Prophylaxis with recombinant factor VIII can prevent joint damage and decrease the frequency of joint and other hemorrhages in young boys with severe hemophilia A. (ClinicalTrials.gov number, NCT00207597 [ClinicalTrials.gov].).

Summary We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors' tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design.

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The Joint Outcome Study Investigators 7Recombinant adeno-associated virus (rAAV) is a promising gene delivery vector and has recently been used in patients with hemophilia. One limitation of AAV application is that most humans have experienced wild-type AAV serotype 2 exposure, which frequently generates neutralizing antibodies (NAbs) that may inhibit rAAV2 vector transduction. Employing alternative serotypes of rAAV vectors may circumvent this problem. We investigated the development of NAbs in early childhood by examining sera gathered prospectively from 62 children with hemophilia A, participating in a multi-institutional hemophilia clinical trial (the Joint Outcome Study). Clinical applications in hemophilia therapy have been suggested for serotypes AAV2, AAV5 and AAV8, therefore NAbs against these serotypes were serially assayed over a median follow-up of 4 years. NAbs prevalence increased during early childhood for all serotypes. NAbs against AAV2 (43.5%) were observed more frequently and at higher titers compared with both AAV5 (25.8%) and AAV8 (22.6%). NAbs against AAV5 or AAV8 were rarely observed in the absence of co-prevalent and higher titer AAV2 NAbs, suggesting that NAbs to AAV5 and AAV8 were detected following AAV2 exposure due to partial cross-reactivity of AAV2-directed NAbs. The results may guide rational design of clinical trials using alternative AAV serotypes and suggest that younger patients who are given AAV gene therapy will benefit from the lower prevalence of NAbs.

Background Pediatric patients experience significant symptoms during cancer treatment. Symptom management is frequently inadequate. We studied perceptions of pediatric oncology care providers regarding early integration of palliative care (PC) for pediatric patients to identify barriers and facilitators that might assist in understanding how care could be improved. Procedures Pediatric oncology providers were recruited to participate in four focus groups. A proposal for early integration of a pediatric palliative care team (PPCT) was presented and followed by a facilitated discussion. Data were analytically categorized into themes by three independent coders using constant comparative analysis and crystallization techniques. A consensus approach was used to indentify final themes. Results Barriers to the proposed care model of early integration of a PPCT included provider role, conflicting philosophy, patient readiness and emotional influence and were more prevalent in the physician participants compared to nurse practitioner, nursing, and social work participants. Facilitators included patient eligibility, improved patient care, education, and evidence-based medicine. Though all participants were invested in providing optimal patient care, physician participants believed the current standard of care model is meeting the needs of patients and family, while the nurse practitioner, nursing, and social work participants working on the same healthcare team believed the proposed care model would improve the overall care of children diagnosed with cancer. Conclusions Differing perceptions among healthcare providers regarding the care of children with cancer suggest that team functioning could be improved. Avenues for pilot testing early integration of PC could provide useful information for a next study.