bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4887: Recurrent NRG1 rearrangements in Caucasian pulmonary mucinous adenocarcinoma: results from an Italian multi-center cohort
Authors: Trombetta Domenico , Graziano Paolo , Sparaneo Angelo , Rossi Giulio , Rossi Antonio , Tiseo Marcello , Maio Massimo Di , Fabrizio Federico P. , Manzorra Maria C. , Centra Flavia , Candia Leonarda Di , Audisio Marco , Maiello Evaristo , Fazio Vito M. , Muscarella Lucia A. 
Published: August 2019

Abstract
Invasive Mucinous Adenocarcinoma (IMA) is a rare histotype of lung adenocarcinoma associated with an unfavorable prognosis due to the lack of effective treatment. The NRG1 rearrangement is a new subtype-specific molecular feature of IMA and acts as a strong oncogenic inductor of the aberrant tyrosine kinase activity of ErbB2/ErbB3 heterodimers through PI3K-AKT/MAPK cellular cascades. We recently described for the first time the occurrence of NRG1 rearrangements in 31% of Caucasian lung IMAs and highlighted a strong association between NRG1 rearrangements and ErbB3 activation.
Here we extended our lung IMA samples cohort by enrolling a total of 71 patients from three different Italian Centers and collected clinical-pathological information and molecular profile, included the mutational status of KRAS, EGFR and ALK genes. We screened all samples by fluorescent in situ hybridization (FISH) for the detection of putative NRG1 rearrangements and by immunohistochemistry (IHC) for the expression of phosphorylated-ErbB3 (pErbB3) receptor. Finally, we customized a new targeted RNA Custom Panel to detect all 9 NRG1-fusion variants published to date to molecular characterize the NRG1 fusion variants in NRG1 rearranged IMAs.
Results showed NRG1 rearrangements in 32% of lung IMAs, displaying both NRG1 FISH split signals and deletions of the 5' portion of the gene. IHC confirmed our previous findings of association between pErbB3 immunoreactivity and NRG1 rearrangements, and the heterogeneity of fluorescent signal distribution and immunostaining along the tissue sections. The CD74-NRG1 remains the most common fusion variant identified in lung IMA samples. Correlation analysis among clinical-pathological data, pErbB3 expression and NRG1 rearrangements are ongoing.
Our results confirm the usefulness of IHC/FISH combined approach for NRG1 broken tumors identification and highlight the role of NRG1 rearrangement as master molecular marker of lung IMAs, potentially useful to select patients for the emerging target therapies.
Citation Format: Domenico Trombetta, Paolo Graziano, Angelo Sparaneo, Giulio Rossi, Antonio Rossi, Marcello Tiseo, Massimo Di Maio, Federico P. Fabrizio, Maria C. Manzorra, Flavia Centra, Leonarda Di Candia, Marco Audisio, Evaristo Maiello, Vito M. Fazio, Lucia A. Muscarella. Recurrent NRG1 rearrangements in Caucasian pulmonary mucinous adenocarcinoma: results from an Italian multi-center cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4887.
Abstract 4895: Natural history and outcome of patients presenting a metastatic breast cancer with PIK3CA mutation
Authors: Mosele Fernanda , Verret Benjamin , Lusque Amelie , Filleron Thomas , Bachelot Thomas , Arnedos Monica , Campone Mario , Dalenc Florence , Lefeuvre Claudia , Sablin Marie Paule , Bonnefoi Hervé , Lacroix Ludovic , Bièche Ivan , Gonçalves Anthony , Jacot William , Jimenez Marta , Jacquet Amelie , Andre Fabrice , Andre Fabrice 
Published: August 2019

Abstract
BACKGROUND: Activating PIK3CA mutations occur in 20-30% of patients with metastatic breast cancer (mBC). A recent study showed that alpha selective PI3K inhibitors improve outcome in patients with PIK3CA mutation, HR+/Her2- mBC. There is a need to better understand the natural history of PIK3CA mutant mBC to optimally position of this drug family.
PATIENTS AND METHODS: 649 patients from SAFIR02 trial (NCT02299999), for which mutational profile was available and with clinical data entered in a database, were selected for this analysis. Associations between PIK3CA mutation, clinical characteristics and outcome were analyzed.
RESULTS: 143 patients (22%) harbor PIK3CA mutation in tumor sample. 10% (n=27) and 34% (n=104) of TNBC and HR+/Her2- mBC presented a PIK3CA mutation respectively (p&lt;0.001). In patients with HR+/Her2- mBC, there is no significant association between PIK3CA mutation and site of metastases or number of metastases (p&lt;0.01). In the same group, patients with PIK3CA mutations were less sensitive to chemotherapy (stable disease or response: 51.3% vs. 69.2% in PIK3CA wild type; p=0.005) (Odds ratio multivariate: 0.40 [95% CI: 0.22-0.71] p=0.002). The median overall survival (OS) for patients with PIK3CA mutated HR+/Her2- mBC was of 19.6 months vs. 23.5 for patients with PIK3CA wild type (p=0.048) (HR multivariate: 1.44 [95% CI: 1.02-2.03] p=0.039). HR+/Her2- mBC with PIK3CA mutations presented more frequently a MAP3K1 mutation (16% vs. 4%, p=0.0002). In the TNBC group, the median OS in patients with PIK3CA mutated cancer was of 24.2 months vs. 14 months in the wild type group (p=0.028).
CONCLUSION: Patients with PIK3CA mutated, HR+/Her2- mBC are less sensitive to chemotherapy and present a shorter survival. These data emphasize the need for new therapies in this setting, and to position these therapies earlier than chemotherapy in the treatment sequences.
Citation Format: Fernanda Mosele, Benjamin Verret, Amelie Lusque, Thomas Filleron, Thomas Bachelot, Monica Arnedos, Mario Campone, Florence Dalenc, Claudia Lefeuvre, Marie Paule Sablin, Hervé Bonnefoi, Ludovic Lacroix, Ivan Bièche, Anthony Gonçalves, William Jacot, Marta Jimenez, Amelie Jacquet, Fabrice Andre, Fabrice Andre. Natural history and outcome of patients presenting a metastatic breast cancer with PIK3CA mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4895.
Abstract 49: ET-1 receptor blockade in engineered 3D high-grade serous ovarian cancer tumoroids
Authors: Rosanò Laura , Pape Judith , Cheema Umber , Loizidou Marilena , Bagnato Anna 
Published: August 2019

Abstract
High-grade serous ovarian cancer (HG-SOC), accounting for 70-80% of ovarian cancer deaths, is characterized by widespred and rapid metastatic nature, suggesting that unraveling determinants of metastasis may implement new therapeutic strategies on clinical care. In this tumor, autocrine or paracrine activation of the endothelin-1 receptors (ET-1R) are recognized drivers of tumor progression, promoting epithelial-mesenchymal transition (EMT), invasion, and metastasis, as well as tumor angiogenesis and lymphangiogenesis. However, since the metastatic spread and response to therapy are influenced by the extracellular matrix (ECM) density and composition of the surrounding tumour microenvironment (TME), the development of a three-dimensional in vitro model mimicking the in vivo tumors is necessary to better understand the dynamic interactions between tumor cells and TME elements, including fibroblasts, endothelial cells and the ECM, regulated by ET-1R. With this in mind, we have developed HG-SOC tumoroids by engineering a dense central artificial cancer mass (ACM) containing HG-SOC cells, nested within a compressed hydrogel representing the stromal compartment comprising type I collagen, laminin, fibronectin, and stromal cells (fibroblasts and endothelial cells). After 21 days, ET-1-stimulated HG-SOC cells showed an altered migration pattern and formed cellular aggregates, mimicking micrometastases that invaded the stroma. As compared to control cells, ET-1 treated cells showed a higher number of cellular aggregates, which were reduced by treatment with the dual receptor antagonist macitentan. In addition, ET-1 increased the size of the invading aggregates compared to control cells. These findings suggest that HG-SOC tumoroids might be useful to investigate the cross-talk between HG-SOC cells and TME in cancer progression and the response to combinatorial treatment, including ET-1R antagonist.
Note: This abstract was not presented at the meeting.
Citation Format: Laura Rosanò, Judith Pape, Umber Cheema, Marilena Loizidou, Anna Bagnato. ET-1 receptor blockade in engineered 3D high-grade serous ovarian cancer tumoroids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 49.
Abstract 4904: High levels of microRNA-210-3p are associated with increased risk of disease progression in breast cancer patients treated with docetaxel
Authors: PASCULLI BARBARA , BARBANO RAFFAELA , RENDINA MICHELINA , FONTANA ANDREA , COPETTI MASSIMILIANO , VALORI VANNA MARIA , MORRITTI MARIA , MAIELLO EVARISTO , FAZIO VITO MICHELE , ESTELLER MANEL , PARRELLA PAOLA 
Published: August 2019

Abstract
MiR-210-3p is the most hypoxia-sensitive miRNA showing overexpression in different human cancers, but its role as biomarker in breast cancer (BC) is still controversial. In our study, we performed the expression analysis of miR-210-3p in a retrospective cohort of breast cancer patients with a median follow-up of 91 months enrolled according to the REMARK guidelines (n=284). As controls, 13 normal breast tissues (NBTs) from reductive mammoplasty were also profiled. By this analysis, we found that miR-210-3p levels were significantly increased in tumours as compared with NBTs (P=0.021). According to the surrogate molecular classification, the Triple Negative subgroup showed the highest levels of miR-210, followed by Luminal B tumours, whereas Luminal A, and HER2-amplified tumours showed the lowest expression levels (P=0.0137). The evaluation of the association of miR-210-3p with time-to-event outcomes in patients without synchronous metastases (n=268) demonstrated an association between risk of disease progression (HR 2.13, 95%CI 0.33-3.39, P=0.002) and higher levels of miR-210-3p in the subgroup treated with docetaxel in sequential therapy with anthracyclines (ECD). Moreover, a cut-off value of 20.966 as established by ROC curve analysis allowed to discriminate patients who developed distant metastases with an accuracy of 85% at 3-years (AUC 0.87, CI 0.69-1) and 83% at 5-years follow up (AUC 0.832, CI 0.656-1). Instead, the accuracy in discriminating patients who died for the disease was of 79.6% at both 5- (AUC 0.804, CI 0.517-1) and 10-years (AUC 0.804 CI 0.517-1) follow up. Overall, our data support the putative involvement of miR-210-3p in the response to treatments including docetaxel and suggest its eligibility to become a biomarker of early metastases development in ECD-treated breast cancer patients.
Citation Format: BARBARA PASCULLI, RAFFAELA BARBANO, MICHELINA RENDINA, ANDREA FONTANA, MASSIMILIANO COPETTI, VANNA MARIA VALORI, MARIA MORRITTI, EVARISTO MAIELLO, VITO MICHELE FAZIO, MANEL ESTELLER, PAOLA PARRELLA. High levels of microRNA-210-3p are associated with increased risk of disease progression in breast cancer patients treated with docetaxel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4904.
Abstract 4910: Neurocognitive effects of central nervous system directed chemotherapy in Non Hodgkin Lymphoma diseased children
Authors: Elmoneim Abeer Abd , Eladawy Ahlam , Elkasem Mona Abu , Hadhood Soumaya 
Published: August 2019

Abstract
Background and Purpose. Because the blood-brain barrier serves as a pharmacological barrier, malignant cells can remain in the central nervous system (CNS) despite systemic chemotherapy. Consequently, CNS-directed treatment is an essential part of therapy for Non-Hodgkin lymphoma (NHL). We aimed in this analysis to determine the neurocognitive effects of CNS-directed chemotherapy in children with NHL.
Methods.
In a cross-sectional study 20 NHL diseased children and 10 healthy controls were tested for neurocognitive functions. The selection criteria were: 3 years or more after the end of NHL chemotherapy only regimen, no anaemia, no CNS or systemic diseases. Both patients and healthy controls were examined for global intelligence quotient (IQ), verbal IQ, performance IQ, attention measures, auditory tests, long and short memory, math skills and academic achievement.
Results.
No decline in global IQ in NHL children compared to healthy controls but there was a significant decline of attention, verbal comprehension and performance IQ. Among 20 NHL diseased children 18 had poor recent and immediate memories while remote memory was normal in 16 children. Young age at diagnosis and treatment intensity were the commonest risk factors.
Conclusion.
In absence of cranial irradiation, childhood survivors of NHL experience long-term neurocognitive deficits after chemotherapy treatment. Global IQ is not a sufficiently sensitive measure to detect specific CNS deficits in NHL diseased children. The deficits are mainly present in basic neurophysiologic processes of attention and executive functioning.
Note: This abstract was not presented at the meeting.
Citation Format: Abeer Abd Elmoneim, Ahlam Eladawy, Mona Abu Elkasem, Soumaya Hadhood. Neurocognitive effects of central nervous system directed chemotherapy in Non Hodgkin Lymphoma diseased children [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4910.
Abstract 4915: Optimal frequency of follow up scans on systemictherapy for advanced malignancies
Authors: Stewart David J. , Macdonald Blair , Katwyk Sasha Van , Awan Arif , Thavorn Kednapa 
Published: August 2019

Abstract
Background: Frequency of follow-up scans is specified in trials but there is little evidence to guide optimal frequency in standard therapy. Progression-free survival (PFS) generally follows first order kinetics and PFS half-lives (calculated by nonlinear regression analysis of more than 300 published PFS curves) correlated strongly with PFS medians (Stewart, AACR 2018).
Method: We used the Excel formula EXP(-tn*0.693/t1/2) to calculate proportion of residual patients remaining progression-free at different time intervals, where tn is the potential time of follow-up scans (eg, every 3 weeks, 6 weeks, etc), * indicates multiplication, 0.693 is the natural logarithm of 2, and t1/2 is the PFS half-life in weeks.
Results: Proportion of remaining patients expected to still remain progression-free at each subsequent scan varied with time interval between scans and with PFS half-life for the individual regimen. For example, with a PFS half-life of 4 months (17.3 weeks) and scans repeated every 6 weeks, 21% of the patients would have progressed by the first scan, 21% of the remaining patients would have progressed by the second scan at 12 weeks, etc. With PFS half-lives of 2, 4, 6, 12 and 20 months (for example), the proportion of remaining patients progressing by the time of each subsequent follow up scan if the scans were repeated every 3 weeks would be 21%, 11%, 8%, 4% and 2%, respectively, while with scans repeated every 6 weeks the proportion progressing would be 38%, 21%, 15%, 8% and 5%, by 12 weeks it would be 62%, 38%, 27%, 15% and 9%, and by 15 weeks it would be 70%, 45%, 33%, 18% and 11%, respectively.
Conclusions: For therapies with short PFS half-lives, scanning every 6 weeks may not be often enough, while with long PFS half-lives, less frequent scans may be warranted. We plan analyses to estimate economic implications of varying scan frequency based on PFS half-life, drug and toxicity costs, opportunity costs (where other effective therapies might be offered if progression is detected), etc. We will also assess how this approach might be adapted for PFS curves that follow exponential 2-phase decay due to presence of distinct good vs poor prognosis subgroups, and we are in the process of using published PFS curves to assess the PFS half-lives for multiple different cancer therapies.
Citation Format: David J. Stewart, Blair Macdonald, Sasha Van Katwyk, Arif Awan, Kednapa Thavorn. Optimal frequency of follow up scans on systemictherapy for advanced malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4915.
Abstract 5124: A machine learning based approach to identify biomarkers of environmental toxicant exposures relevant to liver cancer disparities in rural Illinois
Authors: Smith Brandi , Madak-Erdogan Zeynep 
Published: August 2019

Abstract
Although there have been nationwide reductions in recent cancer death, liver cancer mortality remains to be a problem in rural Illinois. Researchers anticipate that exposure to environmental toxicants in rural Illinois, may be possible causes of increased liver cancer mortality in females. The purpose of our study is to identify potential biomarkers, which are related to early liver toxicity through machine learning. We accessed gene expression data from the open source Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System (TG-GATES) database from rats that had been exposed to over 170 toxicants relevant to liver cancer. We performed a differential gene expression analysis to identify significant features or genes, which are related to hepatotoxicity endpoints, specifically necrosis. Then we built our predictive model using supervised machine learning (ML) through feature selection and classification models. We performed differential gene expression analysis and feature selection to decrease the dimensionality of the gene set. We then used classification modeling to classify genes related to necrosis. Lastly, we tested our predictive model, on an independent data set. Our model predicted specific genes that were highly related to liver toxicant exposure.
Note: This abstract was not presented at the meeting.
Citation Format: Brandi Smith, Zeynep Madak-Erdogan. A machine learning based approach to identify biomarkers of environmental toxicant exposures relevant to liver cancer disparities in rural Illinois [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5124.
Abstract 5125: A novel method for isolating high-quality UHMW DNA from 10 mg of freshly frozen or liquid-preserved animal and human tissue including solid tumors
Authors: Zhang Yang , Broach James 
Published: August 2019

Abstract
High-quality UHMW DNA is key to success in optical mapping of long genomic DNA using Bionano Genomics Saphyr® system for de novo genome assembly and structural variation detection. Ideally, ~100 mg of tissue is frozen immediately upon collection using liquid nitrogen or dry ice, and stored at -80°C before DNA isolation. Practically, tissue amounts may be limited and collection often occurs at sites where low temperature preservation for storage and shipping may be unavailable.
Here we present a novel method to isolate UHMW DNA from 10 mg of either freshly frozen or room temperature preserved animal and human tissue for subsequent enzymatic labeling using direct labeling and staining (DLS) to generate Bionano maps. With a TissueRuptor, 10 mg tissue is homogenized followed by a three-step purification process before embedding the purified nuclei in agarose gel plugs. This process takes less than 3 hours for a batch of 6 samples. Using this method, we have successfully isolated high quality UHMW DNA from various tissue types of rat and human including solid tumors.
The method is very attractive compared to other protocols because: 1) tissue preservation, shipping and handling can be done at room temperature, 2) uses very small amount of tissue - possible application for rare samples and human tissue biopsy tests, and 3) the length and quality of the resulting single molecules generate high quality optical maps for genome finishing and SV calling.
Citation Format: Yang Zhang, James Broach. A novel method for isolating high-quality UHMW DNA from 10 mg of freshly frozen or liquid-preserved animal and human tissue including solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5125.
Abstract 5173: Development of a novel tunable synthetic 3D hydrogel platform for the study of tumor and stromal cell interactions
Authors: Wang Hsu-Kun , Chu Vi , Asbrock Nick 
Published: August 2019

Abstract
Numerous cancer cell models exist used to investigate disease mechanisms and to screen potential cancer therapeutics. Roughly 90% of promising preclinical drugs fail to result in efficacious human treatments. Traditional two-dimensional (2D) tissue culture models lack realistic complexity, while animal models are expensive, time consuming, and too frequently fail to reflect human tumor biology. Recently, three-dimensional (3D) cell culture models are a new method to generate new drug candidates before moving to expensive and time-consuming animal models. We have developed a biochemically defined hydrogel platform formed by mixing various polymers with chemical crosslinkers with enhanced functionality. The hydrogel system employs one of two types of backbone polymers: a synthetic non-degradable polyvinyl alcohol (PVA) or an enzymatically-degradable dextran. Both polymers are functionalized either with fast or slow thiol-reactive groups. Crosslinkers consist of either PEG non-cell-degradable or a CD cell-degradable crosslinkers containing peptide sequences that create cleavage sites for matrix metalloproteases (MMPs) that allow cell migration. The technology provides mechanical and biochemical cues to investigate both morphological and physiological properties of cells in a 3D environment. The hydrogel allows precise control over hydrogel stiffness, gelation speed, cell migration and allows cell recovery for downstream applications. Here, we demonstrate the utility of this hydrogel platform to grow epithelial, fibroblast and tumor cells in 3D cell cultures with high cell viabilities and functionalities. Furthermore, we have constructed a 3D tumor/stromal cell co-culture using the hydrogel to model the dynamic tumor cell microenvironment. This technology will allow the creation of more accurate 3D cancer cell models for basic research and drug discovery applications.
Note: This abstract was not presented at the meeting.
Citation Format: Hsu-Kun Wang, Vi Chu, Nick Asbrock. Development of a novel tunable synthetic 3D hydrogel platform for the study of tumor and stromal cell interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5173.