Sociodemographic Factors Correlate with Late Stage Pediatric Hodgkin Lymphoma and Rhabdomyosarcoma: A Report from the Children's Oncology Group Registries.

BACKGROUND: We examined association between late stage diagnosis and individual- and community-level characteristics among pediatric Hodgkin lymphoma (HL) and rhabdomyosarcoma (RMS) patients. METHODS: We obtained Children's Oncology Group (COG) data from 1999-2021 including summary stage (local (L), regional (R), distant (D)), tumor subtype, demographics, and ZIP code at diagnosis. We linked ZIP codes to county-level redlining scores (C,D=greatest redlining), Child Opportunity Index (COI), and measures of segregation (racial dissimilarity indices (DI)). Logistic regressions calculated odds ratios for late stage diagnosis, and by race within tumor subtype. RESULTS: 5,933 HL and 2,800 RMS patients were included. Late stage diagnosis of HL was correlated with Black race (ORDistant(D) vs regional/local(R&L)=1.38 [1.13-1.68]), being uninsured (ORD vs R&L=1.38 [1.09-1.75]), and subtype (Nodular sclerosis vs Other HL: ORD vs R&L=1.64 [1.34-2.01], Untyped: ORD vs R&L=1.30 [1.04-1.63]). Late stage rhabdomyosarcoma was correlated with bilingual households (ORDistant/regional(D&R) vs local(L)=2.66 [1.03-6.91]) and tumor type (Alveolar vs Embryonal ORD vs R&L=6.16 [5.00-7.58]. Community-level factors associated with late stage HL were greater Black (OR80-100%=1.83; 95% CI=1.11-3.02) and Hispanic (OR60-79%=1.30; 95%CI=1.05-1.60) DI. Late stage diagnosis for RMS was associated with more redlined census tracts within counties (OR=1.54; 95% CI =1.02-2.35) and low/very low COI (OR=1.21; 95% CI=1.02-1.45). CONCLUSION: Novel markers of community deprivation, such as redlining and racial segregation, likely affect cancer outcomes for children with HL and RMS in this first disparities study using COG registries. IMPACT: The interplay of multilevel risk factors provides important consideration for efforts to improve early detection of pediatric cancer diagnosis.

A novel configuration for providing continuous renal replacement therapy via the ECMO circuit in VV ECMO without alarm adjustment.

BACKGROUND: It is common for patients on venovenous extracorporeal membrane oxygenation (VV ECMO) to require continuous renal replacement therapy (CRRT). This can be done using separate vascular access for the CRRT circuit, by placing the CRRT hemofilter within the ECMO circuit, or through a separate CRRT circuit connected to the ECMO circuit. When a CRRT circuit is connected to the ECMO circuit, the inflow and outflow CRRT limbs can both be placed pre-ECMO pump or the CRRT circuit can span the ECMO pump, with the CRRT inflow post-ECMO pump and the outflow pre-ECMO pump. Both configurations require the CRRT alarms to be inactivated due to high positive pressure experienced post-pump and low negative pressure pre-pump. We describe a novel technique that does not require separate venous access and still allows the CRRT alarms to be activated. TECHNIQUE: The CRRT inflow line is connected to the post-oxygenator de-airing port. The CRRT outflow line is connected to the pre-pump side of the ECMO circuit. Pigtails allow for these connections and act as resistors negating the large range of pressures generated by the ECMO centrifugal pump. RESULTS: We implemented this configuration in 11 patients with 100% success rate allowing for alarms to be maintained in all patients. The median number of interruptions per 100 CRRT days was 11.7. The median CRRT filter lifespan was 2.2 days, and the average blood flow was maintained at 311 mL/min. CONCLUSIONS: This configuration allows for efficient use of CRRT in ECMO patients while maintaining the safety alarms on the CRRT machine.

Multi-pronged analysis of pediatric low-grade glioma reveals a unique tumor microenvironment associated with BRAF alterations.

Pediatric low-grade gliomas (pLGG) comprise 35% of all brain tumors. Despite favorable survival, patients experience significant morbidity from disease and treatments. A deeper understanding of pLGG biology is essential to identify novel, more effective, and less toxic therapies. We utilized single cell RNA sequencing (scRNA-seq), spatial transcriptomics, and cytokine analyses to characterize and understand tumor and immune cell heterogeneity across pLGG. scRNA-seq revealed tumor and immune cells within the tumor microenvironment (TME). Tumor cell subsets revealed a developmental hierarchy with progenitor and mature cell populations. Immune cells included myeloid and lymphocytic cells. There was a significant difference between the prevalence of two major myeloid subclusters between pilocytic astrocytoma (PA) and ganglioglioma (GG). Bulk and single-cell cytokine analyses evaluated the immune cell signaling cascade with distinct immune phenotypes among tumor samples. KIAA1549-BRAF tumors appeared more immunogenic, secreting higher levels of immune cell activators and chemokines, compared to BRAF V600E tumors. Spatial transcriptomics revealed the differential gene expression of these chemokines and their location within the TME. A multi-pronged analysis of pLGG demonstrated the complexity of the pLGG TME and differences between genetic drivers that may influence their response to immunotherapy. Further investigation of immune cell infiltration and tumor-immune interactions is warranted. Key points: There is a developmental hierarchy in neoplastic population comprising of both progenitor-like and mature cell types in both PA and GG.A more immunogenic, immune activating myeloid population is present in PA compared to GG. Functional analysis and spatial transcriptomics show higher levels of immune mobilizing chemokines in KIAA1549-BRAF fusion PA tumor samples compared to BRAF V600E GG samples. Importance of the Study: While scRNA seq provides information on cellular heterogeneity within the tumor microenvironment (TME), it does not provide a complete picture of how these cells are interacting or where they are located. To expand on this, we used a three-pronged approach to better understand the biology of pediatric low-grade glioma (pLGG). By analyzing scRNA-seq, secreted cytokines and spatial orientation of cells within the TME, we strove to gain a more complete picture of the complex interplay between tumor and immune cells within pLGG. Our data revealed a complex heterogeneity in tumor and immune populations and identified an interesting difference in the immune phenotype among different subtypes.

Investigating the Impact of Tumor Biology and Social Determinants on Time to Diagnosis and Stage at Presentation of Wilms Tumor.

Delays in diagnosis and time to diagnosis generally are used interchangeably in cancer disparity research, but these terms may have important differences. Although these terms are related, we hypothesize that time to diagnosis is determined by the aggressiveness of the tumor based on intrinsic factors such as tumor biology, whereas delays in diagnosis are caused by extrinsic factors such as socioeconomic status, leading to presentation at higher stage of disease due to barriers of care. We conducted a retrospective study of 306 patients diagnosed with Wilms tumor at Children's Hospital Colorado between 1971 and 2016 identifying patient barriers as extrinsic markers and using unfavorable histology and loss of heterozygosity as markers of aggressive tumor biology. Multivariable logistic regression was performed. Patients with Medicaid were more likely to present greater than 4 days after initial symptoms compared to those with private insurance, and those with housing concerns were more likely to be diagnosed greater than 9 days from initial symptoms. Tumor biology was noted to be associated with higher stage at diagnosis, but patient barriers were not. These findings suggest the interplay between tumor biology, patient barriers, diagnostic timing, and stage at diagnosis is more complex, multifactorial, and in need of further study.

Medical Record Level-Evaluation of Impact of Demographic and Socioeconomic Factors on Pediatric Neuro-Oncology Outcomes at Children's Hospital Colorado.

Purpose: A medical record-level cohort study to investigate demographic and socioeconomic factors influencing treatment, timing of care, and survival outcomes in pediatric patients diagnosed with central nervous system (CNS) tumors. Methods: Using electronic health records of patients at Children's Hospital Colorado from 1986-2020, we identified 898 patients treated for CNS tumors. The primary outcomes of interest were 5-year survival, timing of diagnosis, and treatment. Multivariable logistic regression and Cox regression were used to identify covariates associated with our outcomes of interest. Results: We found that age, race, tumor type, diagnosis year, and social concerns influenced receipt and timing of treatment. Age, race, patient rural vs. urban residence, and tumor impacted survival outcomes. Time to presentation and treatment were significantly different between White and minority patients. American Indian/Alaska Native and Black patients were less likely to receive chemo compared to White patients (OR 0.28, 0.93 p = 0.037, < 0.001). Patients with 3 + social concerns were more likely to survive after 5 years than children with no or unknown social concerns (OR 1.84, p = 0.011). However, with an adjusted hazards ratio, children with 2 social concerns were less likely to survive to 5 years than children with no or unknown concerns (OR 0.58, p = 0.066). Conclusions: Demographic and socioeconomic factors influence timing of care and survival outcomes in pediatric patients with CNS tumors. Minority status, age, social factors, rural, and urban patients experience differences in care. This emphasizes the importance of considering these factors and addressing disparities to achieve equitable care.

Tumor and immune cell types interact to produce heterogeneous phenotypes of pediatric high-grade glioma.

BACKGROUND: Pediatric high-grade gliomas (PHGG) are aggressive brain tumors with 5-year survival rates ranging from <2% to 20% depending upon subtype. PHGG presents differently from patient to patient and is intratumorally heterogeneous, posing challenges in designing therapies. We hypothesized that heterogeneity occurs because PHGG comprises multiple distinct tumor and immune cell types in varying proportions, each of which may influence tumor characteristics. METHODS: We obtained 19 PHGG samples from our institution's pediatric brain tumor bank. We constructed a comprehensive transcriptomic dataset at the single-cell level using single-cell RNA-Seq (scRNA-Seq), identified known glial and immune cell types, and performed differential gene expression and gene set enrichment analysis. We conducted multi-channel immunofluorescence (IF) staining to confirm the transcriptomic results. RESULTS: Our PHGG samples included 3 principal predicted tumor cell types: astrocytes, oligodendrocyte progenitors (OPCs), and mesenchymal-like cells (Mes). These cell types differed in their gene expression profiles, pathway enrichment, and mesenchymal character. We identified a macrophage population enriched in mesenchymal and inflammatory gene expression as a possible source of mesenchymal tumor characteristics. We found evidence of T-cell exhaustion and suppression. CONCLUSIONS: PHGG comprises multiple distinct proliferating tumor cell types. Microglia-derived macrophages may drive mesenchymal gene expression in PHGG. The predicted Mes tumor cell population likely derives from OPCs. The variable tumor cell populations rely on different oncogenic pathways and are thus likely to vary in their responses to therapy.

Targeting diffuse midline gliomas: The promise of focused ultrasound-mediated blood-brain barrier opening.

Diffuse midline gliomas (DMGs), including diffuse intrinsic pontine glioma, have among the highest mortality rates of all childhood cancers, despite recent advancements in cancer therapeutics. This is partly because, unlike some CNS tumors, the blood-brain barrier (BBB) of DMG tumor vessels remains intact. The BBB prevents the permeation of many molecular therapies into the brain parenchyma, where the cancer cells reside. Focused ultrasound (FUS) with microbubbles has recently emerged as an innovative and exciting technology that non-invasively permeabilizes the BBB in a small focal region with millimeter precision. In this review, current treatment methods and biological barriers to treating DMGs are discussed. State-of-the-art FUS-mediated BBB opening is then examined, with a focus on the effects of various ultrasound parameters and the treatment of DMGs.

Vaccination practices of pediatric oncologists from eight states.

BACKGROUND: Vaccinations are a vital part of routine childhood and adolescent preventive care. We sought to identify current oncology provider practices, barriers, and attitudes towards vaccinating childhood and adolescent cancer patients and survivors. METHODS: We conducted a one-time online survey distributed from March-October 2018 to pediatric oncologists at nine institutions across the United States (N = 111, 68.8% participation rate). The survey included 32 items about vaccination practices, barriers to post-treatment vaccination, availability of vaccinations in oncology clinic, familiarity with vaccine guidelines, and attitudes toward vaccination responsibilities. Descriptive statistics were calculated in STATA 14.2. RESULTS: Participants were 54.0% female and 82.9% white, with 12.6% specializing in Bone Marrow Transplants. Influenza was the most commonly resumed vaccine after treatment (7030%). About 50%-60% were familiar with vaccine guidelines for immunocompromised patients. More than half (62.7%) recommended that patients restart most immunizations 6 months to 1 year after chemotherapy. Common barriers to providers recommending vaccinations included not having previous vaccine records for patients (56.8%) or lacking time to ascertain which vaccines are needed (32.4%). Of participants, 66.7% stated that vaccination should be managed by primary care providers, but with guidance from oncologists. CONCLUSIONS: Many pediatric oncologists report being unfamiliar with vaccine guidelines for immunocompromised patients and almost all report barriers in supporting patients regarding vaccines after cancer treatment. Our findings show that further research and interventions are needed to help bridge oncology care and primary care regarding immunizations after treatment.

MRI-guided focused ultrasound blood-brain barrier opening increases drug delivery and efficacy in a diffuse midline glioma mouse model.

Background: Diffuse intrinsic pontine glioma (DIPG) is the most common and deadliest pediatric brainstem tumor and is difficult to treat with chemotherapy in part due to the blood-brain barrier (BBB). Focused ultrasound (FUS) and microbubbles (MBs) have been shown to cause BBB opening, allowing larger chemotherapeutics to enter the parenchyma. Panobinostat is an example of a promising in vitro agent in DIPG with poor clinical efficacy due to low BBB penetrance. In this study, we hypothesized that using FUS to disrupt the BBB allows higher concentrations of panobinostat to accumulate in the tumor, providing a therapeutic effect. Methods: Mice were orthotopically injected with a patient-derived diffuse midline glioma (DMG) cell line, BT245. MRI was used to guide FUS/MB (1.5 MHz, 0.615 MPa peak negative pressure, 1 Hz pulse repetition frequency, 10-ms pulse length, 3 min treatment time)/(25 µL/kg, i.v.) targeting to the tumor location. Results: In animals receiving panobinostat (10 mg/kg, i.p.) in combination with FUS/MB, a 3-fold increase in tumor panobinostat concentration was observed, without significant increase of the drug in the forebrain. In mice receiving 3 weekly treatments, the combination of panobinostat and FUS/MB led to a 71% reduction of tumor volumes (P = .01). Furthermore, we showed the first survival benefit from FUS/MB improved delivery increasing the mean survival from 21 to 31 days (P < .0001). Conclusions: Our study demonstrates that FUS-mediated BBB disruption can increase the delivery of panobinostat to an orthotopic DMG tumor, providing a strong therapeutic effect and increased survival.

Early death from childhood cancer: First medical record-level analysis reveals insights on diagnostic timing and cause of death.

BACKGROUND: Approximately 7.5% of pediatric cancer deaths occur in the first 30 days post diagnosis, termed early death (ED). Previous database-level analyses identified increased ED in Black/Hispanic patients, infants, late adolescents, those in poverty, and with specific diagnoses. Socioeconomic and clinical risk factors have never been assessed at the medical record level and are poorly understood. METHODS: We completed a retrospective case-control study of oncology patients diagnosed from 1995 to 2016 at Children's Hospital Colorado. The ED group (n = 45) was compared to a non-early death (NED) group surviving >31 days, randomly selected from the same cohort (n = 44). Medical records and death certificates were manually reviewed for sociodemographic and clinical information to identify risk factors for ED. RESULTS: We identified increased ED risk in central nervous system (CNS) tumors and, specifically, high-grade glioma and atypical teratoid/rhabdoid tumor. There was prolonged time from symptom onset to seeking care in the ED group (29.4 vs. 9.8 days) with similar time courses to diagnosis thereafter. Cause of death was most commonly from tumor progression in brain/CNS tumors and infection in hematologic malignancies. CONCLUSIONS: In this first medical record-level analysis of ED, we identified socioeconomic and clinical risk factors. ED was associated with longer time from first symptoms to presentation, suggesting that delayed presentation may be an addressable risk factor. Many individual patient-level risk factors, including socioeconomic measures and barriers to care, were unable to be assessed through record review, highlighting the need for a prospective study to understand and address childhood cancer ED.

Hip Abductor Reconstruction with the Use of Mesh and Distal Cerclage Cable Fixation: A Case Report and Surgical Technique.

CASE: This is a case of a 71-year-old female patient with recurrent instability and complex hip abductor deficiency after total hip arthroplasty (THA) who was treated successfully with an abductor reconstruction with gluteal transfer with mesh reconstruction. The patient returned to nonassisted ambulation with no further THA dislocations at the 1-year follow-up. CONCLUSION: Abductor deficiencies after THA are complex and have a high potential for long-term disability if not properly diagnosed and treated. A modified gluteal transfer with mesh reconstruction and distal fixation with cerclage cable allowed for sustained restoration of functional hip abduction and stability after revision THA.

Mapping pediatric brain tumors to their origins in the developing cerebellum.

BACKGROUND: Distinguishing the cellular origins of childhood brain tumors is key for understanding tumor initiation and identifying lineage-restricted, tumor-specific therapeutic targets. Previous strategies to map the cell-of-origin typically involved comparing human tumors to murine embryonal tissues, which is potentially limited due to species-specific differences. The aim of this study was to unravel the cellular origins of the 3 most common pediatric brain tumors, ependymoma, pilocytic astrocytoma, and medulloblastoma, using a developing human cerebellar atlas. METHODS: We used a single-nucleus atlas of the normal developing human cerebellum consisting of 176 645 cells as a reference for an in-depth comparison to 4416 bulk and single-cell transcriptome tumor datasets, using gene set variation analysis, correlation, and single-cell matching techniques. RESULTS: We find that the astroglial cerebellar lineage is potentially the origin for posterior fossa ependymomas. We propose that infratentorial pilocytic astrocytomas originate from the oligodendrocyte lineage and MHC II genes are specifically enriched in these tumors. We confirm that SHH and Group 3/4 medulloblastomas originate from the granule cell and unipolar brush cell lineages. Radiation-induced gliomas stem from cerebellar glial lineages and demonstrate distinct origins from the primary medulloblastoma. We identify tumor genes that are expressed in the cerebellar lineage of origin, and genes that are tumor specific; both gene sets represent promising therapeutic targets for future study. CONCLUSION: Based on our results, individual cells within a tumor may resemble different cell types along a restricted developmental lineage. Therefore, we suggest that tumors can arise from multiple cellular states along the cerebellar "lineage of origin."

Recurrent atypical teratoid/rhabdoid tumors (AT/RT) reveal discrete features of progression on histology, epigenetics, copy number profiling, and transcriptomics.

Atypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors manifesting in infancy. They split into four molecular types. The major three (AT/RT-SHH, AT/RT-TYR, and AT/RT-MYC) all carry mutations in SMARCB1, the fourth quantitatively smaller type is characterized by SMARCA4 mutations (AT/RT-SMARCA4). Molecular characteristics of disease recurrence or metastatic spread, which go along with a particularly dismal outcome, are currently unclear. Here, we investigated tumor tissue from 26 patients affected by AT/RT to identify signatures of recurrences in comparison with matched primary tumor samples. Microscopically, AT/RT recurrences demonstrated a loss of architecture and significantly enhanced mitotic activity as compared to their related primary tumors. Based on DNA methylation profiling, primary tumor and related recurrence were grossly similar, but three out of 26 tumors belonged to a different molecular type or subtype after second surgery compared to related primary lesions. Copy number variations (CNVs) differed in six cases, showing novel gains on chromosome 1q or losses of chromosome 10 in recurrences as the most frequent alterations. To consolidate these observations, our cohort was combined with a data set of unmatched primary and recurrent AT/RT, which demonstrated chromosome 1q gain and 10 loss in 18% (n = 7) and 11% (n = 4) of the recurrences (n = 38) as compared to 7% (n = 3) and 0% (n = 0) in the primary tumors (n = 44), respectively. Similar to the observations made by DNA methylation profiling, RNA sequencing of our cohort revealed AT/RT primary tumors and matched recurrences clustering closely together. However, a number of genes showed significantly altered expression in AT/RT-SHH recurrences. Many of them are known tumor driving growth factors, involved in embryonal development and tumorigenesis, or are cell-cycle-associated. Overall, our work identifies subtle molecular changes that occur in the course of the disease and that may help define novel therapeutic targets for AT/RT recurrences.

Children's Oncology Group's 2023 blueprint for research: Young investigators.

The Children's Oncology Group (COG) Young Investigators (YI) Committee is an administrative committee in which liaisons represent 30 COG committees, and was created to facilitate the integration of YIs into the organization, and prepare them for future COG leadership roles. The mentorship program has mentored over 400 YIs since 2005 and currently has 175 active participants. The COG YI Master Roster is a database YIs can join, which allows them to post their interests and accomplishments to COG leadership, and 321 YIs have already joined this list. The YI Committee has held virtual symposia designed to describe how COG operates and provide guidance on how YIs can reach their goals; over 300 YIs have attended these since 2021 and have consistently rated them as helpful. Through these and other elements of the program, the YI Committee remains committed to developing a future pipeline of new investigators.

A novel preclinical model of craniospinal irradiation in pediatric diffuse midline glioma demonstrates decreased metastatic disease.

Background: Diffuse midline glioma (DMG) is an aggressive pediatric central nervous system tumor with strong metastatic potential. As localized treatment of the primary tumor improves, metastatic disease is becoming a more important factor in treatment. We hypothesized that we could model craniospinal irradiation (CSI) through a DMG patient-derived xenograft (PDX) model and that CSI would limit metastatic tumor. Methods: We used a BT245 murine orthotopic DMG PDX model for this work. We developed a protocol and specialized platform to deliver craniospinal irradiation (CSI) (4 Gy x2 days) with a pontine boost (4 Gy x2 days) and compared metastatic disease by pathology, bioluminescence, and MRI to mice treated with focal radiation only (4 Gy x4 days) or no radiation. Results: Mice receiving CSI plus boost showed minimal spinal and brain leptomeningeal metastatic disease by bioluminescence, MRI, and pathology compared to mice receiving radiation to the pons only or no radiation. Conclusion: In a DMG PDX model, CSI+boost minimizes tumor dissemination compared to focal radiation. By expanding effective DMG treatment to the entire neuraxis, CSI has potential as a key component to combination, multimodality treatment for DMG designed to achieve long-term survival once novel therapies definitively demonstrate improved local control.

Identifying patterns of neurocognitive dysfunction through direct comparison of children with leukemia, central nervous system tumors, and sickle cell disease.

PURPOSE: To quantify and compare the magnitude and type of neurocognitive dysfunction in at-risk children with central nervous system (CNS) tumors, acute lymphoblastic leukemia (ALL), and sickle cell disease (SCD) using a common instrument and metric to directly compare these groups with each other. METHODS: Fifty-three participants between the ages of 7 and 12 years (n = 27 ALL, n = 11 CNS tumor, n = 15 SCD) were enrolled and assessed using the NIH Toolbox Cognition Battery (NIHTCB). Participants with ALL or CNS tumor were 0-18 months posttherapy, while participants with SCD possessed the SS or Sß0 genotype, took hydroxyurea, and had no known history of stroke. RESULTS: Independent sample t-tests showed that participants with ALL and CNS tumor experienced greatest deficits in processing speed (ALL d = -0.96; CNS tumor d = -1.2) and inhibitory control and attention (ALL d = -0.53; CNS tumor d = -0.97) when compared with NIHTCB normative data. Participants with SCD experienced deficits in cognitive flexibility only (d = -0.53). Episodic memory was relatively spared in all groups (d = -0.03 to -0.32). There were no significant differences in function when groups were compared directly with each other by analysis of variance. CONCLUSIONS: Use of a common metric to quantify the magnitude and type of neurocognitive dysfunction across at-risk groups of participants by disease shows that participants perform below age-expected norms in multiple domains and experience dysfunction differently than one another. This approach highlights patterns of dysfunction that can inform disease- and domain-specific interventions.

MRI-Guided Focused Ultrasound Blood-Brain Barrier Opening Increases Drug Delivery and Efficacy in a Diffuse Midline Glioma Mouse Model.

Diffuse intrinsic pontine glioma (DIPG) is the most common and deadliest pediatric brainstem tumor and is difficult to treat with chemotherapy in part due to the blood-brain barrier (BBB). Focused ultrasound (FUS) and microbubbles (MBs) have been shown to cause BBB disruption (BBBD), allowing larger chemotherapeutics to enter the parenchyma. Panobinostat is an example of a promising in vitro agent in DIPG with poor clinical efficacy due to low BBB penetrance. In this study, we hypothesized that using FUS to disrupt the BBB allows higher concentrations of panobinostat to accumulate in the tumor, providing a therapeutic effect. Mice were orthotopically injected with a patient-derived DMG cell line, BT-245. MRI was used to guide FUS/MB (1.5 MHz, 0.615 MPa PNP, 1 Hz PRF, 10 ms PL, 3 min treatment time) / (25 µL/kg, IV) targeting to the tumor location. In animals receiving panobinostat (10 mg/kg, IP) in combination with FUS/MB, a 3-fold increase in tumor panobinostat concentration was observed, with only insignificant increase of the drug in the forebrain. In mice receiving three weekly treatments, the combination of panobinostat and FUS/MB led to a 71% reduction of tumor volumes by MRI ( p = 0.01). Furthermore, FUS/MB improved the mean survival from 21 to 31 days ( p < 0.0001). Our study demonstrates that FUS-mediated BBBD can increase the delivery of panobinostat to an orthotopic DMG tumor, providing a strong therapeutic effect and increased survival. One Sentence Summary: FUS and microbubbles can increase the delivery of panobinostat to a patient-derived xenograft (PDX) orthotopic DMG tumor, providing a strong therapeutic effect and increased survival.

Risk of early death in adolescents and young adults with cancer: a population-based study.

BACKGROUND: Advancements in treatment and supportive care have led to improved survival for adolescents and young adults (AYAs) with cancer; however, a subset of those diagnosed remain at risk for early death (within 2 months of diagnosis). Factors that place AYAs at increased risk of early death have not been well studied. METHODS: The Surveillance, Epidemiology, and End Results registry was used to assess risk of early death in AYAs with hematologic malignancies, central nervous system tumors, and solid tumors. Associations between age at diagnosis, sex, race, ethnicity, socioeconomic status, insurance status, rurality, and early death were assessed. RESULTS: A total of 268 501 AYAs diagnosed between 2000 and 2016 were included. Early death percentage was highest in patients diagnosed with hematologic malignancies (3.1%, 95% confidence interval [CI] = 2.9% to 3.2%), followed by central nervous system tumors (2.5%, 95% CI = 2.3% to 2.8%), and solid tumors (1.0%, 95% CI = 0.9% to 1.0%). Age at diagnosis, race, ethnicity, lower socioeconomic status, and insurance status were associated with increased risk of early death in each of the cancer types. For AYAs with hematologic malignancies and solid tumors, risk of early death decreased statistically significantly over time. CONCLUSIONS: A subset of AYAs with cancer remains at risk for early death. In addition to cancer type, sociodemographic factors also affect risk of early death. A better understanding of the interplay of factors related to cancer type, treatment, and health systems that place certain AYA subsets at higher risk for early death is needed to address these disparities and improve outcomes.

Sociodemographic Disparities in Presentation and Survival of Pediatric Bone Cancers.

Osteosarcoma (OST) and Ewing sarcoma (ES) are the most common pediatric bone cancers. Patients with metastatic disease at diagnosis have poorer outcomes compared with localized disease. Using the Surveillance, Epidemiology, and End Results registries, we identified children and adolescents diagnosed with OST or ES between 2004 and 2015. We examined whether demographic and socioeconomic disparities were associated with a higher likelihood of metastatic disease at diagnosis and poor survival outcomes. In OST, Hispanic patients and those living in areas of high language isolation were more likely to have metastatic disease at diagnosis. Regardless of metastatic status, OST patients with public insurance had increased odds of death compared to those with private insurance. Living in counties with lower education levels increased odds of death for adolescents with metastatic disease. In ES, non-White adolescents had higher odds of death compared with white patients. Adolescents with metastatic ES living in higher poverty areas had increased odds of death compared with those living in less impoverished areas. Disparities in both diagnostic and survival outcomes based on race, ethnicity, and socioeconomic factors exist in pediatric bone cancers, potentially due to barriers to care and treatment inequities.