bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 2572: The novel long non-coding RNA PANCR is an intracellular p53 activator
Authors: Cao Yu
Published: July 2017

Long non-coding RNAs (LncRNAs) function as oncogenes or tumor suppressors in development and progression of cancer. Chromosome 16q22.1 region is frequently deleted in breast cancer, which may contribute to breast carcinogenesis by inactivation of tumor suppressor genes. This study characterized a new LncRNA tumor suppressor, named p53 activating non-coding RNA (PANCR), located in this Chromosome 16q22.1 region. This PANCR LncRNA consists of 1.5kb in length.Our data showed that PANCR was downregulated in breast cancer cell lines and tissues. In the breast cancer cell lines, PANCR expression appeared reversely correlated with cell malignancy, and in breast cancer tissues, PANCR was downregulated over 2 times in 31(62.0%) of 50 cases when compared to adjacent normal breast tissues. In breast cancer cells MCF7 and immortalized human mammary epithelial cells MCF10A, ectopic expression of PANCR induced marked apoptosis, suppressing cell proliferation in culture and tumor growth in xenografts, but in contrast, shRNA-mediated silencing of PANCR promoted cell growth and proliferation. Mechanistic approaches revealed that in both MCF7 and MCF10A cell, PANCR activated p53 and upregulated pro-apoptotic proteins bid and bim and cell cycle inhibitors p21waf/cip1 and p27Kip1. We further explored the mechanism of action that PANCR activates p53, and our results from RNA immunoprecipitation (RIP), RNA pulldown and immunoprecipitation (Co-IP) demonstrated that the PANCR can bind to p53, dissociate p53-MDM2 complex and thus activate p53.Together our data suggest that the novel LncRNA PANCR located in the deleted Chromosome 16q22.1 region is an intracellular p53activator, functioning as a tumor suppressor by activating p53-mediated apoptosis.

Citation Format: Yu Cao. The novel long non-coding RNA PANCR is an intracellular p53 activator [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2572. doi:10.1158/1538-7445.AM2017-2572
Abstract 2583: A model for capturing and integrating complex molecular alterations related to clinically relevant efficacy evidence
Authors: Statz Cara M. , Patterson Sara E. , Yin Taofei , Mockus Susan M.
Published: July 2017

The ability to capture data relevant to different types of oncology-related variations, including single nucleotide variations, deletions, insertions, copy number variations, and fusions in a single system is crucial to a comprehensive understanding of cancer biology. However, collectively linking these varied types of molecular alterations to capture their compound impact to clinically relevant efficacy evidence within a database can prove challenging. Thus, we have built the JAX Clinical Knowledgebase (JAX-CKB), a flexible relational database that allows curation of complex molecular profiles and provides the ability to associate these profiles with documented efficacy evidence, thereby providing a more detailed overview of therapeutic relevance. To demonstrate the utility of creating complex molecular signatures in relation to efficacy evidence, the JAX-CKB was queried to first determine the overall degree of efficacy evidence content related to complex profiles. Additionally, two specific types of complex molecular profiles were queried, which included EML4-ALK plus a missense mutation(s) and BRAF V600E plus any type of molecular alteration(s). Within the JAX-CKB, there are 1,383 unique efficacy evidence lines linked to complex molecular profiles. The complex molecular profiles consisting of EML4-ALK and one or more additional missense mutations were associated with 174 unique efficacy evidence lines. Of the 174 lines, 69 were annotated with a resistant response type, while 68 were annotated with a sensitive response type. The combination of BRAF V600E with one or more molecular alterations was linked to 229 unique efficacy evidence lines. The majority of the lines, 118, were specific to a resistant response type and 83 were associated with sensitivity. Comprehensive genomic profiling of cancer patient samples can often reveal complex molecular signatures. The JAX-CKB is an inclusive knowledgebase that allows one to interpret these complex signatures and rapidly identify appropriate targeted therapies, which could be critical in a clinical setting.

Citation Format: Cara M. Statz, Sara E. Patterson, Taofei Yin, Susan M. Mockus. A model for capturing and integrating complex molecular alterations related to clinically relevant efficacy evidence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2583. doi:10.1158/1538-7445.AM2017-2583
Abstract 2589: Identifying cancer susceptibility variants and genes using whole exome and genome sequencing: a literature review
Authors: Rotunno Melissa , Clyne Mindy , Lam Tram , Mechanic Leah , Daee Danielle , Nelson Stefanie , Gillanders Elizabeth , Goldstein Alisa
Published: July 2017

The application of Next Generation Sequencing (NGS) technologies in cancer research enabled the discovery of novel somatic mutations at an unprecedented speed through efficient high-throughput profiling of DNA variation in tumor samples. In contrast, the identification through NGS studies of germline variation associated with cancer has been more difficult and with limited consensus around best practices for study design and analytical techniques. We performed a review of the 2005-2016 PubMed English literature for genome-wide germline sequencing studies that were aimed at identifying new cancer susceptibility genes or variants. We extracted and summarized the experimental and analytical designs, methods and tools implemented in the selected literature together with their degree of success and limitations in identifying cancer susceptibility variants. About 80 in-scope publications were identified and examined in depth. The most studied cancer types were colorectal, breast, blood and lung and were investigated predominantly via whole exome sequencing (primarily using Illumina HiSeq) in familial cases of Caucasian ethnicity. Only 10 studies used whole genome sequencing and 15 adopted a case control study design. A large fraction of the familial studies was limited to 1 or 2 families and sequenced 2 or less cases per family. Reporting of key data quality information (e.g., human sequence coverage) was inconsistent throughout the publications. While the methods for sequence alignment and variant calling converged towards those implemented in established bioinformatic tools (e.g., BWA, GATK), there were no standard approaches for filtering or prioritizing of variants. Most studies included some degree of technical validation, often restricted to the top few variants or genes. About 60% of the studies included replication in an independent group of cancer patients and 55% functionally validated their findings to some extent. Our work provides valuable data and insights to inform future sequencing studies of cancer genetic susceptibility, and points to the need for improving standardization and completeness in reporting of quality control metrics, study design rationale and interpretation of findings.

Citation Format: Melissa Rotunno, Mindy Clyne, Tram Lam, Leah Mechanic, Danielle Daee, Stefanie Nelson, Elizabeth Gillanders, Alisa Goldstein. Identifying cancer susceptibility variants and genes using whole exome and genome sequencing: a literature review [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2589. doi:10.1158/1538-7445.AM2017-2589
Abstract 2591: A guide to filtering TARGET Complete Genomics germline variants
Authors: Evans James P. , Patidar Rajesh , Vaksman Zalman , Sindiri Sivasish , Stewart Douglas R. , Khan Javed , Wei Jun S. , Diskin Sharon J.
Published: July 2017

With the public release of TARGET’s pediatric cancer data, researchers are eager to investigate and integrate variants from both tumor and germline sequencing data, but caution should be used when interpreting TARGET variant calls from Complete Genomics data, as they unlike the Illumina based calls for which most of our databases and tools are customized. Here, we use germline samples from 55 neuroblastoma cases with both whole genome Complete Genomics variants and whole exome Illumina variants from GATK, Pindel, Platypus, and bam2mpg to investigate differences between germline variant calls from Complete Genomics and Illumina platforms. Our study of ~160,000 single nucleotide polymorphisms (SNPS) and ~19,000 insertions or deletions (indels) reveals that while SNP sets largely agree between Complete Genomics and Illumina, Complete Genomics data have many indels not present in Illumina calls, making it difficult to screen Complete Genomics indels against popular Illumina based variant databases like those provided by the Exome Aggregation Consortium and the National Heart, Lung, and Blood Institute Exome Sequencing Project. Further probing of Complete Genomics indels uncovered inconsistent indel formatting resulting a loss of recurrent variants, and miscalculated read depths in earlier versions of the Complete Genomics platform. To solve these issues and make Complete Genomics variant calls comparable to Illumina calls, we introduce a Snakemake pipeline that reformats Complete Genomics variant files and creates variant features for use in decision tree or random forest classifiers trained to recognize Complete Genomics variants that will be present in Illumina variant call sets. We determine that the most important features for locating Complete Genomics variants likely to be found in Illumina germline variant call sets are the presence of reads from both directions, average variant allele fraction across the cohort, a variant call in the matched tumor, the variant fraction of reads, and read depth. Using ten fold cross validation with our decision tree, we obtain >95% recall and >98% precision for SNPs, and >90% recall and >85% precision for indels. We advocate the use of our pipeline and filtering scheme for making Complete Genomics variant calls comparable to Illumina based calls.

Citation Format: James P. Evans, Rajesh Patidar, Zalman Vaksman, Sivasish Sindiri, Douglas R. Stewart, Javed Khan, Jun S. Wei, Sharon J. Diskin. A guide to filtering TARGET Complete Genomics germline variants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2591. doi:10.1158/1538-7445.AM2017-2591
Abstract 2599: COSMIC Cancer Gene Census: expert descriptions across genes in oncogenesis
Authors: Sondka Zbyslaw , Bamford Sally , Cole Charlotte G. , Dawson Elisabeth , Ponting Laura , Stefancsik Raymund , Ward Sari A. , Tate John , Campbell Peter J. , Forbes Simon A.
Published: July 2017

The Cancer Gene Census is an ongoing effort to catalogue genes for which somatic mutations have been causally implicated in cancer. The Census comprises manually curated summaries of the most relevant information for cancer-driving genes and their somatic mutations and brings together the expertise of a dedicated curation team, cancer scientists and the comprehensive resources of the COSMIC database. Current research focuses on characterising the participation of 609 census genes in hallmarks of cancer and identification of additional genes involved in these biological traits primarily via altered expression, CNA or epigenetic changes. New overviews of cancer gene function focused on hallmarks of cancer pull together manually curated information on the function of proteins coded by cancer genes and summarises the data in simple graphical form. It presents a condensed overview of most relevant facts with quick access to the literature source, aiming to provide summary characteristics of a cancer gene, rather than a full monography, to avoid information overload. This functional characterisation enables the creation of lists of genes of interest focused on the particular role they play in the development of cancer, as well as aiming to identify the cellular functions affected by mutations in particular tumours, and help to choose right targets for targeted therapy or synthetic lethality experiments. The Census is available from the COSMIC website for online use or download at: http://cancer.sanger.ac.uk/census.

Citation Format: Zbyslaw Sondka, Sally Bamford, Charlotte G. Cole, Elisabeth Dawson, Laura Ponting, Raymund Stefancsik, Sari A. Ward, John Tate, Peter J. Campbell, Simon A. Forbes. COSMIC Cancer Gene Census: expert descriptions across genes in oncogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2599. doi:10.1158/1538-7445.AM2017-2599
Abstract 26: Panitumumab interacts with TAS-102 leading to combinational anti-cancer effects by blocking EGFR-mediated tumor response to trifluridine
Authors: Nakamura Kazuhide , Baba Yuji , Tamura Toshiya , Satoh Yoshihiko , Gotou Masamitsu , Sawada Hiroshi , Ebara Shunsuke , Shibuya Kazunori , Soeda Jumpei
Published: July 2017

Panitumumab is a monoclonal antibody raised against the human epidermal growth factor receptor (EGFR). TAS-102 is a novel chemotherapeutic agent containing trifluridine (FTD) as the active cytotoxic component. Both panitumumab and TAS-102 have been approved for the treatment of metastatic colorectal cancer (mCRC). In this study, we show the mechanism underlying the anti-cancer effects of the panitumumab/TAS-102 combination in preclinical models. Co-treatment with panitumumab and FTD exerted additive and synergistic anti-proliferative effects in LIM1215 and SW48 colon cancer cells, respectively. Consistent with the in vitro effects, panitumumab/TAS-102 combination led to tumor regression in LIM1215 and COL-01-JCK colon cancer patient-derived xenograft models. In LIM1215 cells, FTD induced ERK/Akt/STAT3 phosphorylation and subsequent serine/threonine phosphorylation of EGFR, while it had no effects on EGFR tyrosine phosphorylation. Panitumumab and the tyrosine kinase inhibitor erlotinib reduced the basal level of EGFR tyrosine phosphorylation and reversed the FTD-induced ERK/Akt/STAT3 and EGFR serine/threonine phosphorylation. These results suggested that FTD together with the basal activity of the EGFR tyrosine kinase induced downstream pro-survival signaling through ERK/Akt/STAT3. Collectively, we propose that panitumumab interacts with FTD by targeting EGFR-mediated adaptive responses, thereby exerting anti-cancer effects in combination with TAS-102. These preclinical findings provide a compelling rationale to evaluate anti-EGFR antibodies combined with TAS-102 against mCRC.

Citation Format: Kazuhide Nakamura, Yuji Baba, Toshiya Tamura, Yoshihiko Satoh, Masamitsu Gotou, Hiroshi Sawada, Shunsuke Ebara, Kazunori Shibuya, Jumpei Soeda. Panitumumab interacts with TAS-102 leading to combinational anti-cancer effects by blocking EGFR-mediated tumor response to trifluridine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 26. doi:10.1158/1538-7445.AM2017-26
Abstract 2605: Improving data quality in oncology immunotherapy clinical research by big data analytics and data visualization
Authors: Xue Chengsen , Cuomo Joanne , Meyers Walter , Closkey Thomas W. Mc
Published: July 2017

Flow cytometric assessment of cellular and intracellular biomarkers facilitates the development of new classes of cancer immunotherapy therapeutics. This powerful tool has multiple applications including 1) detecting PD1, PDL-1 and caspase-3 for apoptosis, 2) isolating, defining, and quantifying dendritic cells and their intracellular cytokine profile, 3) immunophenotyping subpopulations of B, T, NK, regulatory T, and helper T cells, and, 4) using tetramer analysis to detect and monitor the frequency of antigen-specific cytotoxic T lymphocytes (CTL). However, lack of knowledge of normal distributions and standard ranges for the esoteric reportables generated by flow cytometry is one of the most challenging problems in this promising field.

Here we describe a new method to improve data quality in clinical research by big data analytics and data visualization. Each data point was tagged. By applying a simple statistical analysis, a self-defined range allowed all of the outlier numbers to be identified. By repeating this process, clear patterns emerged, and all questionable data points were marked. In addition, the system can differentiate biodiversity in subjects from a more homogenous population, which can be exploited further for the purpose of personal and precision medicine. Other benefits of the new system are to predict the outcome of the clinical study and to generate new clues in the understanding of the underlying biological mechanisms.

Big data analytics and data visualization show unparalleled advantages in oncology studies through simultaneously monitoring unlimited data points related to surface and intracellular biomarkers. It opens a new avenue in cost saving for long, time-consuming clinical trials by using all available data to detect a status change of the immune system. With the improvement of data quality, big data analytics has become an essential tool and an integrated part of cancer immunotherapy and the development of cancer vaccines.

Citation Format: Chengsen Xue, Joanne Cuomo, Walter Meyers, Thomas W. Mc Closkey. Improving data quality in oncology immunotherapy clinical research by big data analytics and data visualization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2605. doi:10.1158/1538-7445.AM2017-2605
Abstract 2618: Agonist antibodies targeting OX40 and GITR enhance the activity of the IDO1-selective inhibitor epacadostat in preclinical models
Authors: Koblish Holly K. , Horton Brendan , Hansbury Michael , O'Connor Sybil , Lasky Kerri , Stevens Christina , Condamine Thomas , Hall Leslie , Wang Liang-Chuan , Zhang Yue , Nastri Horacio , Hollis Gregory , Huber Reid , Gajewski Thomas , Scherle Peggy
Published: July 2017

The majority of immunotherapeutic agents developed thus far either attempt to stimulate a more productive anti-tumor immune response or to inhibit key proteins in the immunosuppressive tumor milieu. PD-1/PD-L1 axis blockade, CTLA-4 blockade and IDO1 inhibition are examples of the latter approach and have been utilized to reverse the suppressive tumor microenvironment, resulting in clinical benefit for cancer patients. Recent clinical and preclinical data have also demonstrated that combining these approaches results in enhanced therapeutic benefit. Notably, the IDO1-selective inhibitor epacadostat has been shown to increase the efficacy of two checkpoint inhibitors, the anti-CTLA-4 antibody ipilimumab and the anti-PD-1 antibody pembrolizumab, in patients with melanoma. Because both checkpoint receptors and IDO1 serve as negative regulators of the immune response, we also explored the ability of IDO1 inhibition to combine with agents that directly activate T cells through costimulatory receptors of the tumor necrosis factor receptor (TNFR) superfamily. Rodent active surrogate agonist antibodies to 4-1BB, OX40 and GITR were tested with epacadostat in multiple preclinical models. In the B16-SIY melanoma model that does not express IDO1 in tumor cells, both epacadostat and anti-OX40 had little effect, but the combination resulted in enhanced efficacy. This was associated with increased infiltrates of CD8+ T cells and decreased numbers of FoxP3+ TILs. Increased numbers of SIY-reactive T cells were found in both the tumor and the TDLN post-therapy. In contrast, epacadostat did not provide any enhancement to the activity seen with 4-1BB. Clear combinatorial effects were seen with anti-GITR and epacadostat in the more inflamed, IDO1-expressing PAN02 pancreatic cancer model. These data suggest that IDO1 inhibition can be effective in combination with agents that agonize T cell costimulatory receptors as well as with agents that block coinhibitory receptors.

Citation Format: Holly K. Koblish, Brendan Horton, Michael Hansbury, Sybil O'Connor, Kerri Lasky, Christina Stevens, Thomas Condamine, Leslie Hall, Liang-Chuan Wang, Yue Zhang, Horacio Nastri, Gregory Hollis, Reid Huber, Thomas Gajewski, Peggy Scherle. Agonist antibodies targeting OX40 and GITR enhance the activity of the IDO1-selective inhibitor epacadostat in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2618. doi:10.1158/1538-7445.AM2017-2618
Abstract 262: Analysis of demographics, survival and patterns of care of pediatric glioblastoma using National Cancer Database
Authors: Thakkar Jigisha , Liu Meng , Dressler Emily Van Meter , Villano John L.
Published: July 2017

Background

We analyzed the largest clinical database in the United States, the National Cancer Database (NCDB), comprising over 70% of cases diagnosed and/or treated at commission on Cancer approved institutions. We analyzed current hospital-based epidemiologic frequency, survival and patterns of care of pediatric glioblastoma (GBM).

Methods

Cases included patients 0-19 years between 1998-2011. Inclusion criteria for histology codes included for GBM 9440, 9441 and 9442 (9440 (GBM), 9441(Giant Cell) and 9442 (Sarcomatas component) and tumor sites (C70.0-C72.9, C75.1-C75.3) related to the brain: brain stem, cerebellum, cerebrum, ventricle and brain not otherwise specified (NOS). Kaplan-Meier survival estimates were calculated for each demographic criteria and treatment plan and Cox proportional hazards models were employed to assess the risk of mortality. Demographic variables analyzed were age, gender, race, Hispanic origin, income, education, region and insurance status. Comparisons were made among histologic subtypes and primary site.

Results

1173 patients with GBM from age 0 to 19 years were identified from 1998 to 2011 in the United States, of which 21.5%, 24.5% and 54.0% were in age group 0-5, 6-10 and 11-19 years old. The largest group (48%) received advanced care including a combination of radiation (XRT), chemotherapy and surgery. On the other hand, the no treatment group was the smallest comprising of 4% cases. 14% received surgery only, 8% received a combination of XRT and surgery and 9% received a combination of XRT and chemotherapy.

Patients that received combination of XRT, chemotherapy and surgery had significantly improved survival when compared to those without any treatment (p = 0.0048). Patients that received surgery or chemotherapy had significantly improved survival as compared to patients that did not receive the above treatments (p = 0.0027).

Conclusion

We report an extensive demographic and survival analysis of pediatric GBM. Observed difference likely reflect biology across age, gender, race and origin groups. Our analysis demonstrates concern in the delivery of optimal care to a large percentage of pediatric patients. These treatments include surgery and chemotherapy that have demonstrated survival benefits. Adverse effects of chemotherapy and XRT can limit the appropriate administration of treatment.

Citation Format: Jigisha Thakkar, Meng Liu, Emily Van Meter Dressler, John L. Villano. Analysis of demographics, survival and patterns of care of pediatric glioblastoma using National Cancer Database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 262. doi:10.1158/1538-7445.AM2017-262
Abstract 2621: Microsatellite instability is a potential biomarker for immune checkpoint inhibitor in endometrial cancer
Authors: Yamashita Hitomi , Nakayama Kentaro , Ishikawa Noriyoshi , Minamoto Toshiko , Ishibashi Tomoka , Nakamura Kohei , Sanuki Kaori , Ono Ruriko , Ishikawa Masako , Isobe Takeshi , Kyo Satoru
Published: July 2017

[Introduction] In recent years, tumor cells have immune escape mechanism and immune checkpoint inhibitor therapy (anti PD-1/ PD-L1 antibody) has shown benefit in various cancers. Somatic mutations have the potential to encode ‘’non-self’’immunogenic antigens and lymphocytes infiltrate tumor cells in Microsatellite-instable (MSI) endometrial cancers. Therefore, immune checkpoint inhibitor therapy might be effective in MSI endometrial cancers.

[Method] Mismatch repair protein (MLH1, PMS2, MSH2, and MSH6), tumor-infiltrating lymphocytes (CD8), and PD-1/PD-L1 expression were assessed by immunohistochemistry in 60 patients with endometrial cancer. We examined whether MSI status have enhanced immune microenvironment and become the therapeutic effect predictor of PD-1/PD-L1 immunotherapy in endometrial cancer.

[Results] Loss of mismatch repair protein (MSI group) was identified in 8 (13.3 %) of 60 patients with endometrial cancer. Expression of tumor-infiltrating lymphocytes (CD8) and PD-L1/PD-1 were significantly higher in MSI group compared to MSS group (p=0.001, p=0.044 and p=0.013).

[Conclusion]These results suggested that immune checkpoint inhibitor (anti PD-1/PD-L1 antibody) is effective in endometrial cancers with MSI. MSI testing is likely to be a biomarker for PD-1/PD-L1 immunotherapy in endometrial cancer.

Citation Format: Hitomi Yamashita, Kentaro Nakayama, Noriyoshi Ishikawa, Toshiko Minamoto, Tomoka Ishibashi, Kohei Nakamura, Kaori Sanuki, Ruriko Ono, Masako Ishikawa, Takeshi Isobe, Satoru Kyo. Microsatellite instability is a potential biomarker for immune checkpoint inhibitor in endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2621. doi:10.1158/1538-7445.AM2017-2621
Abstract 2625: Clinicopathological features of programmed cell death ligand 1 (PD-L1) expression in resected non-small cell lung cancers
Authors: Ohhara Yoshihito , Kinoshita Ichiro , Tomaru Utano , Hatanaka Kanako C. , Hatanaka Yutaka , Honma Rio , Takeuchi Satoshi , Shimizu Yasushi , Kaga Kichizo , Matsuno Yoshihiro , Dosaka-Akita Hirotoshi
Published: July 2017

Background: Antibodies against programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) have recently demonstrated a survival benefit in several types of cancer, including melanoma and non-small cell lung cancer (NSCLC). PD-L1 expression has provided a predictive biomarker for anti-PD-1/PD-L1 therapy. However, the relationship between PD-L1 expression and clinical and clinicopathological characteristics remains unclear in NSCLCs. The aim of this study was to investigate the relevance of PD-L1 expression to clinical and clinicopathological factors in resected NSCLCs. Materials and Methods: PD-L1 expression was evaluated in 154 surgically resected NSCLC specimens by immunohistochemistry (IHC) using the SP142 antibody. Before the IHC of clinical samples, we performed a concordance study of Western blot analysis and IHC in 17 lung cancer cell lines. We evaluated the relationship between PD-L1 expression and clinical and clinicopathological factors by univariate and multivariate analyses. Survival curves were estimated by the Kaplan-Meier methods, and differences in survival distributions were evaluated by the log-rank test.

Results: PD-L1 expression was well concordantly observed in Western blot analysis and IHC in the lung cancer cell lines analyzed. PD-L1 expression was observed in 51 of 154 (33%) surgically resected NSCLCs. PD-L1 expression was significantly correlated with male, heavy smoking history, squamous cell carcinoma, and moderate/poor differentiation of tumors by univariate analysis. In multivariate analysis, tumor differentiation had a strong relationship with PD-L1 expression (odds ratio: 6.32, 95% CI: 1.70-23.49, P = 0.006). The survival was not statistically different between patients with high and low PD-L1 expression (5-year survival rate: 44.1% versus 58.1%, P = 0.22). PD-L1 expression was not an independent prognostic factor in univariate and multivariate analyses.

Conclusion: PD-L1 expression was strongly associated with tumor differentiation in resected NSCLCs. PD-L1 expression was not a prognostic factor in this cohort of resected NSCLCs.

Citation Format: Yoshihito Ohhara, Ichiro Kinoshita, Utano Tomaru, Kanako C. Hatanaka, Yutaka Hatanaka, Rio Honma, Satoshi Takeuchi, Yasushi Shimizu, Kichizo Kaga, Yoshihiro Matsuno, Hirotoshi Dosaka-Akita. Clinicopathological features of programmed cell death ligand 1 (PD-L1) expression in resected non-small cell lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2625. doi:10.1158/1538-7445.AM2017-2625
Abstract 263: Epidemiology of primary lung cancer and its trend northeast of Iran during 1985-2012
Authors: Salehi Maryam , Shojaee Pardis , Shahidsales Soodabeh , Aledavood Seyed Amir , Seilaniantoosi Mehdi , Goshayeshi Golboo , Khoshroo Fahimeh
Published: July 2017

Introduction: In this study we investigated epidemiology and trends of primary lung cancers in northeast of Iran during 1985-2012.

Methods: In this cross-sectional study records of primary lung cancers from 1985 to 2012 in Mashhad, northeast of Iran, were investigated. Data were obtained from the referral oncologic hospital and private radiation oncology clinic. To study trends, the duration of study was categorized into three periods: 1985-1995, 1995-2005 and 2005-2012. Statistically significant level was considered <0.05.

Results: Of 939 cases with mean age of 60.57 (±12.31) years, 660(70.3%) were male. Male to female ratio was 2.36. Mean age was 61.47±12.01 years for males and 58.45±12.75 for females (p=0.001). Mean age at diagnosis and rate of smokers was unchanged in three intervals (table 1).

Time period1985-19951995-20052005-20012P valueAge(years)60.67±11.7460.57±12.2460.49±12.940.98Gender:Male167(78.4)330(68.6)163(66.5)0.01female46(21.6)151(31.4)82(33.5Male to female ratio3.632.181.99Smoking history:Yes69(76.7)211(67.8)100(65)0.15no21(23.3)100(32.2)54(35)Smokers:Male59(85.5)159(75.4)74(74)0.16Female10(14.5)52(24.6)26(26)Male-to-female ratio of smokers5.93.062.84

Squamous cell carcinoma with relative frequency of 44.2% was the most frequent pathologic subtype in total population followed by adenocarcinoma (18.2%), Small Cell Lung cancer (16.8%), large Cell carcinoma (1.3%) and other subtypes (19.5%). Relative frequency of pathologic subtypes had significant changes in three intervals (p <0.001). Relative frequency of adenocarcinoma and large cell carcinoma were increasing while it was decreasing for SCC and SCLCs during three recent decades. There was statistically significant difference in mean age at diagnosis (p<0.001), rate of smokers (p<0.001) and male to female ratio (p=0.01) between four leading pathologic subtypes. Mean age at diagnosis (55.92±12.90 years), male to female ratio (1.69), and rate of smokers (46.8%) were lowest in adenocarcinomas.

Conclusion: Similar to universal picture, adenocarcinoma showed increasing rates during recent three decades with higher prevalence among younger aged patients, women and nonsmokers. These trends are indicative of changes in exposures and smoking habits and reveal the need for regional studies in this context.

Citation Format: Maryam Salehi, Pardis Shojaee, Soodabeh Shahidsales, Seyed Amir Aledavood, Mehdi Seilaniantoosi, Golboo Goshayeshi, Fahimeh Khoshroo. Epidemiology of primary lung cancer and its trend northeast of Iran during 1985-2012 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 263. doi:10.1158/1538-7445.AM2017-263
Abstract 2652: Favorable outcome of primary mediastinal large B-cell lymphoma treated by Dose Adjusted EPOCH-Rituximab regimen
Authors: Grifi Fatiha , Bougherira Soraya
Published: July 2017

Background Primary Mediastinal Large B-Cell Lymphoma (PMLBCL) is a unique type of B-cell lymphoma probably arising from a putative thymic medulla B-cell. One to 2% of NHL, 7% of all diffuse large B-cell lymphomas (DLBCL), occurring more often in young females. Often presents with superior vena cava syndrome and airway compromise. Treatment is with chemotherapy combined with Rituximab, followed by involved field radiation therapy to mediastinum. PMLBCL has better outcome than others DLBCL. We aimed to develop a more dose-dense/intense regimens that improves the rate of cure with an attempt to avoid mediastinal radiation. Patients and methods A prospective study was conducted in our department from January to December 2015, in 6 patients with untreated primary mediastinal B-cell lymphoma. An infusional dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (DA-EPOCH-R) has been administred according to the protocol Day 1 : Rituximab 375 mg/m2 IV Day 1-4 : Etoposide 50 mg/m2 IV, Doxorubicin 10 mg/m2 AND Vincristine 0.4 mg/m2 Day 5 : Cyclophosphamide 750 mg/m2 Days 1-5 : Prednisone 60 mg/m2 PO BID. Administer G-CSF 5 mcg/kg SQ on day 6 until ANC exceeds nadir Cycles were repeated every 3 weeks for a toal of 6 cycles Results The median age of the patients was 32 years, the male to female ratio : 2:4. Systemic symptoms mainly fever and weight loss, were present in all cases; increased LDH levels were also observed in 50% of cases. Majority of the patients (83%) presented with stage I/II disease, bulky mass with a median tumor diameter 15 cm. Most had features of local extension like pleuro-pericardial effusion. Absence of infradiaphragmatic lymph nodes and no bone marrow involvement at presentation. All patients required biopsy from the mediastinal mass by image guided core biopsy. The patients were treated by RDA-EPOCH, they received 4 to 6 courses, without involved field radiotherapy (only one patient underwent radiotherapy for residual mass). No late morbidity or cardiac toxic effects were found in any patients. After 24 months of follow-up, one patient still received treatment and was not evaluable. 5 patients achieved complete remission and were disease-free at the last visit. Conclusion PMBCL is a specific lymphoma entity seen in the young with good survival. It has a distinct clinical behavior and prognosis, and therefore require a different therapeutic approach. The R/DA-EPOCH regimen need to be confirmed in further prospective study for a large cohort.

Note: This abstract was not presented at the meeting.

Citation Format: Fatiha Grifi, Soraya Bougherira. Favorable outcome of primary mediastinal large B-cell lymphoma treated by Dose Adjusted EPOCH-Rituximab regimen [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2652. doi:10.1158/1538-7445.AM2017-2652
Abstract 266: Trends in age distribution of breast cancer, in north east of Iran: Report of six thousand patients over 30 years
Authors: Salehi Maryam , Shahidsales Soodabeh , Seilaniantousi Mehdi , Noferesti Gholamhosein , Salehi Mahta , bajgiran Amirhossein mohammadian
Published: July 2017

Aim: This study was aimed to evaluate the age at the time of diagnosis of breast cancer and it’s probably changes in distribution among patients during 30 years.

Methods: This cross- sectional study was conducted in Mashhad, Iran from 1981 until 2011. The data of patients were obtained from case records. The duration of study was categorized into three periods: 1981-1990, 1991-2000 and 2001-2011. SPSS software was used for analyses. The difference was considered significant if P<0.05.

Result: From 6274 breast cancer cases, 174 patients were male (2.5%) and the others 6100 were female (97.5%).Mean age at the time of diagnosis was 49.07 ± 12.07 years (male: 56.48 ± 14.14, female: 48.8 ±12.01). There was significant difference in age by sex (p <0.001). Table 1 presents the mean age of studied patients in each 10 years of study. ANOVA test showed that there was not statistical significant difference (P value= 0.1).

DecadesFrequencyMean ageSDYoungestOldest1981-199046747.9712.04318882000-1991177149.0312.33820992001-2011394949.2211.9542098

The most histologic type of breast cancer was ductal carcinoma 65.6% others percent in order were: NOS 19.6%, lobular 3.7%, medullary 2.8%, adenocarcinoma 2.8%, tubular and papillary 0.2% and 5.1% of other types. Relative frequency of histologic types had significant differences among 3 intervals (p <0.001), the frequency of adenocarcinoma was decreasing but ductal carcinoma was increasing during 3 decades. Mean age of ductal carcinoma, lobular, medullary and adenocarcinoma was 48.9±11.8, 50.6±12.4, 46.4±11.4, 50.2±11.9, respectively. Mean age had significant differences among these main histologic types (p =0.002).98% of patients were urban and 2% were rural. Mean age of these 2 groups has statistical significant difference (P = 0.001) and is 10 years older in rural patients. Frequency of people who live in urban area was increased significantly (p<00.1) during these 30 years compare with rural area.

Conclusion: breast cancer occurs in Iranian women at least one decade younger than women in developed countries we found no change in mean age of diagnosis of breast cancer during these 30 years from 1981 to 2011.

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Note: This abstract was not presented at the meeting.

Citation Format: Maryam Salehi, Soodabeh Shahidsales, Mehdi Seilaniantousi, Gholamhosein Noferesti, Mahta Salehi, Amirhossein mohammadian bajgiran. Trends in age distribution of breast cancer, in north east of Iran: Report of six thousand patients over 30 years [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 266. doi:10.1158/1538-7445.AM2017-266
Abstract 2663: Characterization of the pharmacodynamic immune response to a novel immunotherapeutic agent, ALKS 4230, in mice and non-human primates
Authors: Lopes Jared E. , Losey Heather C. , Dean Reginald L. , Flick Heather L. , Huff Michael R. , Moroso Rosemarie A. , Sun Lei , Alvarez Juan C.
Published: July 2017

ALKS 4230 is a selective agonist of the intermediate-affinity IL-2 receptor (IL-2R). A phase 1 study is ongoing to evaluate the safety and tolerability of ALKS 4230 in the treatment of patients with refractory solid tumors. The selectivity of ALKS 4230 is achieved through the stable fusion of circularly permuted IL-2 to the extracellular portion of the IL-2Rα chain, CD25. The resulting fusion protein is sterically prevented from binding to the high-affinity IL-2R complex, comprised of IL-2Rα, IL-2Rβ, and common gamma chain, expressed preferentially on CD4+ FOXP3+ regulatory T cells (CD4+ Tregs) yet retains full ability to signal through the intermediate-affinity IL-2R complex, comprised of IL-2Rβ and common gamma chain, expressed on memory CD8+ T cells and NK cells. Repeated dosing of ALKS 4230 drives the significant expansion of various CD8+ T cell and NK cell populations without activation and minimal expansion of CD4+ Tregs in mice and non-human primates (NHP). The kinetics of the immunological responses in mice and NHP demonstrate that the pharmacodynamic effects persist beyond systemic exposure of ALKS 4230. Data demonstrating the effects of ALKS 4230 on tumor-infiltrating lymphocyte populations in syngeneic tumor models will also be presented.

Citation Format: Jared E. Lopes, Heather C. Losey, Reginald L. Dean, Heather L. Flick, Michael R. Huff, Rosemarie A. Moroso, Lei Sun, Juan C. Alvarez. Characterization of the pharmacodynamic immune response to a novel immunotherapeutic agent, ALKS 4230, in mice and non-human primates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2663. doi:10.1158/1538-7445.AM2017-2663
Abstract 2667: In vitro properties and pre-clinical activity of PF-06801591, a high-affinity engineered anti-human PD-1
Authors: Youssef Sawsan , Abdiche Yasmina , Nguyen HoangKim , Chou Joyce , Chin Sherman Michael , Kamperschroer Cris , Schneider Patricia A. , Kraynov Eugenia , Krupka Heike I. , Rajpal Arvind , Lin John
Published: July 2017

Monoclonal-antibody-based therapies targeting the immune checkpoint receptors have become the new standard of care in many cancers. Antibodies that specifically target programmed death receptor-1 (PD-1) or its cognate ligand, programmed death receptor ligand-1 (PD-L1), alone or in combination, have yielded clinical benefits and durable responses in patient subsets with various cancers (including metastatic melanoma, NSCLC, RCC, urothelial cancer, cHL and others). Here we report on the biophysical characteristics and non-clinical antagonistic activities of PF-06801591. PF-06801591 is a humanized anti-PD-1 antibody of human IgG4 isotype, that binds selectively and with similar potency to human and cynomolgus monkey PD-1 receptor (EC50 ~50 pM) and blocks its interaction with its cognate ligands PD-L1 and PD-L2 (IC50 < 1 nM) with no detectable Fc effector function. The interaction of PF-06801591 to PD-1 rescues T cell suppression and exhaustion that translates into NFAT activation, IL-2 and IFN-gamma secretion and T cell proliferation both in vitro cultures and in vivo using an acute xeno GvHD model with human PBMC transfer. Binding of PF-068001591 to human and cynomolgus PD-1 is characterized by the formation of a very stable complex (T1/2 = 2 h) as measured by SPR at 37 C, resulting in high affinity (KD ~20 pM) as measured in solution by KinExA at 23 C. In addition, we explored therapeutic potential of anti-PD-1 in combination with other immunotherapy agents using surrogate antibodies in non-clinical tumor models. The data presented here support future development of PF-06801591 as a single agent or in combination with other immunotherapies.

Citation Format: Sawsan Youssef, Yasmina Abdiche, HoangKim Nguyen, Joyce Chou, Sherman Michael Chin, Cris Kamperschroer, Patricia A. Schneider, Eugenia Kraynov, Heike I. Krupka, Arvind Rajpal, John Lin. In vitro properties and pre-clinical activity of PF-06801591, a high-affinity engineered anti-human PD-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2667. doi:10.1158/1538-7445.AM2017-2667
Abstract 2674: Fusobacterium nucleatum subspecies animalis influences pro-inflammatory cytokine expression and monocyte activation in human colorectal tumors
Authors: Ye Xiangcang , Wang Rui , Bhattacharya Rajat , Boulbes Delphine R. , Fan Fan , Xia Ling , Harish Adoni , Ajami Nadim J. , Wong Matthew C. , Smith Daniel P. , Petrosino Joseph F. , Venable Susan , Qiao Wei , Baladandayuthapani Veera , Maru Dipen , Ellis Lee M.
Published: July 2017

Chronic infection and associated inflammation have long been suspected to promote human carcinogenesis. Recently, certain gut bacteria, including some in the Fusobacterium genus, have been implicated in playing a role in human colorectal cancer (CRC) development. However, the Fusobacterium species and subspecies involved and their oncogenic mechanisms remain to be determined. We sought to identify the specific Fusobacterium spp. and ssp. in clinical CRC specimens by targeted sequencing of Fusobacterium 16S ribosomal RNA gene. Five Fusobacterium spp. were identified in clinical CRC specimens. Additional analyses confirmed that Fusobacterium nucleatum ssp. animalis was the most prevalent F. nucleatum subspecies in human CRCs. We also assessed inflammatory cytokines in CRC specimens using immunoassays and found that expression of the cytokines interleukin-17A and tumor necrosis factor-alpha was markedly increased but interleukin-21 decreased in the colorectal tumors. Furthermore, the chemokine (C-C motif) ligand 20 was differentially expressed in colorectal tumors at all stages. In in vitro co-culture assays, F. nucleatum ssp. animalis induced CCL20 expression in CRC cells and monocytes. It also stimulated the monocyte/macrophage activation and migration. Our observations suggested that infection with F. nucleatum ssp. animalis in colorectal tissue could induce inflammatory response and promote CRC development. Further studies are warranted to determine if F. nucleatum ssp. animalis could be a novel target for CRC prevention and treatment.

Citation Format: Xiangcang Ye, Rui Wang, Rajat Bhattacharya, Delphine R. Boulbes, Fan Fan, Ling Xia, Adoni Harish, Nadim J. Ajami, Matthew C. Wong, Daniel P. Smith, Joseph F. Petrosino, Susan Venable, Wei Qiao, Veera Baladandayuthapani, Dipen Maru, Lee M. Ellis. Fusobacterium nucleatum subspecies animalis influences pro-inflammatory cytokine expression and monocyte activation in human colorectal tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2674. doi:10.1158/1538-7445.AM2017-2674
Abstract 2685: Modulating tumor microenvironments through inflammasome and IL-1 pathways
Authors: Guo Beichu , Zhang Jinyu , Fu Shun-Jun
Published: July 2017

Chronic Inflammation has been shown to play important roles at all stages of tumor development including initiation, growth, invasion and metastasis. The inflammasome is an important innate immune pathway critical for the production of active IL-1β, a potent inflammatory cytokine. While extensive evidence indicates that inflammasomes are involved in infections and autoimmune diseases, the role of inflammasomes in tumor development remains controversial. To dissect the roles of the inflammasome and IL-1 pathway in tumor development, we utilized the MMTV-PyMT transgenic model, which develops mammary gland tumors with a high incidence of lung metastasis. Our results have demonstrated that inflammasome and IL-1β play a critical role in promoting tumor growth and metastasis. We found that tumor growth was associated with inflammasome activation and elevated levels of IL-1β in tumor microenvironments in mouse mammary tumor models and in human breast cancer tissues. Mice deficient for inflammasome components or IL-1R signaling exhibit significantly reduced lung metastasis. Our data also show that inflammasome activation led to the accumulation of myeloid cells, such as such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in tumor microenvironments. Furthermore, blocking IL-1R signaling with IL-1R antagonist (IL-Ra) or anti-IL-1R antibody inhibited tumor growth and metastasis. Our results suggest that targeting the tumor microenvironment through inflammasome and IL-1 blockade may provide a novel approach for the treatment of breast cancer.

Note: This abstract was not presented at the meeting.

Citation Format: Beichu Guo, Jinyu Zhang, Shun-Jun Fu. Modulating tumor microenvironments through inflammasome and IL-1 pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2685. doi:10.1158/1538-7445.AM2017-2685