Pediatric Cancer Mortality Research Articles

Pediatric cancer mortality: Analyzing early deaths and fatalities in a resource-limited tertiary care context.

Children with suspected cancer may succumb to their bad condition shortly after admission, even before a definitive diagnosis can be reached. We aimed to address the issue of delayed presentation and early deaths among children suspected of having cancer. We analyzed also the types and causes of mortalities across different tumor types. A retrospective review of reports from newly admitted patients between 2006 and 2010 at the pediatric oncology department of the South Egypt Cancer Institute (SECI) was done. Parameters included age, gender, diagnosis, symptoms, the interval between initial symptoms and the first visit to SECI, the duration from admission to death, and the cause of death. Among the 502 patients with confirmed malignancies, 238 (47.4%) succumbed. Causes of death were predominantly treatment-related mortalities (TRM) (66%). Mortalities within hematological malignancies were mainly TRM (81%), whereas solid tumors were primarily disease-related (70%), p <0.0001. The leading causes of TRM was infection (60%). About 5% of patients experienced early death within 48 hours after presenting to SECI. The mean duration from initial symptoms to the first SECI visit was 67 days, and the period from admission to death averaged 27 hours. Common initial symptoms included abdominal swelling (29.6%), or fever (26%). The leading causes of death were respiratory failure (29.6%), tumor lysis syndrome (22%), or septicemia (22%). Delayed presentation leading to early deaths poses a significant obstacle to the successful treatment of childhood cancers. Early diagnosis and improved supportive care are essential to enhancing the overall survival, particularly in patients with hematologigical malignancies.

Temporal trends in pediatric cancer mortality: rare cancers lag behind more common cancers

Temporal trends demonstrate improved survival for many types of common pediatric cancer. Studies have not examined improvement in very rare pediatric cancers or compared these improvements to more common cancers. In this cohort study of the Surveillance, Epidemiology, and End Results (SEER) registry, we examined patients from 1975 to 2016 who were 0–19 years of age at the time of diagnosis. Cancers were grouped by decade of diagnosis and 3 cancer frequency groups: Common, Intermediate, and Rare. Trends in mortality across decades and by cancer frequency were compared using Kaplan–Meier curves and adjusted Cox proportional hazards models. A total of 50,222 patients were available for analysis, with the top 10 cancers grouped as Common (67%), 13 cancers grouped with Intermediate (24%), and 37 cancers as Rare (9%). Rare cancers had higher rates of children who were older and Black. 5-year survival increased from 63% to 86% across all cancers from the 1970s to the 2010s. The hazard ratio (HR) for mortality decreased from the reference point of 1 in the 1970s to 0.27 (95% CI: 0.25-0.30) in the 2010s in Common cancers, while the HR only dropped to 0.60 (0.49–0.73) over that same period for rare cancers. Pediatric oncology patients have experienced dramatic improvement in mortality since the 1970s, with mortality falling by nearly 75% in common cancers. Unfortunately, rare pediatric cancers continue to lag behind more common and therefore better studied cancers, highlighting the need for a renewed focus on research efforts for children with these rare diseases.

Evaluation of sonobiopsy feasibility and safety in a mouse model of diffuse intrinsic pontine glioma

Diffuse intrinsic pontine glioma (DIPG) is a leading cause of pediatric brain cancer mortality, emphasizing the need for precise molecular diagnosis to advance therapeutic development. The tumor's location in the brainstem poses challenges for invasive biopsy, prompting the exploration of liquid biopsies. However, both blood-based and cerebrospinal fluid (CSF)-based liquid biopsies exhibit limited sensitivity in diagnosing DIPG. Sonobiopsy, an innovative technique utilizing focused ultrasound and microbubbles, aims to enhance the sensitivity of liquid biopsies. This study assessed the feasibility and safety of sonobiopsy in a DIPG mouse model. The model was established by intracranial injection of enhanced green-fluorescent-protein (eGFP) transduced DIPG tumor cells. Mice were divided into sonobiopsy and conventional liquid biopsy groups. Sonobiopsy, employing MRI-guided focused ultrasound and microbubbles, demonstrated increases in plasma and CSF eGFP DNA, RNA, and protein concentrations compared to conventional liquid biopsy. The enrichment effect varied based on the biomarker type. No observed hemorrhage or tissue damage attributed to sonication suggests the safety of this approach. These results affirm the feasibility and safety of sonobiopsy in enriching DIPG-specific biomarkers in both plasma and CSF, suggesting sonobiopsy as a promising noninvasive molecular diagnostic tool for DIPG.

An Update on Emergent Nano-Therapeutic Strategies against Pediatric Brain Tumors.

Pediatric brain tumors are the major cause of pediatric cancer mortality. They comprise a diverse group of tumors with different developmental origins, genetic profiles, therapeutic options, and outcomes. Despite many technological advancements, the treatment of pediatric brain cancers has remained a challenge. Treatment options for pediatric brain cancers have been ineffective due to non-specificity, inability to cross the blood-brain barrier, and causing off-target side effects. In recent years, nanotechnological advancements in the medical field have proven to be effective in curing challenging cancers like brain tumors. Moreover, nanoparticles have emerged successfully, particularly in carrying larger payloads, as well as their stability, safety, and efficacy monitoring. In the present review, we will emphasize pediatric brain cancers, barriers to treating these cancers, and novel treatment options.

BSLD-02 ELUCIDATING LEPTOMENINGEAL MICROENVIRONMENT CUES THAT PROMOTE METASTASIS AND CHEMOTHERAPY RESISTANCE IN HIGH-RISK MEDULLOBLASTOMA

Abstract Medulloblastoma is a molecularly heterogenous brain tumor of the cerebellum and is a leading cause of pediatric cancer mortality due to its propensity for leptomeningeal metastasis. Leptomeningeal metastasis occurs in over 20-30% of patients despite age- and risk- adapted chemoradiation therapy. The mechanisms responsible for medulloblastoma metastasis and therapy resistance remain incompletely understood. The leptomeninges represent a fundamentally distinct microenvironment from the primary cerebellar tumor. We hypothesized that unique signaling inputs from the cellular and extracellular milieu of the leptomeninges drive distinct medulloblastoma biology that leads to resistance to current standard of care therapy. We tested this hypothesis using Group 3-MYC amplified (Grp3-MA) cell lines given their high metastatic potential. Primary tumors grow within a glycosaminoglycan (hyaluronan) rich matrix while leptomeningeal metastases grow in a laminar fashion attached to leptomeningeal (pial) cells that were enriched for laminins, collagens, and fibronectin. Analogously, Grp3-MA cells grow in suspension at steady state, but subpopulations readily adhere to a leptomeningeal membrane mimetic in vitro. This attachment required integrin beta 1 (ITGB1) and promoted chemotherapy resistance. We additionally have created a novel co-culture model wherein medulloblastoma cells grow as adherent clusters on a layer of primary leptomeningeal cells in an ITGB1 dependent manner. We are using this co-culture platform to perform single cell RNA sequencing and ligand receptor analysis to understand how cell-cell communication between leptomeningeal cells and medulloblastoma cells promotes tumor cell growth. Collectively, our studies demonstrate that cues from the leptomeningeal microenvironment alter medulloblastoma cell behavior and are attractive targets for developing novel therapies against metastasis.

Neuroblastoma: Emerging trends in pathogenesis, diagnosis, and therapeutic targets

Neuroblastoma (NB) accounts for about 13% of all pediatric cancer mortality and is the leading cause of pediatric cancer death for children aged 1 to 5 years. NB, a developmental malignancy of neural ganglia, originates from neural crest-derived cells, which undergo a defective sympathetic neuronal differentiation due to genomic and epigenetic aberrations. NB is a complex disease with remarkable biological and genetic variation and clinical heterogeneity, such as spontaneous regression, treatment resistance, and poor survival rates. Depending on its severity, NB is categorized as high-risk, intermediate-risk, and low-risk., whereas high-risk NB accounts for a high infant mortality rate. Several studies revealed that NB cells suppress immune cell activity through diverse signaling pathways, including exosome-based signaling pathways. Exosome signaling has been shown to modulate gene expression in the target immune cells and attenuate the signaling events through non-coding RNAs. Since high-risk NB is characterized by a low survival rate and high clinical heterogeneity with current intensive therapies, it is crucial to unravel the molecular events of pathogenesis and develop novel therapeutic targets in high-risk, relapsed, or recurrent tumors in NB to improve patient survival. This article discusses etiology, pathophysiology, risk assessment, molecular cytogenetics, and the contribution of extracellular vesicles, non-coding RNAs, and cancer stem cells in the tumorigenesis of NB. We also detail the latest developments in NB immunotherapy and nanoparticle-mediated drug delivery treatment options.

Multi-institution analysis of tumor mutational burden and outcomes in pediatric central nervous system tumor patients.

Pediatric central nervous system (CNS) tumors are the leading cause of pediatric cancer mortality. Research addressing genomic biomarkers and clinical outcomes is needed to inform therapeutic decision-making. We conducted a retrospective analysis of pediatric patients (age <21) diagnosed with a primary CNS tumor at four upstate New York hospitals from 2008 to 2021. Clinical and histopathologic data were identified from each patient, including genomic analysis of somatic mutations and tumor mutational burden (TMB) where available. These variables were each compared with overall survival using Cox regression analyses. Multivariable analysis was conducted to identify patient characteristics that may independently predict survival. We identified 119 patients. Common tumor types included low-grade glioma (N=51), high-grade glioma (N=29), and medulloblastoma (N=11). Common driver mutations included TP53 inactivation (N=16), BRAF-KIAA1549 fusion (N=16), FGFR1 amplification (N=12), BRAF V600E mutation (N=12), NF1 loss (N=12), and H3F3A K28M mutation (N=6). Median TMB was one mutation/megabase (mut/Mb, range=0-132). Overall survival was 79.9%. Variables associated with poorer survival on univariable analysis were higher TMB (p=.002, HR 4.97), high-grade tumors (p=.009, HR 84.3), and high-grade glioma histology (p=.021, HR 3.14). Multivariable analyses further identified TMB (p=.011, HR 4.46) and high-grade histology (p=.015, HR 5.28) as independently predictive of worse survival. Tumor progression was more common in high-TMB (N=15, 44%) than in low-TMB tumors (N=19, 35%). High TMB is correlated with higher rates of progression and death as compared to low-TMB tumors. These findings may help identify patients who may benefit from alternative treatments, such as immunotherapies.

Population-Based Impact of Rurality and Neighborhood-Level Socioeconomic Disadvantage on Pediatric Cancer Mortality in Washington State.

Childhood cancer-related mortality differs by socioeconomic factors, but the impact of residential location, including rurality and neighborhood-level socioeconomic disadvantage, is not well-characterized. This retrospective cohort study linked Washington State cancer registry data (1992-2013) to state birth (1974-2013) and death records (1992-2013) to identify residents <20 years diagnosed with cancer (n = 4,306). Census-based rural-urban commuting area codes and Area Deprivation Index (ADI) defined rural residence and neighborhood socioeconomic disadvantage at time of cancer diagnosis, respectively. Neighborhoods in the highest state ADI quintile were classified as the most disadvantaged. Kaplan-Meier estimates and Cox hazards models, adjusted for key characteristics, were used to compare mortality by rural and ADI classification. Five-year overall survival for children from non-rural low ADI neighborhoods (referent) was 80.9%±0.8%, versus 66.4%±2.9% from non-rural high ADI neighborhoods, 69.4%±3.8% from rural low ADI neighborhoods, and 66.9%±3.8% from rural high ADI neighborhoods (P < 0.01 for each comparison versus referent). Compared with the referent group, children from comparator neighborhoods had a greater mortality risk: Rural low ADI [hazard ratio (HR), 1.50; 95% confidence interval (CI), 1.12-2.02], rural high ADI (HR, 1.53; 95% CI, 1.16-2.01), and non-rural high ADI (HR, 1.64; 95% CI, 1.32-2.04). Associations of ADI and rurality with mortality varied in sub-analyses by cancer type. Children with cancer living in rural and/or socioeconomically disadvantaged neighborhoods at diagnosis experienced greater mortality relative to those without either factor. Future investigation is needed to examine how rurality and poverty potentially impact healthcare utilization and health-related outcomes in pediatric oncology.

OTHR-28. Multi-institution analysis of tumor mutational burden and outcomes in pediatric CNS tumor patients

Abstract Pediatric CNS tumors are the leading cause of pediatric cancer mortality. Research addressing genomic biomarkers and clinical outcomes is needed to inform therapeutic decision making. Tumor mutational burden (TMB) has been correlated with decreased survival across cancer types. This study is the first to examine TMB and outcomes in pediatric CNS tumor patients across multiple academic medical centers. We conducted a retrospective analysis of 121 pediatric patients (61 female (50%)) with a median age of 9 diagnosed with a primary CNS tumor at Albany Medical Center, Roswell Park Comprehensive Cancer Center, Upstate University Hospital, or University of Rochester Medical Center from 2008 to 2021. Common tumor types included low-grade glioma (N=51), high-grade glioma (N=30), medulloblastoma (N=11), ependymoma (N=7), ganglioglioma (N=4), and 18 other CNS tumors. Seventy-one patients had driver-mutations, including TP53 inactivation (n=17), BRAF-KIAA1549 fusion (n=16), FGFR1 amplification (n=12), BRAF V600E mutation (n=12), NF1 loss (n=12), and H3F3A K28M mutation (n=6). TMB data was available for most patients (N=91), median TMB was 1 mutations/megabase (mut/Mb, range=0-132). There were 26 deaths observed; patients with high TMB (≥3 mut/Mb; N=35) as compared to patients with low TMB (&amp;lt;3 mut/Mb; N=56) were more likely to have a death event, 43% (N=15) vs 9% (N=5), respectively. High TMB tumors were more frequently high-grade (77%) than low-grade (41%). High TMB tumors were more frequently treated with systemic therapy (86%) compared to low TMB tumors (70%). Tumor progression was more common in high TMB (71%) than in low TMB tumors (54%). This multi-institutional analysis suggests that high TMB is correlated with higher rates of progression and death as compared to low TMB tumors. Knowledge of these findings is critical for identifying patients who may benefit from alternative treatments, such as immunotherapies.

Population-based impact of rurality and neighborhood-level socioeconomic disadvantage on pediatric cancer mortality in Washington State.

6537 Background: Emerging evidence suggests mortality among children with cancer differs based on socioeconomic factors. The effects of residential location in relation to these factors are not well-characterized. We examined associations of rurality and neighborhood-level socioeconomic (SE) disadvantage with mortality in pediatric patients with cancer. Methods: We conducted a retrospective cohort study using Washington State (WA) Cancer Registry data (1992-2013) linked to state birth (1974-2013) and death records (1992-2013) to identify all children born in WA diagnosed with cancer &lt; 20 years. We defined rural residence as patient addresses within 2010 census tract level rural-urban commuting area (RUCA) codes of ≥4.0 at diagnosis. Neighborhood-level socioeconomic disadvantage was determined using 2010 census block-group level Area Deprivation Index (ADI) quintiles normalized to WA. Patient addresses within the highest ADI quintile were categorized as having SE disadvantage. children in four mutually exclusive groups was compared using Kaplan-Meier analysis, pairwise log rank testing, and Cox proportional hazard ratios (HR): non-rural with SE disadvantage, rural without SE disadvantage, rural with SE disadvantage, and non-rural without SE disadvantage (). Models were adjusted for sex, race and ethnicity, age at diagnosis, birth year, and cancer type. Results: We identified 4,417 children for analysis. Median length of follow up among survivors was 5.0 years (inter-quartile range: 1.0-11.5). SE disadvantaged and 13% were rural. Pairwise log rank tests showed mortality differences among children living in rural, SE disadvantaged, or rural and SE disadvantaged neighborhoods when compared with children without either factor (individual p-values all &lt; 0.005); no other differences were noted. Relative to children in non-rural areas without SE disadvantage, the mortality HR for those in non-rural areas with SE disadvantage was 1.68 (95% confidence intervals [CI] 1.37-2.07). The HR for children in rural areas without SE disadvantage was 1.59 (95% CI 1.19-2.12). The HR for children in rural areas with SE disadvantage was 1.56 (95% CI 1.20-2.03). In sub-analyses, associations for rurality and SE disadvantage remained significant for leukemia mortality, but CNS and solid tumor mortality was only associated with SE disadvantage (but not rural) status. Acute lymphoblastic leukemia mortality was associated with rural (but not SE disadvantage) status. Conclusions: Children with cancer living in socioeconomically disadvantaged and/or rural neighborhoods at diagnosis had higher mortality relative to those in non-rural areas with lower neighborhood deprivation. Associations varied by disease type. The individual effects of SE disadvantage and rurality suggest that interventions should be designed to target both factors.

Anti-GD2 Based Immunotherapy Prevents Late Events in High-Risk Neuroblastoma Patients over 18 Months at Diagnosis.

Simple SummaryHigh-risk neuroblastoma accounts for 4% of newly diagnosed pediatric malignancies, but for 9–10% of pediatric cancer mortality. To reduce the number of (late) recurrences and subsequently improve survival, anti-GD2 monoclonal antibody based immunotherapy has been added to the maintenance phase of treatment. The first randomized study (ANBL0032) was ground breaking, showing a 20% improved event free survival. Subsequently immunotherapy was included in all international high-risk treatment regimens. Randomization will never be repeated. In this article we present additional data from our retrospective cohort to corroborate the ANBL0032 study. Our cohort contains 84 Dutch high-risk neuroblastoma patients. They were treated with GPOH or POG induction, followed by immunotherapy according to original ANBL0032 protocol (immunotherapy group) or single-agent isotretinoin (historical control group). In the complete cohort, 5 year OS was 64 ± 7% and 49 ± 8% for the immunotherapy group and the control group, respectively (p = 0.16). Five year EFS was 57 ± 7% and 41 ± 8%, respectively (p = 0.16). In the subgroup of patients ≥ 18 months, 5-yr OS was 63 ± 8% and 39 ± 9, respectively (p = 0.04) and EFS 54 ± 8% and 29 ± 8%, respectively (p = 0.05). Our five year data suggest a role for the immunotherapy in preventing late events, especially in patients ≥ 18 months old.Background: Anti-GD2 based immunotherapy has improved overall (OS) and event free survival (EFS) for high-risk neuroblastoma (HR-NBL) patients. Here, we evaluate the long-term efficacy of anti-GD2 immunotherapy in combination with isotretinoin, GM-CSF, and IL-2. Methods: Dutch HR-NBL patients treated with immunotherapy according to the COG-ANBL0032 protocol (n = 47) were included and compared to historical controls (n = 37) treated with single-agent isotretinoin maintenance therapy. Survival time was calculated from start of the maintenance therapy. Results: The study and control group were similar concerning baseline characteristics. In the complete cohort, 5 year OS was 64 ± 7% and 49 ± 8% for the immunotherapy group and the control group, respectively (p = 0.16). Five year EFS was 57 ± 7% and 41 ± 8%, respectively (p = 0.16). In the subgroup of patients ≥ 18 months, 5-yr OS was 63 ± 8% and 39 ± 9, respectively (p = 0.04) and EFS 54 ± 8% and 29 ± 8%, respectively (p = 0.05). Landmark analysis for EFS with landmark point at 6 months after start of maintenance suggests a larger effect on the prevention of late than early events. Conclusions: This study is the first to confirm the results of the COG-ANBL0032 study in a cohort treated with a different induction regimen. Anti-GD2 immunotherapy prevents late events, most significantly in patients older than 18 months of age at diagnosis.

Racial disparities in pediatric cancer care in the United States: An analysis of the Kids' Inpatient Database.

10016 Background: The impact of race and socioeconomic status (SES) on cancer mortality has been elucidated in adult patients, but is not well described in pediatric oncology. We hypothesize that racial and socioeconomic disparities exist in pediatric cancer patients, resulting in higher rates of hospitalization and mortality. Methods: We analyzed the Kids’ Inpatient Database (KID) which shows national estimates of inpatient stays for pediatric patients. Inclusion criteria included patients who were ≤20 with a cancer diagnosis identified through the Clinical Classifications Software (CCS). Variables analyzed were discharge status, patient demographics, hospital characteristics, expected payment source, total visit charge, and length of stay. Initial comparisons between cancer and non-cancer related discharges were performed using a chi-square test. To estimate disparities by race, clinical comparisons were performed across five racial groups: White, Black, Hispanic, Asian/Pacific Islander, and Native American/Other. A multivariable logistic regression model was used to examine predictors of hospitalization and mortality. Results: From 2006-2012, there were 9,488,477 non-cancer related pediatric inpatient stays and 242,489 cancer related stays. Patients with cancer related visits were more likely to be white, male (54.9% vs 46.1%, p &lt; 0.0001), older at admission, have private insurance (52.5% vs 41.7%), and were from a higher income quartile (76th-100th percentile, 25.2% vs 19.9%, p &lt; 0.001). These patients also had a higher rate of death during admission (1.2% vs 0.5%, p &lt; 0.0001), higher cost of visit charge ($25,097 vs $8,267, p &lt; 0.001), longer length of stay (4 vs 2 days), and were less likely to be discharged (85.5% vs 92.0%, p &lt; 0.0001).The four most frequent cancer diagnoses associated with hospital admission were leukemia (n = 75,807), Other and Unspecified Primary (n = 50,076), bone/connective tissue tumor (n = 42,477), and central nervous system tumor (n = 27,958). Patients who were non-white were more likely to die during their inpatient stay (1.5% Non-white versus 0.9% White, p &lt; 0.001). On multivariate logistic regression, Black (OR: 1.61, 95% CI: 1.57-1.66, p &lt; 0.0001) and Native American (OR: 1.39, 95% CI: 1.34-1.44, p &lt; 0.0001) race, as well as lower income quartile (OR: 1.24, 95% CI: 1.19-1.28, p &lt; 0.001) were associated with increased odds of death during admission. Conclusions: This is the largest observational study to date to identify the impact of race and SES on pediatric cancer hospitalization and mortality in the United States. Non-white race and lower SES was associated with significantly increased odds of death during admission. Given the significant difference in mortality by race, healthcare policy makers and insurance companies should investigate the specific drivers of increased admission and mortality and develop strategies to address inequity in cancer care.

Pediatric cancer mortality and survival in the United States, 2001-2016.

Although pediatric cancer mortality and survival have improved in the United States over the past 40 years, differences exist by age, race/ethnicity, cancer site, and economic status. To assess progress, this study examined recent mortality and survival data for individuals younger than 20 years. Age-adjusted death rates were calculated with the National Vital Statistics System for 2002-2016. Annual percent changes (APCs) and average annual percent changes (AAPCs) were calculated with joinpoint regression. Five-year relative survival was calculated on the basis of National Program of Cancer Registries data for 2001-2015. Death rates and survival were estimated overall and by sex, 5-year age group, race/ethnicity, cancer type, and county-based economic markers. Death rates decreased during 2002-2016 (AAPC, -1.5), with steeper declines during 2002-2009 (APC, -2.6), and then plateaued (APC, -0.4). Leukemia and brain cancer were the most common causes of death from pediatric cancer, and brain cancer surpassed leukemia in 2011. Death rates decreased for leukemia and lymphoma but were unchanged for brain, bone, and soft-tissue cancers. From 2001-2007 to 2008-2015, survival improved from 82.0% to 85.1%. Survival was highest in both periods among females, those aged 15 to 19 years, non-Hispanic Whites, and those in counties in the top 25% by economic status. Survival improved for leukemias, lymphomas, and brain cancers but plateaued for bone and soft-tissue cancers. Although overall death rates have decreased and survival has increased, differences persist by sex, age, race/ethnicity, cancer type, and economic status. Improvements in pediatric cancer outcomes may depend on improving therapies, access to care, and supportive and long-term care.

Pediatric thyroid cancer incidence and mortality trends in the United States, 1973–2013

Pediatric thyroid cancer incidence and mortality trends in the United States, 1973–2013

Trends in pediatric cancer mortality and survival in the United States

We investigated the association between social and nutritional adversities in childhood and increased arterial stiffness in adulthood, according to race/skin color.We used baseline data (2008–2010) from 13,365 adults (aged 34–75 years) from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Arterial stiffness was assessed by carotid-femoral pulse wave velocity (cfPWV). Childhood social and nutritional adversities were assessed by maternal education and birth weight. Race/skin color was self-reported.The lower the maternal education, the higher the cfPWV in adulthood in Whites, Browns, and Blacks. This association was no longer significant after adjusting for the participant's education level in Whites, but it persisted after full adjustment among Browns (low vs. high maternal education: β = 0.18, 95% confidence interval: 0.01; 0.34) and Blacks (low vs. high maternal education: β = 0.44, 95% confidence interval: 0.18; 0.70). On the other hand, the association between low birth weight and higher cfPWV was found only among Whites.Our findings regarding the association between maternal education and arterial stiffness are consistent with the disproportionate burden of cardiovascular disease-related morbidity and mortality in Blacks and Browns. The fact that the association between birth weight and arterial stiffness was only present in Whites may have reflected a survival bias.

Abstract 238: Therapeutic activity of the non-internalizing antibody drug conjugate 1959-sss/DM3 targeting galectin3-binding protein in human neuroblastoma

Abstract Neuroblastoma is a solid tumour affecting the peripheral nervous system accounting for ∼13% of all pediatric cancer mortality. Despite immunotherapy with the GD2 antibody has improved the clinical outcome of a fraction of patients with metastatic neuroblastoma, the majority of patients with relapsing, high risk disease cannot be successfully treated. Recently, it has been shown that non-internalizing, linker-less antibody drug conjugates (ADCs) targeting the tumor extracellular environment can exert a potent therapeutic activity against different tumors. We identified LGALS3BP (aka Mac-2 BP or 90K) as an important target for non-internalizing ADC development, as the protein is largely secreted by the majority of human tumors, while being virtually undetectable in normal adult tissues. In this study, we show that a variant of the humanized 1959 antibody, targeting human LGALS3BP, coupled to the maytansinoid drugs DM3 by means of disulfide linker, bound human neuroblastoma cell lines harboring or not N-myc amplification, although with different affinity. Importantly, normal human fibroblasts were not decorated by the antibody. The ADC potently inhibited metastatic lesions in the liver and lungs of NSG mice injected intravenously with the neuroblastoma cell line SKNAS. Our findings offer a preclinical proof-of-concept for the development of a non-internalizing ADC endowed with potent therapeutic activity for neuroblastoma treatment through an innovative mechanism of action. Citation Format: Emily Capone, Sara Ponziani, Francesco Giansanti, Roberta Gentile, Giulia Di Vittorio, Vincenzo De Laurenzi, Michele Sallese, Sandra Bibbò, Arturo Sala, Rodolfo Ippoliti, Jean Frederic Sauniere, Stefano Iacobelli, Gianluca Sala. Therapeutic activity of the non-internalizing antibody drug conjugate 1959-sss/DM3 targeting galectin3-binding protein in human neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 238.

Pediatric Thyroid Cancer Incidence and Mortality Trends in the United States, 1973-2013

The incidence of thyroid cancer is increasing by 3% annually. This increase is often thought to be attributable to overdiagnosis in adults. A previous study reported a 1.1% annual increase in the incidence of pediatric thyroid cancer. However, the analysis was limited to the period from 1973 to 2004 and was performed in a linear fashion, which does not account for changes in incidence trends over time. To analyze trends in pediatric thyroid cancer incidence based on demographic and tumor characteristics at diagnosis. This cross-sectional study included individuals younger than 20 years who had a diagnosis of thyroid cancer in the Surveillance, Epidemiology, and End Results (SEER) 9 database from 1973 to 2013. Cases of thyroid cancer were identified using the International Classification of Diseases for Oncology, Third Edition and were categorized by histologic type, stage, and tumor size. Annual percent change (APC) in the incidence rates was calculated using joinpoint regression analysis. Among 1806 patients included in the analysis, 1454 (80.5%) were female and 1503 (83.2%) were white; most patients were aged 15 to 19 years. The overall incidence rates of thyroid cancer increased annually from 0.48 per 100 000 person-years in 1973 to 1.14 per 100 000 person-years in 2013. Incidence rates gradually increased from 1973 to 2006 (APC, 1.11%; 95% CI, 0.56%-1.67%) and then markedly increased from 2006 to 2013 (APC, 9.56%; 95% CI, 5.09%-14.22%). The incidence rates of large tumors (>20 mm) gradually increased from 1983 to 2006 (APC, 2.23%; 95% CI, 0.93%-3.54%) and then markedly increased from 2006 to 2013 (APC, 8.84%; 95% CI, 3.20%-14.79%); these rates were not significantly different from incidence rates of small (1-20 mm) tumors. The incidence rates of regionally extended thyroid cancer gradually increased from 1973 to 2006 (APC, 1.44%; 95% CI, 0.68%-2.21%) and then markedly increased from 2006 to 2013 (APC, 11.16%; 95% CI, 5.26%-17.40%); these rates were not significantly different from the incidence rates of localized disease. The incidence rates of pediatric thyroid cancer increased more rapidly from 2006 to 2013 than from 1973 to 2006. The findings suggest that there may be a co-occurring increase in thyroid cancer in the pediatric population in addition to enhanced detection.

A phase II clinical study of pomalidomide (CC-4047) monotherapy for children and young adults with recurrent or progressive primary brain tumors.

10035 Background: Central nervous system (CNS) tumors are the most common cause of pediatric cancer mortality and novel therapies are needed for refractory disease. Pomalidomide (pom) is an oral immunomodulatory agent with CNS penetration, anti-angiogenic, anti-inflammatory and cytotoxic activity. Methods: This Phase 2 study evaluated both safety and efficacy of pom in pediatric patients with recurrent/progressive CNS tumors. Using a Simon’s two-stage design, patients were stratified to high-grade glioma [HGG], ependymoma, medulloblastoma or diffuse intrinsic pontine glioma [DIPG] cohorts. Patients received pom 2.6 mg/m2 for 21 days of a 28-day cycle. The primary endpoint was objective response rate (complete response [CR], partial response [PR]) or prolonged stable disease [SD] (defined as ≥ 6 cycles, or ≥ 3 for DIPG). Stage 1 required ≥ 2/9 subjects, within each cohort, to have a response or prolonged SD to move into Stage 2, and ≥ 5/20 responders or patients with prolonged SD at the end of Stage 2 for pom to be deemed effective. Results: Of 52 treated patients (median age 11.5 y/o; range 4-18), 47 were evaluable for primary endpoint. Median treatment duration was 2 cycles (range 1-16). Only the HGG cohort met protocol-defined criteria to advance to Stage 2, with one PR and one prolonged SD in Stage 1. Forty-six of 47 evaluable patients discontinued pom, due to adverse event (n = 1; pneumonia), withdrawal by parent/guardian (n = 2), death (n = 4; 3 progressive disease, 1 sepsis), or progressive disease (n = 39). Nineteen of 52 treated patients experienced ≥ 1 grade 3–4 treatment-emergent adverse event (TEAE) related to pom, neutropenia (n = 15) being the most commonly reported. Twenty-six patients died on study. All deaths were attributed to either disease progression or complications from disease. Conclusions: Single agent pomalidomide failed to meet a clinically meaningful level of efficacy in children with recurrent/progressive HGG, DIPG, medulloblastoma or ependymoma. However, it should be noted that a sustained response was observed in a child with HGG, replicating the outcome observed in one child with HGG in the Phase 1 (PBTC-043) trial. Clinical trial information: NCT03257631.

Trends in Pediatric Central Nervous System Tumor Incidence in the United States, 1998-2013.

Brain and other central nervous system (CNS) cancers are the leading cause of U.S. pediatric cancer mortality. Incidence trends can provide etiologic insight. We report trends in incidence rates of pediatric malignant CNS cancers and pilocytic astrocytoma (nonmalignant but historically registered) in the United States. Age-standardized incidence rates and annual percent changes (APC) in rates during 1998 to 2013 were calculated for children aged 0 to 19, stratified by subtype, age, sex, and for gliomas, histology and location. We estimated the absolute change in number of cases diagnosed U.S.-wide during 2013 compared with the expected number of cases had 1998 rates remained stable. Rates of all pediatric malignant CNS cancer combined (n = 18,612) did not change [APC: 0.16; 95% confidence interval (CI): -0.21-0.53]. There were statistically significant changes in several subtypes; however, glioma incidence (n = 10,664) increased by 0.77% per year (95% CI: 0.29-1.26), embryonal cancer rates (n = 5,423) decreased by 0.88% per year (95% CI: -1.33 to -0.43), and pilocytic astrocytoma rates (n = 6,858) increased by 0.89% per year (95% CI: 0.21-1.58). Of the 1,171 malignant tumors and 450 pilocytic astrocytomas diagnosed in U.S. children in 2013, we estimated 120 excess gliomas, 94 excess pilocytic astrocytomas, and 72 fewer embryonal CNS tumors than would be expected had 1998 rates remained stable. The gradual changes in incidence we observed for specific types of pediatric CNS cancers are likely due to a combination of changes in classification and diagnosis and true changes in CNS cancer. Continued surveillance of pediatric CNS tumors should remain a priority, given their significant contribution to pediatric cancer-related deaths.

Abstract 4901: Inhibition of γ-secretase sensitizes drug-resistant neuroblastoma cells to doxorubicin

Abstract Introduction: Neuroblastoma is the most common extracranial solid tumor in childhood and accounts for ~15% of all pediatric cancer mortality. Approximately 650 new cases are reported annually in the USA, with 90% of cases diagnosed by 5 years of age. Novel therapies are needed as ~50% of cases are high-risk neuroblastoma with a poor (&amp;lt;50%) five-year survival rate due to relapse and treatment resistance. Neuroblastoma cells undergo a mesenchymal change, including the activation of Notch pathway genes, in their transition to a drug-resistant state. The Notch pathway has both oncogenic and tumor-suppressive roles and has been implicated in epithelial-mesenchymal transition (EMT) and chemoresistance. This pathway can be blocked by γ-secretase inhibition, which prevents cleavage of the Notch receptor and therefore Notch signal transduction. Thus, targeting the Notch pathway has been considered a promising anticancer strategy. Underlying mechanisms of the Notch signaling pathway in drug-resistant cancers, including neuroblastoma, are not well understood. Aim: Determine if inhibition of the Notch signaling pathway sensitizes chemoresistant neuroblastoma cells to doxorubicin. Methods: Doxorubicin-resistant (DoxR) cells were generated by incubating doxorubicin-sensitive, wild-type (WT) patient-derived cell lines with incremental doxorubicin concentrations (1 x 10-9 to 1 x 10-6 M) over six months. Cells were considered chemoresistant after surviving five consecutive passages in 1 µM doxorubicin (MTT assay). Differentially expressed genes were identified by microarray (Illumina HumanHT-12 v4 Expression BeadChip) and validated by RT-qPCR. Cells treated with doxorubicin and/or DAPT (γ-secretase inhibitor) were evaluated for cell viability (MTT assay), proliferation (PCNA immunofluorescence and Western blot), senescence (SA-β-Gal immunocytochemistry and p21 Western blot) and proteomic profiling (2D-DIGE). Results: Compared to WT cells, DoxR cells differentially expressed the following Notch pathway genes: downregulation of DLK1 and upregulation of HEY1 and SNAI2, as determined by microarray and RT-qPCR. Compared to WT cells, DoxR cells treated with both doxorubicin and DAPT exhibited significantly decreased cell viability, decreased proliferation and increased senescence. DAPT-treated DoxR cells differentially expressed nine proteins using 2D-DIGE: MCM3, MCM6, CAPN10, ACTN4, TUBA1B, HNRNPK, PDP1, NPM1 and BARD1. Conclusion: The γ-secretase inhibitor DAPT sensitizes DoxR neuroblastoma cells to doxorubicin. Mechanisms underlying the synergistic effect of doxorubicin and DAPT in DoxR cells warrant further investigation. Citation Format: Kathryn A. Solka, Fei Chu, Yi-Yong Qiu, Sandra H. Clark, Mary Beth Madonna. Inhibition of γ-secretase sensitizes drug-resistant neuroblastoma cells to doxorubicin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4901.