bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I/II trial of vandetanib in children and adolescents with hereditary medullary thyroid carcinoma
Authors: Fox E. , Widemann B. C. , Whitcomb P. O. , Aikin A. , Dombi E. , Lodish M. , Stratakis C. A. , Steinberg S. , Wells S. A. , Balis F. M. 
Published: August 2020

10014 Background: Mutations in the RET protooncogenecause hereditary medullary thyroid carcinoma (MTC) including Multiple Endocrine Neoplasia (MEN) Type 2A, Type 2B and familial MTC. Vandetanib inhibits VEGFR, EGFR, and RET tyrosine kinases and is active in adults with hereditary MTC. Methods: We are conducting a trial of vandetanib in children and adolescents with RET mutations and MTC. Safety is evaluated at each dose level in adolescents (13–18 years) prior to enrolling children (5–12 years). In the absence of dose limiting toxicity (DLT), intrapatient dose escalation is permitted after cycle 2. To assess bone toxicity, growth plate volume is measured using MRI. Response is monitored using tumor measurements (RECIST), serum biomarkers, calcitonin (CTN), and carcinoembryonic antigen (CEA). Results: Five adolescents and 2 children were enrolled at the 100 mg/m2 dose level, 3 adolescents were dose escalated to 150 mg/m2. Six have MEN2B (M918T RET mutation). Median (range) baseline CTN was 12,200 pg/mL (2,300–67,000) and CEA was 104 mcg/L (5–325). Dose limiting diarrhea was observed in 1/5 adolescents at the 100 mg/m2 and 1/3 adolescents escalated to 150 mg/m2. No DLTs were observed in children receiving 100 mg/m2. Non-DLT included elevated TSH (n = 6), rash (n = 5), anorexia (n = 3), diarrhea (n = 2), hypertension (n = 1), and fatigue (n = 1). Median (range) percent change in growth plate volume during therapy was -18% (-44% to + 50%). All patients had linear growth during therapy. Serum CTN and CEA decreased by ≥ 50% in 6/7 and 2/7 patients, respectively. Tumor size decreased in 6/6 patients with M918T RET mutations; 2 achieved RECIST partial response after 6 and 12 cycles. Conclusions: Preliminary results suggest that vandetanib has activity in children and adolescents with MEN2B associated MTC. Vandetanib 100 mg/m2 was well tolerated. Linear growth was not impaired. [Table: see text]
Pediatric Preclinical Testing Program (PPTP) testing of the CENP-E inhibitor GSK923295A
Authors: Smith M. A. , Morton C. L. , Carol H. , Gorlick R. G. , Kang M. H. , Keir S. T. , Kolb E. A. , Lock R. B. , Maris J. M. , Houghton P. J. 
Published: August 2020

10015 Background: GSK923295A is a small molecule inhibitor of centromere-associated protein E (CENP-E), a mitotic kinesin that is required for metaphase chromosome alignment and integration of mitotic spindle mechanics with mitotic checkpoint signaling. An initial phase I clinical trial in adults is ongoing. Methods: The PPTP includes a molecularly characterized in vitro panel of cell lines (n = 27) and in vivo panel of xenografts (n = 60) representing most of the common types of childhood solid tumors and childhood acute lymphoblastic leukemia (ALL). GSK923295A was tested in vitro at concentrations from 1.0 nM to 10.0 μM (96 hour exposure) and was tested in vivo using a daily × 3 for 2 weeks schedule, repeated at day 21. GSK923295A was administered IP at a dose of 125 mg/kg. Three measures of antitumor activity were used: 1) an objective response measure modeled after the clinical setting; 2) a time to event measure based on the median event-free survival (EFS); and 3) a treated to control (T/C) tumor volume measure. Results: GSK923295A demonstrated potent in vitro activity against the PPTP cell line panel with a median IC50 of 27 nM (range 12 nM to > 10 μM). 35 of 37 solid tumor xenograft models were evaluable. GSK923295A induced significant differences in EFS distribution compared to controls in 32 of 35 evaluable models. Objective responses were noted in 13 of 35 xenografts, including 9 with maintained complete responses (MCR), 3 with complete response (CR), and 1 with partial response (PR). Three of 5 Ewing sarcoma xenografts achieved MCR or CR, as did 2 of 3 rhabdoid tumor, and 2 of 5 rhabdomyosarcoma models. For the neuroblastoma panel, the best response was progressive disease (PD) with growth delay compared to controls (PD2 response), which was observed in 5 of 6 xenografts. GSK923295A showed activity against the ALL panel, but unexplained toxicity (generally on or after day 21) precluded formal analysis. Conclusions: GSK923295A has substantial in vitro and in vivo activity against the PPTP's preclinical models. The observed high level of preclinical activity for GSK923295A will need to be evaluated in the context of systemic exposures achieved in the xenograft models and those achievable in humans at tolerable doses. (Supported by NCI NO1CM42216) [Table: see text]
Pharmacokinetic and biological study of erlotinib in children as monotherapy for refractory brain tumors or with radiation for newly diagnosed brain stem gliomas
Authors: Geoerger B. , Hargrave D. , Thomas F. , Andreiuolo F. , Varlet P. , Frappaz D. , Doz F. , Riccardi R. , Jaspan T. , Vassal G. 
Published: August 2020

10019 Background: This multicenter phase I study was designed to determine the recommended dose (RD) of erlotinib, a small-molecule EGFR TKI, in patients ≤ 21 years as monotherapy or in combination with radiation therapy (RT). Methods: Group 1 included patients with brain tumors refractory to or relapsing after conventional therapy; receiving erlotinib alone. Group 2 included newly diagnosed patients with brain stem gliomas, who received RT (54Gy) and erlotinib. Conventional 3+3 dose escalation was used for Group 1; a continual reassessment method for Group 2. Four dose levels were planned: 75, 100, 125 and 150 mg/m2/day. Results: A total of 51 patients were enrolled (30 in Group 1; 21 in Group 2); 50 received treatment. Median age was 10 and 6 years, respectively. The RD of erlotinib was 125 mg/m2/day as monotherapy or in combination with RT. 203 adverse events in 44 patients were possibly treatment-related; 188 were G1/2; 9 G3, 2 G4, and 4 G5. Dermatologic and neurologic symptoms were most common; intratumoral hemorrhage was noted in 4 patients. In Group 1, 8 patients (27.6%) had stable disease, 2 with 45% tumor regression. In Group 2, 3 patients (14%) had partial response and 8 (38%) were stabilized; median OS was 12 months. Pharmacokinetic data of 46 patients were analyzed; patients’ weight and erlotinib clearance (CL) were significantly correlated. Mean (± SD) apparent CL and volume of distribution for erlotinib were 143.7 mL/h/kg (± 66.3) and 3.5 L/kg (± 3.0), respectively, and were independent of dose level. Mean half-life for erlotinib was 20.4 hours. Biomarker analyses on archived tumor or biopsy tissue prior to study entry for newly diagnosed brain stem glioma found 18/37 tumors tested were EGFR IHC+; 16/37 and 23/36 were pAKT+ and pMAPK+, respectively. High EGFR expression was more common in supratentorial gliomas; PTEN loss was most common in brain stem glioma (15/19) and was not observed in ependymomas. Conclusions: Erlotinib 125 mg/m2/day has an acceptable tolerability profile in pediatric patients with brain tumors, and can be safely combined with RT. Further studies are required to define the efficacy of this treatment approach and to establish the impact of biomarkers on outcomes in pediatric glial tumors. No significant financial relationships to disclose.
DNA methylation pattern of brain stem pilocytic astrocytomas in children
Authors: Witt H. , Korshunov A. , Remke M. , Janzarik W. G. , Gnekow A. , Scheurlen W. , Kulozik A. E. , Lichter P. , Pfister S. 
Published: August 2020

10021 Background: Pilocytic astrocytoma (WHO grade I) comprises the most frequent brain tumor in childhood. We were recently able to identify BRAF as a centrally important oncogene in these tumors showing duplication or activation in a majority of cases. Although histologically indistinguishable, tumors with brain stem location have a particularly poor prognosis. It is not well established, whether this is due to their close proximity to pivotal anatomic sites or due to distinct biological characteristics. Methods: To identify novel genes involved in astrocytoma pathogenesis, we performed a genome-wide DNA methylation analysis of 78 pilocytic astrocytoma samples from different tumor locations (diencephalic, cerebral, cerebellar, brain stem). BeadChip methylation technology was used to identify genes showing differential promoter methylation among tumors. Two CpG sites were analyzed for each of a total of 14.000 promoters per sample. Clinical and molecular subgroups were compared using Significance Analysis of Microarrays (SAM). Results: In this genome-wide approach, we identified an 11-gene signature that was able to correctly separate all brain stem tumors (n = 8) from the majority of tumors from other locations (56/70). Moreover, from 14 tumors clustering together with the brain stem tumors, 5 patients experienced disease recurrence (38%) as opposed to 20% in the remaining group. Genes contained in the signature most interestingly included three homeobox family genes (HOXB1, HOXD3, and HOXD4), and NES, a tumor stem cell marker. Conclusions: These data suggest that brain stem pilocytic astrocytomas display biologic features different from most tumors of other locations and share a methylation signature with tumors prone to disease recurrence from other locations. We provide first evidence for a role of differentially methylated homeobox family genes in the pathogenesis of pilocytic astrocytoma. No significant financial relationships to disclose.
Phase I and pharmacokinetic (PK) study of lenalidomide (LEN) in pediatric patients with relapsed/refractory solid tumors or myelodysplastic syndrome (MDS): A Children's Oncology Group Phase I Consortium study
Authors: Berg S. L. , Russell H. , Cairo M. , Ingle A. M. , Adamson P. C. , Blaney S. M. 
Published: August 2020

10023 Background: LEN, which has immunomodulatory, antiangiogenic, and antiproliferative effects, is indicated for the treatment of adults with MDS and multiple myeloma. We report the final results of a phase 1 and PK study of LEN in children with recurrent or refractory solid tumors (ST) or MDS. Methods: LEN was administered by mouth once daily for 21 of 28 days. Cohorts of 3 to 12 children with ST were enrolled at 15, 25, 40, 55 and 70 mg/m2/d dose levels. Children with MDS received a fixed dose of 5 mg/m2/d. PK and correlative biology studies were performed in cycle 1. Results: 49 patients (23 female), median age 16 years (range, 1–21) were enrolled and received a median of 1 cycle (range 1–11). 39/46 ST patients and 3/3 MDS patients were fully evaluable for toxicity. 0/3 patients with MDS had DLT. At 15 mg/m2/d, 1/6 ST patients developed DLT (Gr 3 hypercalcemia). At 25 mg/m2/d 1 patient had a cerebrovascular ischemic event of uncertain relationship to LEN; future subjects were screened for thromboembolic risk factors prior to enrollment. At 40 mg/m2/d 3/12 patients developed DLTs (Gr 3 hypophosphatemia/hypokalemia; Gr 4 neutropenia delaying the start of the next cycle for > 7 days; Gr 3 somnolence); at 55 mg/m2/d 1/6 patients developed DLT (Gr 3 urticaria). At 70 mg/m2/d 0/6 patients had DLT. No further dose escalation was attempted. No objective responses were observed. LEN enhanced IL-2 and IL-15 concentrations; NK expansion and activation; and NK and LAK cytotoxicity (Ayello, ASH, 2008). The median apparent LEN clearance and half-life were 135 ± 45 ml/min/m2 and 2.3 ± 1.1 hr. Conclusions: LEN is well tolerated at doses up to 70 mg/m2/d x 21d of 28 days in children with recurrent or refractory ST. Enhancement of immune function is significant. PK parameters in children are similar to those in adults. No significant financial relationships to disclose.
Advanced stage, elevated LDH, primary sites, but not adolescent (A) age (≥ 15 years) as risk factors for disease progression in childhood (C) and adolescent (A) mature B-NHL: Report of the FAB/LMB 96 international trial
Authors: Cairo M. S. , Sposto R. , Gerrard M. , Waxman I. , Goldman S. , Auperin A. , Pinkerton R. , Raphael M. , McCarthy K. , Perkins S. L. , Patte C. 
Published: August 2020

10032 Background: We recently reported the results in C & A with low risk (group A), intermediate risk (group B) and high risk (group C) mature B-NHL treated on FAB/LMB 96 (Gerrard et al, Br J Haematol, 2008; Patte et al, Blood, 2007; Cairo et al, Blood, 2007, respectively). Adolescent age (15–21 yrs) has historically been considered to be an independent risk factor for poor outcome in subsets of mature B-NHL (Hochberg/Cairo et al, Br J Haematol, 2008; Burkhardt et al, Br J Haematol 2005; Cairo et al, Br J Haematol, 2003). Methods: We analyzed the EFS of all pts treated on FAB/LMB 96 and the following risk factors were significant in a univariate and Cox multivariate analysis: age (<15 vs ≥15 yrs), stage I/II vs III/IV, primary sites, LDH <2 vs ≥2 NL and histology (DLBCL vs BL/BLL). Results: 1111 pts (15%, 15–21 years) were treated with group A (N = 132), group B (N = 744), and group C (N = 235) therapy. Five year EFS (CI95) for all, A, B, C pts was 86% (84%,88%), 98% (93%, 100%), 87%% (84%, 89%), and 79%% (73%,84%), respectively. Age (≥15 yrs), LDH ≥2NL, stage III/IV, and BM+/CNS+ and histology were significant univariate risk factors for decreased EFS (P<0.045, <0.0001, <0.0001, <0.0001, and <0.0001 respectively). Multivariate analysis demonstrated age ≥15 yrs and DLBCL histology were no longer independent significant risk factors (p = .82 and 0.08, respectively), but LDH (RR 2.0, p = .001), stage III/IV (RR 3.8, p<0.001), and primary sites including PMBL (RR 4.0, p<.001) and BM+/CNS+ (RR 2.8, p<0.001) were independent significant risk factors for poorer outcome. Conclusions: With the use of modern short but intense FAB-LMB 96 therapy, adolescent age is no longer a poor risk factor in children with mature B-NHL. The independent risk factors identified in this study (stage, LDH, primary site) for decreased EFS in C & A mature B-NHL will form the basis of the next risk adapted international pediatric mature B-NHL trial. No significant financial relationships to disclose.
Pilot study of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia
Authors: Rubnitz J. , Inaba H. , Ribeiro R. , Pounds S. , Pui C. , Leung W. 
Published: August 2020

10034 Background: In the setting of hematopoietic stem cell transplantation (HSCT), donor natural killer (NK) cells exhibit potent anti-leukemic effects without causing graft-versus-host disease. We hypothesized that the transplantation of purified haploidentical NK cells may be a safe and effective form of consolidation therapy that will reduce the risk of relapse among children with acute myeloid leukemia (AML) who are not treated with HSCT. In this pilot study, we assessed the safety, feasibility, and engraftment of NK cell infusions in 10 patients with AML in first remission.Methods: Patients received cyclophosphamide, 60 mg/kg on day -7; fludarabine, 25 mg/m2/day on days -6 through -2; and IL-2, 1 million units/m2, every other day for 6 doses starting on day -1. On day -1, the donor underwent apheresis and the product was purified for CD56+ cells by a two-step procedure. The entire purified product was infused on day 0.Results: The 10 patients had a median age of 2.5 years (range, 8 months to 21 years) and a median leukocyte count of 62 x 109/L (range, 4 to 487) at diagnosis. Leukemic cell genetic abnormalities included CBFβ-MYH11in 4 cases, RBM15-MKL1in 2 cases, MLL-ENL and MLL-AF9 in 1 case each; 2 cases had no detectable abnormalities. Patients received a median of 29 × 106/kg NK cells (range, 5 to 81 × 106/kg). All patients had detectable donor NK cells at one or more time points: donor NK cell chimerism ranged from 0% to 30% during the first 4 weeks after the infusions and was greater than 1% in 9 cases at week 1, 4 cases at week 2, 5 cases at week 3, and 3 cases at week 4. One patient had prolonged NK engraftment (189 days), but no non-hematological toxicity. Grade 3–4 non-hematological toxicity was limited to one respiratory viral infection and one episode of febrile neutropenia. Median length of hospitalization was 2 days (range, 0–3) and median time to neutrophil recovery was 12 days (range, 9–56). With a median follow-up time of 637 days, all patients remain in remission. Conclusions: Haploidentical NK cells can be safely administered to AML patients who are in remission. All patients demonstrated temporary engraftment, which may have antileukemic effects. We have recently opened a new trial to evaluate the efficacy of NK cell therapy in children in first remission of AML. No significant financial relationships to disclose.
Overall survival trends in pediatric osteosarcoma patients over the past three decades
Authors: van Schie R. , Hagleitner M. , Hoogerbrugge P. , Flucke U. , Schreuder H. , te Loo M. 
Published: August 2020

10041 Background: In the late seventies, the combination of chemotherapy and surgery, significantly improved survival of osteosarcoma patients. However, the chemotherapeutic drugs used for treatment of osteosarcoma patients has not significantly changed since then although surgery clearly improved further and adjuvant chemotherapy have been added. In this study, we retrospectively evaluated, whether after the introduction of neoadjuvant chemotherapy in the late seventies, further improvement in outcome of pediatric osteosarcoma patients was achieved. Methods: Since 1978 and 2008, 54 previously untreated pediatric patients with osteosarcoma were enrolled in six consecutive regimens of different agents and intensity. The main difference between the treatment protocols is the addition of either methothrexate or ifosfamide. Overall survival (OS) and event free survival (EFS) in relationship to the different treatment regimens was calculated using the Kaplan-Meier method. Significance of difference in outcome were calculated using the log rank test. Results: The 5-year EFS and OS of the whole group was 54.7% and 61.1%, respectively. There was no significant difference in outcome in patients treated between 1978 and 1993 (n = 18), as compared to patients treated after 1993 (n = 36, OS 47.1% vs 69.4%, p = 0.34). Of all treatment regimens used, OS was the highest in patients treated with cisplatin, doxorubicin, and methotrexate (OS after 5 year 70%). Multivariate analysis showed that EFS and OS significantly correlated with the histological response but not with one of the treatment regimens used. Conclusions: No significant improvement in overall survival has been accomplished in pediatric osteosarcoma patients during the past thirty years. Histological response after neoadjuvant chemotherapy was the most important prognostic factor. No significant financial relationships to disclose.
Association of time to leukemia (TTL) in NOD/SCID mice with expression of apoptosis regulators in pediatric ALL
Authors: Meyer L. H. , Zangrando A. , Eckhoff S. M. , Queudeville M. , Vendramini E. , Basso G. , te Kronnie G. , Debatin K. 
Published: August 2020

10042 Background: Acute lymphoblastic leukemia (ALL) is the most frequent malignant disease in childhood. Although advances in therapy have led to improved long term survival, relapse remains a major challenge. In a recent study we transplanted pediatric leukemia samples from newly diagnosed BCP-ALL patients into NOD/SCID mice. Time to leukemia (TTL) was analyzed for each patient sample as time from transplant to overt leukemia in the recipients. Patients whose leukemia cells engrafted rapidly showed a clearly inferior relapse free survival in contrast to patient samples with prolonged in vivo growth. Multivariate analysis showed an almost 45- fold increased risk for relapse in patients with short TTL. Methods: Gene expression profiles of ALL samples (N = 14) with short versus long TTL in the xenograft model were analyzed using a human whole genome array (Affymetrix U133 Plus 2.0) correlating gene expression values (relative expression) to the time from transplant to manifestation of leukemia in the NOD/SCID mice (TTL, in weeks) by quantitative traits analysis (QTA). Results: Among 5 genes significantly correlated (Spearman correlation, P < .0001) XIAP-associated factor 1 (XAF1) was found to be up-regulated in patients with long TTL. XAF1 abrogates the inhibitory effect of XIAP on caspase-3 thereby sensitizing for apoptosis. In accordance to this caspase-3 activation was also found to be up-regulated in patients with long TTL. Patient samples exhibiting a short time to overt leukemia in the xenotransplant model associated with poor relapse free survival showed down-regulated XAF1 and impaired caspase-3 activation leading to decreased apoptosis of the leukemia cells. Conclusions: Taken together, we used a novel approach directly correlating gene expression values to time from transplant to overt leukemia (TTL) identifying the apoptosis regulator XAF1 to be associated with poor outcome of patients. Small XIAP-inhibiting molecules can be used to substitute the lacking inhibitory effect of down-regulated XAF1 in these poor responding pediatric ALL patients. No significant financial relationships to disclose.
Promoter DNA methylation of CD10 in infant acute lymphoblastic leukemia with MLL/AF4 fusion gene
Authors: Ikawa Y. , Sugimoto N. , Koizumi S. , Yachie A. , Saikawa Y. 
Published: August 2020

10045 Background: Infant ALL displays distinct biologic and clinical features with a poor prognosis. The CD10-negative immunophenotype of infant ALL is a hallmark and provides a predictable signature of MLL rearrangements. While CD10 negativity reflects an earlier stage of B-cell development, complete IgH gene rearrangements (VDJH) show more mature IgH status. Discordance between immunophenotype and genotype of infant ALL suggests an aberrant process in immunophenotypic steps of differentiation or a secondary down-regulation of CD 10 expression associated with MLL rearrangements. We performed methylation analysis of full promoter regions of the CD10 gene to investigate epigenetic mechanisms responsible for CD10 negativity. Methods: CD10-negative infant ALL with MLL/AF4, CD10-positive infant ALL with germ-line MLL, CD10-positive pre-B ALL cell line, infant AML (M5) with MLL/AF9 and pediatric AML (M2) with AML1/ETO were analyzed for VDJH status and methylation of CD10 gene promoters. Results: Three of 4 cases with infant ALL revealed complete rearrangements of VDJH gene with productive joints. Bisulfite sequencing of CD 10 type 1 and 2 promoters identified more than 84% of methylated CpG dinucleotides in all three CD10-negative infant ALL cases with MLL/AF4. The CpG dinucleotides distributed in the clusters of putative Sp 1 binding sites and functionally active regulatory regions of the promoters were fully methylated. In contrast, none or a few of the CpG dinucleotides were methylated in the CD10-positive ALL, AML (M5) with MLL/AF9 or AML (M2) with AML1/ETO. Conclusions: Structural evidence of dense methylation in the CD 10 gene promoter suggested that methylated transcription factor binding sites contribute to CD10 silencing as an epigenetic mechanism. [Table: see text] No significant financial relationships to disclose.