bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A14: Small Tumor Diameter at Cure Threshold (&lt; 20mm) Among Aggressive Lung Cancers Predicts both Chest X-ray and CT Screening Outcomes in a Novel Simulation Framework
Authors: Goldwasser Deborah Lynn , Kimmel Marek 
Published: March 2013

Abstract
Background: The population distribution of lung cancer growth and tumor diameter at cure threshold is an important component of a model of the natural course of lung cancer.
Methods: We simulate outcomes in the Mayo CT lung screening study using an existing simulation model of lung cancer progression calibrated to the Mayo Lung Project (males only) and evaluate the goodness of fit. We perform a likelihood-based analysis to determine whether the conditional probability of five-year lung cancer survival given tumor diameter at detection depends significantly on detection modality. A novel probabilistic model characterizes growth and tumor progression after transformation of a single malignant cell, governed by two parameters f and μ, the branching fraction and cellular mutation rate, respectively. We identify distinct sets of parameter pairs (f,μ), each of which satisfies a method of moments condition given a survival function governing detection in the absence of screening. We examine their goodness of fit with respect to simulated tumor size and five-year lung cancer survival among detected incident lung cancers in the MLP and Mayo CT studies.
Results: An existing model of lung cancer progression under-predicts the number of advanced-stage incident lung cancers among males in the Mayo CT study (p-value = 0.004). The probability of five-year lung cancer survival given size at detection depends significantly on detection modality (p-value = 0.0312). Selected models having a median tumor diameter at cure threshold ranging from 16.7–27.0 mm predict both MLP and Mayo CT outcomes.
Conclusions: The median lung tumor diameter at cure threshold among aggressive lung cancers may be small (&lt; 20 mm).
Abstract A16: Aberrant signaling pathways in squamous cell lung carcinoma
Authors: Sadraei Nooshin Hashemi , Shi Ivy , Duan Zhong-Hui , Shi Ting 
Published: March 2013

Abstract
Lung cancer is the second most commonly occurring non-cutaneous cancer in the United States with the highest mortality rate among both men and women. In this study, we utilized three lung cancer microarray datasets generated by previous researchers to identify differentially expressed genes, altered signaling pathways, and assess the involvement of Hedgehog (Hh) pathway. The three datasets contain the expression levels of tens of thousands genes in normal lung tissues and squamous cell lung carcinoma. The datasets were combined and analyzed. The dysregulated genes and altered signaling pathways were identified using statistical methods. We then performed Fisher's exact test on the significance of the association of Hh pathway downstream genes and squamous cell lung carcinoma. 395 genes were found commonly differentially expressed in squamous cell lung carcinoma. The genes encoding fibrous structural protein keratins and cell cycle dependent genes encoding cyclin-dependent kinases were significantly up-regulated while the ones encoding LIM domains were down. Over 100 signaling pathways were implicated in squamous cell lung carcinoma, including cell cycle regulation pathway, p53 tumor-suppressor pathway, IL-8 signaling, Wnt-β-catenin pathway, mTOR signaling and EGF signaling. In addition, 37 out of 223 downstream molecules of Hh pathway were altered. The pvalue from the Fisher's exact test indicates that Hh signaling is implicated in squamous cell lung carcinoma. Numerous genes were altered and multiple pathways were dysfunctional in squamous cell lung carcinoma. Many of the altered genes have been implicated in different types of carcinoma while some are organ-specific. Hh signaling is implicated in squamous cell lung cancer, opening the door for exploring new cancer therapeutic treatment using GLI antagonist GANT 61.
Abstract A2: Cells of origin of the different subtypes of lung cancer
Authors: Filby Caitlin , Viitaniemi Kati , McQualter Jonathan , Antippa Philip , Irving Lou , Bertoncello Ivan , Asselin-Labat Marie-Liesse 
Published: March 2013

Abstract
Lung cancer is the leading cause of cancer death worldwide. Five-year lung cancer survival is only 15% and lung cancer is responsible for more deaths than prostate, colon, pancreas, and breast cancers combined.
Understanding the cellular and molecular mechanism at the origin of lung cancer will generate great insights for better management of the disease. However, the lack of cell surface markers to identify and isolate early progenitor or stem cells in the normal lung represents a gap of knowledge that needs to be filled to identify cells of origin of lung cancers. By macroscopic isolation of different morphological region of the human lung and staining with cell surface markers, we have isolated distinct cell subpopulations by flow cytometry. Interestingly, these markers are expressed in some types of lung cancers but not others. We are characterizing the different subpopulations by immunostaining of cytospun cells and evaluating their in vitro colony formation capacity. In order to address potential cells of origin for the different lung tumor subtypes, gene signatures of the different normal epithelial subpopulations will be compared to the gene expression profiles of lung carcinomas available from public database.
These cell surface markers may be critical tools to identify stem/progenitor cells in the normal lung that could be the cell of origin of one type of lung cancer and not others.
Abstract A46: Identification of ALDH1A3 as an important biomarker and therapeutic target for non-small cell lung cancer (NSCLC) cancer stem cells (CSCs)
Authors: Shao Chunli , Sullivan James P. , Girard Luc , Sullivan Laura A. , Augustyn Alexander , Xie Yang , Behrens Carmen , Wistuba Ignacio , Minna John D. 
Published: March 2013

Abstract
A considerable amount of evidence reveals the important roles of cancer stem cells (CSCs, also called “cancer initiating cells”) in tumor growth, metastasis, relapse and drug resistance. Our group has identified lung CSCs in both lung cancer cell lines and patient tumor samples by their elevated Aldehyde Dehydrogenase (ALDH) activity and demonstrated that NSCLC patients whose tumors are enriched in ALDH+ cells have inferior survival, and that the ALDH+ subpopulations (ranging from 0.5 to 30% of tumor cells) are self renewing, and significnatly more clonogenic and tumorigencic (in xenograft models) than the ALDH− population. To further define the molecular profile of lung CSCs and to identify key pathways involved in lung CSC function we performed genome wide microarray expression profiling of isolated ALDH+ and ALDH− cell populations from 8 non-small cell lung cancer (NSCLC) lines representing a variety of oncogenotypes to determine genes that are differentially expressed in these two populations. Strikingly we found that different lung cancers exhibited different ALDH+ cell population expression profiles but that the ALDH1A3 isozyme was one of the few commonly genes whose expression was elevated. (Previously our group and other investigators in lung and other cancers had found the ALDH1A1 and not ALDH1A3 isozyme to be a marker of the ALDH+ population). ALDH1A3 differential expression was confirmed by q RT PCR and elevated ALDH1A3 protein levels which in turn was correlated with the % of ALDH+ tumor cells in each tumor. ALDH1A3 mRNA levels in (N = 182) resected lung adenocarcinoma samples showe that the highest levels of ALDH1A3 were associated with inferior survival. Of great importance, shRNA mediated knockdown of ALDH1A3 dramatically reduced both NSCLC cell colony formation in vitro and tumor growth in vivo demonstrating the functional importance of ALDH1A3 expression in NSCLCs. However, ectopic expression of ALDH1A3 in NSCLC cells did not enhance lung cancer cell growth and tumor formation, suggesting that ALDH1A3 alone is not sufficient to promote lung cancer progression. We conclude that ALDH1A3 is the predominant ALDH isozyme responsible for ALDH activity in NSCLCs of many oncogenotypes, is of potential prognostic importance, and a new therapeutic target for eliminating NSCLC stem cells.
Abstract A8: Mutation mapping in non-small cell lung cancer: A meta-analysis by geography and histology (MutMap)
Authors: Dearden Simon P. , Stevens James , Wu Yi-Long , Blowers David 
Published: March 2013

Abstract
This study comprises a meta-analysis of publicly available and newly generated mutation data in non-small cell lung cancer patients to identify differences between histological subtypes and geographical populations. In addition to mutations in individual genes, comparisons are also made between mutation co-occurrences in these subgroups. These patterns of mutation co-occurrence have been termed The MutMap.
Publications reporting mutation data on two or more genes, in histologically and geographically defined populations were identified. Assessments of single gene mutation frequencies and 2-gene mutation co-occurrences were performed in Western and Eastern populations. These were further separated into adenocarcinoma and squamous cell carcinoma histologies.
In total, 21 studies were identified which matched the criteria above. In addition, data were generated at AstraZeneca and the Guangdong Lung Cancer Institute for inclusion in the meta-analysis. Mutation data were collated for 8 genes (EGFR, KRAS, TP53, LKB1, BRAF, PIK3CA, PTEN and ERBB2) in the 4 subgroups. Overall, mutations were more commonly reported in adenocarcinoma cases than squamous cell carcinoma cases. The most commonly mutated gene in NSCLC was TP53, however, mutation frequencies varied between Eastern and Western populations and between adenocarcinoma and squamous cell carcinoma cases. Mutations in EGFR were common (46.3%) in Eastern adenocarcinoma patients but rarer in Western cases (14.8%). Conversely KRAS mutations were more common in Western adenocarcinoma patients (25.7%) than Eastern cases (11.2%). Mutations in LKB1 were also more common in Western patients. Mutations in BRAF, PIK3CA and ERBB2 were rare in all NSCLC subgroups. Mutations in PTEN were common in Eastern squamous samples (9.8%) but rarer in the other 3 subtypes.
Co-occurrences between mutations in 2 genes were also examined. As reported in other studies, mutations in EGFR and KRAS were exclusive to each other. In addition, in Western adenocarcinoma patients, mutations in both EGFR and LKB1 occurred significantly less often than would be expected by chance. There were several 2-gene mutation co-occurrences which were detected at levels &gt;=5% of the NSCLC population, including TP53 with either KRAS or EGFR in adenocarcinoma and TP53 with LKB1 mutation in squamous cell carcinoma.
Overall, this study confirms and expands the observation that mutation prevalence in NSCLC is complex, with variation not only between histological subtypes, but also between geographical populations. The co-occurrence of mutations may also be important in future treatment paradigms as clinically relevant segments of NSCLC possess both activating oncogenic driver mutations and mutations in tumour suppressor genes.
Abstract B42: The lineage-specific transcription factor ASCL1 defines a subtype of neuroendocrine non-small cell lung cancers with poor prognosis and points to potential therapeutic targets
Authors: Augustyn Alexander , Minna John , Tan Christopher , Sullivan James , Borromeo Mark , Girard Luc , Johnson Jane , Behrens Carmen , Wistuba Ignacio , Xie Yang 
Published: March 2013

Abstract
The future of cancer therapy relies on identifying certain patient populations that will respond to one treatment but not another based on the properties of the tumor and additionally creating specific drugs that target genetic pathways required for a particular tumor's formation, growth, and maintenance. We have developed a pre-clinical model for a genetically identifiable clade of non-small cell lung cancer that exhibits neuroendocrine features. We utilized whole-genome mRNA expression array data from 119 NSCLC cell lines to identify a class of NSCLC lines that fit the neuroendocrine phenotype (NE-NSCLC). We identified 11 NSCLC cell lines (9.2%) that display a distinct neuroendocrine gene signature. A gene expressed in all putative NE-NSCLC cell lines is the potent neural-specific transcription factor ASCL1. We hypothesize that ASCL1 acts as a “lineage dependent oncogene” for NE-NSCLC and that associated with ASCL1's function in the molecular pathogenesis of these lung cancers will be a gene expression profile that contributes to the malignant phenotype, which will provide insight towards therapeutic targeting of this subset of NSCLC. In this regard, ASCL1 ChIP-Seq data combined with genome wide mRNA expression data identified a subset of genes whose expression appears to be regulated by ASCL1. In NSCLC patient populations, tumors expressing ASCL1 and the neuroendocrine gene signature demonstrated impaired prognosis compared to the other NSCLCs. Knockdown of ASCL1 in representative NSCLC cell lines reduced target gene expression, caused significant cell cycle defects, and induced marked apoptosis. NSCLC cell lines expressing ASCL1 demonstrate a cancer stem cell marker phenotype similar to that of small cell lung cancer, providing clues to the pathogenesis of the NE-NSCLC disease subset. Our results suggest that neuroendocrine gene expression in NSCLC is of clinical relevance, that ASCL1 is required for survival of the NE-NSCLC disease subset, while the integrated ASCL1 ChIP-Seq and mRNA expression data provide a roadmap for systematically searching for therapeutic targets for this phenotype and their mechanistic role in a cancer stem cell (initiating cell) subpopulation within these tumors.
Abstract IA1: microRNAs and lung cancer
Authors: Slack Frank J. 
Published: March 2013

Abstract
microRNAs are small noncoding RNAs that regulate gene expression to control important aspects of development and metabolism such as cell differentiation, apoptosis and lifespan. let-7 encodes a microRNA implicated in human cancer. Specifically, human let-7 is poorly expressed or deleted in lung cancer, and over-expression of let-7 in lung cancer cells inhibits their growth, demonstrating a role for let-7 as a tumor suppressor in lung tissue. let-7 is expressed in the developing mammalian lung and regulates the expression of important oncogenes implicated in lung cancer, suggesting a mechanism for let-7's involvement in cancer. We are focused on the role of let-7 and other oncomiRs in regulating proto-oncogene expression during development and cancer, and on using miRNAs to suppress tumorigenesis.
Abstract IA14: Cetuximab in NSCLC and predictive markers
Authors: Hirsch Fred R. 
Published: March 2013

Abstract
The role of the EGFR humanized monoclonal antibody cetuximab (Erbitux®, Bristol-Myers Squibb) in the treatment of patients with advanced non-small cell lung cancer (NSCLC) has until recently been controversial. While it is clear that the EGFR pathway plays an important role in NSCLC development and progression, the clinical data with cetuximab in NSCLC has not been consistent from the different studies including the two large phase III studies (BMS -099 and FLEX), despite the overall survival in the FLEX study was statistically significant in favor the combination of chemotherapy plus cetuximab (HR 0.87 [0.76–1.0]) (1, 2). The FLEX study comparing gemcitabine/cisplatin with and without cetuximab required EGFR positive tumor (IHC &gt; 1% positive cells) as inclusion criteria, while the non-significant results from BMS -099 was based on “all comers”. However, most recently a more detailed analysis of the EGFR protein expression in the FLEX study, by using the H-score (intensity:0–3 x percentage of cells within each intensity category:0–100% for a final H-score of 0–300) was presented (3). Patients having tumors with EGFR H-score≥ 200 (about 30% of the patients) had a significant better survival from chemotherapy plus cetuximab compared to cetuximab alone (HR=0.73 [0.58–0.93]), and even better for the largest subgroup of patients; the Caucasians with H-score ≥ 200 (HR=0.64 [0.49–0.83]) with a 3.5 months difference in median survival (11.4 months vs. 7.9 months HR= 0.49 [0.29–0.81]). Patients with high EGFR expression and adenocarcinoma had a median survival of 20.2 months on the combined therapy versus 8.0 months for chemotherapy alone (3). A reproducibility study of the H-score classification showed a high concordance (91%) among 10 pathologists after specific assessment training (4). A previous reported randomized phase II study comparing chemotherapy with concomitant cetuximab versus sequential cetuximab from SWOG (0342) demonstrated a doubling of PFS and OS in the EGFR FISH positive patients compared to the FISH negative patients (5), while he EGFR FISH assay did not show a significant impact on outcomes in the large randomized BMS -099 study or the FLEX study.
Thus, very encouraging biomarker results are achieved retrospectively for selection of patients to chemotherapy plus cetuximab therapy, and these biomarkers are currently being prospectively validated in the large prospective randomized phase III study SWOG 0819, which compare chemotherapy (+/− bevacizumab) with and without cetuximab.
Abstract IA20: Targeted lung cancer chemoprevention through reverse migration
Authors: Ki Hong Waun 
Published: March 2013

Abstract
The hypothesis that lung cancer can be prevented with agents selected on the basis of epidemiologic data has, unfortunately, been disproven in many large randomized trials conducted in the last 25 years.
The results of these trials have overwhelmingly demonstrated not only the lack of benefit of most chemopreventive agents selected in this manner but also, importantly, the harmful effects of some of these agents in subsets of patients including current smokers.
Despite limited progress in the multimodality treatment of lung cancer, the cure rate for this disease is very disappointing; however, more recent discoveries of molecular “driver mutation” targets in lung cancer and treatment approaches with “matched” targeted agents in selected patient cohorts has been highly promising. This latter approach demonstrates that progression of even heterogeneous cancers can be intercepted by “molecularly relevant” targeted agents for the treatment of advanced disease.
A proposed new strategy for lung cancer prevention, therefore, is to apply a “reverse migration” of agents from the advanced disease to the chemopreventive setting; that is, to first identify the molecular drivers in the premalignant target tissue, and then to match these “hallmark” changes with molecularly targeted agents seen to be effective in advanced disease. This approach can be applied in the adjuvant as well as prevention settings, as has been demonstrated by the use of tamoxifen in breast cancer.
Thus, the major points I am going to present include the current landscape of chemoprevention in lung cancer and a new strategy of “reverse migration” for future chemoprevention trials in the 21st century.
Abstract A23: HER2 levels affect sensitivity and resistance to EGFR inhibition in EGFR mutant lung cancer
Authors: Takezawa Ken , Melnick Mary Ann , Riely Greg , Kris Mark , Miller Vincent , Ladanyi Marc , Politi Katerina , Pao William , Pirazzoli Valentina , Song Xiaoling , Arcila Maria , De Stanchina Elisa , Ohashi Kadoaki , Janjigian Yelena , Spitzler Paula , Nebhan Caroline 
Published: March 2013

Abstract
EGFR mutant lung cancers eventually become resistant to treatment with EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib. The combination of an irreversible EGFR TKI, afatinib, and the anti-EGFR monoclonal antibody, cetuximab, depletes both phosphorylated and total EGFR and can overcome resistance in mouse lung tumor models and human patients with acquired resistance. Since afatinib is also a potent HER2 inhibitor, here we investigated the role of HER2 in EGFR mutant tumor cells. We show in vitro and in vivo that afatinib plus cetuximab or the related antibody, panitumumab, significantly inhibits HER2 phosphorylation. HER2 overexpression or knockdown confers resistance or sensitivity, respectively, in all studied cell line models. Fluorescent in situ hybridization analysis revealed that HER2 was amplified in 3 of 26 (12%) tumors with acquired resistance versus only 1 of 99 (1%) untreated lung adenocarcinomas (p=0.03 Fisher's exact test). Notably, HER2 amplification and EGFR T790M were mutually exclusive (0 of 17 T790M-positive versus 3 of 9 T790M-negative cases (p=0.02 Fisher's exact test)). Collectively, these results reveal a previously unrecognized mechanism of resistance to EGFR TKIs and provide a rationale to assess the status and possibly target HER2 in EGFR mutant tumors with acquired resistance to EGFR TKIs.
Abstract A36: Doxorubicin loaded lactoferrin nanoparticles: Treatment of hepatocellular carcinoma in rats induced by diethylnitrosamine
Authors: Golla Kishore , Cherukuvada Bhaskar , Farhan Ahmed , Kondapi Anand Kumar 
Published: March 2013

Abstract
Hepatocellular carcinoma (HCC) is a highly incident malignancy. Doxorubicin is one of the effective chemotherapeutic agents for treating HCC. This problem is addressed in the present study based on an effort to enhance the efficacy of the drug through improvement of bioavailability and reduction of the cardiotoxicity of doxorubicin when intravenously (IV) administered. Doxorubicin-loaded lactoferrin nanoparticles (Nano-Doxo) were prepared by sol-oil chemistry. HCC was induced in rats by feeding drinking water containing 100 mg/l diethylnitrosamine for 8 weeks. Doxorubicin (Doxo) and Nano-Doxo (2 mg of drug/kg body weight) were administered IV. The results showed that Nano-Doxo is preferentially localized in liver and plasma as compared to that in heart, kidney, and spleen suggesting advantage of using Nano-Doxo in treatment of the liver cancer due to its higher bioavailability. The efficacy and safety of the Nano-Doxo and Doxo was further evaluated in terms of nodules formed on the liver. The results showed that the incidence of tumor is significantly decreased in Nano-Doxo treated rats compared to Doxo-treated rats. The higher efficacy of Nano-Doxo compared to Doxo is further confirmed by the levels of tumor-specific gene markers p53, p21, and VEGFR1. The drug-induced toxicity is evaluated in terms of cardiotoxicity by catalase and troponin, liver toxicity by SGPT and SGOT, and kidney toxicity by creatinine and blood urea. In conclusion, Nano-Doxo, with its increased bioavailability and reduced toxicity effects, is a safe and efficacious IV formulation for treatment of liver cancer.