bluuebunny/crossref_metadata_2025_split huggingface dataset:
Renal carcinoma following therapy for cancer in childhood: A report from the Childhood Cancer Survivor Study.
Authors: Wilson Carmen Louise , Ness Kirsten K. , Neglia Joseph Philip , Hammond Sue , Leisenring Wendy M. , Stovall Marilyn , Robison Leslie L. , Armstrong Gregory T. 
Published: March 2020

9528 Background: Limited data exists describing the incidence of and risk factors for subsequent renal carcinoma among long-term survivors of childhood cancer. Methods: The study included 14,351 five-year survivors of childhood cancer diagnosed between 1970 and 1986 who participated in the Childhood Cancer Survivor Study. Chemotherapy and radiotherapy exposures were abstracted from medical records; total dose of radiation to the renal beds was estimated by a radiation physicist. Standardized incidence ratios (SIRs) were calculated using age-, sex-, and calendar-specific incidence data from the Surveillance, Epidemiology and End Results (SEER) program. Cumulative incidence was calculated treating death as a competing risk. Poisson regression analyses were used to assess associations between diagnosis and treatment characteristics and the risk of subsequent renal carcinoma while adjusting for changes in risk due to age. Results: Twenty-six survivors were diagnosed with a renal carcinoma at a median follow-up of 19.3 years (range: 1 month to 34.3 years) from study entry at 5 years post diagnosis. Eight patients received ≥5Gy radiotherapy to a renal bed, 16 received chemotherapy, seven of whom seven received both radiotherapy ≥5Gy and chemotherapy. Cumulative incidence of renal carcinoma at 20 years was 0.16% (95% CI 0.12-0.20). The SIR was 8.1 (95% CI 5.3-11.8) comparing survivors to the general population. Highest risk for renal carcinoma was observed among survivors of neuroblastoma (SIR 87.1, 95% CI 38.4-175.2), non-Hodgkin lymphoma (SIR 9.3, 95% CI 1.9-27.4), and bone tumors (SIR 7.0, 95% CI 1.4-20.4). In multivariable analyses, the risk of subsequent renal carcinoma was elevated among survivors exposed to platinum-based chemotherapy (Rate Ratio 3.1, 95% CI 0.9-10.6) or renal bed radiotherapy ≥5Gy (RR 3.6, 95% CI 1.5-8.4). Conclusions: While cumulative incidence is low, survivors of childhood cancer are at an eight-fold increased risk for subsequent renal carcinoma compared to the general population. In addition to a primary diagnosis of neuroblastoma, radiotherapy directed to the renal bed increased the risk for renal carcinoma.
Tumor location and neurocognitive impairment in adult survivors of pediatric brain tumors: A report from the St. Jude Lifetime Cohort (SJLIFE).
Authors: Brinkman Tara M. , Liu Wei , Armstrong Gregory T. , Gajjar Amar J. , Merchant Thomas E. , Kimberg Cara I. , Kun Larry E. , Srivastava Deo Kumar , Gurney James G. , Robison Leslie L. , Hudson Melissa M. , Krull Kevin R. 
Published: March 2020

9531 Background: Follow-up guidelines identify supratentorial tumor location as a risk factor for poor neurocognitive outcomes during childhood; yet few studies have systematically compared long-term cognitive outcomes between adult survivors of childhood infratentorial and supratentorial brain tumors. Methods: Neurocognitive functions were evaluated in 130 adult survivors of pediatric brain tumors (58 supratentorial and 72 infratentorial, mean [SD] current age = 27.4 years [5.2], age at diagnosis = 8.6 years [4.6], and time since diagnosis = 18.8 years [4.8]) participating in the SJLIFE long-term follow-up protocol. Age-adjusted standard scores for measures of intelligence, attention, memory, processing speed, and executive functioning were calculated, with clinical impairment defined as scores <10th percentile. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable logistic regression models to examine associations between neurocognitive functions and tumor location. Results: As a group, survivors performed below average across multiple neurocognitive domains, including full scale IQ (mean=88.1; SD=18.2), with 34% demonstrating impaired IQ. Survivors of infratentorial tumors were more likely to be impaired on measures of focused attention (OR=2.19, 95% CI=1.03-4.65) and fine motor dexterity (OR=2.62, 95% CI=1.21-5.66) compared to survivors of supratentorial tumors. After adjusting for sex, age at diagnosis, shunt placement and cranial radiation (yes/no), infratentorial tumor location was only associated with reduced performance on a task of visual abstract reasoning (OR=3.76, 95% CI=1.40-10.1). Cranial radiation therapy was independently associated with impaired short-term memory (OR=15.6, 95% CI=1.64-147.8) and processing speed (OR=3.86, 95% CI=1.15-13.0). Conclusions: Tumor location was not associated with neurocognitive impairment after adjusting for treatment exposures. To further delineate potential differences associated with tumor location, future studies will examine factors including radiation dose/volume, extent of surgical resection, and medical complications.
Relationship of fusion protein status and outcome for children with intermediate-risk rhabdomyosarcoma: A Children's Oncology Group report.
Authors: Skapek Stephen , Anderson James Robert , Barr Frederick G. , Bridge Julia Ann , Gastier-Foster Julie M , Parham David , Rudzinski Erin R. , Triche Timothy J. , Hawkins Douglas S. ,   Children's Oncology Group
Published: March 2020

9535 Background: Rhabdomyosarcoma (RMS) includes both alveolar (ARMS) and embryonal (ERMS) subtypes, with ARMS generally having a worse prognosis. Most ARMS express one of two fusion genes generated by balanced translocations fusing DNA binding domains of PAX3 or PAX7 with FOXO1 (P3F and P7F, respectively). The prognostic value of fusion gene versus histological subtype is not clear. We carried out a multi-institutional clinical trial through the Children’s Oncology Group (COG) to evaluate this molecular feature. Methods: All participants were enrolled on COG D9803 from 1999-2005 for children and young adults with intermediate risk ARMS or ERMS, and were treated with vincristine, dactinomycin, and cyclophosphamide (+/- topotecan), radiotherapy, and surgery. Diagnostic specimens were reviewed centrally and fusion gene was assessed by fluorescence in situ hybridization (FISH), RT-PCR, or both. Event-free (EFS) and overall survival (OAS) at 5 years (yr) was correlated with histology and fusion gene status. Results: Of 327 cases included in a re-review of the pathology, 295 could be classified biologically. Cases with ARMS but unknown trans status (N=23) and those with mixed or RMS-NOS histology without trans (N=17) and 12 with inadequate clinical data were excluded. ARMS cases with detectable fusion gene were defined as ARMS P3F+, ARMS P7F+, while ARMSn was reserved for those without detectable fusion. P3F and P7F were not observed in ERMS. An additional 189 pts with ERMS tumors not re-reviewed were also included in the survival analysis. There was a trend toward better EFS for those with ARMSn than for ERMS (p=0.15); EFS for ARMS P3F+ and P7F+ were worse than that for ERMS (p<0.001). Only ALV P3F+ cases had poorer OAS (p=0.004). Conclusions: ARMSn has an outcome similar to ERMS and a superior EFS compared to ARMS with P3F or P7F, when given therapy designed for intermediate risk RMS. This analysis, from a single, prospective trial restricted to those with non-metastatic disease and with near universal molecular evaluation, supports incorporating fusion status into treatment allocation. [Table: see text]
Carboplatin (CBP) versus cisplatin (CP) within prognostic groups in pediatric extracranial malignant germ cell tumors (MGCTs).
Authors: Hale Juliet , Olson Thomas Arthur , Nicholson James , Dang Ha , Krailo Mark D. , Billmire Deborah , Donachie Paul , Thornton Claire , Rodriguez-Galindo Carlos , Frazier A. Lindsay 
Published: March 2020

9539 Background: It is established that CBP is inferior to CP in adult MGCTs when used at AUC 5 or 400mg/m2. There are no randomised data for paediatric MGCTs, so conclusions from adult MGCTs have been generalised despite differences in site, histology and biology. A database, pooling patients from US and UK paediatric MGCT studies, was established to determine prognostic factors in paediatric MGCTs. We examined the effect of CBP and CP in identified prognostic groups. Methods: A dataset of 1110 paediatric MGCTs was created, treated 1983 to 2009. Treatment was CBP (JEB, AUC 7.9) in the UK and CP (PEB) in the US. After excluding patients with surgery only, pure germinoma or immature teratoma , 697 patients remained. The cure model was used to assess the prognostic significance of chemotherapy regimen after adjustment for patient characteristics. Results: Analysis stratified prognosis according to age (0-10 v 11+yrs) and stage (1-3 v 4) at diagnosis by site (testis: ovary: extragonadal). Outcome for CBP and CP in these prognostic groups is shown in the table. Conclusions: Interpretation of the results of this nonrandomised comparison requires caution. However, after adjustment for other prognostic factors, the risks of failure for JEB and PEB were not statistically different . This is particularly true for 0-10yrs. At AUC7.9 CBP is tolerable in paediatric patients, with potentially fewer late toxicities than CP. [Table: see text]
A phase I trial of AT9283 (a selective inhibitor of Aurora kinases) given for 72 hours every 21 days via intravenous infusion in children and adolescents with relapsed and refractory solid tumours.
Authors: Hargrave Darren R , Pearson Andrew DJ , Moreno Lucas , Morland Bruce , Elliott Martin , Makin Guy , Campbell-Hewson Quentin , Wyld Peter J. , Halford Sarah E. R. , Lock Victoria , Lyons John F. , Boddy Alan V. , Yule Murray 
Published: March 2020

9542 Background: AT9283, is a multi-targeted inhibitor, against Aurora A and B, JAK & ABL kinases. Aurora kinases are potential therapeutic targets in paediatric solid cancers. Methods: A phase I dose escalation study was performed using a 72 hour intravenous infusion repeated 3 weekly using a rolling 6 design for patients aged >2 to <19 years with relapsed/ refractory solid tumours. Results: Eighteen patients treated with a median age of 10 (range 3 to 16) years. Four dose cohorts of 7, 9, 11.5 and 14.5 mg/m2/day. The diagnoses included; 5 high grade glioma, 4 rhabdoid tumours, 3 neuroblastomas, 3 sarcomas & 3 others. There has been only one dose limiting toxicity; Grade 3 febrile neutropenia at 11.5 mg/m2/day. The majority of adverse events (AEs) have been grade 1/2 & considered unrelated/ unlikely related to study drug. Two patients have experienced Grade 3 or 4 AEs considered at least possibly related to study drug: Grade 3 haemoglobin and Grade 4 neutrophils in a patient treated at 9 mg/m2/day & Grade 3 lymphopenia, neutrophils, infection with normal neutrophil count and aspartate transaminase in a patient treated at 11.5 mg/m2/day. Pharmacokinetics of AT9283 in this population are largely in keeping with those seen in adult patients at similar doses (Arkenau et al., 2011) although there may be greater variability. Pharmacodynamic evidence of aurora B inhibition, as manifested by a reduction in histone H3 phosphorylation in normal skin biopsies pre & post infusion, has been documented at all dose levels tested. Stable disease (up to 6 cycles) has been observed in 3 patients. Conclusions: This paediatric phase I study has demonstrated AT9283 administered as a 72 hour continuous infusion can be given at a dose level of 11.5 mg/m2/day which is higher than the maximum tolerated dose observed in adult patients (9 mg/m2/day) with advanced solid tumours. Myelosuppresion is the main toxicity but the regimen is well tolerated with preliminary anticancer activity seen in heavily pre-treated paediatric patients. [Table: see text]
Safety and biological activity of the FLT3 inhibitor lestaurtinib in infant MLL-rearranged (MLL-r) ALL: Children's Oncology Group protocol AALL0631.
Authors: Sun Di , Kaeding Allison , Magoon Daniel , Jones Tamekia , Devidas Meenakshi , Carroll Andrew J , Heerema Nyla A. , Loh Mignon L. , Raetz Elizabeth A. , Winick Naomi Joan , Carroll William L. , Dreyer ZoAnn Eckert , Hunger Stephen , Hilden Joanne M. , Brown Patrick Andrew 
Published: March 2020

9548 Background: MLL-r infant ALL overexpresses activated FLT3. Lestaurtinib potentiates chemotherapy(chemo)-induced cytotoxicity in MLL-r ALL. AALL0631 therapy is stratified based on age and MLL status: high risk (HR) <90 days, MLL-r; intermediate risk (IR) ≥ 90 days, MLL-r; standard risk any age, not MLL-r. IR and HR patients (pts) get intensive chemo and are eligible for lestaurtinib. A safety/activity (S/A) phase to determine a safe and biologically active dose of lestaurtinib is followed by an efficacy phase randomizing MLL-r patients to chemo +/- lestaurtinib. The S/A phase proceeds independently for IR & HR pts, as optimal lestaurtinib dosing may differ between neonates and older infants. We previously reported successful completion of the S/A phase for IR pts; here, we report results of the S/A phase for HR pts. Methods: Lestaurtinib-related dose limiting toxicities (DLTs) were defined as grade ≥ 3 non-heme toxicities excluding those expected with chemo alone (e.g., F&N/infection); a dose of lestaurtinib was “safe” if 0 or 1 DLTs were seen in 5 evaluable pts. FLT3 inhibition was assessed using a plasma inhibitory activity (PIA) assay that measures % inhibition of phospho-FLT3 at 5 trough time points relative to pre-treatment baseline. A dose of lestaurtinib was “biologically active” if PIA was > 90% for the majority (≥3 of 5) of troughs in at least 3 of 5 pts. Results: 11 eligible HR pts received lestaurtinib, 6 at dose level 1 (DL1, 3.5 mg/kg/day) and 5 at DL2 (4.25 mg/kg/day). There were no DLTs in 5 evaluable pts at DL1. The inevaluable pt discontinued lestaurtinib due to parental refusal, not toxicity. There was 1 DLT in 5 evaluable pts at DL2. The DLT was grade 4 intestinal perforation secondary to severe typhlitis during neutropenia following reinduction, possibly related to lestaurtinib. The pt was taken off protocol and chemo and died of progressive disease. By PIA assay, 2 of 5 pts treated at DL1, and 4 of 5 at DL2 demonstrated FLT3 inhibitory biologic activity. Conclusions: DL2 is safe and biologically active in HR pts. The efficacy phase of AALL0631 is expanding such that HR pts will join IR pts in being randomized (1:1) post-induction to chemo +/- lestaurtinib at DL2.
Preclinical study of a Bcl-2 inhibitor in neuroblastoma.
Authors: Belounis Assila , Addioui Anissa , Conan Anne-Hélène , Thanvilay Dominic- Vidaroun , Cournoyer Sonia , Nyalendo Carine , Teira Pierre , Beaunoyer Mona , Brito Rose- Marie , Sartelet Hervé 
Published: March 2020

9563 Background: Neurblastoma (NB) is the most common and deadly extracranial solid tumor of childhood. This malignant tumor exhibits a broad spectrum of clinical features, including spontaneous regression or maturation without any treatment or progression to metastisis leading to death. However, in spite of many therapeutic improvements, only 60% survive long term. In fact, 40% of patients with high-risk NB still relapse and eventually die of the disease despite aggressive combinations of multi-agent chemotherapy. In those cases, new therapeutic strategies must be developed. Studies have shown that BCl-2, a central anti-apoptotic protein, is over-expressed in NB. Although Bcl-2 is not a significant prognostic factor in NB, its increased expression would contribute to chemotherapy resistance. BCl-2 is also shown to be involved in the modulation of autophagy by inhibiting Beclin-1. Therefore, BCl-2 protein represents an attractive target for new therapeutic strategies in NB.The objective of this study is to determine the efficacy in vitro of Obatoclax (OB), a BCl-2 inhibitor, used in monotherapy or in combination to cisplatine (CP), a classical chemotherapeutic agent used in NB treatment, on NB cell survival. Methods: Six NB cell lines (SK-N-DZ, SK-N-FI, SK-N-SH, N91, NB8 and NB10) were treated with OB alone or in association to CP. Cell survival was measured by MTT test. Autophagy was measured by MDC test. Western Blots (WB) were done to evaluate the modulation of apoptotic and autophagic pathways in treated cells. Results: OB used in monotherapy shows promising results on NB cell lines with an average IC50 of 0.12µM. Also, OB demonstrates synergistic effects when associated to CP. The IC50 of CP treated cells varied from 3.183µM to 6.837µM but dropped from 0.003µM to 0.008µM when combined with 0.5µM of OB. Moreover, our WB show an increase in cleaved Caspase-3 and PARP-1 expression, suggesting an upregulation of apoptosis in treated cells. Autophagy is also upregulated confirmed by an increase in autophagic vacuoles and cleaved LC3 II protein. Conclusions: OB used in monotherapy or in combination at potentially therapeutic doses shows promising results in NB. These results will allow for the improvement of NB treatments by introducing a new therapeutic strategy.
Circulating myeloid-derived suppressor cells in pediatric solid tumor patients.
Authors: Goldberg John M. , Zidan Abdel-Aziz , Siddiqi Rabia , Zayas Myriam , Brown Camille D. , Forster Lourdes , Ludwig David A. , Montero Alberto J. , Diaz-Montero C Marcela 
Published: March 2020

9565 Background: Cure rates have reached a plateau for many pediatric solid tumors. Identifying new therapeutic targets, biomarkers of response and prognostic indicators should improve clinical outcomes. Accumulation of myeloid derived suppressor cells (MDSCs) is an important mechanism of tumor mediated immune evasion. Increased levels of MDSCs in adult cancer patients correlate with a worse prognosis, and decrease in levels with treatment is associated with benefit. Little is known about MDSCs in childhood, or in children with cancer. This pilot measured levels of MDSCs in pediatric patients with cancer and healthy children. Methods: We enrolled subjects using an Institutional Review Board approved protocol after obtaining informed consent. Blood was obtained from 14 children with newly diagnosed or recurrent solid tumors at start of therapy. In 10 of these patients, levels were also drawn after therapy. Blood was obtained once from 6 healthy children in a primary care office. Samples were obtained concurrently with complete blood counts. MDSCs were measured on fresh whole blood and were defined as Lin-1+/HLADR-/CD 33+/CD11b+/ by flow. Total MDSC numbers were then calculated. Results: The mean total number of MDSCs was 596 cells/ul at diagnosis for the 14 children with cancer and 170 cells/ul for the 6 healthy children (t(18) = 3.02, p = .0073). For the 10 children with cancer who had repeat values measured after treatment, MDSCs decreased in 4 and increased in 6. The mean initial MDSC count for these children was 494 cells/ul, and the mean post treatment count was 1716 cells/ul (t(9) = 1.81, p = .1036). Larger change scores tended to be associated with children treated with alkylator therapy followed by G-CSF. The results for percent MDSC in white cells mirrored those of total number. Conclusions: Circulating MDSCs were higher in pediatric cancer patients than healthy controls. Cancer treatment did not reliably reduce MDSC levels. After some treatments, the levels increased, potentially increasing immune tolerance. Further research is needed to determine if circulating MDSCs are a reliable predictive or prognostic marker in pediatric cancer, and whether they represent a potential target for therapeutic intervention.
Pharmacokinetics (PK) of the chimeric anti-GD2 antibody, ch14.18, in children with high-risk neuroblastoma.
Authors: Desai Ami Vijay , Fox Elizabeth , DiSipio Theresa C. , Smith L. Mary , Lim Allison , Maris John M. , Balis Frank M. 
Published: March 2020

9576 Background: The PK of ch14.18, a chimeric monoclonal antibody (cMoAb) that significantly improves survival in high-risk neuroblastoma, was previously reported to be highly variable in children, and its clearance (CL, 130 mL/h · m2) and volume of distribution (Vdss, 32 L/m2) were >10-fold higher than the CL and Vdss of other cMoAbs. Characterizing the PK of ch14.18 and the factors responsible for its variability could lead to alternative dosing strategies that reduce toxicity. Methods: Detailed PK sampling was performed prior to, during and for 25 d after 4 daily 10 h infusions of 25 mg/m2 of ch14.18 administered with sargramostim (ANBL0032) in children enrolled on an IRB-approved institutional correlative protocol supported by United Therapeutics Corp. Ch14.18 concentrations were measured with a validated ELISA with a lower limit of detection of 0.44 mcg/mL. PK parameters were derived using non-compartmental methods and reported as median (range). Results: 5 males and 4 females, median (range) age 3.5 (1-7) yrs, have been enrolled. Six were studied on cycle 1 (C1), 2 on C5 and 1 on C3; 3 of 6 patients studied on C1 were re-studied on C3. Data from 3 patients are not included because pre-treatment plasma samples contained a substance that interfered with the ELISA. The Cmax after the 4th daily infusion was 14 (10-24) mcg/mL, and ch14.8 was undetectable at day 25 in 3/6 patients. The half-life was 220 (120-390) h, and the CL was 11 (3.8-16) mL/h · m2, which is similar to the average CL of 4 other cMoAbs (11 mL/h · m2). The Vdss of 2.8 (1.2-3.9) L/m2 approximated blood volume and was similar to the Vdss of other cMoAbs (1.7 L/m2) and humanized MoAbs (2.8 L/m2). AUC0-∞ in 2 patients studied twice were 3440 and 1540 mcg · h/mL on C1 and 2760 and 2690 mcg · h/mL on C3. Conclusions: Ch14.18 CL, Vdss and half-life in children are similar to those in adults receiving ch14.18 at the same dose and similar to other cMoAbs. Ch14.18 PK in children was less variable than previously reported. The identity of the interfering substance in the plasma of some patients requires further investigation. A limited sampling strategy will be developed from these data for use in larger multi-institutional PK studies of ch14.18.