bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2794: CD8+ natural regulatory T cells as antitumor immune effectors in carcinomas of breast and lung
Authors: Sawant Anandi , Lee Carnella , Schafer Cara , Deshane Jessy , Ponnazhagan Selvarangan 
Published: May 2015

Abstract
CD8+ T cells are cytolytic effectors of adaptive immunity against invading pathogens, and under various pathological conditions including cancer. In syngeneic, immunocompetent murine models of epithelial cancers, including breast and lung cancer, we observed up-regulation in frequencies of a unique CD8+ T cell population, characterized as CD8+CD25-Foxp3+, referred here as CD8+ natural regulatory T cells. This regulatory cell population was present in very high numbers during initial stages of tumor growth. However, a drastic reduction in CD8+ natural regulatory T cells was observed as tumor burden increased, and also with the onset of metastasis to distant sites, including bone in the case of breast cancer. Upon further investigation of these cells, we observed that they are highly cytotoxic towards the cancer cells. Adoptive transfer of these CD8+ natural regulatory cells obtained from mice with minimal tumor burden resulted in significantly reduced tumor growth in the tumor-bearing recipients.
There was also an inverse relationship between CD8+ natural regulatory T cells and plasmacytoid dendritic cells (pDC) as tumor burden increased. Additionally, depletion of pDC, either using depletion antibody or by using a transgenic mouse model lacking pDC, showed increased numbers of CD8+ natural regulatory T cells that resulted in decreased tumor burden. Analysis of a possible molecular mechanism on the role of CD8+ natural regulatory T cells as anti-tumor effectors demonstrated that these cells express PD-1. Furthermore, PD-L1, a ligand for PD-1, is expressed by both pDC and cancer cells in vivo. Ongoing experiments are focused on deciphering a possible role of PD-1 and PD-L1 interaction in determining the fate of CD8+ natural regulatory T cells in the presence of pDC and cancer cells through in vitro assays and using transgenic murine models and depletion antibodies for both PD-1 and PD-L1. Collectively, these data suggest a novel anti-tumor immune population that has a potential to be used as immunotherapy for cancer in conjunction with conventional treatments.
Citation Format: Anandi Sawant, Carnella Lee, Cara Schafer, Jessy Deshane, Selvarangan Ponnazhagan. CD8+ natural regulatory T cells as antitumor immune effectors in carcinomas of breast and lung. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2794. doi:10.1158/1538-7445.AM2014-2794
Abstract 281: Work history and cancer mortality risks in 90,268 United States radiologic technologists
Authors: Liu Jason J. , Doody Michele M. , Little Mark P. , Freedman D Michal , Alexander Bruce H. , Kitahara Cari M. , Sigurdson Alice J. , Lee Terrence , Rajaraman Preetha , Miller Jeremy S. , Kampa Diane M. , Simon Steven L. , Preston Dale L. , Linet Martha S. 
Published: May 2015

Abstract
Objectives: There have been few studies on medical radiation work history factors and cancer mortality. In this nationwide prospective cohort study of United States radiologic technologists, we expanded our previous evaluation of work history and cancer mortality risks, by extending follow-up by 11 years and examining a broader range of cancers.
Methods: Using Cox proportional hazards models, we estimated cancer mortality risks through 2008 according to work history and other data derived from questionnaire responses provided during 1983-89 by 90,268 U.S. radiologic technologists. We controlled for potential confounding by age, birth year, pack-years of cigarettes smoked, body mass index, race, and gender.
Results: There were 9,564 deaths and 3,329 deaths from cancer. After controlling for potential confounding factors, we found that technologists who began working before 1950 had marginally increased risk of dying from all cancers (p-trend=0.08), as well as increased risk of dying from female breast cancer (p-trend=0.01) and stomach cancer (p-trend=0.01) compared to those who began working in 1970 or later. Other work history factors, including starting work at a younger age, working greater number of years, or holding patients for x-rays more often, were not consistently associated with increased cancer mortality risks.
Conclusions: We found that radiologic technologists who worked before 1950 had increased risk of dying from certain cancers, which may reflect higher occupational radiation exposures before the late 1950s.
Note: This abstract was not presented at the meeting.
Citation Format: Jason J. Liu, Michele M. Doody, Mark P. Little, D Michal Freedman, Bruce H. Alexander, Cari M. Kitahara, Alice J. Sigurdson, Terrence Lee, Preetha Rajaraman, Jeremy S. Miller, Diane M. Kampa, Steven L. Simon, Dale L. Preston, Martha S. Linet. Work history and cancer mortality risks in 90,268 United States radiologic technologists. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 281. doi:10.1158/1538-7445.AM2014-281
Abstract 2836: Development of a companion diagnostic IHC assay for the biomarker-driven selection of C4.4a positive patients
Authors: Schneider Claudia , Couto Joseph , Zhu Yifei , Liao Zhiming , Pytela Robert , Hiscox Alton , Wittemer-Rump Sabine , Forssmann Ulf , Linden Lars , Willuda Joerg , Forler Daniel , Nelson Matthew , Finnern Ricarda , Krahn Thomas , Asadullah Khusru 
Published: May 2015

Abstract
C4.4a (LYPD3), a GPI-anchored cell surface protein, has been identified previously as a cancer- and metastasis-associated cell surface protein. It is expressed in a variety of cancer indications and, particularly, in the squamous cell subtype of non-small cell lung cancer (NSCLC) and head and neck cancer. Targeting C4.4a with a specific antibody-drug conjugate showed a potent and selective antitumor activity in various human xenograft models and in patient-derived NSCLC tumor models (Willuda J et al., AACR 2014). Since it has been previously shown in vivo that the expression of C4.4a is required for the response to anti-C4.4a treatment, we initiated the development of an IHC assay that might be used to detect C4.4a expression in patient tumor samples. For the development of this companion diagnostic IHC assay, a novel monoclonal rabbit anti-C4.4a antibody was generated. Since C4.4a is post-transcriptionally modified by shedding, we aimed to identify an antibody that binds to a similar epitope as the therapeutic C4.4a antibody. The immunizations of rabbits with specific peptide sequences of C4.4a and with the full length C4.4a recombinant protein produced several antibody candidates. Those antibody candidates were characterized in regard to their staining characteristics, domain binding, and specificity for C4.4a. Furthermore, the staining pattern of the antibody candidates and the therapeutic C4.4a antibody were compared side by side to ensure that stainings using the newly generated antibodies are predictive for anti-C4.4a treatment. The most promising antibodies were selected to set up and optimize an IHC assay on the Ventana staining platform. In summary, we developed a companion diagnostic IHC assay that might be used to detect C4.4a expression in patient tumor samples.
Citation Format: Claudia Schneider, Joseph Couto, Yifei Zhu, Zhiming Liao, Robert Pytela, Alton Hiscox, Sabine Wittemer-Rump, Ulf Forssmann, Lars Linden, Joerg Willuda, Daniel Forler, Matthew Nelson, Ricarda Finnern, Thomas Krahn, Khusru Asadullah. Development of a companion diagnostic IHC assay for the biomarker-driven selection of C4.4a positive patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2836. doi:10.1158/1538-7445.AM2014-2836
Abstract 2840: Evaluation of HER-2 RNA and protein levels in a large cohort of breast cancer specimens to support development of a diagnostic immunofluorescence assay quantified by AQUA® Technology
Authors: Bordeaux Jennifer , Chandrasekaran Krupa , Beruti Sue , Nerenberg Mike , Ramos Corinne , Rimm David , Lameh Jelveh , Dakappagari Naveen 
Published: May 2015

Abstract
With the advent of multiple HER-2 targeting agents, the need for a diagnostic test that accurately predicts the levels of HER2 in newly diagnosed breast cancer patients has never been greater. The goal of this study was to develop an immunofluorescence based assay to objectively and reproducibly quantify HER-2 protein level in Formalin-Fixed Paraffin-Embedded (FFPE) specimens using AQUA Technology and to provide a binary readout, thus eliminating reflex testing and enabling quick treatment decisions.
Methods: Three well known HER-2 antibody clones, A0485, CB11, and SP3 were evaluated across a three-log dilution series under four different antigen retrieval conditions on a tissue microarray (TMA) containing 80 breast cancer cases with known central HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) amplification status. The top six immunofluorescence assay combinations out of 108 conditions were quantified by AQUA scoring based on the their ability to accurately separate negative and positive cases using receiver operating characteristic (ROC) analysis. These top six assay conditions were then assessed on an independent TMA containing 94 breast cancer cases and their AQUA scores were compared to HER2 protein levels determined by reverse phase protein microarray (RPMA®), HER2 mRNA levels assessed by RNAscope® as well as to the current “gold standard” IHC and FISH amplification.
Results: Top three conditions clearly segregating HER2 positive and HER2 negative breast cancer cases were selected and analyzed on an independent TMA. Conditions associated with both SP3 and A0485 antibodies demonstrated high correlations with both HER2 protein levels determined by RPMA analysis and HER2 mRNA levels assessed by RNAscope (spearman's rho &gt;0.85).
Conclusion: Assessment of HER2 status using AQUA Technology was confirmed using two expression platforms, including both protein (RPMA) and RNA (RNAscope) supporting the utilization of the AQUA methodology for diagnostic test development.
Citation Format: Jennifer Bordeaux, Krupa Chandrasekaran, Sue Beruti, Mike Nerenberg, Corinne Ramos, David Rimm, Jelveh Lameh, Naveen Dakappagari. Evaluation of HER-2 RNA and protein levels in a large cohort of breast cancer specimens to support development of a diagnostic immunofluorescence assay quantified by AQUA® Technology. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2840. doi:10.1158/1538-7445.AM2014-2840
Abstract 2841: Characterization of ALK fusions in circulating tumor cells (CTCs) of NSCLC
Authors: Lu David , Krupa Rachel , Bales Natalee , Louw Jessica , Marrinucci Dena , Dittamore Ryan 
Published: May 2015

Abstract
Background:
Many NSCLC patients have insufficient tumor sample or have high co-morbidities preventing access to tissue biopsies for FISH or IHC to determine ALK fusion and subsequent eligibility to Crizotinib therapy. We developed a gene/protein assay for the ALK fusion and examined CTCs and CTC subpopulation incidence and molecular characterization in newly diagnosed NSCLC patients.
Methods:
10 samples from newly diagnosed NSCLC patients prior to therapy were recruited and blood specimens were collected and shipped to Epic Sciences. 2/10 had known ALK rearrangement through tissue analysis. All nucleated cells were plated onto glass slides and subjected to IF staining and CTC identification by fluorescent scanners and algorithmic analysis. CTCs, defined as classic (CK+ CD45- w/intact DAPI nuclei and morphologically distinct), apoptotic (CK+, CD45-, non-intact nuclei) and CK- (CK-, CD45-, intact and distinct) were identified. Samples were characterized with ALK IF to assess expression. Patients with known ALK rearrangements in tissue also had their CTCs assessed with ALK FISH.
Results:
Assays for the ALK protein and ALK gene rearrangement were developed and specificity confirmed utilizing H2228 (ALK positive) & A549 (ALK negative) cells spiked into donor blood and run through the Epic Assay. Expression of ALK fusions was visualized in CTCs of 1/2 patients with known ALK rearrangements and 0/8 patients with no ALK rearrangements. ALK fusion protein expression was seen in classic, apoptotic, small and CK- CTCs.
Conclusion:
ALK fusion protein and ALK rearrangement assessment with FISH utilizing the Epic CTC platform demonstrates sensitivity and specificity to identification of patients eligible to Crizotinib. The identification of ALK in CTC subpopulations identifies unique tumor cell morphology and suggests evidence of epithelial plasticity. Further clinical studies are ensuing to determine the sensitivity and specificity of ALK in CTCs and the relevance of CTC subpopulations related to Crizotinib therapy and NSCLC progression.
Citation Format: David Lu, Rachel Krupa, Natalee Bales, Jessica Louw, Dena Marrinucci, Ryan Dittamore. Characterization of ALK fusions in circulating tumor cells (CTCs) of NSCLC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2841. doi:10.1158/1538-7445.AM2014-2841
Abstract 2850: Biomarkers for detection of exfoliated tumor cells in the peritoneal cavity in rectal cancer
Authors: Kristensen Annette T. , Solbakken Arne , Larsen Stein G. , Giercksky Karl-Erik , Hovig Eivind , Lothe Ragnhild , Lind Guro E. , Guren Marianne G. , Flatmark Kjersti 
Published: May 2015

Abstract
During tumor growth, and possibly by manipulation during surgery, cells from rectal tumors may be shed into the peritoneal cavity. Such cells may contribute to development of metastatic disease, in the form of peritoneal carcinomatosis. Detection of cancer cells in the peritoneal cavity at the time of primary surgery might therefore be of value for prediction of disease recurrence with subsequent prognostic implications.
We previously investigated the incidence of exfoliated cancer cells in peritoneal lavage fluid after resection of locally advanced rectal cancer (LARC). DNA from cells obtained by peritoneal lavage was analyzed with respect to mutations in hotspots of the K-RAS gene. K-RAS mutations were present in 30% of the primary tumors, and were detected in 8% of the lavage fluids examined. The presence of cells with K-RAS mutations in lavage fluid was associated with poor survival, suggesting that a molecular approach for detection of exfoliated tumor cells may be feasible, but K-RAS, although highly specific for detection of tumor cells, is insufficient as the only biomarker. Furthermore, since lavage fluid was collected only at the end of the surgical procedure, the relevance of spontaneous versus iatrogenic tumor cell exfoliation could not be determined.
Based on these encouraging results, a prospective study was initiated, in which lavage is performed before and after surgical removal of the primary tumor to provide data regarding the cause of tumor cell exfoliation and their respective contributions to patient outcome. To increase detection sensitivity, a set of highly specific DNA methylation-based biomarkers is explored. In a pilot experiment, a panel of 12 biomarkers has been evaluated in primary tumors from 17 LARC patients using quantitative methylation specific polymerase chain reaction. Methylation of six genes, CNRIP1, MAL, SPG20, FBN1, SNCA and CDO1 was present at high frequencies in this cohort (in 55-88 % of the samples analyzed), and this biomarker panel has been selected for further comparative analysis in lavage samples. The presence of K-RAS, B-RAF and PIK3CA mutations is analyzed using denaturant capillary electrophoresis of PCR-amplified genes. Results from these genetic analyses of the primary tumors and lavage samples of 50 LARC patients will be presented.
Citation Format: Annette T. Kristensen, Arne Solbakken, Stein G. Larsen, Karl-Erik Giercksky, Eivind Hovig, Ragnhild Lothe, Guro E. Lind, Marianne G. Guren, Kjersti Flatmark. Biomarkers for detection of exfoliated tumor cells in the peritoneal cavity in rectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2850. doi:10.1158/1538-7445.AM2014-2850
Abstract 2859: The genetic polymorphisms of ATG5 and COL4A3 are associated with the prognosis of patients with esophageal squamous cell carcinoma
Authors: Lee Jang-Ming , Yang Pei-Wen , Chiang Tzu-Hsuan , Huang Ya-Chuan , Hsieh Ching-Yueh 
Published: May 2015

Abstract
PURPOSE: To investigate the association between the prognosis of patients with esophageal squamous cell carcinoma (ESCC) and the autophagy or collagen related single nucleotide polymorphisms (SNPs).
PATIENTS AND METHODS: The study was analyzed retrospectively. A total of 570 patients diagnosed with ESCC were enrolled in the study and randomly assigned to a training set (n=188) or replication set (n=382). The genotypes of 16 candidate SNPs involved in autophagy or collagen-related functions were analyzed using iPLEX Gold technology from the genomic DNA of peripheral leukocytes. The association of the genotypes and the overall survival or progression-free survival of patients was analyzed by multivariate Cox regression analysis and Kaplan-Meier survival function.
RESULTS: Among these subjects, 239 patients were with early stage (stage IIa or earlier), and 331 patients were with advanced stages (stage IIb or advanced). In patients with early stages, the genetic variants of ATG5:rs1322178, ATG5:rs3804329 and COL4A3: rs28381984 was associated with increased risk of death in the training set. The associations were confirmed in the replication set and in the combined set (HR[95 % CI]=2.47 [1.31-4.65], P=0.005 in ATG5:rs1322178; HR[95 % CI]=2.16[1.08-4.31], P=0.029 in ATG5:rs3804329; HR[95 % CI]=1.48[1.00-2.20], P=0.052 in COL4A3: rs28381984, in combined set). In cumulative effect analysis of multiple SNPs, patients carrying the unfavorable genotypes at all these 3 genes exhibited a 3.87 fold increasd risk of death in early ESCC patients (HR[95 % CI]=3.87 [1.37-10.93], P=0.011). Finally, the Kaplan-Meier survival curves were constructed for overall survival by the number of unfavorable genotypes. The overall survival duration differed significantly between those with 0, 1, 2, and 3 cumulative unfavorable genotypes (log-rank P=0.012).
CONCLUSION: The hereditary genetic polymorphisms of ATG5 and COL4A3 genes can serve as prognostic predictors of the patients with early ESCC.
Citation Format: Jang-Ming Lee, Pei-Wen Yang, Tzu-Hsuan Chiang, Ya-Chuan Huang, Ching-Yueh Hsieh. The genetic polymorphisms of ATG5 and COL4A3 are associated with the prognosis of patients with esophageal squamous cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2859. doi:10.1158/1538-7445.AM2014-2859
Abstract 2867: EGFR expression in T1/T2 oral tongue and floor of the mouth carcinoma
Authors: Kelner Natalie , Pinto Clovis Antonio Lopes , Kowalski Luiz Paulo , Coutinho-Camillo Claudia Malheiros 
Published: May 2015

Abstract
Epidermal growth factor receptor (EGFR) is a molecular maker that regulates the cell growth and plays an important role in tumor proliferation, invasion and metastasis formation. Objective: In this study we examined the association of immunohistochemical expression of EGFR with clinicopathological parameters, lymph node metastasis, regional recurrence and survival in selected cases of early squamous cell carcinoma (SCC) of the oral tongue and floor of the mouth. Methods: Patients with early stage SCC of oral tongue and floor of the mouth were treated surgically at a single institution from 1980 to 2010. Specimens from 139 patients were analyzed for EGFR expression using monoclonal antibody. Results: This study included 139 patients, 96 men (69%), with ages ranging from 21 to 85 years old (mean, 58 years). The tumor site was the tongue in 105 cases (75.5%) and the floor of the mouth in 34 (24.5%). With regard to pathological T-stage, 69 cases were pT1 (52.7%) and 62 were pT2 (47.3%). EGFR was overexpressed in 18 cases (13%) and was significantly associated with pT (p=0.017), thickness greater than 4mm (p=0.017), muscular invasion (p=0.014), desmoplastic reaction (p=0.021), inflammatory infiltrate (p=0.029), lymphatic embolization (p=0.016), mode of invasion (p=0.027) and perineural invasion (p=0.007). The overexpression of EGFR was also associated with lymph node metastasis (p=0.038) and regional recurrence (p=0.014). The cancer-specific survival in 5 years decreased from 90% in the group without EGFR expression to 75.3% in the EGFR overexpression group (p=0.019). Conclusion: The EGFR overexpression was associated with more aggressive pathological features, lymph node metastasis and regional recurrence in patients with early oral tongue and floor of the mouth squamous cell carcinoma.
Citation Format: Natalie Kelner, Clovis Antonio Lopes Pinto, Luiz Paulo Kowalski, Claudia Malheiros Coutinho-Camillo. EGFR expression in T1/T2 oral tongue and floor of the mouth carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2867. doi:10.1158/1538-7445.AM2014-2867