Pilot study to determine effect of an altruism intervention focusing on herd immunity to enhance influenza vaccination rates.

OBJECTIVE: A prospective, single-arm clinical trial was conducted to evaluate an altruism-tailored educational intervention to improve parental attitudes and vaccine uptake in vaccine-hesitant parents. METHODS: Vaccine-hesitant parents at two primary care sites, spanning two influenza seasons from 2020 to 2021 were provided an intervention (spoken and written communication) which highlighted altruistic benefits of accepting the seasonal influenza vaccine to optimize herd immunity to help protect pediatric cancer patients. Eligible parents included those with children eligible for the seasonal influenza vaccine, those who were proficient in English, and those with scores on the adjusted Vaccine Hesitancy Scale (aVHS) suggesting vaccine hesitancy (score ≥ 3). Enrollees completed a demographic questionnaire, underwent the educational intervention, and repeated the aVHS. Vaccination status at that visit was assessed. The primary outcome was change in aVHS scores obtained pre- and post-intervention. Influenza vaccine acceptance, along with demographic information, were also analyzed. RESULTS: We enrolled 510 parents of influenza vaccine eligible children and identified 73 vaccine-hesitant parents. There was an overall trend toward lower aVHS score, with a mean change in hesitancy score of -0.4 (P < 0.01). 43/73 (58.9 %) of the cohort experienced a positive effect toward a lower aVHS score, and 27/73 (37.0 %) of vaccine hesitant subjects became non-hesitant on the aVHS. Several demographic characteristics were associated with vaccine hesitancy in the screening population: educational level lower than bachelor's degree (p = 0.03), household income < 400 % of federal poverty level (p < 0.01), unmarried (p = 0.02), and identifying with a political affiliation other than Democrat (p < 0.01). However, no demographic characteristics were significantly associated with an individual becoming non-hesitant. Our altruism-tailored communication approach carried the largest positive impact on the altruism-specific question on the aVHS, decreasing the post-intervention response value by nearly 25 % (P < 0.01). CONCLUSIONS: Our altruism-tailored communication approach significantly improved attitudes regarding childhood influenza vaccine among vaccine-hesitant parents. CLINICALTRIALS: gov Identifier: NCT04568590.

COVID-19-Related Reduction in Emergency Health Care Utilization Among Febrile Pediatric Oncology Patients.

The severe acute respiratory syndrome coronavirus (SARS-CoV-2) pandemic has disrupted normal health care utilization patterns worldwide, including decreasing emergency department (ED) visits for various medical emergencies. We examined whether this pattern was present in febrile pediatric oncology patients. In this single-center cohort study, we conducted a retrospective chart review of ED visits of febrile pediatric oncology patients during the first 4 months of the global SARS-CoV-2 pandemic and compared those data to the same time periods in the previous 2 years. During the first 5 months of the pandemic, 25 pediatric oncology patients with fever visited our ED; 65 children visited during the same time period in 2018; and 60 visited in 2019. Compared with 2018 and 2019, encounters for 2020 were decreased by 62% and 58%, respectively. A significantly higher percentage of febrile pediatric oncology patients (84%) were admitted to our hospital during the pandemic compared the previous years (58%). Of concern is the possibility that fear of exposure to coronavirus disease-19 (COVID-19) at our health care facility prompted caregivers of pediatric oncology patients to avoid seeking care for their child with fever. Consistent communication with families about the life-threatening nature of fever should be prioritized among pediatric oncology providers.

Multi-Cell Type Glioblastoma Tumor Spheroids for Evaluating Sub-Population-Specific Drug Response.

Glioblastoma (GBM) is a lethal, incurable form of cancer in the brain. Even with maximally aggressive surgery and chemoradiotherapy, median patient survival is 14.5 months. These tumors infiltrate normal brain tissue, are surgically incurable, and universally recur. GBMs are characterized by genetic, epigenetic, and microenvironmental heterogeneity, and they evolve spontaneously over time and as a result of treatment. However, tracking such heterogeneity in real time in response to drug treatments has been impossible. Here we describe the development of an in vitro GBM tumor organoid model that is comprised of five distinct cellular subpopulations (4 GBM cell lines that represent GBM subpopulations and 1 astrocyte line), each fluorescently labeled with a different color. These multi-cell type GBM organoids are then embedded in a brain-like hyaluronic acid hydrogel for subsequent studies involving drug treatments and tracking of changes in relative numbers of each fluorescently unique subpopulation. This approach allows for the visual assessment of drug influence on individual subpopulations within GBM, and in future work can be expanded to supporting studies using patient tumor biospecimen-derived cells for personalized diagnostics.

Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes.

Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an "intrinsic" spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. SIGNIFICANCE: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion-positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype.See related commentary by Szulzewsky and Cimino, p. 904.This article is highlighted in the In This Issue feature, p. 890.

Treatment of Pediatric Glioblastoma with Combination Olaparib and Temozolomide Demonstrates 2-Year Durable Response.

For pediatric patients with high-grade gliomas, standard-of-care treatment includes surgery, chemotherapy, and radiation therapy; however, most patients ultimately succumb to their disease. With advances in genomic characterization of pediatric high-grade gliomas, the use of targeted therapies in combination with current treatment modalities offer the potential to improve survival in this patient population. In this report, we present the case of a 3-year-old girl with glioblastoma who continues to experience an exceptional and durable response (>2 years) to the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib. Our patient presented with persistent and progressive seizure activity that upon workup was the result of a large heterogeneously enhancing, mixed cystic and solid mass in the left frontal-parietal-temporal region. Histopathologic analysis of resected tumor tissue confirmed the diagnosis of glioblastoma, and comprehensive genomic profiling demonstrated absence of any BRAF or H3F3A mutations. Genomic profiling, however, did reveal a probable germline heterozygous BRCA2 Lys3326Ter (K3226*) nonsense variant. After debulking surgery, the patient received standard-of-care treatment with radiation and temozolomide. Nine months later the PARP inhibitor olaparib was administered in combination with temozolomide for 16 cycles. This regimen was well tolerated by the patient and serial imaging showed reduction in tumor size. Since completion of the regimen, the patient remains neurologically intact with no evidence of tumor recurrence. To our knowledge, this represents the first case of a pediatric glioblastoma that maintains a durable response to a therapeutic strategy that included the PARP inhibitor olaparib and more generally highlights the potential clinical utility of incorporating these agents into the treatment of pediatric high-grade gliomas. KEY POINTS: Germline mutations detected in pediatric gliomas may represent a cancer predisposition syndrome. Integrating molecular testing into routine clinical care for pediatric patients with glioma is critical to identify therapeutic targets and patients with a cancer predisposition syndrome. Patients with glioma with defects in DNA repair pathway components (e.g., BRCA1/2) may show increased responsiveness to poly (ADP-ribose) polymerase (PARP) inhibitors. Combining PARP inhibitors with temozolomide (standard-of-care treatment) revealed no adverse events or toxicities over the course of 18 months.

Embryonal Tumors of the Central Nervous System in Children: The Era of Targeted Therapeutics.

Embryonal tumors (ET) of the central nervous system (CNS) in children encompass a wide clinical spectrum of aggressive malignancies. Until recently, the overlapping morphological features of these lesions posed a diagnostic challenge and undermined discovery of optimal treatment strategies. However, with the advances in genomic technology and the outpouring of biological data over the last decade, clear insights into the molecular heterogeneity of these tumors are now well delineated. The major subtypes of ETs of the CNS in children include medulloblastoma, atypical teratoid rhabdoid tumor (ATRT), and embryonal tumors with multilayered rosettes (ETMR), which are now biologically and clinically characterized as different entities. These important developments have paved the way for treatments guided by risk stratification as well as novel targeted therapies in efforts to improve survival and reduce treatment burden.

Dexamethasone Chemotherapy Does Not Disrupt Orexin Signaling.

BACKGROUND: Steroid-induced sleep disturbance is a common and highly distressing morbidity for children receiving steroid chemotherapy for the treatment of pediatric acute lymphoblastic leukemia (ALL). Sleep disturbance can negatively impact overall quality of life, neurodevelopment, memory consolidation, and wound healing. Hypothalamic orexin neurons are influential wake-promoting neurons, and disturbances in orexin signaling leads to abnormal sleep behavior. A new class of drug, the orexin receptor antagonists, could be an intriguing option for sleep disorders caused by increased orexinergic output. Our aim was to examine the impact of ALL treatment doses of corticosteroids on the orexin system in rodents and in children undergoing treatment for childhood ALL. METHODS: We administered repeated injections of dexamethasone to rodents and measured responsive orexin neural activity compared to controls. In children with newly diagnosed standard risk B-cell ALL receiving dexamethasone therapy per Children's Oncology Group (COG) induction therapy from 2014-2016, we collected pre- and during-steroids matched CSF samples and measured the impact of steroids on CSF orexin concentration. RESULTS: In both rodents, all markers orexin signaling, including orexin neural output and orexin receptor expression, were preserved in the setting of dexamethasone. Additionally, we did not detect a difference in pre- and during-dexamethasone CSF orexin concentrations in children receiving dexamethasone. CONCLUSIONS: Our results demonstrate that rodent and human orexin physiology is largely preserved in the setting of high dose dexamethasone. The data obtained in our experimental model fail to demonstrate a causative role for disruption of the orexin pathway in steroid-induced sleep disturbance.

Bilateral conjunctival extranodal marginal zone B-cell lymphoma.

Extranodal marginal zone B-cell lymphomas (EMZLs), while relatively common in adults, are rare entities in the pediatric population. A subclass of the typically aggressive non-Hodgkin lymphomas, the few reported pediatric cases indicate that, as in adults, these tumors tend to be indolent. We present a case of EMZL arising in the conjunctivae in a 9-year-old male with bilateral disease. The patient was treated with surgical excision alone and has remained disease-free 6 years after the operation.

dic(7;9)(p11-13;p11).

Dicentric (7;9)(p11-13;p11) is a rare but recurrent abnormality in pediatric and adult precursor B acute lymphoblastic leukemia (B-ALL). The rarity precludes a deep understanding of its biology and associated prognosis. However, recent findings have correlated dic(7;9) and PAX5 mutations, highlighting this cytogenetic event's involvement in leukemogenesis and may also shed light on the overall prognosis of dic(7;9) B-ALL.