bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of chromosome complexity with age and metastasis in synovial sarcomas: Validation of expression and genomic prognostic signatures.
Authors: Chibon Fred , Lagarde Pauline , Przybyl Joanna , Brulard Celine , Italiano Antoine , Orbach Daniel , Bui Nguyen Binh , Terrier Philippe , Sciot Raf , Debiec-Rychter Maria , Coindre Jean-Michel 
Published: March 2020

9536 Background: Synovial sarcoma (SS) is one of the rare sarcomas that occurs in adolescents as well as in adults. Nevertheless, metastasis occurs with a lowest frequency in the former, 10 vs 50% respectively. In almost all cases, a characteristic translocation t(X;18)(p11.2;q11.2) exists and the importance of this translocation in SS oncogenesis is well established, but the genetic basis of SS metastasis is still poorly understood. We recently published expression (CINSARC) and genomic (GI) signatures related to chromosome integrity control that predict outcome in undifferentiated sarcomas and GIST and ask whether these signatures could also predict outcome in SS. Methods: To asses this issue we selected in the European sarcoma database CONTICABASE 92 primary untreated SS for expression and genomic profiling. Results: As demonstrated by metastasis-free survival, CINSARC and GI have strong and independent prognostic values (p = 1.6 x 10-5 and p = 4 x 10-6, respectively). Comparing expression profiles of tumors with or without metastasis in a training series of 58 SS, a 52-genes signature was identified and validated in an independent series of 34 SS. Fourteen of these genes are common with CINSARC and these 52 genes are involved the same pathways than CINSARC, mitosis checkpoints and chromosome integrity. Comparing genomic profiles of adult versus pediatric SS we show that in both situations metastasis is associated to genome complexity and that the adult genome is highly more frequently rearranged. In line with this, the pediatric good-prognosis patients, according to GI, do not develop metastasis. Conclusions: Results clearly indicate that SS metastasis development is strongly associated with chromosome complexity and that CINSARC and GI are powerful prognostic factors. Data also mean that the metastasis frequency difference between adult and children likely is associated to the genome instability which is highly more frequent in adults. Finally, among these tree signatures, GI is potentially the best overall and clearly the most clinically relevant considering that CGH from FFPE samples is already used in the daily practice of pathology.
A phase I trial of IMC A12 and temsirolimus in children with refractory solid tumors: A Children’s Oncology Group study.
Authors: Fouladi Maryam , Perentesis John Peter , Wagner Lars M. , Ingle Ashish M , Thomas George , Krueger Darcy A. , Houghton Peter , Vinks A.A. , Doyle L. Austin , Weigel Brenda , Blaney Susan 
Published: March 2020

9541 Background: IMC-A12, a fully recombinant IgG1 monoclonal antibody that targets the human IGF-IR and inhibits downstream signaling of MAPK and PI3K/AKT, and temsirolimus, an mTOR inhibitor, have demonstrated preclinical single agent, antitumor activity against many pediatric tumors. A phase I and pharmacokinetic (PK) trial evaluating the combination of these agents was conducted in children with refractory solid and CNS tumors. Methods: Using a modified 3+3 design, IMC-A12 and temsirolimus were administered intravenously once every 7 days in 28 day cycles. Serial PK studies were obtained on day 1, cycle 1 and trough samples were obtained on days 15 and 28. Biology studies included assessment of IGFR and insulin receptor expression and phosphorylation in archival tumor samples and phosphorylation of IGFR and mTOR downstream targets in peripheral blood mononuclear cells (PBMC) pre and post therapy. Results: Thirty-nine patients [20 male, median age 11.8 years (range 1-21.5)] with rhabdomyosarcoma (n=10), osteosarcoma (n=6), Ewings sarcoma (n=5), astrocytoma (n=5), or other tumors (n=13) were enrolled; 33 were evaluable for toxicity. At dose level 1 [IMC-A12 (6 mg/kg); temsirolimus (15 mg/m2)], 2 DLTs (grade 3 hypercholestrolemia, mucositis) occurred among 6 evaluable patients. Six more patients were accrued and 3 additional DLTs were observed (grade 3 ALT, fatigue and prolonged thrombocytopenia > 14 days). At dose level 0 [IMC-A12 (6 mg/kg); temsirolimus (10 mg/m2)], dose-limiting mucositis occured in 2/6 patients. At dose level -1 [IMC-A12, (4 mg/kg) and temsirolimus at (8 mg/m2)], 0 of 3 patients experienced a DLT. At an intermediate dose level [IMC-A12 (6 mg/kg) and temsirolimus (8 mg/m2)], 1 of 6 patients experienced mucositis; among an expanded PK cohort for children <12 years, none of 6 patients experienced a DLT. Target inhibition (decreased S6K1 and PAkt) in PBMCS were noted at all dose levels. At 8 mg/m2, the median sirolimus AUC was 225 μg/ml · h (159-226), and median temsirolimus AUC was 3340 μg/ml · h (1894-4387), and median Cmax 1176 μg/ml (480-2231). Conclusions: The recommended pediatric phase II doses for the combination of IMC-A12 and temsorolimus are 6 mg/kg and 8 mg/m2, respectively.
Pharmacokinetic (PK) and pharmacodynamics (PD) properties of SC-PEG e. coli L-asparaginase (EZN-2285) in the treatment of patients with acute lymphoblastic leukemia (ALL): Results from Children's Oncology Group (COG) study AALL07P4.
Authors: Angiolillo Anne L. , Schore Reuven J. , Reaman Gregory H. , Winick Naomi Joan , Devidas Meenakshi , Zheng Hao W. , Wood Charlotte , Lane Ashley R. , Raetz Elizabeth A. , Carroll William L. , Hunger Stephen 
Published: March 2020

9543 Background: Asparaginase is a critical therapeutic agent in the treatment of childhood ALL, and pegaspargase (Oncospar, ONC) is now the preferred product in COG frontline ALL trials. EZN-2285 replaces the succinimidyl succinate linker in ONC with a succinimidyl carbamate linker creating a more stable molecule. AALL07P4 was designed to determine the PK comparability of EZN-2285 to ONC when given intravenously in newly diagnosed patients with NCI high-risk (HR) B-precursor ALL. Methods: 162 eligible patients were randomized to receive EZN-2285 at 2100 (LD, n=66) or 2500 (HD, n=42) IU/m2 vs. 2500 IU/m2 of ONC (n=51) in a 2:1 manner based on the prednisone/Capizzi methotrexate arm of COG AALL0232. All groups were similar demographically with the exception of number of patients over the age of 16 years were 6, 5, and 19 in the ONC, HD and LD, respectively. Results: PK, PD and targeted AEs (Gr 3-5) after the first doses of study drug are presented in the table below. Adverse events in induction were not significantly different between arms with the exception of a higher incidence of hyperglycemia (p=0.042). Conclusions: Based on Cmax , AUC0-25d , and asparaginase activity 25 days post drug, EZN-2285 2500 IU/m2 appears to have an improved PK/PD profile compared to pegaspargase 2500 IU/m2 and a comparable toxicity profile in children with HR ALL. [Table: see text]
The application of radiotherapy to the pediatric preclinical testing program: Results of a pilot study.
Authors: Pelloski Christopher E. , Kaplon Rita , Hadziahmetovic Mersiha , Bondra Kathryn , Lu Lanchun , Sommerfeld James , Leasure Justin , Li Ning , Singh Mamta , Nguyen Phuoung , Chronowski Christopher , Kurmasheva Raushan , McHugh Kelsey , Sebastian Nikhil , Houghton Peter 
Published: March 2020

9544 Background: The Pediatric Preclinical Testing Program (PPTP) has been successfully utilized to determine the efficacy of novel agents by testing via its mouse-flank in vivo model. We report on the feasibility and biologic outcomes of a pilot study using rhabdomyosarcoma (RMS) xenograft lines treated with radiotherapy (RT) alone and concurrently with the mTOR tyrosine kinase inhibitor, AZD8055, using the PPTP model. Methods: We developed a mouse flank irradiation device for daily delivery of RT in clinically relevant doses (2 Gy per fraction up to 40 Gy).Two RMS xenograft lines of the PPTP, Rh30 (alveolar) and Rh18 (embryonal), were implanted into SCID mice, grown to appropriate volumes and were subjected to fractionated RT. In a second study, daily co-administration of AZD8055 (5-20 mg/Kg, gavage) with RT was performed. Cure rates (durable complete response >12 weeks post-treatment) and RT dose densities (given dose / initial xenograft volume, Gy/cc) were compared between groups. Results: With RT alone at mean dose-densities of 59-60 Gy/cc, cure was achieved in only 4/18 (22%) of the Rh30-bearing mice and 9/12 (75%) of the Rh18-bearing mice (p=0.006). Profiling data revealed higher levels of Fanconi anemia pathway gene expression in Rh30 compared to the more sensitive Rh18. Since recent data showed conditional knockout of mTOR resulted in the loss of FANCD2 gene expression, we postulated that blockade of TORC1/TORC2 with AZD8055 would reduce FANCD2 and increase the RT-sensitivity of Rh30. The addition of AZD8055 to RT resulted in a selective sensitization of the Rh30 line. With a mean RT dose-density of 27 Gy/cc, the cure rate in Rh30-bearing mice improved to 11/15 (73%). For the Rh18 group, the cure rate was 7/15 (46%) at a mean dose density of 44 Gy/cc. Western blot analysis showed the co-administration of AZD8055 abrogated the brisk increase in mTOR signaling and FANCD2 expression after the first several 2 Gy fractions of RT; most strikingly in Rh30. Conclusions: This study demonstrates the feasibility of applying RT to the PPTP model. It recapitulated the expected clinical radiobiology and demonstrated its utility in preclinical testing and the discovery of novel mechanisms of RT resistance in pediatric tumors.
Fever at diagnosis of pediatric acute lymphoblastic leukemia (ALL): Are antibiotics really necessary?
Authors: Khurana Monica , Feusner James Henry , Lee Brian 
Published: March 2020

9553 Background: Great variability exists in the management of suspected bacteremia in febrile, neutropenic pediatric ALL patients during chemotherapy. The National Comprehensive Cancer Network and Infectious Diseases Society of America encourage immediate, empiric antibiotics in patients with chemotherapy-induced fever and neutropenia to reduce infection-related mortality. No standard recommendation exists for patients with isolated fever at initial presentation of their ALL. This study evaluates bacteremic episodes in this subpopulation of pediatric patients. Methods: We retrospectively analyzed 245 consecutive patients with ALL at Children’s Hospital Oakland from 2000 through 2011. Using electronic medical records, we investigated each patient’s history and outcome. We surveyed bacteremic episodes up to 60 days after presentation per National Healthcare Safety Network’s guidelines. Inclusion criteria were patients with fever at presentation, which prompts a blood culture, and were started on antibiotics. We stratified bacteremic episodes into community-acquired (up to three days from admission) and nosocomial (four to 60 days). Results: Seventy-seven patients met the inclusion criteria, five of whom had positive cultures – four were contaminants (three coagulase-negative Staphylococcus and one non-anthracis Bacillus) and one was a true nosocomial bactermic episode (E coli). There were no infection-related deaths in the first 60 days of diagnosis in this cohort. Conclusions: Given our institution’s rarity of bacteremic episodes, we contemplate a more judicious use of antibiotics, including quicker narrowing of broad-spectrum antibiotics coverage and discontinuing all antibiotics sooner. These modifications may decrease bacterial resistance to antibiotics, reduce costs, and shorten patients’ hospitalization. We encourage other institutions to conduct a similar investigation.
YM155 sensitivity in pediatric acute lymphoblastic leukemia.
Authors: Chang Bill H. , Jemal Abdusebur , Tyner Jeffrey , Thayer Mathew , Muschen Markus , Druker Brian J. 
Published: March 2020

9555 Background: Despite advances in treatment and outcomes in pediatric acute lymphoblastic leukemia, there continue to be subsets of patients that are refractory to standard intensive chemotherapy. Therefore, novel agents are needed to further advance treatment for this disease. YM155 (Astellas) is a selective suppressant of survivin expression. Survivin has been shown to be over-expressed in malignant cells and in relapsed ALL. Early adult phase I/II studies show promise in both tolerability and possible efficacy in B-cell malignancies. Methods: Fresh diagnostic leukemic patient samples, ALL cell lines, and xenograft samples were obtained and subjected to YM155 at doses ranging from 1nM to 10µM. Samples were then tested for viability using standard methane-thiosulfate, apoptosis using Guava nexin Annexin V binding, protein expression using immunoblot, and P53 activation with phospho-flow cytometry. Results: The median IC50 for viability and apoptosis for the samples are: NCI standard risk ALL 5.3nM ±3.47, NCI high risk ALL 91.76 nM ±93.42, T-ALL 336.6nM ±147.7, AML 333.6nM ±489, Ph+ALL xenografts 3.8nM ±1.04, and ALL cell lines 18.5nM ±135. Ph+ALL samples, including primary patient, xenograft, and dasatinib (BMS) resistant samples remain significantly sensitive to YM155. For dasatinib sensitive samples, combination therapy suggests an additive effect by isobologram analysis. Immunoblot and RT2-PCR Arrays (Qiagen) identify that multiple protein expression are decreased with YM155 treatment. Conclusions: Our data supports the model of the use of YM155 as a treatment for ALL including an added benefit in combination with dasatinib in Ph+ALL. Although initial studies suggested that YM155 is a selective suppressant of survivin, subsequent studies are beginning to identify off target effects. These off target effects may enhance the drugs potential for activating cell death. Finally, we show that screening primary samples with YM155 has the potential to select a target population that is more sensitive to YM155 treatment. Future studies will be designed to develop YM155 as an additional therapeutic agent for pediatric acute lymphoblastic leukemia.
Diffuse pontine gliomas in children: Do changing strategies change results?
Authors: Kebudi Rejin , Cakir Betul , Agaoglu Fulya Yaman , Darendeliler Emin , Gorgun Omer , Dagoglu Nergis , Ayan Inci , Dizdar Yavuz , Zulfikar Bulent , Koc Basak 
Published: March 2020

9567 Background: The prognosis of children with diffuse intrinsic pontine gliomas (DIPG) is dismal. Despite various studies undertaken to improve outcome, radiotherapy (RT) remains the standard treatment, which is mostly palliative. This study aims to evaluate characteristics and treatment outcome of children with DIPG in a single center. Methods: We retrospectively reviewed the demographic, clinical characteristics and treatment outcome of children with DIPG treated at Istanbul University, Oncology Institute from 1999 to 2011. We also evaluated the group that prospectively recieved RT with concurrent and adjuvant temozolamide after 2004. Results: 47 children (24 female, 23 male) with the median age of 7 years (6 months-16 years) were analyzed. The median duration of symptoms was 30 days (2-630 days). The frequent clinical findings were ataxia, strabismus and motor weakness. All patients received RT, 54-60 Gy to the tumor site. 12 recieved only RT. 35 had concomitant and/or adjuvant chemotherapy with RT. 8 recieved cisplatinum, 7 vincristine. Since 2004, 20 patients recieved the institutional protocol consisting of temozolomide (TMZ) (75 mg/m2/day) for 6 weeks concurrent with RT, followed by TMZ (200 mg/m2/day) for 5 days every 28 days for 12 cycles or until progression. There was no major side effect due to TMZ, thrombocytopenia being the most frequent, but managable side effect. The median overall survival after diagnosis was 13 months (3-132 mo.) for the whole group. The median overall survival in 20 patients that received RT and TMZ [ 17 months (3-132 months)], was significantly superior than that in 12 patients that recieved only RT [ 12 months (3-20 months)] ( (p=0.03). Nimotuzumab was given to 4 patients that progressed after RT and TMZ. There was no major side effect due to nimotuzumab. One was stable for 1 year with significant clinical improvement, the others were stable for 5, 2 and 2 months after nimotuzumab. Conclusions: In our series, the median survival was significantly superior in patients who received RT with concurrent and adjuvant temozolamide in comparison to patients that recieved RT alone. Nimotuzumab may be promising in some progressive patients, its role as upfront treatment needs further investigation.
High-dose thiotepa: Neurotoxicity and risk factors in children with solid tumors.
Authors: Maritaz Christophe , Lemare Francois , Cherif Amani , Demirdjian Sylvie , Valteau Couanet Dominique , Dufour Christelle 
Published: March 2020

9572 Background: Thiotepa (TTP) is a cytotoxic agent used in children with solid tumors at high doses followed by autologous stem cell transplantation (ASCT). During these treatments, neurological adverse events (NAE) were observed. Causal relationships and risk factors were investigated. Methods: Patients with solid tumors treated with high-dose thiotepa with ASCT between May 1987 and March 2011 were retrospectively identified. Clinico-biological data were collected and NAE were identified from medical and nursing records. Toxicity was graded according to the NCI CTCAE v4.03 classification. Imputability of thiotepa was assessed according to Begaud et al. method. Analysis of risk factors was assessed with Fisher's exact test (alpha 0.05) and relative risk was estimated by calculating odds ratios with their 95% confidence interval. Results: 251 patients received 307 courses (56 patients received twice) of high-dose thiotepa (600 mg/m²: 82 courses; 720 mg/m²: 76 courses; 900 mg/m²: 149 courses) with ASCT. The median age was 8.33 years (range, 1 - 31.2 years). 81 NAE (26.4%) were described. NAE were considered “possibly” related to TTP in 9 courses, “likely” related to TTP in 35 courses and “very likely” related to TTP in 13 courses. Other NAE were assessed “doubtful” or “incompatible”. In these 57 NAE, neurological symptoms appeared at a median time of 2 days (range, 0 - 4 days) after the introduction of TTP. Symptoms were headache, tremor, dizziness and confusion, blurred vision, seizure, pyramidal tract syndrome, cerebellar syndrome, opsoclonus-myoclonus syndrome and coma. These events disappeared without sequelea in a median time of 3 days (range, 1 - 8 days). TTP was reintroduced in 21 cases. NAE reappeared in 12 cases. For 3 patients with seizure during the first course, premedication with clonazepam prevented NAE during the second course. The use of analgesic for moderate to severe pain, such as tramadol or codeine, increased the probabiblity to have NAE (OR 5.6467; 95CI [1.5523-21.2786]; p 0.037). Conclusions: In our study, the incidence of NAE related to TTP was 18.6%. The outcome was favorable without sequelea in all cases. TTP could be reintroduced after NAE. The association of TTP with tramadol increases the risk of neurotoxicity.
Development of an open-source, flexible framework for interinstitutional data sharing and collaboration.
Authors: Kirby Chaim , Ambros Peter F , Billiter David , London Wendy B. , Mendonca Eneida , Monclair Tom , Pearson Andrew DJ , Cohn Susan Lerner , Volchenboum Samuel Louis 
Published: March 2020

9583 Background: Clinical information, “-omic” datasets, and tissue samples are becoming more difficult to harmonize and manage for advanced data mining. We believe that clinical research data can be centralized and provide direct access to sample availability and associated data from a variety of information stores. Methods: We obtained a standardized set of anonymized patient data from the International Neuroblastoma Risk Group. The cohort consists of more than 11,000 children diagnosed worldwide between 1974 and 2002. The data consist of 34 metrics, such as age at diagnosis, stage of tumor, and other clinical and biological markers. We instantiated the dataset into a Postgres database, and using the Django web framework, created a data model for rapid development of tools and views and built a front-end interface for generating complex queries. To test the feasibility of accessing information on disparate and geographically distinct data samples, we have a formal agreement with the Children's Oncology Group Tumor Bank at The Research Institute at Nationwide Children's Hospital. Based on query results, we consume the Tumor Bank tissue inventory data through a web-facing application programming interface. The end-user is presented only with the number of patients who match their query search terms and for whom tissue samples are available. Results: We have completed our initial implementation and have agreements for collaboration with other international consortium groups. We have created a paradigm for statisticians to securely update and add data, and a verification system checks for internal validity and provides a report of the transaction. Our system can initiate queries and accept results in a variety of standards-compliant formats, and will be available in demonstration form by May 2012. Conclusions: Querying patient data while interrogating external sources allows researchers to observe which ancillary data and samples are available and to quickly download data or request any samples. While designed around a neuroblastoma dataset, our system can be applied to a variety of clinical scenarios and will be made available through an open-source license.
Patient-perceived facilitators in the transition of survivorship care from the pediatric to adult care setting.
Authors: Sadak Karim Thomas , DiNofia Amanda , Reaman Gregory H. 
Published: March 2020

9587 Background: Survival rates in childhood cancer continue to rise. A new challenge has emerged in optimizing the transition of pediatric survivorship care to similarly focused programs that are age-appropriate. The purpose of this study is to identify components of a clinical survivorship program that facilitate the transition of care for adult survivors of childhood cancer from the pediatric to adult care-setting. Methods: A descriptive study of childhood cancer survivors was conducted using a cross-sectional study design. A questionnaire was used to identify which clinical components of a survivorship program most influenced the decision to transition care to an adult medical center. Primary data collection occurred through the mail. Secondary mechanisms included an online version of the questionnaire and in-person enrollment during survivorship clinic visits. 140 survivors were eligible but only 129 had valid addresses and received the questionnaire. The study endpoint was achieved when the response rate reached 80% (n=103). A descriptive review of clinical program components was performed using a frequency analysis. Results: Of 129 invited survivors, 103 participated (80%). Mean and median age-range was 20-24 years. There were 49 males (48%) and 54 females (52%). The most common diagnoses were leukemia (40/103), lymphoma (20/103), and CNS tumors (9/103). When asked if the participant was willing to transition their survivorship care to an adult facility, 97 (95%) responded affirmatively. The clinical components most frequently rated “Very Important” in the decision to transition survivorship care were the acceptance of insurance (80/103, 78%) followed by the presence of providers knowledgeable in childhood cancer (68/103, 66%). The clinical components most frequently rated “Very Important” or “Important” were flexible scheduling (102/103, 99%) followed by comprehensive care being offered (101/103, 98%). Conclusions: The decision to transition survivorship care to age-appropriate care-settings is complex and not well understood. Issues related to insurance, clinical team composition, and scheduling appear to be most important for young adult survivors making this decision.