Collaborative Innovations in Childhood Cancer Therapies.

The outcome for children with cancer has improved significantly over the past 60 years, with more than 80% of patients today becoming 5-year survivors. Despite this progress, cancer remains the leading cause of death from disease in children in the United States and Europe, with significant short- and long-term toxicity of treatment continuing to impact most children. While the past 15 years have witnessed dramatic scientific innovation for certain cancers in adult patients, pediatric cancer treatment innovation lags increasingly behind.

Rescuing Drugs That are Discontinued in Adult Oncology Development for the Benefit of Children and Adolescents With Cancer - An ACCELERATE Multistakeholder Consensus.

Better therapies for childhood cancer remain an unmet need to improve the dismal prognosis of certain malignancies and to reduce the burden of toxicity. Rescuing discontinued or shelved drugs for children, adolescents, and young adults is a strategy to identify new uses for approved or investigational medicines outside the scope of their original medical indication. Our proposed multistakeholder consensus focuses on the development of innovative, patent-protected targeted agents, sourced from previously shelved or discontinued programs that have the potential to provide significant benefit to underserved patient populations, with unmet medical needs.

Model-Informed Precision Dosing Guidance of Ethosuximide Developed from a Randomized Controlled Clinical Trial of Childhood Absence Epilepsy.

Ethosuximide was identified as the optimal option for new-onset childhood absence epilepsy (CAE) in a randomized, two-phase dose escalation comparative effectiveness trial of ethosuximide, lamotrigine, and valproic acid. However, 47% of ethosuximide initial monotherapy participants experienced short-term treatment failure. This study aimed to characterize the initial monotherapy ethosuximide exposure-response relationship and to propose model-informed precision dosing guidance.

Global Perspectives on Beauty.

Beauty is a mystical and powerful, indeed existential, force. Beauty can be described philosophically, quantified mathematically, and defined biologically. Our individual attractiveness confers real benefits and impacts our reproductive success.

Rates of laboratory adverse events by course in paediatric leukaemia ascertained with automated electronic health record extraction: a retrospective cohort study from the Children's Oncology Group.

Background: Adverse events are often misreported in clinical trials, leading to an incomplete understanding of toxicities. We aimed to test automated laboratory adverse event ascertainment and grading (via the ExtractEHR automated package) to assess its scalability and define adverse event rates for children with acute myeloid leukaemia and acute lymphoblastic leukaemia.

Methods: For this retrospective cohort study from the Children's Oncology Group (COG), we included patients aged 0-22 years treated for acute myeloid leukaemia or acute lymphoblastic leukaemia at Children's Healthcare of Atlanta (Atlanta, GA, USA) from Jan 1, 2010, to Nov 1, 2018, at the Children's Hospital of Philadelphia (Philadelphia, PA, USA) from Jan 1, 2011, to Dec 31, 2014, and at the Texas Children's Hospital (Houston, TX, USA) from Jan 1, 2011, to Dec 31, 2014.

Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: a phase 1b/2 trial.

CEP290-associated Leber congenital amaurosis type 10 (LCA10) is a retinal disease resulting in childhood blindness. Sepofarsen is an RNA antisense oligonucleotide targeting the c.2991+1655A>G variant in the CEP290 gene to treat LCA10.

ACCELERATE - Five years accelerating cancer drug development for children and adolescents.

Rapid evaluation and subsequent regulatory approval of new drugs are critical to improving survival and reducing long-term side-effects for children and adolescents with cancer. The international multi-stakeholder organisation ACCELERATE was created to advance the timely investigation of new anti-cancer drugs. ACCELERATE has enhanced communication and understanding between academia, industry, patient advocates and regulators.

Dose-Adjusted Etoposide, Doxorubicin, and Cyclophosphamide With Vincristine and Prednisone Plus Rituximab Therapy in Children and Adolescents With Primary Mediastinal B-Cell Lymphoma: A Multicenter Phase II Trial.

Purpose: A dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone plus rituximab (DA-EPOCH-R) regimen has been shown to deliver excellent survival for adults with primary mediastinal large B-cell lymphoma (PMLBL) without the use of radiotherapy. No international prospective evaluation of this regimen has previously been reported in children and adolescents.

Patients And Methods: We conducted an international single-arm phase II trial involving patients younger than age 18 years with PMLBL who were to receive six courses of DA-EPOCH-R.

Phase I/II trial of vorinostat and radiation and maintenance vorinostat in children with diffuse intrinsic pontine glioma: A Children's Oncology Group report.

Background: A phase I/II trial of vorinostat (suberoylanilide hydroxamic acid), an oral histone deacetylase inhibitor, was conducted in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) through the Children's Oncology Group (COG) to: 1) determine the recommended phase II dose (RP2D) of vorinostat given concurrently with radiation therapy; 2) document the toxicities of continuing vorinostat as maintenance therapy after radiation; and 3) to determine the efficacy of this regimen by comparing the risk of progression or death with a historical model from past COG trials.

Methods: Vorinostat was given once daily, Monday through Friday, during radiation therapy (54 Gy in 30 fractions), and then continued at 230 mg/m2 daily for a maximum of twelve 28-day cycles.

Results: Twelve patients enrolled in the phase I study; the RP2D of vorinostat given concurrently with radiation was 230 mg/m2/day, Monday through Friday weekly.

First Metatarsal Phalangeal Joint Arthrodesis without the Use of Hardware after Failed Arthroplasty: A Case Report.

Introduction: First metatarsal phalangeal joint (MTPJ) arthroplasty has a high failure rate due to aseptic loosening, which leads to bone loss. The salvage procedure is conversion to an arthrodesis, but bone loss can make obtaining screw fixation difficult. Herein, we report a unique case of revision first-metatarsal arthrodesis without the use of hardware after a failed arthroplasty.

Antisense oligonucleotide-based treatment of retinitis pigmentosa caused by USH2A exon 13 mutations.

Mutations in USH2A are among the most common causes of syndromic and non-syndromic retinitis pigmentosa (RP). The two most recurrent mutations in USH2A, c.2299delG and c.

Activity of Crizotinib in Patients with ALK-Aberrant Relapsed/Refractory Neuroblastoma: A Children's Oncology Group Study (ADVL0912).

Purpose: Anaplastic lymphoma kinase (ALK) aberrations are a promising target for patients with neuroblastoma. We assessed the activity of first-generation ALK inhibitor crizotinib in patients with no known curative treatments and whose tumors harbored an activating ALK alteration.

Patients And Methods: Twenty patients with relapsed/refractory ALK-positive neuroblastoma received crizotinib at the recommended phase II dose of 280 mg/m/dose.

Safety, tolerability and pharmacokinetics of crizotinib in combination with cytotoxic chemotherapy for pediatric patients with refractory solid tumors or anaplastic large cell lymphoma (ALCL): a Children's Oncology Group phase 1 consortium study (ADVL1212).

Purpose: This phase 1 study aimed to determine the safety, tolerability and recommended phase 2 dose (RP2D) of crizotinib in combination with cytotoxic chemotherapy for children with refractory solid tumors and ALCL.

Methods: Pediatric patients with treatment refractory solid tumors or ALCL were eligible. Using a 3 + 3 design, crizotinib was escalated in three dose levels: 165, 215, or 280 mg/m/dose BID.

Paediatric Strategy Forum for medicinal product development of epigenetic modifiers for children: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

The fifth multistakeholder Paediatric Strategy Forum focussed on epigenetic modifier therapies for children and adolescents with cancer. As most mutations in paediatric malignancies influence chromatin-associated proteins or transcription and paediatric cancers are driven by developmental gene expression programs, targeting epigenetic mechanisms is predicted to be a very important therapeutic approach in paediatric cancer. The Research to Accelerate Cures and Equity (RACE) for Children Act FDARA amendments to section 505B of the FD&C Act was implemented in August 2020, and as there are many epigenetic targets on the FDA Paediatric Molecular Targets List, clinical evaluation of epigenetic modifiers in paediatric cancers should be considered early in drug development.

Paediatric Strategy Forum for medicinal product development for acute myeloid leukaemia in children and adolescents: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

Purpose: The current standard-of-care for front-line therapy for acute myeloid leukaemia (AML) results in short-term and long-term toxicity, but still approximately 40% of children relapse. Therefore, there is a major need to accelerate the evaluation of innovative medicines, yet drug development continues to be adult-focused. Furthermore, the large number of competing agents in rare patient populations requires coordinated prioritisation, within the global regulatory framework and cooperative group initiatives.

Pediatric cancer research: Surviving COVID-19.

A diverse panel of pediatric cancer advocates and experts, whose collective experience spans the continuum of international academic medicine, industry, government research, and cancer advocacy, recently discussed challenges for pediatric cancer research in the context of coronavirus disease 2019 (COVID-19). Specifically, this special report addresses the following focus areas: (a) the critical role that translational research has played in transforming pediatric cancer outcomes; (b) the current and potential future impact of COVID-19 on pediatric cancer research; (c) target areas of COVID-19 research that may have application in immunity, oncogenesis, and therapeutic discovery; and (d) future considerations and directions in maintaining pediatric cancer research during and after COVID-19.

Rituximab for High-Risk, Mature B-Cell Non-Hodgkin's Lymphoma in Children.

Background: Rituximab added to chemotherapy prolongs survival among adults with B-cell cancer. Data on its efficacy and safety in children with high-grade, mature B-cell non-Hodgkin's lymphoma are limited.

Methods: We conducted an open-label, international, randomized, phase 3 trial involving patients younger than 18 years of age with high-risk, mature B-cell non-Hodgkin's lymphoma (stage III with an elevated lactate dehydrogenase level or stage IV) or acute leukemia to compare the addition of six doses of rituximab to standard lymphomes malins B (LMB) chemotherapy with standard LMB chemotherapy alone.

The safety of foot and ankle procedures at an ambulatory surgery center.

Background: This study evaluates the safety of foot and ankle outpatient surgeries at a freestanding ambulatory surgery centers.

Methods: A total of 1352 cases were evaluated for adverse events in a retrospective review of all foot and ankle cases performed over a 5-year period at a single center.

Results: The rate of adverse events was 2.