCTH in their daily clinical practice., Methods and Analysis: A retrospective data set of 150 NCCTH will be compiled, to include 60 control cases and 90 cases with intracranial haemorrhage, hypodensities suggestive of infarct, midline shift, mass effect or skull fracture. The intracranial haemorrhage cases will be subclassified into extradural, subdural, subarachnoid, intraparenchymal and intraventricular. 30 readers will be recruited across four National Health Service (NHS) trusts including 10 general radiologists, 15 emergency medicine clinicians and 5 CT radiographers of varying experience. Readers will interpret each scan first without, then with, the assistance of the qER EU 2.0 AI tool, with an intervening 2-week washout period. Using a panel of neuroradiologists as ground truth, the stand-alone performance of qER will be assessed, and its impact on the readers' performance will be analysed as change in accuracy (area under the curve), median review time per scan and self-reported diagnostic confidence. Subgroup analyses will be performed by reader professional group, reader seniority, pathological finding, and neuroradiologist-rated difficulty., Ethics and Dissemination: The study has been approved by the UK Healthcare Research Authority (IRAS 310995, approved 13 December 2022). The use of anonymised retrospective NCCTH has been authorised by Oxford University Hospitals. The results will be presented at relevant conferences and published in a peer-reviewed journal., Trial Registration Number: NCT06018545., Competing Interests: Competing interests: DR, SK and ST are employees of Qure AI. NW declares consultancy fees from InHealth and SM Radiology not related to the current submission. MH declares consultancy fees from Qure AI not related to the current submission. DJL declares an institution grant for additional research activity on a separate product unrelated to the current submission. AN declares another NHSX grant in collaboration with Qure AI for research unrelated to the current submission. SA declares grants from Qure AI for other research activity unrelated to the current submission., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Fever and infection are an important complication of childhood cancer therapy. Most research and guideline development has focussed on febrile neutropenia, with a paucity directed at non-neutropenic fever (NNF). We describe the clinical presentation, management and outcomes of NNF in children with cancer, and externally validate the Esbenshade Vanderbilt (EsVan) clinical decision rules (CDR) to predict bacteraemia., Method: Using a prospective database, retrospective data were collected on consecutive NNF episodes (fever ≥38.0°C and absolute neutrophil count >1.0 cells/mm 3 ). Sensitivity, specificity and area under the receiver operator characteristic curve (AUC-ROC) of the CDR were compared to derivation study., Results: There were 203 NNF episodes occurring in 125 patients. Severe sepsis was uncommon (n = 2, 1%) and bacteraemia occurred in 10 (4.9%, 95% confidence interval [CI]: 2.7%-8.8%) episodes. A confirmed or presumed bacterial infection requiring antibiotics occurred in 31 (15%) patients. Total 202 (99%) episodes received at least one dose of intravenous broad-spectrum antibiotic and 141 (70%) episodes were admitted to hospital. Six (3%) episodes required intensive care unit (ICU)-level care and there were no infection-related deaths. The EsVan 1 rule had an AUC-ROC of 0.67, 80% were identified as low risk, and sensitivity and specificity were 50% and 81.5%, respectively, for a risk threshold of 10%., Conclusions: Serious infection and adverse outcome are uncommon in children with NNF. Many children did not have a bacterial cause of infection identified, but were still treated with broad-spectrum antibiotics and admitted to hospital. National clinical practice guidelines should be developed for this important cohort to enable risk stratification and optimise antibiotic management. Further research is required to determine appropriateness of EsVan CDR in our cohort., (© 2022 Wiley Periodicals LLC.)

Background: The development of high-throughput drug screening (HTS) using primary cultures provides a promising, clinically translatable approach to tailoring treatment strategies for patients with cancer. However, this has been challenging for solid tumors because of often limited amounts of tissue available. In most cases, in vitro expansion is required before HTS, which may lead to overgrowth and contamination by non-neoplastic cells., Methods: In this study, hematoxylin and eosin staining and immunohistochemical staining were performed on 129 cytopathology cases from 95 patients. These cytopathology cases comprised cell block preparations derived from primary tumor specimens or patient-derived xenografts as part of a pediatric precision oncology trial. Cytopathology cases were compared with the morphology and immunohistochemical staining profile of the original tumor. Cases were reported as tumor cells present, equivocal, or tumor cells absent. The HTS results from cytopathologically validated cultures were incorporated into a multidisciplinary tumor board report issued to the treating clinician to guide clinical decision making., Results: On cytopathologic examination, tumor cells were present in 77 of 129 cases (60%) and were absent in 38 of 129 cases (29%), whereas 14 of 129 cases (11%) were equivocal. Cultures that contained tumor cells resembled the tumors from which they were derived., Conclusions: Cytopathologic examination of tumor cell block preparations is feasible and provides detailed morphologic characterization. Cytopathologic examination is essential for ensuring that samples submitted for HTS contain representative tumor cells and that in vitro drug sensitivity data are clinically translatable., (© 2021 American Cancer Society.)

Children with low-grade gliomas have excellent long-term survival outcomes. The development of therapies targeted to the driver mutations along the Mitogen Activated Protein (MAP) kinase signalling pathway are providing long-term stability for many patients with these tumours. Given the frequency of these tumours residing within or near the suprasellar region, our patients commonly suffer from hormone deficiencies. In Australia, the Pharmaceutical Benefits Scheme currently restricts growth hormone therapy to patients who are not being actively treated for cancer, including those receiving targeted therapies. This viewpoint hopes to facilitate an important discussion amongst our colleagues as to whether this should be changed to allow growth hormone to become available to children on chronic tumour suppressive therapy., (© 2021 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

In pediatric low-grade gliomas not amenable to complete resection, various chemotherapy regimens are the mainstream of treatment. An excellent overall survival of these patients makes justification of the intensification of chemotherapy difficult and calls for the development of new strategies. Bevacizumab, a humanized monoclonal antibody directed against Vascular endothelial growth factor (VEGF), has been successfully used in combination with irinotecan in a number of adult and pediatric studies and reports. Fifteen patients at median age of 7 years old (range 3 months to 15 years) were treated with bevacizumab in combination with conventional low-toxicity chemotherapy. The majority had chiasmatic/hypothalamic and midline tumors, seven had confirmed BRAF pathway alterations including neurofibromatosis type 1 (2). Fourteen patients had more than one progression and three had radiotherapy. No deaths were documented, PFS at 11 and 15 months was 71.5% ± 13.9% and 44.7% ± 17.6% respectively. At the end of follow-up 40% of patients has radiologically stable disease, three patients progressed shortly after completion of bevacizumab and two showed mixed response with progression of cystic component. Rapid visual improvement was seen in 6/8 patients, resolution of endocrine symptoms in 2/4 and motor function improvement in 4/6. No relation between histology or BRAF status and treatment response was observed. Treatment-limiting toxicities included grade 4 proteinuria (2) and hypertension (2) managed with cessation (1) and pausing of therapy plus antihypertensives (1). In conclusion, bevacizumab is well tolerated and appears most effective for rapid tumor control to preserve vision and improve morbidity., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The TP53 gene is fundamental to genomic integrity, cell cycle regulation, and apoptosis; it is the most commonly mutated gene in human cancer. Heterozygous germline mutations cause the autosomal dominant cancer predisposition syndrome, Li-Fraumeni Syndrome. Homozygous germline TP53 mutations in humans are rare. We report an infant from a consanguineous family who presented with synchronous malignancies. Remarkably, he carries a homozygous germline TP53 mutation (NM&#95;000546.4:c.52delA), predicted to cause protein truncation. The family history is consistent with Li-Fraumeni syndrome.