Germline genome sequencing in childhood cancer precision medicine trials may reveal pathogenic or likely pathogenic variants in cancer predisposition genes in more than 10% of children. These ...findings can have implications for diagnosis, treatment, and the child's and family's future cancer risk. Understanding parents' perspectives of germline genome sequencing is critical to successful clinical implementation.
A total of 182 parents of 144 children (<18 years of age) with poor-prognosis cancers enrolled in the Precision Medicine for Children with Cancer trial completed a questionnaire at enrollment and after the return of their child's results, including clinically relevant germline findings (received by 13% of parents). Parents' expectations of germline genome sequencing, return of results preferences, and recall of results received were assessed. Forty-five parents (of 43 children) were interviewed in depth.
At trial enrollment, most parents (63%) believed it was at least "somewhat likely" that their child would receive a clinically relevant germline finding. Almost all expressed a preference to receive a broad range of germline genomic findings, including variants of uncertain significance (88%). Some (29%) inaccurately recalled receiving a clinically relevant germline finding. Qualitatively, parents expressed confusion and uncertainty after the return of their child's genome sequencing results by their child's clinician.
Many parents of children with poor-prognosis childhood cancer enrolled in a precision medicine trial expect their child may have an underlying cancer predisposition syndrome. They wish to receive a wide scope of information from germline genome sequencing but may feel confused by the reporting of trial results.
Background: Fetal Lung Interstitial Tumor (FLIT) is a rare benign lung tumor. There have been 18 cases of FLIT described in the literature. FLIT is characterized by a region of arrested lung ...development and must be differentiated from other congenital lung lesions with poorer prognoses.
Case Presentation: We report the first two known cases of FLIT in Australia and New Zealand. In both cases, the patients developed respiratory distress at birth requiring intubation. Imaging revealed solid lesions and echocardiography demonstrated pulmonary hypertension. The patients underwent surgical resection without any complications or recurrence.
Conclusion: FLIT is a rare benign congenital lung tumor that can be adequately managed with surgical resection.
Acquired TP53 alterations are present in > 90% of cases of paediatric low-hypodiploid acute lymphoblastic leukaemia (ALL), and ≈ 50% of patients with this subtype harbor germline pathogenic / likely ...pathogenic (P/LP) TP53 alterations. Despite dose intensified, conventional chemotherapy, survival in low-hypodiploid ALL remains dismal compared to other paediatric ALL. Individuals with underlying Li-Fraumeni Syndrome (LFS) are known to have increased sensitivity to genotoxic effect of chemotherapy and radiotherapy. Recent evidence shows a 25.1% 5-year cumulative incidence of SMNs post ALL therapy in an LFS population as compared to 0.7% in patients with either a wild type or VUS TP53. The parallel high risks of both relapse and SMN present unpalatable choices facing clinicians.
The Zero Childhood Cancer Program is a precision medicine program to benefit children with poor-outcome, rare, relapsed or refractory cancer. Using tumor and germline whole genome sequencing (WGS) ...and RNA sequencing (RNAseq) across 252 tumors from high-risk pediatric patients with cancer, we identified 968 reportable molecular aberrations (39.9% in WGS and RNAseq, 35.1% in WGS only and 25.0% in RNAseq only). Of these patients, 93.7% had at least one germline or somatic aberration, 71.4% had therapeutic targets and 5.2% had a change in diagnosis. WGS identified pathogenic cancer-predisposing variants in 16.2% of patients. In 76 central nervous system tumors, methylome analysis confirmed diagnosis in 71.1% of patients and contributed to a change of diagnosis in two patients (2.6%). To date, 43 patients have received a recommended therapy, 38 of whom could be evaluated, with 31% showing objective evidence of clinical benefit. Comprehensive molecular profiling resolved the molecular basis of virtually all high-risk cancers, leading to clinical benefit in some patients.
Recently, several authors have reported specific criteria to support the widely accepted use of a convex operational model for bulk energy storage in the formulation of power system operation and ...planning problems involving binary variables. Using two counterexamples, we show that this modeling simplification may give rise to impractical solutions featuring simultaneous charging and discharging, even though the recently published criteria are satisfied. Thus, both counterexamples invalidate those criteria and demonstrate that the customarily used convex model may be unsuitable for the precise incorporation of bulk storage in such instances of mixed-integer programming.
IntroductionIdentifying an underlying germline cancer predisposition (CP) in a child with cancer has potentially significant implications for both the child and biological relatives. Cohort studies ...indicate that 10%–15% of paediatric cancer patients carry germline pathogenic or likely pathogenic variants in cancer predisposition genes, but many of these patients do not meet current clinical criteria for genetic testing. This suggests broad tumour agnostic germline testing may benefit paediatric cancer patients. However, the utility and psychosocial impact of this approach remain unknown. We hypothesise that an approach involving trio whole-genome germline sequencing (trio WGS) will identify children and families with an underlying CP in a timely fashion, that the trio design will streamline cancer risk counselling to at-risk relatives if CP was inherited, and that trio testing will not have a negative psychosocial impact on families.Method and analysisTo test this, we present the Cancer PREDisposition In Childhood by Trio sequencing study (PREDICT). This study will assess the clinical utility of trio WGS to identify CP in unselected patients with cancer 21 years or younger in New South Wales, Australia. PREDICT will perform analysis of biological parents to determine heritability and will examine the psychosocial impact of this trio sequencing approach. PREDICT also includes a broad genomics research programme to identify new candidate genes associated with childhood cancer risk.Ethics and disseminationBy evaluating the feasibility, utility and psychosocial impact of trio WGS to identify CP in paediatric cancer, PREDICT will inform how such comprehensive testing can be incorporated into a standard of care at diagnosis for all childhood cancer patients.Trial registration numberNCT04903782.
Germline testing in pediatric cancer presents opportunities and challenges. Understanding family perspectives, experiences, and preferences will optimize integration into routine care.
Following ...PRISMA guidelines, we searched four 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 was extracted, organized, and summarized by research question and themes.
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.
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.
LBA12068
Background: There is limited published data regarding safety and toxicity of Sars-CoV-2 vaccination in patients with cancer. This may contribute to vaccine hesitancy amongst some members of ...this vulnerable cohort (Nguyen 2022). Methods: SerOzNET (ACTRN12621001004853) is a large prospective cohort study of adults and children with cancer undergoing Sars-CoV-2 vaccination. Participants undertake surveys by text message link sent to their mobile phone, or on an iPad provided in clinic. A validated hesitancy survey is undertaken at enrolment (Oxford COVID-19 Vaccine Confidence and Complacency Scale), and prior to the 3
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vaccine dose. For children, a parental survey is also collected. Quality of life is assessed with serial EORTC QLQ-C30 (adults) or PedsQL (children, self- and parent- report) at baseline and serially throughout the study. Patient- reported vaccine toxicity is assessed by patient-reported CTCAE items for common vaccine related AEs and patient-reported impact of vaccination on cancer treatment (delays, hospitalisations). Medically ascertained vaccine toxicity is assessed by study investigators one month after the 3
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vaccination dose. Results: Five hundred and four participants have been enrolled (403 adults (80%) and 101 children (20%)). Hesitancy: At baseline, 351 adults (88%) and 56 children (55%) responded. The adult cohort was predominantly female (67.2%) with an average age of 53.8 years. Preliminary analysis showed similar levels of vaccination concerns between baseline (mean score = 18.4, SD = 5.1) and follow-up pre-3
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dose (mean score = 17.9, SD = 5.7) in adults. We will present results regarding whether self-reported COVID-19 vaccine toxicity after the first dose was related to change in hesitancy scores at follow-up, which may have implications for COVID-19 vaccine booster willingness. Patient toxicity surveys have been returned post dose 1 for 445/497 (91%), post dose 2 for 417/457 (91%) and post dose 3 for 280/334 (84%). Incidence of any AEs was high (77-100% depending on age and dose), however the incidence of severe AEs (patient reported) was low (0-10% depending on age and dose). Interruptions to cancer treatment after vaccination were uncommon (2-12%). Pain at the injection site was the most commonly reported AE for all ages and doses. Hospital admissions (any reason) were reported post dose 1 in 4/15 children aged 5-12, but were uncommon in older adolescents and adults. The most common systemic adverse effect was rigors in children 5-12, while adolescents and adults reported fatigue most frequently. Quality of life analysis is ongoing and will be presented at the meeting. Conclusions: It is feasible to collect detailed toxicity and quality of life data in a large cohort of cancer patients receiving COVID-19 vaccinations. Data to date are reassuring that severe adverse events and interruptions to cancer therapy are uncommon. Clinical trial information: ACTRN12621001004853.
Abstract
Noonan Syndrome (NS) is a genetic condition, known to be associated with low grade central nervous system tumours in children but only very rarely associated with high-grade gliomas. Here we ...describe the first reported case of a spinal high-grade astrocytoma with piloid features (HGAP) in a child with NS. This case presented as a diagnostic and treatment dilemma, prior to comprehensive molecular profiling with whole-genome germline and tumour sequencing, tumour transcriptome sequencing and DNA methylation analysis. The methylation profile was a strong match for HGAP and was critical to establish this child’s diagnosis, as this is an essential diagnostic criteria for confirmation of this relatively new tumour group. Sequencing results identified activation of the MAPK signalling pathway with somatic variants in FGFR1 and NF1 and the previously known germline pathogenic variant in PTPN11. The somatic molecular profile was consistent with those previously reported in other HGAP case series and reports, whereas the germline finding has not been previously described in individuals with this tumour type. This patient’s molecular profile adds to the small group of paediatric cases reported in the literature, continuing to expand our understanding of this new WHO diagnostic category. Confirmation of this rare diagnosis was critical to this child’s management and targetable aberrations were identified, providing alternative therapeutic options. The therapeutic targets included known drivers within the MAPK pathway, but also changes not previously associated with HGAP such as differential expression of VEGFA and PD-L1. Together this case underscores the power of precision medicine from a diagnostic, therapeutic and clinical management perspective, and describes an association between HGAP and NS which has not previously been reported.
