bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of the necessity of bilateral bone marrow aspirates and biopsies for the diagnosis of metastatic disease in pediatric patients with solid tumors.
Authors: Abrantes Fernanda L. , Vergamini Lucas B. , Rodriguez-Galindo Carlos , Hofmann Inga , London Wendy B. , Ribeiro Karina Braga , Frazier A. Lindsay , Sun Pengling 
Published: March 2020

10054 Background: Standard practice for staging solid tumors has been to perform bilateral bone marrow aspirates (BMA) and biopsies (BMB). However, the diagnostic yield of performing all 4 tests has not been thoroughly evaluated. This study evaluated the concordance between test types (aspirate and biopsy) and sites (right and left) to evaluate whether one type or one side would be sufficient. Methods: All patients with solid tumors who underwent a diagnostic bilateral bone marrow biopsy and aspirate performed between 2006 and 2011 at Children’s Hospital Boston were identifed in a search of hematopathology records.. Kappa coeffcients were estimated. Results: A search of the hematopathology data records revealed a total of 112 patients who had had a diagnostic bilateral BMA and BMB including patients with neuroblastoma (n=70 ), Ewing’s Sarcoma (n=11), rhabdomyosarcoma (n=25), retinoblastoma (n=5), and undifferentiated sarcoma (n=1). 73% (n=82) of the patients were negative for all tests; 27% (n=30) had at least one positive test. The results between right and left and aspirate and biopsy were highly correlated.(Kappa statistics: BMA and BMB (0.85); BMA-left and BMB-left (0.82); BMA-right and BMB-right (0.84); BMA-left and BMA-right (0.77); BMB-left and BMB-right (0.95). All 4 tests were positive in 63%, 3 tests positive in 10%, 2 tests positive in 13% and one test positive in 13%. The distribution of positive results did not differ by disease. Among 11 patients with less than 4 positive tests, 10 would have been diagnosed correctly with bilateral aspirates; only one patient (neuroblastoma) had positive results on biopsy only. In this patient, neither aspirate had spicules and was therefore likely an inadequate specimen. Conclusions: Bone marrow biopsy may not be essential for accurate diagnosis of metastatic disease in pediatric solid tumor patients. Further confirmation of these findings in a larger sample is warranted.
Biomarkers of radiation exposure in children with neuroblastoma treated with 131I-mIBG.
Authors: Karski Erin E , Matthay Katherine K. , Allen M. Shelly , Coleman Matthew , Kohlgruber Ayona , Haas-Kogan Daphne A. , Olow Aleksandra E , DuBois Steven G. 
Published: March 2020

10060 Background: Neuroblastoma (NB) is the most common solid extra-cranial tumor of childhood. 131I-mIBG is a targeted radiopharmaceutical for patients with advanced NB and is one of the most active agents in this treatment resistant population. To date, no clinically relevant biomarkers of response or toxicity have been reported in patients treated with 131I-mIBG. Methods: Patients with relapsed or refractory NB who received 131I-mIBG at UCSF were eligible to participate in this prospective correlative study. Blood samples were obtained at baseline and 72 hours after 131I-mIBG infusion. We quantified a panel of biomarkers shown to be effected in patients receiving other forms of radiation, including: serum amylase; plasma Flt-3 ligand; plasma monocyte colony stimulating factor (MCSF); and CDKN1A mRNA in mononuclear cells. Extent of modulation of each marker was evaluated using paired t-tests at hour 0 and 72. We assessed potential differential modulation between groups based on response (PR/CR vs SD/PD), toxicity (grade 3 non-hematologic toxicity; grade 4 neutropenia or thrombocytopenia) or administration of combination therapy (131I-mIBG alone vs in combination with vincristine/irinotecan or vorinostat) using unpaired t-tests. Results: 26 patients (21 male; median age 7 years) participated and received a median 131I-mIBG dose of 18 mCi/kg. 16 patients received 131I-mIBG in combination. We observed robust modulation of amylase (median fold increase from baseline 3.1; p <0.0001), Flt-3 ligand (median fold increase from baseline 3.6; p=0.0005), and CDKN1A mRNA (median fold decrease from baseline 4.3, p=0.0002). No differences were noted in MCSF (p=0.80). Patients receiving combination 131I-mIBG had more robust modulation of Flt-3 ligand (mean difference 296 pg/mL; p=0.02) compared to single agent 131I-mIBG. No correlations with clinical response or toxicity were found. Conclusions: Amylase, Flt-3 ligand, and CDKN1A mRNA all show robust modulation after 131I-mIBG treatment. Patients receiving 131I-mIBG in combination demonstrated the largest changes in plasma Flt-3 ligand. In this initial analysis, no associations were found between response or toxicity and the proposed biomarkers.
Health practices and behaviors of childhood cancer survivors not attending a comprehensive survivor clinic.
Authors: Iyer Neel Subramanian , Mitchell Hannah-Rose , Gross Cary Philip , Ma Xiaomei , Kadan-Lottick Nina 
Published: March 2020

10063 Background: Little is known regarding the health practices and behaviors of childhood cancer patients who have not received recommended survivorship care, a group that represents the majority of survivors. Methods: Using the Yale Tumor Registry, consisting of patients from Southern Connecticut, we identified patients who were diagnosed from 2000-2011 with an invasive cancer at age ≤18 years, are currently alive and cancer-free at least one year after therapy, live within 100 miles of Yale HEROS Childhood Cancer Survivor Clinic, never previously attended a survivor clinic, and consented to a research study to investigate survivor care. Participants completed postal or on-line surveys regarding health communication preferences, utilization of services, and behaviors. Results: The 68 participants had a mean age of 16.8 (range 6-27) years at evaluation and 6.7 years since diagnosis with 53% female and 50% currently >18 years. Overall, 100% had seen a primary care physician and 71% their pediatric oncologist in the past year. Forty-six percent had also seen a subspecialist with orthopedics (10%), dermatology (9%), endocrinology (6%), and OB/GYN (6%) as the most common specialties; 16% reported two or more subspecialists. Most (83%) had commercial insurance, while 17% had federal insurance. For communication preferences with their providers, willingness to communicate by cell phone, text messages, and email were 59%, 56%, and 87%, respectively. For health behaviors, only 16% of participants met CDC guidelines for fruit and 19.1% for vegetable intake. Among adults, 12% were active smokers. Only 6% of children and 33% of adults met age-specific CDC recommendations for moderate weekly physical activity. Conclusions: Survivors of childhood cancer were overall highly connected to primary care and other health services, despite not participating in survivorship care. However, inadequate diet and physical activity results suggest patients could benefit from behavioral interventions.
First results of prophylaxis for bacterial and fungal infections in pediatric patients with high-risk acute lymphocytic leukemia (ALL).
Authors: Beaugrand Annick , Oliveira Renato Guedes , Gorender Ethel , Melaragno Renato , Epelman Sidnei 
Published: March 2020

10065 Background: Bacterial and invasive fungal infections remain a major contributor to treatment related morbidity and mortality in cancer patients. It has been published data of potential prevention; in immunocompromised hosts derive primarily from adult studies. However, children differ from adults in terms of the infections types as they develop or manifest, as well as their metabolism of treatment agents. From April 2010 to January 2011, 6 ALL patients received 35 intensive chemotherapy cycles during the first 6 months after diagnosis, 2 died due to infection. Methods: From April 2011 to January 2012, a prospective analysis in 8 high risk ALL patients ( BFM criteria) after 31 cycles of intensive chemotherapy were performed during the first 6 months of treatment followed by antibacterial and antifungal prophylaxis. Drugs are: ciprophloxacin 1000mg per day when weight highest than 30 kg and 500mg per day when lower weigh and fluconazole 100mg per day for the lower weigh and 150mg for the higher. All patient received granulocyte colony-stimulating factor after each cycles until complete neutrophils recovery. Results: In 20/31 cycles, hospitalization was needed, due to febrile neutropenia. Diarrhea, sepsis and renal failure were other reasons for hospitalization. Platelet transfusions and blood transfusions were performed in 12 and 9 hospitalization respectively. The majority of proven infections (n=7) were bacterial, Gram negative (Pseudomonas aeruginosa and Klebsiella spp), Gram positive, Candida (1 cycle). Hospitalization time was between 2 and 25 days (median time 10 days). In 4 cycles, intensive care unit was needed. No death occurred. Conclusions: Bacterial and fungal infections continue to be a leading cause of morbidity and mortality in children receiving intensive therapy. Pharmacologic prophylaxis can contribute to decrease mortality due to infection in this population.
Attitudes to the return of incidental and targeted genomic findings obtained in a high-risk pediatric cancer versus an inherited genetic condition research setting.
Authors: Fernandez Conrad Vincent , Jabado Nada , Boycott Kym , Malkin David , Bouffet Eric , O'Connell Colleen , Avard Denise , Knoppers Bartha , Sorensen Poul , Orr Andrew C , McMaster Christopher 
Published: March 2020

10066 Background: The disclosure of clinically significant, validated incidental and target findings to participants in genomic research is often recommended. There have been no reports on whether attitudes of parents differ if these findings emerge from an acquired pediatric cancer versus an inherited genetic condition setting. Methods: Parents in 3 large-scale projects [Canadian Pediatric Cancer Genome Consortium (CPCGC), the Finding of Rare Genes Canada Consortium (FORGE) and the Orphan Diseases: identifying Genes and Novel Therapeutics to Enhance Treatment Project (IGNITE)] were surveyed using a mailed, validated 29-item questionnaire. Two reminders were sent. Analysis was by descriptive and Chi-square statistics. Results: Response rate: 64% (n=307/480). 40% were > 50 yrs age; more than half had a grade 12 education. 86 were parents of poor risk pediatric cancer patients and 221 were parents or individuals with rare inherited conditions. Most stated a very strong or strong right to genomic research results, irrespective if from the target condition (97%) or incidental (86%). 70% wish genetic counselling pre- and post-research testing; an additional 20% were uncertain what this entails. Almost all indicated that genomic research for childhood onset conditions should occur, regardless of whether therapy existed (99%) or not (91%). A few indicated that they would not want incidental results showing an untreatable fatal condition (17%). Most want results, even if these suggest susceptibility to multiple conditions (87%) or are of uncertain health impact (84%). Most felt a right to genomic research that showed a serious condition in siblings, whether treatable (94%) or not (89%). 74% strongly support that results discovered after death of the proband be shared with family. Conclusions: Parents of children in both cancer and inherited rare conditions genomic research do not differ in indicating a strong right and desire to receive research results, even if they are of uncertain impact, of childhood onset, or after death of the proband. Clear delineation of what will or will not be offered from genomic research should be established at the time of consent.
Next-generation sequencing to find predictors for chemotherapy response in triple-negative breast cancer (TNBC).
Authors: Lips Esther H. , Michaut Magali , Mulder Lennart , Besselink Nicolle , Hoogstraat Marlous L. , Koudijs Marco J. , Voest Emile E. , Bernards Rene , Wesseling Jelle , Wessels Lodewyk F. A. , Rodenhuis Sjoerd 
Published: March 2020

1010 Background: In TNBC initial response to chemotherapy is often favorable, but relapse and chemotherapy resistance frequently occur in advanced disease. Hence there is an urgent need for targeted treatments in this breast cancer subtype. Methods: To identify biomarkers of chemotherapy resistance and putative directed treatment targets, we performed next generation sequencing (NGS) of 2,000 genes implicated in oncogenesis. DNA from 31 pre-treatment biopsies and matched normal blood was sequenced. Biopsies were derived from patients scheduled to receive neoadjuvant chemotherapy with doxorubicin/cyclophosphamide. For the analysis, the tumors were divided in responders and non-responders, depending on whether or not a pathological complete remission (pCR) was achieved. Two definitions of pCR were employed: either the complete absence of infiltrating tumor cells in the breast (n=18) or a pCR of both the breast and lymph nodes (n=15). Tumors with partial or no responses were grouped in the non-responder category. Results: As a positive control, we verified that all patients with a known germline BRCA1 mutation (n=8) could be detected by the NGS analysis. In further analyses, we focused only on somatic mutations. Overall, the mutation rate was slightly higher in the non-responders (per tumor, average=12, range=[3-25]) than in the responders (average=8, range=[3-19]) (p=0.17). The analysis of individual genes did not reveal significant differences between responders and non-responders. However, pathway analysis showed that mutations in phosphatidylinositol signaling (e.g., PIK3CA, CALML5) were significantly more frequent in the non-responders, with mutations present in 10/13 non-responders and 2/18 responders (adjusted p=0.013). The chemokine and integrin signaling pathways also revealed a significantly higher mutation rate in the non-responders. Conclusions: Mutations in genes of the phosphatidylinositol pathway occur frequently in TNBCs that do not achieve a pCR on a neoadjuvant chemotherapy regimen consisting of doxorubicin and cyclophosphamide. After validation, alternative chemotherapy regimens and targeted agents should be investigated for these tumors.
Molecular identification of basal-like breast cancer through genomic analyses across five cancer types.
Authors: Prat Aleix , Adamo Barbara , Fan Cheng , Vidal Maria , Galvan Patricia , Felip Enriqueta , Del Campo Jose Maria , Tabernero Josep , Cortes Javier 
Published: March 2020

1011 Background: Common molecular alterations in different types of cancer are being identified and these might be successfully targeted regardless of the tumor´s tissue of origin. To better understand the genomic relationships among different types of cancer, we explored global gene expression patterns across breast, lung, ovarian, brain and colorectal cancers. Methods: A unified set of 1,707 samples of 5 human cancer types (breast [n=547], lung [squamous and adenocarcinomas, n=249], ovarian [serous carcinoma, n=489], brain [glioblastoma multiforme, n=202] and colorectal [n=220]) from The Cancer Genome Atlas (TCGA) project was evaluated. All microarrays were performed at the University of North Carolina under the same protocol and platform. All samples provided in each publication of TCGA were used, except for lung adenocarcinomas where we used TCGA public data. Consensus clustering was used to identify molecular entities, and breast cancer intrinsic subtyping was performed using the PAM50 predictor. Results: A total of 6 distinct and robust molecular entities were identified representing tumors from breast luminal/HER2-enriched, breast Basal-like, lung, ovarian, brain and colorectal cancers. Strikingly, 55%, 26%, 16% of Basal-like breast cancers were found to be more similar to squamous cell lung carcinomas, lung adenocarcinomas and ovarian cancers, respectively, compared to breast luminal/HER2-enriched tumors. Breast cancer intrinsic subtyping identified a Basal-like profile in 55% of squamous cell lung cancers, 53% of ovarian cancers and 8% of lung adenocarcinomas. Finally, single genes and gene signatures tracking cancer-related biological processes such as proliferation, angiogenesis and immune activation were found highly expressed in different proportions across the 6 molecular entities. Conclusions: These data suggest that breast tumors of the Basal-like subtype have a distinct cell of origin compared to luminal/HER2-enriched tumors. Clinical trials focusing on tumors with common profiles and/or biomarker expression rather than their tissue of origin are warranted with a special focus on Basal-like breast cancer, squamous cell lung carcinoma and serous ovarian cancer.
Correlation of intratumor gene expression heterogeneity with chemotherapy sensitivity in breast cancer.
Authors: Natowicz Rene , Jiang Tingting , Shi Weiwei , Qi Yuan , Delpech Yann , Symmans William Fraser , Pusztai Lajos 
Published: March 2020

1013 Background: The goal of this study was to develop a method to quantify intratumor heterogeneity of cancers using gene expression data. We compared gene expression heterogeneity between different molecular subtypes of breast cancer and between basal like cancers with or without pathologic complete response (pCR) to neoadjuvant chemotherapy. Methods: Affymetrix U133A gene expression data of 335 stage I-III breast cancers were analyzed. Molecular class was assigned using the PAM50 predictor. All patients received neoadjuvant chemotherapy. We measured tumor heterogeneity by the Gini index (GI) calculated individually for each case over the expression of all probe sets and random subsets. The GI was used as a metric of inequality of gene expression distributions between cases. The higher the GI, the greater the inequality of the expression distribution. Results: Basal like cancers (n=138) had greater heterogeneity than luminal cancers (n=197) (mean GI values 24.51 vs 23.05, p<0.001) and luminal B (n=71) cancers had greater heterogeneity compared to Luminal A (n=126) cancers (24.49 vs 22.25, p<0.001). Among the basal-like cancers, those with pCR (n=44) had significantly higher heterogeneity compared to cancers with residual disease (RD, n=94) (26.10 vs 23.77, p<0.001). Significant differences in GI between cancer subtypes remained for as low 2500 randomly selected probe sets. Conclusions: Breast cancer subtypes differ in intratumor gene expression heterogeneity. Greater degree of heterogeneity correlate with greater chemotherapy sensitivity. Importantly, among basal-like cancers only the heterogeneity metric differed significantly between cases with pCR or RD but not individual genes expression values or gene signatures.
Radiation-induced increases in PARP1 activity to predict for long-term radiosensitization by PARP1 inhibition in preclinical breast cancer models.
Authors: Feng Felix Yi-Chung , Liu Meilan , Wilder-Romans Kari , Speers Corey , Jagsi Reshma , Pierce Lori J. 
Published: March 2020

1025 Background: Sustained locoregional (LR) control of breast cancer (BCa) is a significant issue for patients with inflammatory disease or chest wall recurrences. Inhibition of poly(adenosine diphosphate-ribose) (PAR) polymerase 1 (PARP1), a DNA damage response protein, is a promising strategy for radiosensitization (RS). We investigated RS by PARP1 inhibition and aimed to identify early biomarkers (BMs) predictive of long-term treatment efficacy in preclinical BCa models. Methods: Clonogenic survival assays in 12 BCa and normal epithelial cell lines were used to determine the degree of RS conferred by the PARP1 inhibitor ABT-888 and to optimize the sequencing of therapy. Immunoblots, immunofluorescent staining, flow cytometery, and xenograft studies were used to evaluate for pre-/intra-treatment BMs predicting for subsequent response to therapy. Results: ABT-888 preferentially radiosensitized BCa (vs. normal) cells (enhancement ratios (EnhR) up to 2.3 across different subtypes). The highest EnhRs resulted from concurrent and adjuvant ABT-888. The degree of RS did not correlate with pretreatment markers of PARP1 activity (e.g., PAR levels), DNA damage/repair (e.g. gamma-H2AX & RAD51 foci), or cell cycle distribution. However, increases in PARP1 activity from pretreatment to 24 hours after RT, was associated with long-term clonogenic death after treatment with ABT-888 + radiation (RT) (Spearman's coefficient=0.8, p=0.002). The four cell lines significantly radiosensitized by PARP1 inhibition (EnhR>1.5) averaged a 2-fold increase in PAR levels following RT. Findings were also confirmed in SKBR3 and MDA-231 BCa xenograft models. Conclusions: Our study demonstrates that PARP1 inhibition improves the therapeutic index of RT in BCa cell lines. Treatment-induced increase in PARP1 activity 24 hours after RT predicts for long-term radiosensitization by PARP1 inhibition and is a potential biomarker of response. These studies have led to a clinical trial, incorporating intratreatment BM analyses, of PARP inhibitors and RT in BCa patients currently open for accrual through the Translational Breast Cancer Research Consortium.
Randomized phase III study of adjuvant chemotherapy for node-positive early breast cancer (BC) patients (pts) comparing epirubicin plus cyclophosphamide followed by docetaxel (EC-T) versus epirubicin plus docetaxel followed by capecitabine (ET-X): Efficacy analysis of the GEICAM/2003-10 trial.
Authors: Bermejo Begoña , Ruiz Amparo , Ruiz Borrego Manuel , Ribelles Nuria , Rodriguez-Lescure Alvaro , Munoz-Mateu Montserrat , Gonzalez Sonia , Margeli Mireia , Barnadas Agust , Ramos Vazquez Manuel , del Barco Sonia , Calvo Lourdes , Mendiola Cesar , Crespo Carmen , Rodriguez Cesar Augusto , Martinez Eduardo , Casas Maria Isabel , Camara M Carmen , Carrasco Eva Maria , Martin Miguel ,   Spanish Breast Cancer Research Group (GEICAM)
Published: March 2020

1027 Background: X is an active drug in metastatic breast cancer. GEICAM/2003-10 is an adjuvant trial investigating the integration of capecitabine into an epirubicin and docetaxel containing regimen for node-positive early breast cancer pts. Methods: Pts aged 18-70, with T1-T3/N1-3 operable BC were eligible. HER2+ pts were initially allowed. In October 2005, after 803 pts were included in the trial, the study was amended to exclude them. Pts were stratified by site, menopausal status, number of axillary nodes (1-3, 4-9, >9) and hormonal receptor status and randomized to receive EC (90/600 mg/m2 x4) followed by T (100 mg/m2 x4) or ET (90/75 mg/m2 x4) followed by X (1,250 mg/m2 BID, d1–14, x 4) all every three weeks. The primary endpoint was DFS. The trial was designed to detect an absolute 5-y DFS increase of 7% (72% EC-T, 79% ET-X); a sample size of 1,184 evaluable pts (592 per arm) was required to detect this difference (a=0.05, β=80%). Assuming a drop-out rate of 17%, 1,382 pts were required. The first analysis of DFS was planned after 290 events. Results: Between February 2004 and February 2007, 1384 pts (EC-T 669, ET-X 715) were randomized. Patient characteristics were balanced between arms, median age was 51, 84% of pts were HR positive and 11% HER2 positive; 66, 25 and 9% had 1-3, 4-9 and > 9 nodes respectively. The median relative dose intensity was 99% for EC, 99% for T, 99% for ET and 94% for X. The most frequent grade 3-4 toxicities (>5% in either arm) with EC-T vs. ET-X were neutropenia (19% vs. 10%) with 7% febrile neutropenia in both arms, hand-foot syndrome (2% vs. 20%), fatigue (13% vs. 11%), diarrhea (3% vs. 11%), stomatitis (6% vs. 5%) and vomiting (5% vs. 5%). After a median follow-up of 6.6 years and 292 events, the proportion of patients disease free at 5 years is 86% and 82% with EC-T and ET-X (HR for relapse 1.314, 95% CI: 1.042 – 1.657); log-rank p-value=0.0208. Overall survival was not different between treatment arms (HR 1.113, 95% CI: 0.809 – 1.531); log rank p-value=0.511. Conclusions: DFS has been in favour of EC-T in pts with node-positive early BC. Clinical trial information: NCT00129935.