bluuebunny/crossref_metadata_2025_split huggingface dataset:
IQ change within three years of radiation therapy in pediatric brain tumor patients treated with proton beam radiation therapy versus photon radiation therapy.
Authors: Kahalley Lisa , Okcu M. Fatih , Ris M. Douglas , Grosshans David , Paulino Arnold , Chintagumpala Murali M. , Moore Bartlett , Stancel Heather , Wickham Robert , Mehta Paras , Mahajan Anita 
Published: March 2020

10009 Background: Radiation therapy (RT), an essential treatment for pediatric brain tumors, increases the risk of cognitive impairment. Advanced RT techniques reduce the volume of normal tissues receiving radiation dose. Proton beam radiation therapy (PBRT) minimizes irradiation to surrounding healthy brain tissue, with the potential to preserve cognitive function better than photon radiotherapy (XRT). We examined change in IQ over time between patients treated for pediatric brain tumors with PBRT versus XRT. Methods: IQ scores obtained in the first 3 years post-RT were abstracted for pediatric brain tumor patients treated with PBRT or XRT. Results: Baseline and follow-up IQ scores were available for 53 survivors (31 PBRT, 22 CRT). A linear regression model predicted follow-up IQ scores controlling for baseline IQ, age-at-RT, time-since-RT, and craniospinal irradiation (CSI), F(7,45)=23.4, p<.001. Follow-up IQ scores were significantly lower in the XRT group compared to the PBRT group (p<.05). The XRT group lost 10.3 IQ points on average with each additional year post-RT (p<.01), while the PBRT group remained stable, losing only 0.1 points per year on average (p<.05). CSI was associated with IQ decline in both groups (p<.05), while age-at-RT was not in either group (p=.154). Total RT dose was not associated with IQ with the above variables in the model. Conclusions: Findings suggest significant cognitive risk is associated with XRT, with IQ scores declining by more than half a standard deviation with each additional year post-RT. In contrast, IQ remained stable in the PBRT group. Preliminary findings suggest that PBRT may spare cognitive functioning in the first 3 years post-RT. Future research should replicate these findings with a larger sample and should study longer-term cognitive outcomes in patients treated with PBRT versus XRT. [Table: see text]
Pleuropulmonary blastoma: The causative role of germ-line DICER1 mutations.
Authors: Doros Leslie Ann , Yang Jiandong , Field Amanda , Rossi Christopher , Williams Gretchen M , Schultz Kris Ann Pinekenstein , Dehner Louis P , Messinger Yoav H. , Hill D Ashley 
Published: March 2020

10024 Background: Pleuropulmonary blastoma (PPB) is a rare, aggressive childhood lung cancer that is often the first manifestation of the PPB-DICER1 familial tumor predisposition which includes other benign and malignant conditions. The initial genetic mutation is inherited by a germ-line loss of function of DICER1 gene which was discovered by Hill et al. It is proposed that loss of DICER1 expression alters miRNA regulation of key regulatory cellular mechanisms which promote tumor growth. PPB can progress from the purely cystic, curable Type I to a high-grade Type III having a dismal prognosis. We sought to determine the frequency of DICER1mutation in the largest cohort of PPB patients to date. Methods: We obtained germ-line DNA from saliva or blood samples from 113 PPB patients collected from 2005-2012. DNA was extracted using the Maxwell 16 Research System (Promega Corporation, Madison WI). Sample quality and quantity was checked using the Nanodrop 2000 (Thermo Scientific, Wilmington, DE). Sequencing was performed using the Sanger sequencer. For a subset of cases we used targeted sequencing services or full gene sequence analysis (Ambry Genetics, Aliso Viejo, CA). Results: Seventy-four (65.5%) PPB patients were found to have deleterious DICER1germ-line mutations. The most common mutation type found was small insertion/deletions. These 74 samples were composed of 7 (9.5%)Type Ir PPBs, 22 (29.7%)Type I PPBs, 24 (32.4%) Type II PPBs, and 21 (28.4%)Type III PPBs. The following Table shows a summary of mutation types identified. Conclusions: Our results confirm that DICER1 germline mutations are the most common genetic alterations in PPB making it critical for genetic testing to be performed at diagnosis. Additionally, this underscores the need for important correlative studies to describe the genotype-phenotype relationship in order for appropriate screening guidelines to be developed and implemented to allow for early detection. While a majority of cases are explained by germline DICER1 mutations using current sequencing methods, further investigation is warranted to elucidate other possible mechanisms in the development of PPB. [Table: see text]
Estimated long-term outcomes in children newly diagnosed with standard risk acute lymphoblastic leukemia (ALL) based on similarly treated members of the childhood cancer survivor study (CCSS) cohort.
Authors: Essig Stefan , Li Qiaozhi , Chen Yan , Hitzler Johann , Leisenring Wendy M. , Greenberg Mark L. , Sklar Charles A. , Hudson Melissa M. , Armstrong Gregory T. , Krull Kevin R. , Neglia Joseph Philip , Oeffinger Kevin C. , Robison Leslie L. , Yasui Yutaka , Nathan Paul C. 
Published: March 2020

10032 Background: Therapy for ALL has evolved such that the risk for late effects in children treated in early eras is likely different from those that will occur in children treated today. In order to estimate future risks for late effects in newly diagnosed children with standard risk ALL, we examined the long-term outcomes in a cohort of patients enrolled in the CCSS who were treated in a manner analogous to contemporary ALL therapies. Methods: We assessed outcomes that occurred ≥5 years from diagnosis in survivors of ALL enrolled in the CCSS who were aged 1-9.9 years at diagnosis, treated with 0-120 mg/m2 of anthracyclines and 0-1000 mg/m2 of alkylating agents, and no radiotherapy. We compared their risks for death, second malignant neoplasms (SMN), chronic physical health conditions and decreased health status with the general population (death and SMN) and the CCSS sibling cohort (remaining outcomes). Results: 556 survivors were eligible. At last assessment, they were a median of 27.8 years old (range 9.1 to 45.7) and 23.4 years (range 5.0-38.0) from diagnosis. 29/556 (5.2%) died (standardized mortality ratio 3.6, 95% CI 2.4-5.2); 12 of these deaths were due to ALL recurrence. Compared to siblings, the rate ratio for ≥1 chronic condition was 1.4 (95% CI 1.3-1.6), and for a severe/life threatening chronic condition was 1.7 (95% CI 1.3-2.3). Four survivors (0.7%) developed a SMN (standardized incidence ratio 1.7, 95% CI 0.5-4.5), 114 were obese (odds ratio (OR) 1.2, 95% CI 1.0-1.5), and 2 (0.4%) reported a stroke. No survivors reported symptomatic congestive heart failure. The OR for reporting adverse general health was 1.2 (95% CI 0.8-1.8), poor mental health 1.3 (95% CI 1.0-1.8), decreased functional status 2.1 (95% CI 1.4-3.0), and activity limitations 1.4 (95% CI 1.1-1.8). Conclusions: Children treated for standard risk ALL on contemporary protocols are at increased risk for future chronic health conditions and decreased health status. Despite excellent survival after leukemia therapy, such survivors will likely benefit from life-long medical care focused on the long-term risks stemming from their therapy.
A randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto).
Authors: Von Minckwitz Gunter , Schneeweiss Andreas , Salat Christoph , Rezai Mahdi , Zahm Dirk Michael , Klare Peter , Blohmer Jens U. , Tesch Hans , Khandan Fariba , Jud Sebastian , Jackisch Christian , Mehta Keyur , Loibl Sibylle , Untch Michael ,   German Breast Group
Published: March 2020

1004 Background: Use of carboplatin in neoadjuvant chemotherapy (NACT) has never been prospectively examined in breast cancer. Cohort studies suggest a high sensitivity to DNA-damaging agents (e.g., carboplatin in triple negative breast cancer [TNBC]), which have a high prevalence of BRCA mutations. Two trials examining carboplatin in HER2+ metastatic disease have shown conflicting results, but one was biased by different dosage of docetaxel in treatment arms. GeparSixto investigates the impact of carboplatin in addition to an identical, optimized cytotoxic-targeted regimen on pathological complete response (pCR) in these two breast cancer subtypes. Methods: In GeparSixto trial (NCT01426880) patients were treated for 18 weeks with paclitaxel 80mg/m² q1w and non-pegylated-liposomal doxorubicin (NPLD) 20mg/m² q1w. HER2+ patients received concurrently trastuzumab 6(8) mg/kg q3w and lapatinib 750mg daily. TNBC patients received concurrently Bevacizumab 15mg/kg i.v. q2w. All patients were randomized 1:1 to receive concurrently carboplatin AUC 1.5-2 q1w vs not, stratified by subtype. Primary objective is pCR rates (ypT0 ypN0), secondary objectives are pCR rate in predefined subgroups or by other definitions, clinical response rate, compliance and tolerability of carboplatin. Carboplatin dose was reduced from AUC 2.0 to 1.5 by an amendment after 330 patients due to carboplatin-related toxicity at pre-planned safety analyses. Results: 595 patients were recruited (8/2011 - 12/2012) in 51 German centers, 299 did not receive carboplatin. Median age was 47/48 years (no carb/carb), 36.8/36.5% were postmenopausal; 14.0/13.3% had T3, 5.0/3.7% T4, 41.8/37.6% N+, 93.0/92.9% ductal invasive, 64.5/65.3% G3 tumors; 46.2/46.3% had HER2+, 53.8/53.7% TNBC. 225 patients had a SAE (149 no carb/177 carb) and 3 died (postoperative pneumonia; reduced general condition; acute myocardial infarct), all in no carb arms. Final analysis on primary endpoint will be presented. Conclusions: This is first study, evaluating efficacy and safety of the addition of carboplatin to anthracycline-taxane containing NACT in patients with primary HER2+ and TNBC. Clinical trial information: NCT 01426880.
The role of c-Met inhibition for neuroblastoma treatment.
Authors: Zage Peter , Scorsone Kathy , Zhang Linna 
Published: March 2020

10041 Background: Neuroblastoma is the most common extra-cranial solid tumor of childhood. Many children present with high-risk disease characterized by rapid tumor growth, resistance to chemotherapy, and widespread metastasis, and novel therapies are needed. Previous studies have identified a role for the HGF/c-Met pathway in the pathogenesis of neuroblastoma. We hypothesized that EMD1214063 would be effective against neuroblastoma tumor cells and tumors in preclinical models via inhibition of HGF/c-Met signaling. Methods: We determined the expression of c-Met in a panel of neuroblastoma tumor cells and neuroblastoma cell viability after treatment with EMD1214063 using MTT assays. Analyses were performed for changes in cell morphology, cell cycle progression, and cell death via apoptosis after EMD1214063 treatment. To investigate the efficacy of EMD1214063 against neuroblastoma tumors in vivo, neuroblastoma cells were injected orthotopically into immunocompromised mice, and the mice in which tumors developed were treated with oral EMD1214063. Results: All neuroblastoma cell lines were sensitive to EMD1214063, and IC50 values ranged from 2.4 - 8.5 mcM. EMD1214063 treatment inhibited HGF-mediated c-Met phosphorylation in neuroblastoma cells. EMD1214063 induced cell cycle arrest in neuroblastoma tumor cells with high c-Met expression, and induced apoptosis in all tested cell lines. In mice with neuroblastoma xenograft tumors, EMD1214063 inhibited tumor growth. Conclusions: Treatment of neuroblastoma tumor cells with EMD1214063 inhibits HGF-induced c-Met phosphorylation and results in cell death. Furthermore, EMD1214063 induces cell cycle arrrest prior to cell death in neuroblastoma tumor cells with high c-Met expression. EMD1214063 treatment is effective in reducing tumor growth in vivo in mice. Inhibition of c-Met represents a potential new therapeutic strategy for neuroblastoma, and further preclinical studies of EMD1214063 are warranted.
Effect of a novel small molecule yk-4-279 on the "undruggable" target EWS-FLI1.
Authors: Toretsky Jeffrey , Gamble S. Ellen , Monroe Philip J. , Hong S. Peter , Summer Stephen J. , Uren Aykut , Hong Sung-Hyeok 
Published: March 2020

10042 Background: Chimeric transcription factors are ideal anti-cancer targets since they are only present in tumor cells, however they are often considered ‘undruggable’ proteins. The EWS-FLI1 fusion protein of Ewings sarcoma (ES) has been validated as an anticancer target both alone and as a partner of RNA Helicase A (RHA). Our prior work identified (S)-YK-4-279 as an enantiospecific inhibitor of EWS-FLI1 by blocking the interaction with RHA leading to apoptosis. Methods: Pharmacokinetic (PK) models of YK-4-279 for both IP and IV administration were developed in SD rats and BL6 mice using drug concentrations determined by a validated LC-MS/MS assay. Xenograft ES mice validated PK models with apoptosis measured by TUNEL. A novel nude rat ES orthotopic xenograft was created give (S)-YK-4-279 by continuous IV infusion. Results: SD rat and BL6 mouse PK modeling demonstrated an elimination half-life t1/2 of 30 minutes following IV administration; SCID/bg mice demonstrated 50% faster clearance. A survival curve showed maximal killing of ES cells between 1 and 3 microM YK-4-279 over a 40-hour time course. Clonogenic replating assays demonstrated 3 microM exposure for 72 hours would reduce replating efficiency of ES cells to less than 0.01%. SCID/bg ES xenografts treated with IP YK-4-279 BID for 6 doses showed a 25-35% enantiospecific tumor regression with an average 3.5-fold increase in apoptosis. A nude rat xenograft, with continuous infusion (S)-YK-4-279 maintained an average level of 4.9 microM in plasma for 26 days. The ES1 xenograft tumor responded in 4 of 5 animals, with complete regression in 2 of 5, without toxicity. Conclusions: A combination of PK modeling and cell culture studies confirmed that (S)-YK-4-279 is required to be present at low microM levels for optimal tumor response. These levels were achieved in a novel rat xenograft of ES in order to demonstrate an important proof of efficacy. These PK-driven xenograft therapy studies are useful for development of PK models to compare YK-4-279 levels with functional activity. Targeting ‘undruggable’ protein-protein interactions with small molecules is novel and the ES model shows that continuous IV infusion may be required for optimal clinical translation.
Are adult and pediatric neuroblastoma clinically different entities?
Authors: Conter Henry Jacob , Gopalakrishnan Vancheswaran , Ravi Vinod , Ater Joann , Patel Shreyaskumar , Araujo Dejka M. 
Published: March 2020

10049 Background: It is unknown if the presentation, treatment, and outcomes differ between adults and pediatric patients with neuroblastoma. Methods: Medical records of 118 adults (patients >17 years old) and 112 pediatric patients (ages 2-17), who were treated for neuroblastoma at the University of Texas M.D. Anderson Cancer Center from 1994 to September 2012, were reviewed. International Neuroblastoma Risk Group (INRG) variables were abstracted. These include age, stage, tumor histology, and molecular and cytogenetic characteristics. The primary outcome of interest was overall survival (OS). Results: Median age of pediatric patients was 5 years (range 3-16) and 47 years (range 18-82) for adult patients. Beyond age and stage, other components of the INRG classification were not available for any adult patient. Cytogenetic and molecular studies were performed in 32 (26%) of pediatric patients. Adults with L1 disease experienced an actuarial OS of 94%, 90%, and 69% at years 3, 5, and 10, respectively. The cohort who presented with L2 disease had an estimated OS of 83% at 3 year, 73% at 5 years, and 41% at 10 years. Adults with M disease experienced an actuarial OS of 68%, 33%, and 13% at years 1, 2 and 5, respectively. In the adult cohort, the INRG stage was prognostic in univariate analysis (p<0.001). For all stage-matched risk categories, adults did not have a statistically different prognosis than children (L1-p=0.40, L2-p=0.54, M-p=0.73). Conclusions: Adult and pediatric patients with neuroblastoma achieve similar survival outcomes, with good prognosis for early-stage patients. Future work should focus on developing predictive markers for determining which patients benefit from more aggressive therapy. [Table: see text]
Clinical prognostic factors in pediatric Ewing sarcoma.
Authors: Abou Ali Bilal , Nader Ralph , Muwakkit Samar , Abboud Miguel , El Solh Hassan M.B. , Saab Raya Hamad 
Published: March 2020

10052 Background: Treatment of Ewing sarcoma necessitates coordinated multi-disciplinary care that includes chemotherapy, surgery, and/or radiation. In developed countries, patients with localized disease have an overall survival of 70-80%, compared to 20-30% for those with metastases. The outcome of children with Ewing sarcoma in less developed countries has not been adequately described. We analyzed prognostic factors for Ewing sarcoma patients treated at a single institution in Lebanon, a developing country with available multidisciplinary treatment modalities. Methods: We reviewed characteristics and outcome of 42 pediatric patients treated at a multidisciplinary cancer center in Lebanon, between January 1999 and October 2012. Kaplan Meier curves were generated to estimate survival. Results: Median age at presentation was 10 years (range 1-18), and median follow-up was 41 months (range 8-110). Commonly affected primary sites included the extremity (36%, n=15), chest wall (19%, n=8), and pelvis (14%, n=6). Tumor size was ≥ 8cm in twenty (47.6%) patients. Thirty-two patients (76%) had localized disease, and ten (24%) had metastatic disease. All patients received 14 cycles of chemotherapy, with VDC alternating with IE. Local control was surgery alone (29%, n=12), radiotherapy alone (33%, n=14), or combination (38%, n=16). For patients with localized disease, the 5-year OS and DFS rates were 68% and 55% respectively, while for metastatic disease they were 28% and 25%. Tumor recurrence was local in 8 patients, distant in 8, and combined in 2. Factors associated with improved outcome included localized disease, extremity site, surgery, and timely local control. In multivariate analysis, timing of local control and metastatic disease were prognostically significant determinants of outcome. Conclusions: Treatment of childhood Ewing sarcoma in a multidisciplinary cancer center in Lebanon results in similar survival to that in developed countries when similar protocols are applied. Strong prognostic factors included stage (localized vs. metastatic), and timing of local control. Patients who had a local control time delay of more than 3 weeks fared worse, strongly suggesting that delays in local control should be actively minimized in Ewing sarcoma.
The Children’s Oncology Group and QuadW Foundation osteosarcoma banking experience.
Authors: Glover Jason Michael , Gorlick Richard Greg , Khanna Chand , Barkauskas Donald A. 
Published: March 2020

10053 Background: Survival rates of osteosarcoma patients have remained stagnant over the last twenty years. Predictive biomarkers of response to treatment and likelihood of recurrence are yet to be developed. In order to develop new therapeutics and better risk-stratified regimens, a greater understanding of osteosarcoma biology is needed. The Children’s Oncology Group (COG) addressed this need by banking more than 10,000 tumor and tissue samples from over 1500 patients with osteosarcoma, but many samples lacked clinically relevant data. Methods: 1105 eligible patients enrolled on the COG osteosarcoma biology study P9851. Of those, 510 patients were not enrolled on a concurrent therapeutic trial, which limited the clinical annotation of those samples. 589 patients have enrolled on the successor study AOST06B1. The lack of clinical annotation of the P9851 specimens limited their value, and the lack of statistical support slowed the analysis of several biology studies. The QuadW Foundation, CureSearch, and the COG formed the Childhood Sarcoma Biostatistics and Annotation Office (CSBAO) in 2008 to link clinically annotated patient data to the samples and to provide statistical support. Results: In 2008, only 5.3% of samples from the 510 P9851 patients not enrolled on a therapeutic study had full clinical annotation. The efforts of the CSBAO have linked clinical annotation to 90.8% of those specimens and provided statistical analyses. As a result, 18 biology studies in osteosarcoma are completed, with 11 published in peer-reviewed journals. Samples were provided to the TARGET program (for gene expression arrays, copy number analysis, and sequencing data); the resulting data will be available to the scientific community for in silico studies. Conclusions: The efforts of the CSBAO have led to a substantial increase in the value of a large osteosarcoma biospecimen repository by clinically annotating the specimens and providing statistical resources for analyses of planned and completed studies. These samples with annotated patient information are available by request to the research community for basic and translational science projects to improve the biological understanding of, and the treatment of patients with osteosarcoma. Clinical trial information: NCT00899275.
Prognostic impact and detection of minimal residual disease (MRD) in neuroblastoma patients.
Authors: Druy Alexander , Tsaur Grigory , Popov Alexander , Verzhbitskaya Tatiana , Shorikov Egor , Saveliev Leonid , Fechina Larisa 
Published: March 2020

10055 Background: Bone marrow (BM) involvement and MRD detection in neuroblastoma (NB) seems to be useful tool for patients’ prognosis, stratification and risk-adapted treatment. Real-time PCR (RQ-PCR) of tumor-specific gene transcripts and flow cytometry (FC) are commonly applied for this purpose. Aim. RQ-PCR MRD marker definition, its qualitative concordance with FC and prognostic impact in NB patients. Methods: We analyzed 331 BM samples from 57 NB patients and 26 ‘normal’ BM samples from 20 patients without malignancies for PHOX2B, TH, ELAVL4 and GD2 genes expression. BM samples were defined as positive either in case of positivity for PHOX2B or in case of NB cells presence in BM. 326 BM samples from 52 NB patients were analyzed by RQ-PCR and FC together. Results: PHOX2B and TH were not detecting in normal BM samples. Out of 224 negative BM samples TH was identified in 5 only, while ELAVL4 and GD2 expression was detected in the majority of normal and negative BM samples: 20 and 15 from 26 normal; 209 and 197 out of 224 negative samples correspondingly. TH, ELAVL4 and GD2 expression in positive BM samples was significantly higher comparing to negative and normal BM samples.Threshold levels of each gene expression were established by ROC-analysis and subsequently applied for overall correct prediction (OCP) calculation. OCP for PHOX2B and TH achieved 0.994 and 0.952, while OCP for ELAVL4 and GD2 were significantly lower: 0.828 and 0.767 respectively. Analytical sensitivity of RQ-PCR for PHOX2B achieved 1E-06, while sensitivity of FC ranged from 1E-03 to 1E-05. In 193(59.2%) out of 326 evaluated samples BM was negative by both methods. 38(11.7%) samples were negative by FC but positive by RQ-PCR for PHOX2B expression. 31(9.5%) samples were positive by FC but negative by RQ-PCR. 64(19.6%) samples were positive by both techniques. Thus qualitative concordance between RQ-PCR and FC achieved 78.8%. Conclusions: Patients with detectable PHOX2B expression have lower event-free survival comparing to patients with PHOX2B negative BM: 0.30±0.10 and 0.77±0.27 respectively, p=0.002 and overall survival is 0.51±0.11 and 0.79±0.07 correspondingly, p=0.083. Median of follow up in our NB patients series is 42 months, ranged from 1 to 156.