bluuebunny/crossref_metadata_2025_split huggingface dataset:
PrECOG 0105: Final efficacy results from a phase II study of gemcitabine (G) and carboplatin (C) plus iniparib (BSI-201) as neoadjuvant therapy for triple-negative (TN) and BRCA1/2 mutation-associated breast cancer.
Authors: Telli Melinda L. , Jensen Kristin C. , Kurian Allison W. , Vinayak Shaveta , Lipson Jafi A. , Schackmann Elizabeth A. , Wapnir Irene , Carlson Robert W. , Sparano Joseph A. , Head Bobbie , Goldstein Lori J. , Haley Barbara B. , Dakhil Shaker R. , Manola Judith , Ford James M. 
Published: March 2020

1003 Background: TN and BRCA1-deficient breast cancer (BC) cell lines exhibit enhanced sensitivity to DNA damaging agents. This study was designed to assess efficacy, safety and predictors of response to iniparib in combination with GC in early-stage TN and BRCA1/2 mutation-associated BC. Methods: This single-arm, phase II study (NCT00813956) enrolled pts with clinical stage I-IIIA (T ≥ 1cm by MRI) ER-negative (≤ 5%), PR-negative (≤ 5%), and HER2-negative or BRCA1/2 mutation-associated BC. Neoadjuvant G (1000 mg/m2; IV; D1, 8), C (AUC 2; IV; D1, 8), and iniparib (5.6 mg/kg; IV; D1, 4, 8, 11) were given every 21 days for 4 cycles, until the protocol was amended to increase the treatment duration to 6 cycles, with enrollment of 80 pts at multiple PrECOG institutions. The primary endpoint is pathologic complete response (pCR), defined as no invasive carcinoma in the breast and axilla. Pathologic response was centrally assessed by the residual cancer burden (RCB) index. Assuming 76/80 eligible and treated pts, the regimen would be deemed effective if the lower bound of a 90% exact binomial CI on the pCR rate exceeded 25%. Secondary endpoints are safety, MRI response, and breast conservation. Results: Among 80 eligible pts treated with 6 cycles, median age is 48 years, 19 pts have germline BRCA1/2 mutations (90% tested to date) and clinical stage is I (13%), IIA (36%), IIB (36%), IIIA (15%). Pathologic response data (ITT population) are detailed below. 69 pts completed treatment per protocol: 5 progressed, 5 discontinued due to an AE and 1 mutation carrier was lost to follow-up. Most common G3/4 adverse events are neutropenia (49%), elevated ALT/AST (14%), and anemia (10%). Conclusions: Preoperative GC plus iniparib is active in the treatment of early-stage TN and BRCA1/2 mutation-associated BC. Clinical trial information: NCT00813956. [Table: see text]
Comparison of Taqman low density array (TLDA) five-gene assay for tumor cells in bone marrow and blood with histologic bone marrow examination and imaging for disease assessment and outcome in patients with recurrent/refractory neuroblastoma (NBL): A new approaches to neuroblastoma therapy (NANT) study.
Authors: Marachelian Araz , Villablanca Judith , Asgharzadeh Shahab , Liu Wei Yao , Liu Betty , Young Sabrina , Weiss Brian D. , Katzenstein Howard M. , Cohn Susan Lerner , Baruchel Sylvain , Twist Clare , Granger Meaghan , Matthay Katherine K. , Malvar Jemily , Sposto Richard , Seeger Robert 
Published: March 2020

10039 Background: Accurate quantification of tumor burden in NBL patients is needed to define homogenous populations for therapy and establish response criteria that predict outcome. The 5-gene TLDA assay was developed for quantification of NBL cells in bone marrow (BM) and blood (BLD). Methods: Expression of CHGA, DCX, DDC, PHOX2B, and TH (NBL genes) was quantified with TLDA and reported as the geometric mean cycle threshold for the 5 genes (DGS=detection gene score; inversely related to tumor content, 40=negative). Sixty-three patients with recurrent/refractory NBL had TLDA performed on 107 BM and 99 BLD samples (66 paired) at 140 time points. Based on central review of reports, tumor longest diameter (LD) on CT/MRI (n=118), and number of 123I-MIBG avid sites (n=120) were recorded. Percentage of tumor cells in BM was from institutional reports of bilateral BM aspirates/biopsies (n=109). Overall response was assessed per NANT Response Criteria. Spearman rank correlation was performed. Results:TLDA detected tumor cells in 62/99(63%) BLD (average DGS=37.45) and 91/107(85%) BM samples (average DGS=33.42). 39/91(42%) with positive BM TLDA were negative by morphology. BLD and BM TLDA were correlated r = 0.6540, p< 0.0001 with stronger correlation with lower BM DGS scores. The BM and BLD DGS correlated with % BM involvement (BM r= -0.63, p<0.0001; BLD r= -0.35, p=0.0023) and number of MIBG sites (BM r=-0.34, p=0.001, BLD r=-0.51 p<0.0001) but not LD. Number of MIBG sites was also correlated with % BM involvement (r= 0.45, p<0.001) and LD (r= 0.28, p=0.0039). Analysis of 43 BM pairs demonstrated decreasing DGS correlated with overall progressive disease (r= 0.39, p=0.01). Conclusions: This TLDA assay detects NBL cells in both BM and BLD at high rates, and frequently detects tumor cells when BM morphology is negative. Quantification of tumor with DGS correlates with % BM involvement and number MIBG sites. TLDA may provide an additional parameter to delineate response in NBL. Clinical trial information: NCT01587300.
Integrated analysis of RNAi screens in pediatric rhabdomyosarcoma.
Authors: Arnaldez Fernanda Irene , Chakka Sirisha , Smith Carly J , Yeung Choh L , Caplen Natasha , Helman Lee J. 
Published: March 2020

10040 Background: Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. Embryonal RMS (ERMS) are characterized by 11p15 LOH, while alveolar RMS (ARMS) harbor a translocation between PAX3 or PAX7 and FOXO1. Relapsed or metastatic RMS has a poor prognosis with a 5-year survival rate of 25%. We hypothesized that a reduction in proliferation of ARMS cell lines as result of the loss of function (LOF) of a specific protein via RNAi likely point to novel targets that exhibit “synthetic lethality” with the PAX3/7-FOXO1 translocation, and can be used to reveal unique ARMS vulnerabilities. Methods: We are using two complementary screening strategies to identify genes critical for RMS cell growth and survival. One RNAi screening strategy used an inducible LOF shRNA screen of 15,000 shRNA -5,000 genes- introduced into RH30 (ARMS) or RD (ERMS) cells. Data analysis after subtraction of targets related to common survival pathways revealed 40 genes with close association with RMS cell growth. Follow up analysis included further comparison of the effects of gene specific LOF in ARMS and ERMS cell lines and assessment in orthotopic xenografts. To increase the strength of our findings, we have also conducted parallel siRNA screens of the human kinome targeting 704 kinase genes (3 siRNAs per gene) in RH30 or RD cells. Results: Of the 40 genes identified by shRNA screening, 15 genes were identified as selectively needed for ARMS cell growth. Follow up analysis of one of these genes, TNK-2 (tyrosine kinase, non-receptor 2) in orthotopic xenografts, confirmed that LOF of TNK2 markedly decreases ARMS cell growth. The siRNA screen has identified a further putative 26 genes that selectively reduce ARMS cell growth. These screens have led us to focus on members of the ERK, PI3K and IGF1R pathways as potential targets for the treatment of ARMS. Conclusions: RNAi screening affords an unbiased method for the discovery and elucidation of gene function. Ongoing efforts are focused on the integration of results obtained to gain further insight into the signaling networks influencing alveolar rhabdomyosarcoma biology and thus identify a small group of druggable genes that could represent alveolar rhabdomyosarcoma specific vulnerabilities.
Double akylating agents treatment with ifosfamide (IFOS) and cyclophosphamide (CYCLO) for relapsed pediatric solid tumors.
Authors: Epelman Sidnei , Gorender Ethel , Beaugrand Annick , Melaragno Renato , Meirelles Priscila , Oliveira Renato Guedes 
Published: March 2020

10057 Background: CYCLO and IFOS are two of the most active agents in childhood cancer. There is non-cross resistance between CYCLO and IFOS and they have dissimilar toxic side effects. In vitro, tumor model systems document that alkylator resistance may be overcome by several fold increases in drug concentration. We developed a strategy in attempt to limit side effects and increase anticancer activity of high doses oxazaphosphorines therapy: an association of IFOS plus CYCLO, giving an equivalent to 20g/m2 of IFOS or 5g/m2 of CYCLO. The schedule is the association of these two drugs: CYCLO 2,5g/m2 (corresponding to 10g/m2 of IFOS) plus IFOS 10g/m2. Methods: Eligibility included recurrent/refractory measurable disease, life expectancy > 6 weeks, adequate renal, hepatic and bone marrow function. CYCLO (2,5g/m2) and IFOS (10g/m2) with Mesna, with interval of 21 days. Responses were evaluated after 2 cycles.So far, 13 patients were enrolled: median age 17 years (5-26), 9M:4F,6 osteosarcoma, 1 hemangioperycitoma, 2 medulloblastoma, 1 nasopharyngeal carcinoma, 1 Wilms tumor,1 synoviosarcoma, 1 retinoblastoma. Six patients received IFOS previously (Total= 38 - 63 g/m²) and 5 CYCLO. Results: Thirty four cycles were evaluated. Toxicity was tolerable with no death. Main adverse event was neutropenia grade (GR) 4 in all cycles, median duration of seven days (3-15), GCS-F was used in all cycles; anemia GR 3 and 4 and thrombocytopenia GR 4 in 14 cycles; infection GR 3 and 4 in 15 cycles; hemorrhage cystitis GR 1 in 2 cycles and neurologic toxicity GR 2 in 6 cycles. No acute renal toxicity was observed. Responses were 2 complete response (CR), 5 partial responses (PR), 3 stable disease, and 3 progress disease. Conclusions: This schedule is feasible with high response rate (CR+PR=54%). Due to lack of new agents, innovative approaches for high risk patients can have a potential benefit. More patients are warranted.
Treatment results of children with neuroblastoma in Hospital Infantil de Mexico Federico Gomez.
Authors: Juarez Villegas Luis , Zapata-Tarres Marta , Lezama del Valle Pablo 
Published: March 2020

10059 Background: Neuroblastoma (NB) is the main extracraneal cancer in children. Progress in survival has not been the same as in other neoplasms despite molecular markers research and new drugs. Our aim was to describe low and high risk patients at Hospital Infantil de México Federico Gómez (HIMFG) and their results. Methods: We included children from 0 to 18 years con NB diagnosed at HIMFG between january, 2002 and december 2011. We perform a retrospective, retrolective and descriptive study analyzing demographic variables and survival with Kaplan Meier. Results: 64 consecutive patients were included. 73.4% had metastasis at diagnosis (bone marrow 23.4%, liver 18.8%, bone 17.2%, 4.7% central nervous system, 9.4% other). 87.5% of patients received neoadyuvant chemotherapy. Patients were treated with POG 8104 y 8441. Global survival of patients with E4 stage was 50% at 120 months, with E3 of 76.5% at 110 months; stage 1, 2 patient´s survival was 4S 100% at120 months. Conclusions: At HIMFG, in Mexico City, 75% of patients with NB arrive with metastatic disease. Clinical prognosis factors are still current in development countries. Our results are similar as in developed countries suggesting that with low resources, we can obtain satisfactory results only with clinical evaluation.
Predictors of declining levels of physical activity among adult survivors of childhood cancer.
Authors: Wilson Carmen L , Leisenring Wendy M. , Oeffinger Kevin C. , Nathan Paul C. , Wasilewski-Masker Karen , Hudson Melissa M. , Castellino Sharon M. , Stovall Marilyn , Armstrong Gregory T. , Brinkman Tara M. , Robison Leslie L. , Ness Kirsten K. 
Published: March 2020

10062 Background: Childhood cancer survivors are at increased risk of developing obesity-related diseases, yet many survivors do not meet established guidelines for physical activity. We aimed to identify demographic and health-related predictors of declining physical activity among participants in the Childhood Cancer Survivor Study (CCSS). Methods: Analyses included 6617 >5 year childhood cancer survivors diagnosed between 1970-86 who completed the CCSS 2003 and 2007 follow-up questionnaires, and1992 siblings. Participants were classified as active if they reported engaging in any physical activity other than their regular job duties in the prior month. Generalized linear models using a log-link and Poisson distribution were used to compare participants whose physical activity levels fell from active to inactive over the study interval to those who remained active or whose activity levels improved. In addition to analyses comparing survivors to siblings, selected demographic factors and chronic conditions (CTCAE v4.0 Grade 3 and 4) were evaluated as risk factors in an analysis among survivors alone. Risk ratios (RR) with 95% confidence intervals (CI) are reported. Results: The median age at last follow-up among survivors and siblings was 36 (range: 21-58) and 38 (range: 21-62) years, respectively. Approximately 14% of survivors and 9% of siblings reported declines in physical activity across the study interval (p<0.01). Factors that predicted declining levels of physical activity included BMI≥30kg/m2 (RR=1.4, 95% CI=1.3-1.7, p<0.01), BMI<18.5kg/m2 (RR=1.4, 95% CI=1.0-1.8, p=0.03), not completing high school (RR=1.7, 95% CI=1.2-2.2, p<0.01), and black race (RR=1.6, 95% CI=1.2-2.1, p<0.01). In a model limited to survivors, declining levels of physical activity were more likely among survivors who reported the presence of Grade 3 or 4 neurological (RR=1.5, 95% CI=1.2-1.8, p<0.01) or cardiac conditions (RR=1.5, 95% CI=1.3-1.9, p<0.01). Conclusions: Childhood cancer survivors are at increased risk of becoming inactive over time compared to siblings. Interventions targeting survivors at highest risk of decline are required to reduce the risk of chronic diseases associated with an inactive lifestyle.
Turkish National Pediatric Cancer Registry 2002-2008 (Turkish Pediatric Oncology Group and Turkish Pediatric Hematology Society).
Authors: Kutluk M. Tezer , Yesilipek Akif ,   Turkish Pediatric Oncology Group and Turkish Pediatric Hematology Society
Published: March 2020

10067 Background: In childhood cancers cure rates increased up to 80% in the developed countries. On the other hand cure rates goes down 10-20% percent in countries with low resource settings. Reliable pediatric cancer data is essential for all countries. We established a nationwide pediatric cancer registry. Methods: Turkish Pediatric Oncology & Pediatric Hematology Society established a web-based database for the registry of all pediatric cancers. 11898 cases were registered between 2002-2008 from 65 centers. Various demographic data & survival endpoints were recorded & analyzed. Diseases were grouped according to the International Classification of Childhood Cancer. Results: In all 11898 cases, median age was 6 years (M/F= 6786/5112=1.32). Distribution in age groups were: 0-4 years, 42.5%; 5-9 years, 27.2%; 10-14 years, 23.4%; 15-19 years, 6.8%; >19 years, 0.1%. Only 3.8% of cases were diagnosed with clinical+radiological, the rest with histopathological data Distribution of cases in disease groups were [median age in yrs, M/F]: Leukemias (n=3777) 31.7% [5.5, 2137/1640=.31]; Lymphomas (n=2040) 17.1% [8.3, 1405/635=2.21]; CNS tumors (n=1588) 13.3% [6.9, 913/675=1.3 ]; Sympathetic tumors (n=889) 7.5% [2.1, 453/436=1.03]; Retinoblastoma (n=371) 3.1% [2, 181/190=0.95]; Renal tumors (n=655) 5.5% [3, 333/322=1.03]; Hepatic (n=166) 1.4% [1.8, 101/65=1.5]; Bone tumors (n=717) 6% [12.2, 407/310=1.3]; Soft tissue tumors (n=773) 6.5% [6.5, 442/331=1.3]; Germ cell tumors (n=531) 4.5% [5, 210/321=0.6 ]; Carcinomas and other malignant epithelial tumors (n=323) 2.7% [12, 164/159=1.03]; Others/unspecified malignant tumors (n=68) 0.6% [4.5, 40/28=1.4]. Five-year overall survival in all cases was 65%. Conclusions: This registry provides a critical information about the distribution of childhood cancer since this is the only nationwide pediatric cancer registry in Turkey. With the recent trends in non-communicable diseases at global level, registry data will be very helpful for national cancer control plans, which will also be used to compare at national and international level. This will also be a good example for many other countries with similar resources to do such projects.
Access to cancer chemotherapy and predictors of early mortality for childhood cancers in Uganda.
Authors: Mutyaba Innocent , Orem Jackson , Wabinga Henry , Phipps Warren , Casper Corey 
Published: March 2020

10070 Background: Although many childhood cancers respond well to chemotherapy, survival among children with cancer in sub-Saharan Africa is poor. Little is known about children’s access to specialized cancer care in SSA or factors contributing to poor early outcomes. We aimed: 1) To estimate the proportion of childhood cancer patients without access to chemotherapy in Uganda; 2) To describe 30-day survival rates and predictors of mortality post diagnosis among children with lymphoma or Kaposi sarcoma (KS), the two most common pediatric cancers in Uganda. Methods: A retrospective study of incident childhood (age< 20 years) cancers diagnosed in Kyandondo County, Uganda from 2006-2009. We compared records of the population-based Kampala Cancer Registry (KCR) and patient records at the Uganda Cancer Institute (UCI), Uganda’s sole dedicated cancer treatment center. Patient characteristics were compared using Mann-Whitney and Pearson’s chi-square tests. Kaplan-Meier method and Cox regression models were used to describe mortality. Results: Of the 658 pediatric cases recorded in the KCR, only 238 (36%) presented to UCI. Patients identified in the KCR who did not present for care were more likely to be female, diagnosed in earlier years of the study, and to have a cancer other than KS or lymphoma. Of the 177 lymphoma and KS cases at UCI, 43.7% were Burkitt lymphoma (BL), 32.5% KS, and 23.8% other lymphomas. The post diagnosis 30-day overall survival rate was 77%. In multivariate analysis, age, gender, HIV status, platelets, and stage of cancer did not impact mortality. An increased risk of death at 30 days was predicted by presence of B-symptoms (HR=10.3, p=0.05), a diagnosis of BL compared to other lymphomas (HR=14.8, p=0.007), poor performance status (Karnofsky score <70, HR=14.7, p<0.001), and anemia (HR 1.5-fold per 1g/dL decrease in hemoglobin, p=0.002). Conclusions: Childhood cancer patients in Uganda have limited access to comprehensive care. Among those presenting to the UCI, a significant proportion die before they can benefit from chemotherapy. BL diagnosis, B-symptoms, performance status and hemoglobin level may be important predictors of early mortality among childhood cancer patients in sub-Saharan Africa.
NFKBIA deletion in triple-negative breast cancer.
Authors: Bredel Markus , Kim Hyunsoo , Thudi Nanda K. , Scholtens Denise M. , Bonner James A. , Sikic Branimir I. 
Published: March 2020

1012 Background: While effective, target-directed therapies are available for ER-positive and HER2-amplified breast cancer, adjuvant therapeutic options for triple-negative breast cancer (TNBC) are limited in the absence of well-defined molecular targets. Constitutive activation of oncogenic nuclear factor kB (NFkB) has been associated with ER-negative or basal-like (BL) breast cancers, but the underlying mechanism of this activation remains undefined. We previously showed that deletion of the endogenous NFkB repressor gene NFKBIA associates with EGFR non-amplified glioblastoma multiforme and portends unfavorable clinical outcome (Bredel et al. NEJM 2011). Methods: We analyzed >5,000 human breast cancers for deletions, mutations and/or expression of NFKBIA. We studied tumor suppressor activity of NFKBIA and the effect of targeted NFkB inhibition in cell culture with various NFKBIA genotypes. We compared molecular results with outcomes of affected persons. Results: NFKBIA is often (10.8%) deleted but not mutated in breast cancer. NFKBIA deletions are significantly associated with TNBC (32.8%) and particularly frequent in the BL subtype (36.7%). Loss of NFKBIA exerts a haploinsufficient effect on NFKBIA expression and the transactivation of several NF-kB target genes with important roles in breast carcinogenesis. Restoration of NFKBIA expression or pharmacologic NFkB inhibition attenuates the malignant phenotype of cells cultured from TNBC with NFKBIA deletion. Deletion and low expression of NFKBIA are highly associated with unfavorable overall survival, independent of patient age, tumor stage, nodal status, and tumor subtype. Loss of NFKBIA expression portends significantly poorer disease-specific survival, recurrence-free survival, and distant metastasis-free survival. Moreover, NFKBIA expression is significantly associated with duration of metastasis-free survival in subgroups of patients with brain or lung metastases from breast cancer. Conclusions: NFKBIA is a new, prognostically relevant, molecular target in TNBC, which remains a clinically challenging subtype of breast cancer with limited treatment options.
Evaluation of flap endonuclease-1 (FEN1) as a prognostic, predictive, and therapeutic target in breast (BC) and ovarian cancer (OVC).
Authors: Abdel-Fatah Tarek M. A. , Russell Roslin , Maloney David J. , Mohan Vivek , Dorjsuren Dorjbal , Rueda Oscar , Gorguc Ipek , Mukherjee Abhik , Jadhav Ajit , Simeonov Anton , Wison III David M. , Agarwal Devika Ravindra , Ball Graham , Chan Stephen , Caldas Carlos , Ellis Ian O. , Madhusudan Srinivasan 
Published: March 2020

1016 Background: FEN1 is a multifunctional protein with essential roles in long patch base excision repair (LP-BER), Okazaki fragment maturation during replication, resolution of tri-nucleotide repeat sequence-derived secondary structures, rescue of stalled replication forks, maintenance of telomere stability and apoptotic fragmentation of DNA. In the current study we have evaluated FEN1 as a prognostic, predictive and therapeutic target in BC and OVC. Methods: Clinico-pathological significance of FEN1 mRNA expression was evaluated in a BC training cohort [n=128], test cohort (n=249) and validated in a large cohort of 1,980 BC (METABRIC). Neural network analysis (NNA) was conducted to identify FEN1 interaction genes. FEN1 protein expression was investigated in three consecutive series of BC and OVC: 568 ER negative (ER- BC), 894 ER positive (ER+ BC) and 195 OVC cohorts. Pre-clinically, FEN1 deficient and proficient HeLa cell lines were investigated for chemotherapy sensitization. A high throughput screening (HTS) strategy was developed to identify FEN1inhibitors for therapeutic application. Results: FEN1mRNA overexpression is associated with adverse clinicopathological features such as high grade, high mitotic index, and triple negative (ps<0.0001). High FEN1 mRNA expression was highly significantly associated with PAM50 Her2, PAM50 Basal and PAM50 LumB (ps<0.0001) BC. FEN1 mRNA overexpression is associated with resistance to chemotherapy (p=0.019), endocrine therapy (p<0.0001) and independently with poor survival (p<0.0001). NNA revealed novel interaction genes with predominant roles in proliferation, cell growth, DNA repair, differentiation, invasion, migration, metabolism and apoptosis. FEN1 protein overexpression is significantly associated with aggressive clinico-pathological features and independently with poor survivals in ER+ BC, ER- BC and in OVC (ps<0.001). HTS assay has identified novel FEN1 inhibitors for therapeutic development. Conclusions: This is the first study to investigate FEN1 in BC and OVC. We provide confirmatory evidence that FEN1 is a promising biomarker as well as a therapeutic anti-cancer drug target for clinical application.