bluuebunny/crossref_metadata_2025_split huggingface dataset:
The HERBY study: A phase II open label, randomized, multicenter, comparative study of bevacizumab (Bv)-based therapy in pediatric patients with newly diagnosed supratentorial high-grade glioma (HGG).
Authors: Grill Jacques , Hargrave Darren R , Varlet Pascale , Jaspan Tim , Jones Chris , Massimino Maura , Cañete Adela , Azizi Amedeo A. , Le Deley Marie-Cécile , Saran Frank , Morgan Paul , Zahlmann Gudrun , Viviers Louis , Bachir Jeanette , Shang Aijing , Rousseau Raphael F. , Vassal Gilles ,   on behalf of the European Innovative Therapies for Children with Cancer (ITCC) Consortium, The SIOP-E Brain Tumour Group and the Australian Children's Cancer Trials Group
Published: March 2020

TPS9596 Background: Despite therapeutic advances, outcomes in pediatric HGG remain poor. The phase I study (Glade-Bender et al., J Clin Oncol. 2008) indicated that Bv is well tolerated in children with refractory solid tumors and yielded pharmacokinetic (PK) data that support further studies of Bv in childhood cancer. Reports of Bv used in children with solid tumors showed safety profiles consistent with data from adults. Methods: 120 evaluable patients aged 3-18 years with newly diagnosed histologically confirmed WHO grade 3or 4 HGG are randomized to receive standard combined modality therapy as currently adopted worldwide by the pediatric neuro-oncology community with or without Bv. Treatment consists of 6 weeks of concomitant TMZ and local radiotherapy, followed by a 4-week TMZ treatment break and 48 weeks of adjuvant TMZ with or without Bv every other week. Primary endpoint is event-free survival (EFS). Progression is based on RANO criteria. Secondary endpoints are overall survival (OS), safety, feasibility, and tolerability. PK sampling is performed during cycles 1-4 of the adjuvant TMZ phase on all patients randomized to receive Bv. Health-related quality of life, neurocognitive functions, MGMT methylation status, functional changes in tumor based on magnetic resonance diffusion & perfusion imaging and spectroscopy are explored as well as the correlation of biomarkers with clinical activity and adverse events. All randomized patients will be followed for at least 3 years. Analysis of EFS and secondary endpoints will be performed after the 120 patients evaluable for EFS have been followed for 1 year. Multimodal imaging will provide a platform to develop new imaging criteria for pediatric neuro-oncological treatment response. An updated OS and safety analysis will be performed 3 years after the last patient has been randomized. The first patient was randomized in October 2011; completion of the study is expected in 2016.
RTOG 0825: Phase III double-blind placebo-controlled trial evaluating bevacizumab (Bev) in patients (Pts) with newly diagnosed glioblastoma (GBM).
Authors: Gilbert Mark R. , Dignam James , Won Minhee , Blumenthal Deborah T. , Vogelbaum Michael A. , Aldape Kenneth D. , Colman Howard , Chakravarti Arnab , Jeraj Robert , Armstrong Terri S. , Wefel Jeffrey Scott , Brown Paul D. , Jaeckle Kurt A. , Schiff David , Atkins James Norman , Brachman David , Werner-Wasik Maria , Komaki Ritsuko , Sulman Erik P. , Mehta Minesh P. 
Published: March 2020

1 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Sunday, June, 2, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.
Hyaluronidase synthase 3 (HAS3) variant and anthracycline-related cardiomyopathy: A report from the Children’s Oncology Group.
Authors: Sun Can-Lan , Wang Xuexia , Liu Wei , Armenian Saro , Hankonarson Hakon , Hageman Lindsey , Ding Yan , Landier Wendy , Keller Frank G. , Neglia Joseph Philip , Desai Sunil J. , Sklar Charles A. , Castellino Sharon M. , Cherrick Irene , Dreyer Zoann , Yasui Yutaka , Relling Mary V. , Bhatia Smita 
Published: March 2020

10004 Background: The strong dose-dependent association between anthracyclines and cardiomyopathy limits the therapeutic potential of this extremely effective class of agents, demanding identification of those at highest risk, such that anthracycline exposure may be tailored. Methods: In a two-stage design, we investigated host susceptibility to anthracycline-related cardiomyopathy in cancer survivors by using the ITMAT/Broad/CARe cardiovascular SNP-array to profile common SNPs in 2100 genes considered most relevant to de novo cardiovascular disease. All cases of cardiomyopathy fulfilled American Heart Association (AHA) criteria for cardiac compromise and were confirmed echocardiographically. Results: Using a matched case-control design (93 cases, 194 controls, all non-Hispanic white survivors of childhood cancer) we identified a common SNP rs2232228 in hyaluronan synthase (HAS3) gene that exerts a substantial modifying effect on anthracycline dose-dependent risk of cardiomyopathy. Among individuals with GG genotype, cumulative anthracycline exposure was not associated with cardiomypathy risk at any dose. Individuals with AA genotype, exposed to >250mg/m2 anthracyclines, had an 8.5-fold increased cardiomyopathy risk (95%CI, 2.0-35.6, p=0.004). Replication in an independent set of 76 patients (adult-onset and childhood cancer; all races) with anthracycline-related cardiomyopathy revealed the odds of cases with AA genotype in the high-dose anthracycline group to be 4.5-times higher (95%CI, 1.1-18.4, p=0.04). Hyaluronan (HA) – produced by HAS3 – is a ubiquitous component of extracellular matrix (ECM). ECM is involved in tissue remodeling; the extent of cardiac remodeling/repair after anthracycline-induced cardiac injury is possibly modulated by variability in HA production. Conclusions: The significant modifying effect of HAS3 genotype on the dose-dependent association between anthracycline and cardiomyopathy risk suggests that, upon confirmation in prospective studies, genotyping HAS3 may be considered when evaluating risk of anthracycline-related cardiomyopathy.
Second non-ocular tumors among survivors of retinoblastoma treated with proton therapy.
Authors: Sethi Roshan V , Shih Helen Alice , Kim David , Yeap Beow Y. , Mouw Kent , Marcus Karen Chayt , Grabowski Eric , Yock Torunn I. , Tarbell Nancy , Mukai Shizuo , MacDonald Shannon M. 
Published: March 2020

10018 Background: The leading cause of death for patients with hereditary retinoblastoma is second malignancy. Proton radiation allows for significant sparing of non-target tissue. We sought to determine the risk of second malignancy for the largest and oldest cohort of retinoblastoma patients treated with proton therapy. Methods: We performed a retrospective review of patients treated at the Massachusetts General Hospital (MGH) between 1986 and 2011. Results: Fifty-two patients were identified (see Table). Forty-four patients (85%) were hereditary survivors. Patients were followed for a median of 6.9 years from the start of radiation therapy (range, 11.3 months to 24.4 years). The median age at follow-up was 9.0 years (range, 31.3 months to 24.5 years). Fifteen patients had more than 10 years of follow-up from the start of radiation therapy, and 20 patients were more than 10 years old at last follow-up. With 417.2 person-years of follow-up, we identified one secondary malignancy, an osteosarcoma of the distal femur. The cumulative incidence of second tumor was 5% at 10 years. No radiation-associated malignancies were reported. Conclusions: Retinoblastoma is highly responsive to radiation. The central objection to the use of radiation—the risk of second malignancy—is founded on studies of patients treated with relatively non-conformal techniques. We present the first series of patients treated with the most conformal of current available modalities. While longer follow up is necessary, our preliminary data suggest that the risk of radiation-associated malignancy is minimal with proton therapy. [Table: see text]
The effect of surgery type on survival and recurrence in very young women with breast cancer.
Authors: Quan May Lynn , Paszat Lawrence Frank , Fernandes Kimberley , Sutradhar Rinku , McCready David R. , Rakovitch Eileen , Warner Ellen , Wright Frances Catriona , Hodgson Nicole , Brackstone Muriel , Baxter Nancy 
Published: March 2020

1002 Background: Young age has been identified as an independent predictor of recurrence and mortality in women with breast cancer. The equivalence of breast conserving surgery (BCS) with mastectomy remains unclear in this population in an era of multimodal therapy. We sought to determine the effect of surgery type on the risk of recurrence and survival in a large, population based cohort of very young women. Methods: All women diagnosed with breast cancer aged ≤35 between 1994 and 2003 in Ontario were identified from the Ontario Cancer Registry, a population based registry of all incident invasive breast cancers in the province. A retrospective chart review was undertaken to identify patient, tumor and treatment variables, as well as locoregional, distant recurrences and death. Univariable and multivariable Cox proportional hazards regression models were fit to determine the effect of primary surgery type on overall survival while controlling for known confounders. To examine time to recurrence in a multivariable analysis, the proportional subdistribution hazards model (Fine and Gray) was used to account for death being a competing risk. Results: A total of 1,381 patients were identified; the median age was 33 (range 18 – 35), median follow up was 11 years. Primary surgical treatment was BCS in 793 (57%) patients of which 89% had adjuvant radiotherapy. Of the 588 (43%) having mastectomy, 53% underwent post mastectomy radiation. Overall, 38% of patients sustained a recurrence of any type and 31% had died. After controlling for tumor size, margin status, node status, grade, LVI, ER/PR, HER2 and treatment (chemotherapy, radiation, hormones) there was no difference in overall survival (HR 0.99, 95% CI 0.79,1.26) or recurrence (HR 0.96, 95% CI 0.73,1.26) among women treated with BCS or mastectomy. Predictors of recurrence were size ≥2 cm, ≥ 1 positive node, neoadjuvant chemotherapy, and lack of radiation. Predictors of death were similar and included high grade and presence of LVI. Conclusions: Very young women selected for BCS had similar outcomes to those selected for mastectomy after controlling for known prognostic factors for recurrence and death.
Pulmonary function after treatment for embryonal brain tumors on SJMB03 that included craniospinal irradiation.
Authors: Green Daniel M. , Merchant Thomas E. , Billups Catherine A , Stokes Dennis C , Broniscer Alberto , Srinivasan Ashok , Chintagumpala Murali M. , Hassall Timothy E , Bouffet Eric , Gururangan Sridharan , Kellie Stewart J , Ashley David M , Cohn Richard J , Fisher Michael J. , Gajjar Amar J. 
Published: March 2020

10021 Background: Treatment of children with embryonal brain tumors (EBT) includes craniospinal irradiation. There are limited data regarding the effect of radiation therapy (RT) on pulmonary function. Methods: Protocol SJMB03 enrolled patients 3 to 21 years of age with EBT. Pulmonary function tests (PFTs) [forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) by spirometry, total lung capacity (TLC) by plethysmography and diffusing capacity of the lung for carbon monoxide (DLCO)] were obtained following completion of RT, prior to each of four courses of high-dose chemotherapy (cumulative cyclophosphamide dose, 16 g/m2), and 24 months after completion of treatment (ACT). Differences between PFTs obtained following the completion of RT and 24 months ACT were compared using exact Wilcoxon signed rank tests. Results: 303 eligible patients were enrolled between June 24, 2003 and March 1, 2010, 258 of whom had at least one PFT. Median age at diagnosis - 8.9 years (range, 3.1 to 20.4 years). Median spinal RT dose - 23.4 Gy (range, 23.4 to 50.4 Gy). Median cyclophosphamide dose was 16.24 g (range, 0 to 34.38 g). 24 months ACT, DLCO was < 75% predicted in 23% (27/115 evaluated), FEV1 was < 80% predicted in 21% (32/150 evaluated), FVC was < 80% predicted in 27% (46/168 evaluated) and TLC was < 80% predicted in 18% (24/135 evaluated) of patients. DLCO was significantly decreased 24 months ACT compared to the end of RT (median difference (MD) in % predicted, - 3.00%; p = 0.035). Race and cumulative cyclophosphamide dose were not significant predictors of DLCO. DLCO was significantly higher among males (p = 0.037) than females in a model that included time point, sex, RT dose group, RT dose*time interaction and age at diagnosis. The differences in FEV1 ((MD, - 1.00%), FVC (MD, 0.00%) and TLC (MD, -2.00%) were not statistically significant. Conclusions: Among patients with EBT treated with spinal RT, DLCO was significantly decreased 24 months after completion of treatment compared to immediately post-RT. TLC was decreased 24 months ACT, suggesting that a significant minority of patients have restrictive lung disease. Continued monitoring of this cohort to five years ACT is planned. Clinical trial information: NCT00085202.
A phase I study of ridaforolimus (MK-8669) in pediatric patients with advanced solid tumors.
Authors: Pearson Andrew DJ , Federico Sara Michele , Aerts Isabelle , Hargrave Darren R , DuBois Steven G. , Iannone Robert , Geschwindt Ryan , Wang Ruixue , Trippett Tanya M. , Geoerger Birgit 
Published: March 2020

10027 Background: Deregulation of the PI3K/AKT/mTOR signaling pathway occurs in many poor prognosis childhood malignancies and inhibition of this pathway is a promising novel therapeutic strategy. Ridaforolimus (MK-8669) is a highly selective orally bioavailable small molecule inhibitor of mTOR. This multi-centre, phase I dose escalation study of orally administered Ridaforolimus was designed to evaluate the maximum tolerated dose (MTD), safety profile, pharmacokinetic profile (PK), antitumor activity and pharmacodynamic (PD) biomarkers (phosphorylated Akt [pAkt] in platelet-rich plasma). Methods: Patients (pts) from 6 to <18 years (yrs) with advanced solid tumors were enrolled. Dose escalation was by a modified Toxicity Probability Intervals method (mTPI, Ji Y, et al. Clin Trials 2007) targeting a 30% dose limiting toxicity (DLT) ratio. Pts received 28 day cycles of Ridaforolimus (MK-8669), orally, five days out of seven. Dosing started at 22 mg/m2, escalated to 28 and 33 mg/m2, with an expansion cohort treated at the maximum administered dose. Results: 19 pts, age 8-17 (median 13.5 years), were enrolled and 18 treated from 6 international sites. Diagnoses included ependymoma (5), osteosarcoma (3), Ewings sarcoma (3) and other histologies (7). Four pts received dose level (DL) 1; 3 DL 2 and 11 DL 3. Pts received between 1-12+ courses. There was only one DLT (DL 2: grade 3 elevated alanine transaminase [ALT]) and no other grade 3-4 treatment-related toxicities. Preliminary analysis shows the most frequent drug-related adverse events were manageable grade 1-2 stomatitis (70.6%) and fatigue (52%). Dose escalation stopped at DL3 (33 mg/m2, 150% of the adult recommended phase 2 dose [RP2D]). There were no objective responses by RECIST1.1. Two pts remain on study, with continuing stable disease (pineoblastoma [12 courses], diffuse intrinsic pontine glioma [6 courses]). PK and PD analyses will be presented. Conclusions: Ridaforolimus is a safe and well tolerated, orally bioavailable mTOR inhibitor. The RP2D for Ridaforolimus in children is 33 mg/m2. Prolonged disease stabilization was observed in two patients. PK/PD data will provide further data to support the RP2D. Further combination studies are warranted. Clinical trial information: NCT01431547.
Characterization of neuroblastic tumors as developmental cancers with survival determined by histology, age, and location.
Authors: Effinger Karen Elizabeth , Merrihew Lindsey Elizabeth , Fisher Paul Graham 
Published: March 2020

10046 Background: Mortality associated with peripheral neuroblastic tumors (pNT), comprising neuroblastoma (NB) and ganglioneuroblastoma (GNB), varies with some tumors spontaneously regressing and others showing poor response to therapy, indicating different biologic mechanisms. We aimed to determine how epidemiologic constructs inform the underlying biology of pNT. Methods: Using the Surveillance Epidemiology and End Results (SEER 18) population-based registry, we identified 3,540 pNT (3,003 NB and 537 GNB) in patients from 1973-2009. Differences in histology (NB vs. GNB), gender, age (<18 months, 18 months-4 years, 5-14 years, or ≥15 years), race (white, black, or other), location of primary tumor (adrenal, abdominal, chest, head/neck, pelvic, or other), and stage (locoregional vs. metastatic) were evaluated with chi-squared tests using SAS 9.3. Kaplan Meier curves with log-rank tests as well as univariate and multivariate Cox proportional hazard regression methods were employed to determine the influence of these factors on survival. Results: NB occurred more frequently in infants (50%), arose in the adrenals (45%), and were metastatic at diagnosis (57%), while GNB more often affected children 18 months-4 years (48%, p <0.001), occurred in the chest (31%, p <0.001), and were locoregional (78%, p <0.001). The 5-year overall survival (OS) rate in NB was 59% compared to 80% in GNB (p <0.001). In NB, the 5-year OS rate was 81% in infants <18 months and 21-39% in the older groups (p <0.001); however, in GNB, the 5-year OS was 40% in subjects >15 years and 81-93% in the younger groups (p <0.001). In multivariate analysis of pNT, neuroblastoma, age >18 months, adrenal site of primary tumor, and metastatic disease were independent poor prognostic factors. Chest (HR 0.27 [0.21-0.35]), head/neck (HR 0.34 [0.20-0.52]), and pelvic (HR 0.35 [0.24-0.52]) tumors had the most improved survival compared to adrenal primaries. Conclusions: Although pNT are often evaluated together, NB and GNB represent two significantly distinct diseases. For each, survival is strongly determined by age, primary tumor location, and stage. These differences may stem from unique developmental mechanisms underlying tumorigenesis.
A phase I dose-escalation study of intratumoral herpes simplex virus-1 mutant HSV1716 in pediatric/young adult patients with refractory non-central nervous system solid tumors.
Authors: Cripe Timothy P. , Racadio John M , Conner Joe , Towbin Alexander , Brunner Marianne M , Stockman Beth A , Currier Mark , Geller James I. 
Published: March 2020

10047 Background: HSV1716 is a mutant herpes simplex virus type 1 deleted in the RL1 gene which encodes the protein ICP34.5, a specific determinant of virulence. Mutants lacking the RL1 gene are capable of replication in actively dividing cells but not in terminally differentiated cells – a phenotype exploited to selectively kill tumor cells. Studies in adult patients with high grade glioma, melanoma and squamous cell carcinoma report that HSV1716 is safe when administered by intra-tumoral injection. This is the first study of HSV1716 in pediatric/young adult patients. Methods: The primary endpoint of the study is to assess safety of intratumoral HSV1716 in pediatric/young adult patients, and to determine any dose-limiting toxicities (DLT) at the doses given. Patients undergo long-term follow up in accordance with FDA guidelines for viral vectors. The secondary endpoints of the study are to measure: (i) antiviral immune response; (ii) systemic viremia and viral shedding and (iii) the antitumor activity of HSV1716 by radiological response within the confines of a Phase I study. Patients aged 7 to 30 with solid non-CNS tumors refractory to standard therapy (or for which no therapy exists) are eligible for the study provided the target lesion is accessible to image-guided injection. Eligible patients receive a single dose of HSV1716 (Virttu Biologics Limited) at either 105 or 2x106 plaque forming units (pfu) HSV1716 administered directly into the tumor via ultrasound or CT-guided injection by an interventional radiologist. Tumor response between baseline and day 28 is assessed by modified RECIST criteria. Patients showing at least stable disease may receive up to a 3 additional doses of HSV1716. Results: Recruitment of the first cohort of 3 patients has been completed without DLT or procedure related severe adverse events. In the second cohort, 2 patients have been treated without DLT or procedure related SAE. Conclusions: The trial is in progress and the study is open to recruitment. Clinical trial information: NCT00931931.
Multicenter phase I/II trial of topotecan (T) and ifosfamide (I) combination as second-line therapy for pediatric solid cancer: Phase II results.
Authors: Kawamoto Hiroshi , Oba Mari Saito , Hosono Ako , Ishida Yuji , Taga Takashi , Kosaka Yoshiyuki , Inagaki Jiro , Mugishima Hideo , Okamoto Yasuhiro , Ogawa Atsushi 
Published: March 2020

10050 Background: Both of T and I are key drugs for recurrent pediatric solid malignancies but rarely used in combination. Results of the phase I portion of the combination of T and I chemotherapy (TI) which is dose-finding study by CRM method in ASCO 2010. We hereby report the results of efficacy and safety screening of TI conducted as a phase II portion. Methods: Recurrent pediatric solid malignancies with history of chemotherapy no more than 20 cycles (Cs) are eligible. Combination of I (1.2g/m2/day) and T (0.6 mg/m2/day) were administered day 1 through 5 up to six Cs. In the phase II portion, a Simon optimal two-stage design was adopted using treatment compliance with 4 Cs of TI as primary endpoint. Unacceptable compliance was set at 20% and promising one at 40%. If more than two patients (pts) among initial 13-15 pts successfully complete 4 Cs, patients’ enrollment is allowed to continue until a total of 33 pts in the phase II portion. Complete or Partial Response (CR+PR) was evaluated according to RECIST 1.0 criteria and toxicity, CTCAE v3.0. Results: 35 pts, median age 12 years (range 1-28) has been registered in both phase I and II between March 2008 and January 2013 in 8 centers: 7 neuroblastoma (NB), 8 rhabdomyosarcoma (RMS), 8 osteosarcoma (OS), 6 Ewing’s sarcoma (ES), 2 hepatoblastoma (HB), and 4 others. 13 pts out of total 34 pts (38%) completed 6 Cs. 13 pts out of 28 pts (36%, the phaseII portion) received more than 4 Cs without meeting stopping criteria of protocol treatment. This has reached the predefined efficient level. No Grade 4 non-hematological toxicity occurred. Grade 2-4 fatigue, anorexia, and nausea were 20% or less. Grade 3 or 4 neutropenia was frequent (105/127 Cs, 83%), though only 9 % (12 Cs) developed febrile neutropenia. 2 CR (HB, ES) and 2 PR (RMS, OS) were observed at best response among 22 pts with measurable disease, leading to an estimated OR rate of 18% (95%CI 5-40%). 14 patients had disease stabilization. One year progression-free survival rate and overall survival rate are 21% and 64%. Conclusions: TI achieved very good compliance and favorable toxicity as well as good tumor control rate. This combination is a new promising 2nd line therapy for pediatric solid malignancies. Clinical trial information: UMIN000001037.