bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of TNK2 as a critical kinase in rhabdomyosarcoma through a loss of function shRNA screen.
Authors: Arnaldez Fernanda Irene , Yeung Choh L , Smith Carly J , Caplen Natasha , Helman Lee J. 
Published: March 2020

9511 Background: Rhabdomyosarcoma is the most common pediatric soft tissue sarcoma. Embryonal rhabdomyosarcomas (ERMS) are characterized by 11p15 LOH while alveolar rhabdomyosarcomas harbor a translocation between PAX3 or PAX7 and FOXO1. Relapsed or metastatic disease has a 5-year survival rate of 25%. Methods: We sought to identify critical genes for rhabdomyosarcoma cell growth and survival. We performed a loss-of-function shRNA screen where a library of 15,000 shRNAs was introduced in RH30 (ARMS) and RD (ERMS) cells engineered to express the bacterial tetracycline repressor in a tet-on system. Relative abundance of cells containing a certain shRNA was determined using specific barcodes. We subtracted “hits” that are common to 4 lymphoma cell-lines to eliminate common survival pathways. Forty genes were associated with rhabdomyosaroma cell growth, of which 15 cause greater suppression in ARMS. We performed a subsequent validation of these 15 genes in multiple ARMS and ERMS cell lines using three different shRNA sequences using lentiviral constructs. In addition, we validated our results in an independent siRNA screen of the protein kinome in RMS cells. Results: TNK2 (tyrosine kinase, non-receptor 2) was identified as tyrosine kinase involved in rhabdomyosarcoma cell growth independently in the inducible shRNA screen and in the non-inducible siRNA platform. This molecule has been involved in downstream signaling from EGFR and integrins. Amplification of the TNK2 gene, located at 3q29, has been described in breast, prostate and lung cancer. More recently, a siRNA screen identified it as a potential therapeutic target in Ewing’s sarcoma. We confirmed TNK2 expression across patient tumor samples in a publically available database; where patients with high TNK2 expression showed lower overall survival. TNK2 knock down resulted in decreased rhabdomyosarcoma cell growth in vitro and in orthotopic xenografts. We confirmed specificity of our findings with a rescue experiment. Conclusions: We identified TNK2 as a potential therapeutic target in rhabdomyosarcoma using a loss-of-function shRNA screen and subsequent validation. Further work is ongoing to fully characterize the molecular mechanisms involved in these findings.
A large prospective trial of children with unilateral retinoblastoma with and without histopathologic high-risk features and the role of adjuvant chemotherapy: A Children’s Oncology Group (COG) study.
Authors: Chintagumpala Murali M. , Langholz Bryan , Eagle Ralph , Albert Daniel , Ali Mohammed Javed , Khetan Vikas , Honavar Santosh , O'Brien Joan , Leahey Ann , Matthay Katherine K. , Meadows Anna T. , Chevez-Barrios Patricia ,   Children's Oncology Group
Published: March 2020

9515 Background: The definition of histopathologic high-risk features (HRF) in enucleated eyes of children with unilateral retinoblastoma and their contribution to metastases is controversial. The COG completed a large, prospective international study to determine the prevalence of strictly defined histopathologic HRF that are predictors of recurrence and the role of chemotherapy to prevent recurrences. Methods: All patients who underwent enucleation for unilateral retinoblastoma were eligible for the study. Pathology slides were submitted for central review within 21 days of enucleation. Patients with evidence of one or more high-risk features (posterior uveal invasion grades IIC and D, concurrent optic nerve and choroid involvement and post-lamina optic nerve involvement) as determined by central review, received 6 cycles of chemotherapy consisting of carboplatin, vincristine and etoposide. All others were observed. All patients were followed for extraocular recurrences. Results: Patients were enrolled from February of 2005 until May 2010. As of July 2011, the median follow-up from enrollment was 1.9 years (max=5.3 years). Of 312 patients with central histopathology review, 49 patients had their risk classification changed (13% with no HRF had HRF, 24% with HRF had no HRF). Two patients developed extraocular disease and one patient died of unknown cause. The death and one of the extraocular relapses occurred among the 93 (2/93=2.2%, upper 95% CI 3.4%) patients assigned by the central review to receive chemotherapy, while one patient experienced extraocular relapse among the 209 (1/209=0.5%, upper 95% CI 0.6%) assigned to observation only. There is no evidence of a difference in the EFS and OS in these two groups. Conclusions: Preliminary results strongly suggest that a central review of pathology can spare a significant number of patients from exposure to chemotherapy. Chemotherapy may have contributed to fewer relapses in patients with high-risk features as defined in this study. The preliminary results from this study indicate an excellent outcome with this approach.
Treatment of pediatric stage IA lymphocyte-predominant Hodgkin lymphoma with surgical resection alone: A report from the Children's Oncology Group.
Authors: Appel Burton , Ehrlich Peter , Chen Lu , Hutchison Robert E. , Hodgson David C. , Constine Louis S. , Schwartz Cindy L. ,   Children's Oncology Group
Published: March 2020

9524 Background: Lymphocyte-predominant Hodgkin lymphoma (LPHL) is an uncommon histologic subtype comprising up to 10% of cases in pediatric series. Patients with LPHL typically present with low stage disease and are responsive to regimens used for classical HL. Recurrence is uncommon; secondary malignant neoplasms or evolution to non-Hodgkin lymphoma are more common events. Small retrospective studies have suggested that some patients with stage I LPHL can be cured with surgery alone. We report the results of a large prospective study using a treatment algorithm in which a selected subset of patients received surgery alone. Methods: Patients ages 0-21 years with newly-diagnosed, low risk LPHL were eligible for AHOD03P1. Low risk was defined as clinical Stage IA and IIA in the absence of bulk disease (a mediastinal mass > 1/3 of the thoracic diameter or a nodal aggregate > 6 cm). Central pathology review was performed to confirm LPHL histology. Baseline evaluations included CT and FDG-PET. Patients with Stage IA disease in a single node that was completely resected were observed without further therapy. Total resection (TR) was confirmed by rapid central review of CT and FDG-PET. In some cases the extent of resection was equivocal; repeat imaging 6-7 weeks after initial evaluation was used to allocate such patients to either observation or chemotherapy. Patients who recurred were assigned to treatment with 3 cycles of AV-PC (doxorubicin/vincristine/prednisone/cyclophosphamide). Results: Between January 2006 and November 2010, 52 patients with Stage IA, single node LPHL were enrolled with a confirmed TR. Nine patients have experienced a relapse; 8 were Stage I and 1 was Stage II at relapse. The median time to relapse was 10 (range 1-17) months. The median follow up among the 43 remaining patients is 26 (range 4-60) months. The current 2 year EFS estimate among these patients is 80.3% (95% CI: 65.3% -89.3%). Overall survival for the 52 patients is 100%. Conclusions: With this strategy of surgical resection followed by observation in a highly select cohort of pediatric LPHL, up to 80% of patients may be spared chemotherapy. Follow up is limited but overall survival to date is excellent.
Outcome analysis of non-high-risk neuroblastoma patients enrolled on Children’s Oncology Group trials P9641 and A3961.
Authors: Meany Holly Jane , Attiyeh Edward F. , Naranjo Arlene , Twist Clare , London Wendy B. , Villablanca Judith , Schmidt Mary Lou , Baker Dave , Strother Douglas R. , Shimada Hiroyuki , Matthay Katherine K. , Cohn Susan Lerner , Maris John M. , Park Julie R. 
Published: March 2020

9533 Background: Patients with non-high-risk neuroblastoma (low- and intermediate-risk) generally have an excellent event free (EFS) and overall (OS) survival with current therapy. However, within this heterogeneous patient population, there are patients that may benefit from further therapy reduction and patients that may benefit from augmented therapy. Methods: Survival tree regression analysis was performed in patients enrolled on P9641 and A3961 with OS the primary endpoint. Univariate Cox proportional hazards models determined statistically significant prognostic factors. Secondary analysis of cases with MYCN non-amplified, non-high-risk neuroblastoma classified patients by age, INSS stage, Shimada histology and genomic features to determine 5-year EFS and OS. Favorable genomics were defined as hyperdiploid tumors without 1p or 11q loss of heterozygosity (LOH). Those with LOH at 1p or 11q or with a diploid DNA index were considered unfavorable. Patients without genomic data were excluded. Results: In the survival tree analysis, ploidy and genomic features were found to be statistically significant. In the secondary analysis, patients <18 months of age with stage 2 or 3, favorable histology tumors with favorable genomic profile had 5-year EFS and OS rates of 92.9±3.9% and 100% respectively. Patients with stage 2 and 3 tumors, unfavorable histology and unfavorable genomic features had EFS of 68.4±8.0% and OS of 78.4±7.0%. Patients <12 months of age with stage 4 disease and either unfavorable histologic or genomic features had EFS of 69.1±5.4% and OS of 88.5±3.8%. Conclusions: Excellent outcomes in non-high-risk neuroblastoma patients with favorable histologic and genomic features suggest further reduction in therapy is possible in this cohort while maintaining survival and decreasing side effects. Select patients with unfavorable features have suboptimal OS and would benefit from modifications in therapy. Histologic and genomic criteria can be used to identify patients with non-high-risk neuroblastoma that may benefit from modifications in therapy. These data support the conduct of a cooperative group clinical trial to refine therapy for patients with non-high-risk disease.
Ipilimumab: First results of a phase I trial in pediatric patients with advanced solid tumors.
Authors: Merchant Melinda S. , Baird Kristin , Wexler Leonard H. , Rodriguez-Galindo Carlos , Mackall Crystal 
Published: March 2020

9545 Background: Ipilimumab is a fully-human IgG1 monoclonal anti-CTLA-4 antibody which has been approved by the FDA for adult patients with metastatic melanoma . Although the approved dose is 3mg/kg every 21 days, the dose of 10mg/kg IV every 21 days for 4 doses in combination with chemotherapy was well tolerated in a phase III trial enrolling adult patients with melanoma. Methods: This pediatric phase I, dose escalation study examined the safety, tolerability, pharmacokinetics, and immunogenicity of ipilimumab administered to patients <21yo with recurrent or progressive solid tumors. Ipilimumab was administered at 1, 3, 5, and 10mg/kg IV in a standard 3 + 3 design with 4 doses of induction therapy q3 weeks followed by maintenance q3 months until disease progression or unacceptable toxicity. Tumors were measured after 6 weeks, 12 weeks, and then every 3 months. Results: Twenty one patients (melanoma n=6, osteosarcoma n=6, soft tissue sarcomas n=7, neuroblastoma, and renal cell carcinoma) received a total of 57 doses of Ipilimumab to date. One of 6 patients treated at 5mg/kg developed a dose-limiting grade 3 pancreatitis. .At the highest dose level of 10mg/kg, two of three patients under 12yo developed DLT: grade 3 colitis and concurrent norovirus in one patient, and self-resolving grade 3 transaminitis in a second patient. Three of three patients between the ages of 12 and 21yo tolerated the 10mg/kg dosing schedule without DLT. Across all dose levels, grade 2 or 3 adverse events included colitis (n=1), transaminitis (n=3), pancreatitis (n=1), autoimmune thyroiditis (n=2), and hypophysitis (n=1) observed between C1D8 and C4D21. A single grade 1 rash was observed. Stable disease was the best response in 5 patients with a duration of 3 to 18 months. Conclusions: Ipilimumab can be safely administered to pediatric patients. Adolescents are able to tolerate the highest dose of 10mg/kg. Younger children (<12yo) had 2 DLTs in 3 patients at 10 mg/kg . Expansion of the 10 mg/kg cohort for adolescents and of the 5 mg/kg dose for the <12yo for further safety and pharmacokinetic information is underway. The spectrum of adverse events appears similar to those described in the adult trials, although there were no grade 2 or higher incidents of rash.
Diminished asparaginase turnover due to a germ-line mutation in cathepsin B.
Authors: Te Loo Dunja Maroeslea W.M. , Levers Marloes , Waanders Esme , Venselaar Hanka , Hoogerbrugge Peter , Leeuwen Frank van , Meer Laurens van der 
Published: March 2020

9550 Background: ASNase is a key component of multi-agent chemotherapy protocols used in the treatment of pediatric as well as adult acute lymphoblastic leukemia (ALL). Patients that are treated according to fixed shedules show a strong inter individual variation in serum ASNase levels. While underexposure may compromise therapeutic benefits, strongly elevated serum levels may lead to serious adverse effects. In at least 10% of the patients the desired ASNase levels are either not reached or exceeded. Therefore our understanding of ASNase dynamics in vivo needs to be improved. Here we describe the identification of a novel mutation in the gene encoding Cathepsin B to diminished ASNase turnover in a pediatric patient with ALL. Methods: Sequencing, biochemical experiments and immunofluorescence. Results: A 3-year-old girl diagnosed with ALL experienced serious toxicity in the form of hyperammonemic encephalopathy during treatment with ASNase derived from Erwinia chrysantemi. Pharmacokinetic data showed a strongly delayed clearance of the ASNase, which with the standard treatment protocol resulted in extremely high serum ASNase levels. Plasmapheresis was performed and dosage frequencies were adjusted to improve the clinical status of the patient. No underlying metabolic disorder could be diagnosed. Based on a previous report describing the role of proteases in degradation of ASNase in vitro, we hypothesized that the cysteine protease Cathepsin B might be implicated in the strongly reduced clearance of ASNase in this patient. Sequencing of the open reading frame of the Cathepsin B gene (CTSB) revealed a single codon deletion in the germline of the patient, affecting a lysine residue in the carboxy terminus of the protein. Immunofluorescence and biochemical experiments show that this single amino acid deletion leads to a protein product that is retained in the endoplasmic reticulum and is inefficiently processed. Conclusions: ASNase degradation assays show that the mutant Cathepsin B has lost its ability to efficiently degrade ASNase which could explain the high levels of ASNase as observed in our patient.Together, these findings suggest that variations in Cathepsin B activity may influence serum ASNase levels in the patients.
Contribution of diet and physical activity to metabolic parameters among survivors of childhood leukemia.
Authors: Tonorezos Emily S. , Kent Debra A. , Moskowitz Chaya S. , Oeffinger Kevin C. 
Published: March 2020

9552 Background: Survivors of childhood acute lymphoblastic leukemia (ALL) are at increased risk for obesity, insulin resistance and increased visceral adiposity. A history of cranial radiation therapy (CRT) worsens this risk. In non-cancer populations, adherence to a Mediterranean Diet has been shown to improve metabolic parameters and risk of diabetes mellitus. Whether diet may contribute to insulin resistance and increased adiposity in ALL survivors is not known. Methods: We surveyed 117 adult survivors of childhood ALL using the Harvard Food Frequency Questionnaire. Physical activity energy expenditure (PAEE) was measured with the SenseWear Pro2 Armband. Fasting blood was obtained on all subjects and insulin resistance was estimated using the Homeostasis Model for Insulin Resistance (HOMA-IR). Visceral adiposity was measured by abdominal CT. Adherence to a Mediterranean Diet pattern was calculated using the index developed by Trichopoulou. Subjects were compared using univariate analysis. Results: Subjects were majority female (56%); 25% were minority or Hispanic white. A history of CRT was present in 15 (29%) men and 25 (38%) women. Among all subjects, greater adherence to a Mediterranean diet pattern was associated with improved HOMA-IR (p=0.14), visceral adiposity (p=0.03), subcutaneous adiposity (p=0.005), waist circumference (p=0.02), and body mass index (p=0.03) (all unadjusted analyses). The effect of adherence to a Mediterranean diet on insulin resistance was especially notable in men who did not receive CRT (p=0.06). Higher dairy intake was found to worsen HOMA-IR (p=0.014), but other individual components of the Mediterranean diet, such as low intake of meat and high intake of fruits and vegetables, were not significant. Inclusion of PAEE did not alter our findings, although higher PAEE was associated with lower body mass index. Conclusions: Adherence to a Mediterranean diet pattern, especially low consumption of dairy products, may improve insulin resistance in survivors of childhood ALL. Further study is warranted.
Evaluation of renal function in children with solid tumors: Comparison between estimation with Schwartz formula and EDTA clearance.
Authors: Serrano Carole , Benazzouna Rana , Maritaz Christophe , Dufour Christelle , Valteau Couanet Dominique , Borget Isabelle , Lumbroso Jean , Remy Herve , Lemare Francois 
Published: March 2020

9560 Background: Using the [51Cr]-ethylenediamine tetra acetic acid ([51Cr]-EDTA) method provides an accurate measure of glomerular filtration rate (GFR) for each patient. However, this method is not always feasible in routine. Thus, several mathematical equations have been developed to predict creatinine clearance. The most widely used in pediatric patients is the Schwartz formula, based on patient height and serum creatinine. However, this method has not been validated in pediatric cancer patients. The aim of the present study was to compare GFR measured with the 51Cr-EDTA method to GFR estimated with the Schwartz formula in patients younger than 18 years of age and treated for solid tumors. Methods: Data have been retrospectively collected on consecutive children treated between 2001 and 2011 at Institut Gustave Roussy. All of the patients had undergone assessment of GFR via 51Cr-EDTA clearance and estimation of renal function by the Schwartz formula. Exclusion criteria were serum creatinine under 25µmol/L or no recent dosage available. GFR analysis was realized using the slope intercept method after a single injection of 51Cr-EDTA solution.. Values of the GFR were calculated by multiplying the volume of dilution by the slope of the single exponential fit to the three data points and then expressed in ml/min/1.73m². Student paired t-test (alpha = 0.05) was used to compare results obtained for each patient with the two methods. Results: 196 patients (120 males, 76 females), treated with various types of cancer (neuroblastoma, osteosarcoma, Ewing sarcoma, lymphoma…) Mean age was 6.7 years. Mean GFR was 127.5 ml/min/1.73m² with the 51Cr-EDTA method versus 148.1 ml/min/1.73m² with the Schwartz formula. Mean of difference was 20.7 ml/min/1.73m² with a confidence interval [-25.7 ; -15.6] (p < 0.0001). Conclusions: GFR estimated with the Schwartz formula is statistically different from the isotopic method. In most cases, GFR estimated with the Schwartz formula is overestimated. This study highlights the lack of accuracy of this equation in pediatric population with cancer. The 51Cr-EDTA method must be preferred when a reliable and accurate evaluation of renal function is needed.
Familial risk in pediatric cancer and implications for practice.
Authors: Curtin Karen , Smith Ken R , Fraser Alison M , Pimentel Richard , Kohlmann Wendy , Schiffman Joshua David 
Published: March 2020

9561 Background: Using a unique genealogical resource, the Utah Population Database, we examined risk of cancer in 1st- through 3rd-degree relatives of 4,482 pediatric cancer cases ≤18 years old diagnosed between 1966 and 2009. We quantified cancer risk in relatives of children with cancer in order to determine evidence of a familial aggregation of cancer, identify high-risk pedigrees, and inform counseling protocols for genetic testing and screening. Methods: We estimated cancer risk in relatives of pediatric cases compared to random population controls matched 5:1 on sex, birth year, and birthplace. Odds ratios were calculated using conditional logistic regression, adjusting for number of biological relatives, their degree of relatedness, and their person-years at risk. We included all relatives of cases and controls with followup who linked to a pedigree of ≥2 generations; this approach has been shown to lead to unbiased risk estimates. As observations within families are non-independent, a robust variance estimator for cluster-correlated data was incorporated. Results: Mostly siblings, 1st-degree relatives (N=49 affected) of pediatric cases were at 2-fold increased risk of being diagnosed at age<19 with cancer themselves (p<10-4); siblings of cases diagnosed at age<5 had a 4-fold risk of pediatric cancer (p<10-7). Likewise, 2nd-degree relatives (N=61 affected) and cousins (N=105 affected) of cases had a ~2-fold risk of childhood cancer (p<10-4). Proband siblings were at increased risk for leukemia, brain tumor, epithelial neoplasia, and bone cancer. While 1st-degree relatives of pediatric cases had a slight increased risk of adult-onset cancer, when they do develop cancer they exhibit a 50% increased risk of a Li-Fraumeni Syndrome-related tumor diagnosis (N=142 affected relatives; p<10-4). Conclusions: Our findings provide evidence of familial aggregation of cancer and suggest a higher percent of pediatric cancers are related to hereditary syndromes than are adult cancers. We encourage a 3-generation family history be collected and routinely updated for all pediatric cancer patients, and those children with family histories of early-onset cancer be referred for genetic counseling and early surveillance when appropriate.