bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of the effect of care at NCI comprehensive cancer centers (NCICCCs) on disparities in outcome within adolescents and young adults (AYAs) with cancer.
Authors: Wolfson Julie Anna , Sun Can-Lan , Kim Heeyoung , Kang Tongjun , Bhatia Smita 
Published: March 2020

9512 Background: AYAs (15-39y at diagnosis) with cancer have not seen the survival improvement evidenced by younger and older age groups with similar diagnoses, leaving an AYA Gap. While treatment on pediatric protocols is associated with superior survival in 15-21 year-olds, the impact of site of care on survival for vulnerable AYA subpopulations (age at diagnosis or race/ ethnicity) between 22-and 39y at diagnosis remains unstudied. Methods: We constructed a cohort of 10,727 patients newly diagnosed between the ages of 22- and 39y with lymphoma, leukemia, brain tumors, melanoma, thyroid and GU cancers, and reported to the LA County cancer registry between 1998 and 2008. Multivariable Cox regression analysis was conducted, and included race/ethnicity, age at diagnosis, SES, insurance status, primary cancer diagnosis and diagnosis year in the model; the analysis was stratified by site of care (NCICCC vs. non-NCICCC). Results: A total of 928 (9%) patients received treatment at the 3 NCICCCs (City of Hope, Jonsson Cancer Center and Norris Cancer Center) in LA County, and 9,799 received care elsewhere. Five-year overall survival (5y OS) was significantly worse for patients treated at non-NCICCC (87%) when compared with those treated at NCICCC (84%, p=0.02). In addition, 5y OS was worse for African Americans (71%) vs. non-Hispanic whites (89%, p<0.0001) and for older patients (31-39yo: 84%, vs. 22-30yo: 86%, p=0.0004). Multivariable analysis adjusting for SES, insurance status, diagnosis and diagnosis year revealed that African Americans (HR=1.4, p=0.0002) and older AYAs (31-39y: HR=1.24, p<0.0001) were at an increased risk of death. Among patients treated at NCICCC, the difference in risk of death due to race (African Americans: HR=0.8, p=0.7) and age (31-39yo: HR=1.1, p=0.6) was abrogated. On the other hand, among patients treated at non-NCICCC, these differences in outcome persisted (African Americans: HR=1.45, p =0.0002; 31-39yo: HR=1.25, p<.0001). Conclusions: Population-based data reveal that receipt of care at an NCICCC abrogates the effects of race and older age on mortality in AYAs with cancer. Barriers to accessing care at NCICCCs are being explored.
Use of whole genome sequencing to identify novel mutations in distinct subgroups of medulloblastoma.
Authors: Robinson Giles W. , Parker Matthew , Kranenburg Tanya , Lu Charles , Chen Xiang , Ding Li , Phoenix Timothy , Huether Robert , Thiruvenkatam Radhika , Wang Jianmin , Easton John , Onar-Thomas Arzu , Gajjar Amar J. , Ellison David W. , Mardis Elaine , Wilson Richard K. , Downing James , Zhang Jinghui , Gilbertson Richard J. 
Published: March 2020

9518 Background: Medulloblastoma is a malignant childhood brain tumor comprising four discrete subgroups (SHH-subgroup, WNT-subgroup, subgroup-3 and subgroup-4). The genetic alterations that drive these subgroups and that might serve as treatment targets are largely unknown. Methods: We sequenced entire genomes of 37 tumors and matched normal blood. 136 somatically mutated genes identified in this discovery cohort were sequenced in an additional 56 medulloblastomas. All tumors were classified into the 4 subgroups by expression profiling and immunohistochemistry. All mutations were validated by custom capture, 454, or Sanger sequencing. Results: Recurrent mutations were detected in 49 genes: 41 are not yet implicated in medulloblastoma. Several target distinct components of the epigenetic machinery in different disease subgroups, e.g., regulators of H3K27 and H3K4 trimethylation in subgroup-3 and 4 (e.g., KDM6A and ZMYM3), and CTNNB1-associated chromatin remodellers in WNT-subgroup tumors (e.g., SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours, identified genes that maintain this cell lineage (DDX3X) as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumourigenesis. Conclusions: We have identified several new recurrent somatic mutations that are enriched in specific subgroups of medulloblastoma. Alterations affecting subgroup-3 and 4 tumors appear to disrupt chromatin marking, most notably H3K27me3, potentially preserving a stem cell-like state in tumor cells. Mutations in WNT subgroup tumors affect binding partners of CTNNB1 that regulate WNT-response gene transcription. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development.
Real-time dynamic and sequential tracking of tumor propagation and associated immune responses in the CNS microenvironment.
Authors: Huang Alex Yee-Chen , Myers Jay T. , Othman Youmna , Barkauskas Deborah Sim , Petrosiute Agne 
Published: March 2020

9520 Background: Ex vivo experimental systems are often unable to fully capture complex intercellular communication between tumor cells and surrounding tissues - a critical feature in understanding cancer development and immune evasion. Imaging modality such as bioluminescence lacks the resolution necessary to discern subtle structural differences and heterogeneity in the tumor niche. Microscopic examination of fixed specimens is devoid of the 3-dimensional context or evolution of tumor progression within the same host. Methods: New insights have come from studies involving the use of intravital 2-photon laser scanning microscopy (2P-LSM), which allows deep visualization (>300um) with single-cell resolution (<1um), thus enables direct observation of cellular behavior in intact tissues at a suitable dynamic spatial-time resolution. We study the role of tumor niche in shaping immune repertoire and develop strategies to modify tumor niche to enhance anti-tumor immunity. Results: One example is our study of glioblastoma multiforme (GBM), which contains a cellular hierarchy with a CD133+ sub-population representing self-renewing and tumorigenic GBM stem cells (GSCs). In a xeno-transplant model, GSC was capable of tumor initiation in the mouse brain. To directly test the relative tumorigenic potential of GSCs (CD133+) and non-GSCs (CD133-), we inoculated paired tumor populations from the same primary GBM tumor cells and monitored tumor competition by serial 2P-LSM through implanted cranial windows. Serial 2P-LSM imaging shows that after 35 days, GBM formation was driven exclusively by GSCs but not non-GSCs. To interrogate tumor-associated immune responses, we inoculated syngeneic mouse glioma tumors into C57BL/6 mice. Using this and CNS-inflammatory models, we have begun to undercover the role of perivascular antigen-presenting cells and microglia in guiding the recruitment of CNS-bound lymphocytes. Conclusions: Our data provide the first direct functional evidence that CSCs are responsible for tumor propagation in GBM, and represent an in vivo experimental platform to monitor immunotherapeutic interventions.
Genome-based outcome prediction in MYCN nonamplified high-risk neuroblastoma.
Authors: Morales La Madrid Andres Eduardo , Stricker Thomas , Pytel Peter , Gosiengfiao Yasmin C. , Shohet Jason , Shimada Hiroyuki , Furman Wayne Lee , Zage Peter E. , Park Julie R. , Perlman Elizabeth , Guerrero Lisa , Salwen Helen , Chlenski Alexandre , London Wendy B. , Cohn Susan Lerner 
Published: March 2020

9534 Background: Less than 40% of children with high-risk neuroblastoma achieve long-term survival, and at diagnosis, it is not possible to identify patients who will be cured. Microarray studies have proposed expression signatures associated with outcome within high-risk cohorts. However, integrating this technology as a clinical test has been difficult, in part due to the lack of available frozen tissue and high quality RNA. The nCounter overcomes this obstacle, using formalin-fixed paraffin embedded tissue (FFPE). Our objective is to test the correlation of a previously published “ultra high-risk” microarray gene signature developed in the MYCN nonamplified high-risk population (Asgharzadeh et al, J Natl Cancer Inst, 2006) with the gene expression signature obtained with the nCounter (NanoString Technologies) using RNA isolated from FFPE MYCN nonamplified high-risk neuroblastoma samples. Methods: FFPE tumor samples linked to clinical outcome data were obtained from 6 collaborative institutions. Tumor content of each sample was assessed morphologically. RNA was isolated using the RNeasy FFPE-kit. Customized probes corresponding to the candidate genes were designed by NanoString. Hybridization reactions were performed in duplicate using 100 ng of RNA. Positive and negative control probes and housekeeping probes were included in every reaction and were used to normalize data for differences in purification, hybridization, and capture efficiencies Results: Forty-two MYCN nonamplified high-risk neuroblastoma samples were analyzed by the nCounter. The cohort 5-year event-free survival and overall survival were 44.6 +/- 8.0% and 53.8 +/- 8.4% respectively. Highly degraded RNA (RIN ~ 1.5-2.8) was obtained. Unsupervised clustering and principle components analysis on normalized expression data showed differential expression of most of the genes with clustering of cases depending upon outcome (FDR = 0.05). Conclusions: Our results demonstrate that the nCounter can yield gene expression profiles that are similar to microarray gene signatures. Further investigation of the clinical utility the nCounter technology to prognosticate outcome in patients with high-risk neuroblastoma is warranted.
Evaluation of local control strategies in patients with localized Ewing sarcoma of bone: A report from the Children’s Oncology Group.
Authors: DuBois Steven G. , Krailo Mark D. , Gebhardt Mark C. , Donaldson Sarah S. , Marcus Karen Chayt , Dormans John P. , Shamberger Robert C. , Sailer Scott Lee , Nicholas Richard W. , Healey John H. , Tarbell Nancy , Devidas Meenakshi , Meyer James S. , Granowetter Linda , Womer Richard , Bernstein Mark L. , Marina Neyssa , Grier Holcombe E. 
Published: March 2020

9537 Background: Patients (pts) with Ewing sarcoma (EWS) require local control, either with surgery alone (S), radiation alone (R), or a combination of surgery + radiation (S+R). Optimal choice of local control for disease control remains unclear. Our primary aim was to determine the mode of local control associated with the highest event-free survival (EFS). Methods: Pts with localized EWS of bone treated on INT0091, INT0154, or AEWS0031 phase III trials were included if they had complete local control data, did not have cranial tumors, received local control starting 2-6 months after enrollment, and were randomized to receive standard dose 5-drug chemotherapy every 3 weeks. We used propensity scores to control for differences in age, tumor site, and year of diagnosis between local control groups. We constructed Cox models controlling for local control propensity scores to assess the impact of local control type on EFS and overall survival (OS) from the start of local control. Results: 465 pts were included. Pts selected for S were treated more recently (p < 0.001), more likely to have appendicular tumors (p < 0.001), and younger (p = 0.02). Pts treated with R, compared to S, had higher unadjusted risk of any event (HR 1.70; 95% CI 1.18 - 2.44; p = 0.004) or death (HR 1.84; 95% CI 1.18 – 2.85; p = 0.006). Pts treated with S+R, compared to S, had higher unadjusted risk of death (HR 1.75; 95% CI 1.10 – 2.76; p = 0.02). After adjusting for propensity scores, there was a trend of higher risk of any event for pts treated with R (HR 1.42; 95% CI 0.94 – 2.14; p = 0.10) compared to S, though this was not statistically significant. No other differences in adjusted risk of event or death between local control groups were statistically significant. We confirmed these results with standard Cox models using age, tumor site, and year of diagnosis as covariates. Conclusions: In this large group of uniformly treated pts, investigator choice of local control approach was not significantly related to EFS. These data support current practice of surgical resection when feasible, while validating radiotherapy as a reasonable alternative in selected pts.
Phase I trial of temsirolimus (TEM), irinotecan (IRN), and temozolomide (TMZ) in children with refractory solid tumors: A Children's Oncology Group study.
Authors: Bagatell Rochelle , Norris Robin Elizabeth , Ingle Ashish M , Ahern Charlotte H , Saggio Jennifer , Little Anthony , Weigel Brenda , Blaney Susan 
Published: March 2020

9540 Background: Inhibitors of mTOR have demonstrated activity in preclinical pediatric solid tumor models. A phase I trial to define the dose limiting toxicities (DLTs) associated with the mTOR inhibitor TEM in combination with IRN and TMZ was conducted in patients (pts) with refractory solid tumors. Methods: Escalating doses of TEM were administered intravenously on days (d) 1 and 8 of a 21-d cycle for a maximum of 1 year (y). IRN (50 mg/m2/dose) was administered orally on d1-5. TMZ (100 mg/m2/dose) was administered orally on d1-5. When the maximum planned dose of TEM was reached (35 mg/m2/dose), IRN was escalated stepwise from 50 to 90 mg/m2/dose. Pts were enrolled on 6 dose levels using the rolling-six design. Results: 46 eligible pts (30 male, median age 11y, range 1 – 21) were enrolled; 37 were fully evaluable for toxicity [neuroblastoma (9), osteosarcoma (4), Ewing sarcoma (3), rhabdomyosarcoma (3), CNS (10) or other (8) tumors]. 173 cycles, median 2 (range 1 – 17) have been delivered. Dose-limiting hyperlipidemia was observed during cycle 1 in 2 pts at dose level 3 (TEM 25 mg/m2, IRN 50 mg/m2, TMZ 100 mg/m2); both pts were on chronic corticosteroids. The protocol was amended to preclude chronic systemic steroid use and modify hyperlipidemia management. Dose-limiting hyperlipidemia was not observed in subsequent pts. Cycle 1 DLT (elevated GGT) was observed in 1 pt treated with TEM 35 mg/m2, IRN 65 mg/m2, TMZ 100 mg/m2. DLT has not been observed in 4 of the first 6 pts treated at the highest planned dose level (TEM 35 mg/m2, IRN 90 mg/m2, TMZ 100 mg/m2). Additional ≥Grade 3 regimen-related toxicities occurring in >1 evaluable pt include neutropenia (12), lymphopenia (10), leukopenia (6), thrombocytopenia (4), anemia (2), nausea or vomiting (5), hypokalemia (4), hypophosphatemia (2), diarrhea (2), elevated transaminases (2), and infection (2). 1 pt had a Grade 3 allergic reaction to TEM. 1 pt had a confirmed partial response and 4 have remained on protocol therapy for ≥1 year. Conclusions: The combination of TEM (35 mg/m2/dose) d 1 and 8, IRN (90 mg/m2/dose) d 1-5, and TMZ (100 mg/m2/dose) d 1-5 of a 21-d cycle appears to be well tolerated in children with refractory solid tumors.
Trends in body mass index (BMI) during and after treatment for standard risk (SR) acute lymphoblastic leukemia (ALL): A report from the Children’s Oncology Group (COG).
Authors: Lindemulder Susan Joy , Stork Linda C. , Bostrom Bruce C. , Lu Xiaomin , Devidas Meenakshi , Neglia Joseph Philip , Kadan-Lottick Nina 
Published: March 2020

9546 Background: Obesity is a potential complication in children treated for ALL. Limited data exist regarding timing of BMI changes and risk in long-term survivors of ALL treated without cranial radiation (CRT). This study describes temporal trends in BMI during and after therapy for SR-ALL and identifies associated factors. Methods: We conducted a retrospective cohort study of children with SR-ALL enrolled on two sequential clinical trials between 1993 and 2000 and on the COG ALTE02C2 follow-up study. Therapy included prednisone or dexamethasone during induction, the same steroid in maintenance phases, and no CRT. Standing height and weight was ascertained at diagnosis (dx), start of consolidation, start of maintenance, start of the last cycle of maintenance, and at least one year off therapy. Age and gender-specific BMI percentiles (BMI%) were calculated using 2000 CDC growth charts for patients 2-20 years. Results: The 269 subjects were a median of 3.5 years at dx, 46.7% female, 82.3% white, and a median of 9.1 years since dx at the last timepoint. The BMI% was associated with elapsed time since dx: BMI% increased between dx and consolidation (50.9%-68.3%, p < 0.0001), remained stably elevated until the end of maintenance, and then decreased somewhat from the end of maintenance to the last timepoint (74.1%-70.6%, p = 0.03). After therapy, 18.1% of survivors were overweight (BMI% 85-95) and 20.9% were obese (BMI% ≥ 95). By unadjusted linear regression, higher dx BMI% was positively associated with BMI% post-therapy (p < 0.0001). There was an interaction with steroid and dx BMI% such that the association between dx BMI% and post therapy BMI% was significantly greater for the dexamethasone group than the prednisone group (p = 0.01). There was no association with age at dx, gender, or race. Conclusions: In this retrospective study of SR-ALL survivors treated without CRT, we found that BMI% increased significantly in the month after dx and remained substantially elevated even several years after the end of therapy. Dx BMI% was highly associated with off-therapy BMI%, particularly in patients who had received dexamethasone rather than prednisone.
Pharmacokinetics (PK) of bendamustine in pediatric patients with relapsed/refractory acute leukemia.
Authors: Darwish Mona , Megason Gail C. , Bond Mary , Hellriegel Edward , Robertson Philmore , Clementi Regina , Phillips Luann , Grasela Thaddeus , Fraser Christopher 
Published: March 2020

9547 Background: The PK profile of bendamustine in adult patients is well characterized. The objective of this analysis was to describe the pediatric PK profile of bendamustine relative to the adult PK profile and correlate the systemic exposure of bendamustine to efficacy and safety parameters. Methods: Samples were obtained after a single dose from patients aged 1-19 years with relapsed/refractory acute leukemia who were enrolled in an open-label, nonrandomized study of bendamustine (90–120 mg/m2, infused over 60 minutes). Samples were obtained prior to bendamustine infusion and preselected time points through 24 hours after start of infusion on day 1. Population PK modeling was performed using plasma concentration data from these patients. PK data from adults were used for comparison. Results: Systemic exposure of pediatric patients to bendamustine was similar to that obtained previously in adult patients. Mean Cmax was 6806 ng/mL and mean AUC0-24 was 8240 ng*hr/mL in pediatric patients, compared with a mean Cmax of 5746 ng/mL and AUC0-24 of 7121 ng*hr/mL in adults. Similarity in exposure despite the large range of body surface area across the pediatric and adult populations confirms appropriateness of the body surface area–based dosing scheme. In pediatric patients, age, race, sex, or disease state had no statistically significant effect on systemic exposure to bendamustine. No changes in systemic exposure to bendamustine in the presence of a CYP1A2 inhibitor/inducer were observed. Differences in PK were not observed in pediatric patients with mild renal impairment as compared with patients with normal renal function. Exposure in 2 pediatric patients with moderate hepatic dysfunction appeared to be higher. No clear exposure-response relationship was observed. Infection was the only adverse event for which the probability of occurrence increased with increase in exposure to bendamustine. Conclusions: The PK profile of bendamustine in pediatric patients was similar to the known PK profile in adults, demonstrating that exposures reflective of the therapeutic range in adults were attained following administration of 120 mg/m2 to pediatric patients. Support: Teva Pharmaceutical Industries Ltd., Frazer, PA.
Diagnostic and treatment challenges of adolescent and young adult oncology patients.
Authors: Xu Yanqing , Cardoso Mauro , Palumbo Michael Ostaric , Ishibashi Olivia , Kavan Petr 
Published: March 2020

9557 Background: Adolescent and young adult (AYA) cancer patients are faced with obstacles and challenges related to their diagnosis and treatment compared to children and older adults. The aim of this study was to explore the patient and health care system-related delays in the interval from cancer symptom onset to diagnosis and treatment as well as to identify the possible contributing factors to these delays in the AYA group. Methods: This study was based on a questionnaire conducted in 2010-2011 completed by patients diagnosed with a malignancy between the ages of 16 and 39 in addition to older patients diagnosed with a pediatric type malignancy. Four categories of delays: patient delay (time from patient symptom onset until first health care contact date), health care system delay (time from first health care contact until diagnosis date), treatment delay (time from diagnosis date until first treatment) and oncologist delay (time from first health care contact until first medical oncologist meeting) were calculated. Median delay (in days) with interquartile interval (IQI) was the main outcome measure. Median time for each category of delay was further analysed to explore how they vary with different patient characteristics. Results: We identified a median patient delay of 30 days (IQI 1-131), a median health care system delay of 53 days (IQI 1-213), a median treatment delay of 36 days (IQI 5-92) and a median oncologist delay of 77 days (IQI 30-281). Patient delay was affected by patient gender, age at diagnosis and type of first health care contact. Health care system delay was associated with patient marital status, financial situation and attitude of first health care professional. Treatment delay was related to type of cancer. Conclusions: The health care system delay (including oncologist delay) accounts for much of the delay from symptom onset to first treatment. Professional characteristics of frontline medical personnel as well as socioeconomic and biological characteristics of the patients may contribute to delay. Healthcare professionals and the general community as a whole need to be aware of the factors contributing to delay in diagnosis and treatment in the underserved patient population.