bluuebunny/crossref_metadata_2025 huggingface dataset:
A prospective longitudinal study of cancer-related fatigue in patients undergoing breast-conserving surgery and radiation with or without chemotherapy for breast cancer.
Authors: Torres Mylin Ann , Pace Thaddeus , Felger Jennifer , Liu Tian , Godette Karen D. , Stapleford Liza Jane , Mister Donna , Miller Andrew H.
Published: March 2020

9122

Background: We prospectively evaluated risk factors for persistent cancer-related fatigue in women with breast cancer undergoing lumpectomy with or without chemotherapy (CTX) prior to whole breast radiotherapy (XRT). We assessed the potential role of inflammatory mediators, demographic characteristics, and treatment history including CTX. Methods: Following lumpectomy, 60 women received a definitive course of whole breast XRT (50 Gy plus a 10 Gy boost). Prior to XRT, at week 6 of XRT, and 6 weeks post XRT, subjects completed the Multidimensional Fatigue Inventory (MFI) and underwent blood draws for inflammatory mediators (protein and mRNA). Results: Independent multivariate analyses of clinical and demographic factors revealed that CTX (p<.001) , given neoadjuvantly or adjuvantly, and age <50 (p=.03) were significant predictors of higher fatigue scores post XRT. Mean MFI scores in patients treated with CTX (n=24) were 20 points higher than patients not treated with CTX (p<.001) with a clinically meaningful difference in scores being 10 points on the MFI. Gene ontology analysis of differentially expressed genes indicated increased activation of genes involved in immune and inflammatory responses in fatigued vs. non-fatigued patients (p<.001). Of the inflammatory mediators, plasma IL-6 prior to XRT was the strongest predictor of post XRT fatigue (p=.02). Moreover, plasma IL-6 concentrations prior to XRT were significantly higher in patients who received CTX (mean 4.96 vs. 2.53, p=.01). Patients who received CTX also had significantly higher levels of NF Kappa B DNA binding 6 weeks post XRT (p<.001), and transcription factor binding analysis revealed a greater representation of genes with the NF Kappa B DNA binding motif in fatigued vs. non-fatigued patients (p =.05). Conclusions: Collectively, these data suggest an interaction between CTX and XRT leading to inflammation and fatigue several weeks post XRT. This relationship was independent of whether CTX was given pre or post-operatively. Treatments targeting inflammation before XRT may reduce fatigue post therapy, particularly in patients previously treated with CTX.
The relationship among age, anxiety, and depression in older adults with cancer.
Authors: Weiss Talia , Nelson Christian J , Tew William P. , Hardt Molly , Mohile Supriya Gupta , Owusu Cynthia , Klepin Heidi D. , Gross Cary P. , Gajra Ajeet , Lichtman Stuart M. , Ramani Rupal , Katheria Vani , Zavala Laura , Hurria Arti ,   Cancer and Aging Research Group
Published: March 2020

9123

Background: Depression and anxiety are common psychological sequelae of cancer, resulting in decreased adherence to treatment regimens and longer hospital stays. In men with prostate cancer, aging is associated with reduced anxiety and increased depression. The overall goal of this study was to examine the association among age, anxiety, and depression in a cohort of older adults receiving chemotherapy (chemo). Methods: This is a secondary analysis of a prospective longitudinal study investigating chemotherapy toxicity in older adults with cancer. Eligibility included: age > 65, diagnosis of cancer, and scheduled to receive a new chemo regimen. Baseline data (pre-chemotherapy) included: age, sociodemographics, tumor and treatment factors (including tumor type and stage), geriatric assessment parameters (functional status, comorbidities, psychological state, nutritional status, social support). Anxiety and depression were measured by the Hospital Anxiety and Depression Scale (HADS). Univariate and multiple regression analyses were conducted to test the relationship between age, anxiety, and depression. Results: The average age of the 500 patients (56% females) was 73.1 (range 65-91, SD+6.18) with 5% Stage I, 12% Stage II, 22% Stage III and 61% stage IV. Mean depression and anxiety scores were: 3.6+3.17; 4.7+3.60. Clinically significant depression was reported in 12.6% (n=62). Clinically significant anxiety was reported in 20.9% (n=103). In univariate analyses, there was no association between anxiety and age, or depression and age. In multivariable analyses, older age (beta= -0.07, p = 0.05) was associated with decreased anxiety, as well as lack of social support (p < 0.01) and increased number of comorbidities (p < 0.01). In multivariable analysis, depression was associated with lack of social support (p < 0.01), increased number of comorbidities (p < 0.01), and advanced stage (p < 0.01). Conclusions: This study supports previous research that anxiety decreases with age in older adults with cancer. However, depression remained constant with increasing age. Greater resources and attention to identifying and treating the psychological sequelae of cancer in older adults are warranted.
Prevalence of cancer-related fatigue in a population-based sample of colorectal, breast, and prostate cancer survivors.
Authors: Jones Jennifer M , Howell Doris , Olson Karin Lou , Jiang Haiyan , Catton Charles N , Catton Pamela , Fleshner Neil Eric , McCready David R. , Wong Rebecca , Pintilie Melania , Dirlea Mihaela , Krzyzanowska Monika K.
Published: March 2020

9131

Background: Cancer-related fatigue (CRF) is the most prevalent and distressing cancer-related symptom and has a greater negative impact on patients' daily activities and quality of life than other cancer-related symptoms, including pain and depression. However, the prevalence and severity of persistent CRF and related disability in the post-treatment survivorship period has seldom been examined in populations other than breast cancer. The primary objective of the study was to describe the prevalence of significant CRF and associated levels of disability in a mixed cancer population sample at 3 time points in the post-treatment survivorship trajectory. Methods: Based on cancer registry data, a self-administered mail based questionnaire using Dillman's Tailored Design Method was sent to 3 cohorts of disease-free cancer survivors (6-18 months; 2-3 years; and 5-6 years post-treatment) previously treated for non-metastatic breast, prostate or colorectal cancer. Fatigue was measured using the FACT-F and disability was measured with the WHO-Disability Assessment Schedule. Clinical information was extracted from chart review. Frequencies of significant fatigue by disease sites and time points were studied and compared using chi-square test. Disability between those with and without CRF was also compared using Cochran-Armitage trend test. Results: 1294 questionnaire packages were completed (63% response rate). The FACT-F score was 39.1+10.9; 29% (95% CI: [27%, 32%]) of the sample reported significant fatigue (FACT-F≤34) and this was associated with much higher levels of disability (p<0.0001). Breast (40% [35%, 44%]) and colorectal (33% [27%, 38%]) survivors had significantly higher rates of fatigue (≤34) compared to the prostate group (17% [14%, 21%]) (p<0.0001). Fatigue levels remained relatively stable across the 3 time points. Conclusions: CRF was a significant and debilitating symptom for a substantial minority of the respondents across all 3 time points. Effective CRF management strategies are needed and have the potential to significantly reduce morbidity associated with cancer and its treatments and to improve quality of life for the growing population of cancer survivors.
Longitudinal study of hope, meaning/peace (M/P), and quality of life (QOL) in patients (pts) with ovarian cancer (OC).
Authors: Ramondetta Lois M. , Urbauer Diana , Zhukovsky Donna S. , Bevers Michael W. , Brown Jubilee , Bodurka Diane C. , Thaker Premal H. , Anderson Sonya , Gallegos Jessica , Sun Charlotte C.
Published: March 2020

9134

Background: M/P may be the most valued end point of life. How hope, faith, physical and psychological factors impact M/P is unknown. We evaluated factors affecting M/P in pts with OC. Methods: OC pts at a cancer center (CC), academic hospital (AH) and county hospital (CH for primarily uninsured) participated. Surveys completed at initiation of chemotherapy (CTX); completion of CTX; and 1 yr later. Surveys included FACT-O, -SP, Herth Hope Index, Hospital Anxiety and Depression Scale (HADS), ESAS, and Locus of Control (LOC). Results: N=115. Median age=55 yrs, married 64%, Christian 96%. CH had more AA/Hispanics pts (p=.001) and unmarried pts (p=.001). QOL and symptoms improved for all sites over time (p =.03); CH pts had the worst scores (p= <.001). CC pts expressed more hope, less anxiety and depression (A/D) compared to CH and AC pts for all time points (p=.03). CH pts had higher and increasing A/D over time while CC pts had the least (p=.02). LOC scores differed by site (p=.01). CH pts held strongest belief that life was controlled by chance and “others”; CC pts had the least. There was no association between site/time for belief of internal control over one’s life. CH pts consistently had the lowest M/P scores (p=004). Adjusting for site, disease status and time, higher M/P associated with higher hope, better QOL, symptoms and faith (p= <.0001). Lower M/P associated with increased A/D (p=.003) and symptoms (p<.0001). Poorer M/P over time correlated with belief that life was controlled by chance (p=.01) and "powerful others"(p=.02). Level of M/P did not correlate with belief of internal control over one’s life. Conclusions: M/P did not change over time. CC pts had highest M/P. Higher M/P associated with higher hope and faith, better QOL, less symptoms and A/D. Lower M/P associated with sense that life is controlled by chance and powerful others. Data show medically underserved pts have poorer QOL, more symptoms and A/D and may believe the future is determined by luck/chance and by “others”. Triaging for spiritual crisis may be important in these pts. Interventions to decrease A/D and symptoms may improve pts’ sense of M/P over the cancer journey.
Development of prognostic molecular markers in pediatric rhabdomyosarcoma based on gene expression and copy number variations.
Authors: Missiaglia Edoardo , Williamson Dan , Chisholm Julia C. , Wirapati Pratyaksha , Pierron Gaëlle , Thway Khin , Oberlin Odile , Pritchard-Jones Kathy , Delattre Olivier , Delorenzi Mauro , Shipley Janet
Published: March 2020

9510

Background: Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and comprises two major histological subtypes: alveolar and embryonal. The majority of alveolar tumors harbor PAX/FOXO1 fusion genes. Current patient risk stratification, unlike other pediatric embryonal tumors, does not utilize any molecular data. Therefore, we aimed to improve the risk stratification of RMS patients through the use of molecular biological data. Methods: Two independent data sets of gene expression profiling for 124 and 101 RMS were used to derive prognostic gene signatures by meta-analysis. Genomic array CGH data for 109 RMS was also evaluated to develop a prognostic marker based on copy number variations (CNVs). The performance and usefulness of these derived metagenes and CNVs as well as a previously published metagene signature were evaluated using rigorous leave-one-out cross-validation analyses. Results: The new prognostic gene expression signature, MG15, and one previously published (MG34) (Davicioni. JCO. 2010) performed well with reproducible and significant effects (HR 3.2 [1.7-5.9] p < 0.001 and HR 2.5 [1.5-4.3] p < 0.001, respectively). However, they did not significantly add new prognostic information over the fusion gene status (PAX3/FOXO1, PAX7/FOXO1 and Negative). Similarly, a prognostic CNV marker, although showing HR 2.9 [1.5-5.6] p < 0.01, was also not improving models with fusion gene status. Within fusion negative RMS, the analysis identified prognostic markers based on either gene expression or CNVs and showed significant association with patients outcome (HR 6.3 [1.5-26.3] p ≤ 0.016 and HR 11.2 [2.5-50.7] p < 0.010, respectively). Moreover, these were able to identify distinct risk groups within the COG (Children's Oncology Group) risk categories, which is currently used to guide treatment. Conclusions: Molecular signatures derived using all RMS effectively stratify patients by their risk, but most of their prognostic information is contained in the PAX/FOXO1 fusion gene status which is simpler to assay. New markers developed within the fusion negative population seem improving current RMS risk classifier and should be tested in follow-up studies.
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.
Intensive alternating 6-drug chemotherapy for high-risk nonmetastatic rhabdomyosarcoma in children and adolescents: Impact on survival.
Authors: Demian Gerges Attia , Hussein Hany , Ebeid Emad Nabil , Elbadawy Samy
Published: March 2020

9566

Background: Both 5-year overall survival (OS) and event free survival (EFS) for pediatric rhabdomyosarcoma (RMS) has increased in the last 3 decades through multimodality, risk-adapted management. The reported EFS for high risk RMS in children treated at the NCI in Egypt during the 1990s was 50%. Using an intensive 6 drug alternating chemotherapy regimen in addition to local control measures was our aim to improve the outcome for this group of patients. Methods: Forty-six previously untreated patients, younger than 21 years of age, with localized high risk RMS received this regimen. High risk criteria included: (1) Localized tumors (T1) biopsied or incompletely resected, ortumors extending beyond the tissue or organ of origin (T2) completely or incompletely resected at any site (excluding orbit, uterus, vagina, and paratestis); (2)All node positive patients with primary tumor at any site; and (3) All RMS with alveolar histology at any site. Chemotherapy regimen comprised 27 weeks of alternating 6 drugs (carboplatin, doxorubicin hydrochloride, ifosfamide, actinomycin D, etoposide, vincristine). Local therapy (surgery, radiotherapy, or both) was offered at week 9. Results: Forty-six patients meeting high-risk criteria were recruited from September 2000 to November 2005. Median follow-up of survivors was 62 months. The 5-year OS and EFS for the whole group was 64% ± 10% and 47% ± 8% respectively. The EFS was significantly affected by: the size of the tumor (≤5 cm vs. > 5 cm, p= 0.03), SIOP UICC clinical stage (p = 0.004), IRS stage (p = 0.01), lymph node status (p = 0.02), surgery vs. incisional biopsy (p=0.01) and overall duration of time in which therapy was delivered (p = 0.04). There was significant toxicity, mainly hematologic, but only one treatment related fatality. Conclusions: The use of intensified alternating 6-drug CT did not improve the EFS compared with historical control although it was feasible to be delivered safely in a variety of outpatient settings. Surgical resection of the tumor is essential. Delivering therapy in a timely fashion appears to impact outcome and future investigations will focus on impediments to administering chemotherapy as scheduled.
Long-term outcomes of children with Xp11.2 translocation renal cell carcinoma.
Authors: Asanuma Hiroshi , Mizuno Ryuichi , Masuda Aya , Satoh Hiroyuki , Matsui Zenichi , Kono Hidaka , Shinoda Kazunobu , Kikuchi Eiji , Nagata Hirohiko , Miyajima Akira , Nakagawa Ken , Oya Mototsugu
Published: March 2020

9569

Background: We aimed to assess the clinico-pathological characteristics and the long-term prognosis of Xp11.2 translocation renal cell carcinoma (Xp-RCC) in children. Methods: A total of 52 Japanese children with renal tumors were presented to our institutions. Of these, 5 (10%) had RCC, and all RCCs were Xp11.2 translocation subtype with positive nuclear transcription factor E3 immunostaining. We retrospectively reviewed the pathological and hospital records of these 5 patients. Results: In the 1 boy and 4 girls with an average age of 9 years 7 months at diagnosis, the most common presenting complains were gross hematuria (60%) and palpable abdominal mass (40%). All patients had unilateral disease and there was no special family or medical history in any children. Computerized tomography revealed characteristic calcification within the tumor in 4 of the 5 patients (80%). In the remaining case, the lesion had high density areas with microcalcification, as confirmed by histopathological study. In 3 patients with regional lymph node metastasis, calcification was also observed in the metastatic lesions. Stage of the disease were stage I in 1 patient, II in 1, IV without and with distant metastasis in 2 and 1, respectively. All patients underwent transabdominal nephrectomy with regional lymphadenectomy. One patient with stage I disease had multiple metastases 15 months after surgery and died of disease in spite of interferon and chemotherapy 4 years postoperatively. Three patients received adjuvant interferon therapy and 2 of them are without evidence of recurrence postoperative 19 and 14 years, respectively. One of them had lymph node and lung metastases 12 years postoperatively. The remaining one patient had multiple lymph node, lung, bone, and dura mater metastases at diagnosis. The latter 2 patients have received targeted therapy (sunitinib, temsirolimus) without their progression for 6 and 12 months, respectively. Conclusions: Calcification within the tumor and/or metastatic lesions is characteristic findings suggestive of Xp-RCC in children. Regional lymphadenectomy or targeted therapy may provide some benefit in selected pediatric patients. Long-term follow-up is essential in pediatric patients with RCC.
Ifomide/pirarubicin/etoposide/carboplatin (ITEC) as second-line chemotherapy for hepatoblastoma.
Authors: Hiyama Eiso , Kamimatsuse Arata , Ogura Kaoru , Hishiki Tomoro , Watanabe Kenichiro , Yano Michihiro , Kondo Satoshi , Tajiri Tatsuro , Ida Kohmei , Sasaki Fumiaki
Published: March 2020

9577

Background: The Japanese Study Group for Pediatric Liver Tumor is running cooperative treatment studies on hepatoblastoma (HBL) since 1991. The main aim in JPLT-1 study was to evaluate the efficacy of cisplatin/pirarubicin (CITA). A total of 145 cases were registered and their 5-year overall survival (OS) and event-free survival (EFS) were 73.4% and 66%, respectively (J Pediatr Surg 37: 851-6, 2002). Then, JPLT-2 protocol, in which CITA is kept as the first-line treatment, and ifomide, etoposide, pirarubicin, and carboplatin (ITEC) is the second-line regimen for CITA-resistant cases, was launched to evaluate the cure rate of risk-stratified HBL: standard risk HBL (a tumor involving three or fewer sectors of the liver) and high risk HBL (a tumor involving all sectors of the liver or with metastasis). Methods: In JPLT-2, 281 HBL cases were registered in JPLT-2 between 1999 and 2010, and 69 cases underwent ITEC protocol due to poor response to the CITA regimen. To evaluate the efficacy of the ITEC regimen, surgical resectability and outcome of these 69 patients who underwent this treatment. Results: These 69 cases were divided into 53 high-risk (metastatic, involvement of all sectors of the liver, vascular invasion and/or extra-hepatic intra-abdominal disease) and 16 standard-risk HBL (all others). All cases were initially treated with the CITA regimen and then underwent the ITEC regimen due to poor response to CITA. Complete resection of the liver tumor could be achieved in 48 patients (69.6%) consisting of 13 (81%) standard, 35 (66%) high- risk cases. The 5-year OS and EFS of the cases with standard risk HB were 96% and 76%, while that of the cases with high risk HB was 54% and 34%. The late phase complications in 281 cases were 3 cases with maldevelopment, 13 with cardiac complications, 20 with ototoxicity and 5 with second malignancies. Conclusions: As compared with the CITA-sensitive cases, ITEC regimen achieved similar rates of survival for CITA-resistant cases both in standard and high-risk HBL cases, indicating ITEC is effective as a second-line chemotherapeutic regimen for HBL.
Proton radiotherapy for rhabomyosarcoma: Preliminary results from a multicenter prospective study.
Authors: Yock Torunn I. , Szymonifka Jackie , Friedmann Alison M. , Mahajan Anita , Yeap Beow Yong , MacDonald Shannon M. , Kasper Hallie Bieber , Grosshans David , Marcus Karen Chayt , Tarbell Nancy
Published: March 2020

9585

Background: Pediatric rhabdomyosarcoma (RMS) is commonly cured with chemotherapy and radiation. However, late effects of radiotherapy (RT) can be disabling. Proton RT irradiates less normal tissue, which should result in fewer late side effects of treatment. The purpose of this study was to describe the disease control and side effect profile of proton RT in RMS patients (pts). Methods: Eligible pts included those with localized disease and metastatic embryonal RMS if age 2-10. All pts were treated with VAC (vincristine, actinomycin, cyclophosphamide) based chemotherapy and proton RT, median dose 50.4 Gy (36-50.4 GyRBE). Concurrent enrollment in COG protocols was allowed. All pathology/imaging was reviewed at the treating institution. Results: 47 pts with RMS were prospectively enrolled from January 2005 to June 2011 and evaluable for analysis. Median age was 3.1 yrs, (range 0.6-15.6 years; M/F ratio 23:24). There were 1, 7, 37, and 2 Group I, II, III and IV and 14, 12, 19 and 2, Stage I-IV pts respectively, and 33 with embryonal 14 with alveolar/other. Most common sites included PM (48.9%), orbital (23.4%) bladder/prostate (6.4%), H&N non-PM (6.4%), extremities (4.3%), trunk/abdomen 2.1%), perineal/anal region (2.1%) and other (6.4%). Median follow-up is 15.2 months. One/two-year overall survival (OS) and progression-free survival (PFS) for the entire group is 94/81% (OS) and 79/73% (PFS). 2-year OS for stage I,II/III,IV pts is 91/66% (OS, p=0.114) and two-year PFS for these pts is 86/57%, respectively, (p=0.083. 16 (34%) had grade 3/4 acute toxicities attributable to the radiation during treatment, the most common of which was mucositis/oral pain (12.8%), anorexia (4.3%), and erythema (4.3%). Among the 24 pts analyzable for late toxicities with at least 2 yrs of follow up, there were no grade 3 or 4 late toxicities attributable to radiation. Conclusions: Early results of this prospective trial demonstrate comparable disease outcomes and thus far limited late effects in a young pediatric RMS population. However, additional follow up is needed to determine if protons truly reduce rates and severity of late effects compared with photon cohorts published in the literature.
Effectiveness of using cardiac biomarkers to detect late anthracycline cardiotoxicity in childhood leukemia survivors.
Authors: Mladosievicova Beata , Urbanova Dagmar , Radvanska Eva , Mikuskova Eva , Simkova Iveta
Published: March 2020

9592

Background: Cardiotoxicity is usually detected only when clinical symptoms or progressive cardiac dysfunction has already occurred. Cardiac biomarkers (troponin T and N-terminal fragment brain natriuretic peptide precursor) have been hypothesized to reflect subclinical anthracycline cardiotoxicity earlier than echocardiography. This study aims to assess the effectiveness of using cTNT and NTproBNP in asymptomatic long-term survivors of childhood leukemia treated with and without antracyclines (ANT). Methods: Sixty-nine childhood leukemia survivors 5 - 25 years after completion of therapy were evaluated with immunochemical analysis of cTnT and NT-proBNP and echocardiography. Patients from group I (n = 36) received combined therapy with anthracyclines (ANT) with total cumulative dose 95-600 (median 221) mg/m2, patients from group II (n = 33) received therapy without anthracyclines (nonANT). Control group consisted from 44 age- and gender-matched apparently healthy subjects. Results: Levels of NTproBNP were significantly higher in ANT group than in controls (median 51,52 vs 17,37 pg/ml; p=0.0026). Patients treated with ANT had significantly increased median values of NTproBNP compared with patients in non ANT group (51,52 vs 12,24 pg/ml; p=0.0002). CTnT levels remained below the diagnostic cut-off levels in all groups. No patient had echocardiographic abnormalities, but significant differences were found in mean values of left ventricular ejection fraction and deceleration time between patients treated with and without ANT. Conclusions: Assessment of plasma NTproBNP concentrations may be an effective tool for detection of late subclinical cardiac damage in survivors of childhood leukemia previously treated with low ANT doses. Higher NTproBNP levels in patients after ANT therapy might reflect an initial stage of cardiotoxicity before the development of echocardiographic abnormalities. This study was supported by a grant from Ministry of Health 2007/42-UK-18, Slovakia.