bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5543: Low ATM expression is associated with improved progression-free and overall survival in advanced gastric cancer patients treated with platinum-based chemotherapy
Authors: Bhangoo Munveer S. , Luu Hubert Y. , Kim Seung Tae , Lee Jeeyun , Chao Joseph , Klempner Samuel J. 
Published: August 2018

Abstract
Introduction: Platinum-based combination chemotherapy regimens represent standard approaches for locally advanced and metastatic gastric adenocarcinoma. Ataxia-teleangiectasia mutated protein (ATM) plays a critical role in repairing DNA damage to double-stand breaks. Tumors deficient in ATM (defined as pathologic loss measured by IHC) are hypothesized to demonstrate increased susceptibility platinum chemotherapy.
Methods: We retrospectively reviewed patients from a single center (Samsung Medical Center, Seoul, South Korea) with advanced, unresectable gastric cancer (stage 3b or higher) receiving capecitabine/oxaliplatin (XELOX) from 2013-2017. Clinicopathologic data, treatment response, progression-free survival (PFS), and overall survival (OS) were analyzed according to level of ATM expression by immunohistochemistry (IHC). Low-expression of ATM was defined as greater than 50% loss by IHC. Two-tailed, unpaired t-tests and Fisher's exact tests were used to compare outcomes between patients with preserved ATM versus low ATM expression. Kaplan-Meier survival analysis was used to compare disease-free survival and overall survival; the log-rank test was used to determine statistical significance.
Results: During the study period, 138 patients underwent treatment with XELOX for a diagnosis of advanced gastric cancer. Median (IQR) follow-up time was 11.8 mo. (6.8-17.3). Between patients with ATMintact or ATMlow, there were no significant differences in mean age, sex, final pathologic diagnosis, or mean number of cycles of chemotherapy received. Kaplan-Meier analysis demonstrated that patients with ATM low were associated with a longer PFS (ATMlow 14.9 mo versus ATMintact 6.8 mo.) (HR 0.24, [0.18-0.34, 95% CI], p&lt;0.0001), and longer OS (ATMlow 30.0 mo. versus ATMintact 14.7) (HR 0.23, [0.17-0.33, 95% CI], p&lt;0.0001). There was no difference in response rates between the two groups.
Conclusions: This retrospective, case-control study in patients with advanced gastric cancer shows improved survival in patients with ATMlow tumors compared with ATMintact tumors after treatment with platinum-based chemotherapy. Findings are suggestive and require prospective validation in cohorts of patients with ATMlow/ATMintact tumors.
Citation Format: Munveer S. Bhangoo, Hubert Y. Luu, Seung Tae Kim, Jeeyun Lee, Joseph Chao, Samuel J. Klempner. Low ATM expression is associated with improved progression-free and overall survival in advanced gastric cancer patients treated with platinum-based chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5543.
Abstract 5546: eFT508, a potent and highly selective inhibitor of MNK1 and MNK2, regulates T-cell differentiation promoting an antitumor immune response
Authors: Sharma Rajesh K. , Goel Vikas K. , Staunton Jocelyn , Barrera Maria , Parra Ana , Sung Eric , Chiang Gary G. , Webster Kevin R. 
Published: August 2018

Abstract
An effective and durable T-cell response is a cornerstone of current immunotherapies. We show that eFT508, a potent, selective inhibitor of MNK1 and MNK2, establishes a regulatory program that promotes multiple steps in the cancer immunity cycle including expansion of memory T cells and prevention of T-cell exhaustion. Using OT-I and OT-II transgenic systems, we show that eFT508 shifts the distribution of T cells towards a CD62LhighCD44high central memory (CM) phenotype in both CD4 and CD8 T cells upon activation with SIINFEKL peptide in vitro without adverse effects on T-cell proliferation, interferon-γ production or cytotoxic function. Similar effects are seen in vivo, where eFT508 treatment also enriches the CM T-cell pool in a SIINFEKL vaccine-induced OT-I adoptive T-cell transfer model, which results in increased persistence as demonstrated by a higher memory-recall T-cell response upon rechallenge. In addition, the CM bias elicited by eFT508 remains dominant when combined with agonists of co-stimulatory molecules, such as 4-1BB, OX-40 and GITR, or checkpoint inhibitors, such as PD-1, PD-L1 and CTLA-4, suggesting that eFT508 can affect the rate of T-cell differentiation in these combinations. eFT508 treatment also reduces the expression of exhaustion markers such as PD-1, LAG3 and TIM3, leading to increased cytotoxic T-cell function. eFT508 is currently under evaluation as a single agent in two phase 1/2 clinical trials for patients with advanced solid tumors and patients with advanced lymphoma. In addition, a phase 2 study evaluating eFT508, alone or in combination with avelumab, a PD-L1 immune checkpoint inhibitor, in microsatellite stable relapsed or refractory CRC patients is ongoing. The preclinical studies presented here provide further evidence that eFT508 may combine well with additional immunotherapies beyond checkpoint blockade.
Citation Format: Rajesh K. Sharma, Vikas K. Goel, Jocelyn Staunton, Maria Barrera, Ana Parra, Eric Sung, Gary G. Chiang, Kevin R. Webster. eFT508, a potent and highly selective inhibitor of MNK1 and MNK2, regulates T-cell differentiation promoting an antitumor immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5546.
Abstract 556: Oncogenic properties and response to HDAC inhibitor treatment of H1299 cells expressing GOF p53 mutants
Authors: Flores Brianna , Hull Elizabeth E. 
Published: August 2018

Abstract
The tumor suppressor p53 protein is mutated in over 50% of cancers. The most frequent mutations in p53, termed “hotspot” mutations, occur in the DNA binding domain of the p53 protein. These mutations not only remove normal p53 function but also convey additional oncogenic properties greater than loss of tumor suppressor activities associated with loss of wild-type (WT) p53 activities. With newly acquired oncogenic properties, mutations in the DNA binding domain of p53 are classified as gain of function (GOF) mutations. GOF p53 mutants can be subdivided into conformational mutations (e.g. R175H, H193Y) involving residues necessary for maintenance of structure and contact mutations (e.g. R248Q, R273H) involving resides necessary for DNA interaction. Cancer cells bearing a GOF p53 mutation increase metastasis with application of histone deacetylase inhibitors (HDACi). This uncharacterized pro-oncogenic GOF p53 property is of clinical relevance as HDACi are FDA approved for hematological cancers but have failed in clinical trials for solid tumors. To explore this hypothesis, metastatic capacity and proliferation rates of common GOF p53 mutations were assessed with and without HDACi treatment and in the presence or absence of specific inhibitors of target GOF p53. The p53-null, H1299 non-small cell lung carcinoma line was transfected with GOF p53 mutants and WT p53 using a tetracycline inducible expression system. Inducible expression of stable subclones was varified by immunofluorescence and western blot. Proliferation rate was measured by incorporation of EdU and metastatic capacity was assessed by measuring MMP activity and migration assays with and without HDACi treatment. Specific GOF p53 mutations possess a subset of the oncogenic properties of the entire GOF p53 class. Data suggest that the GOF p53 mutants display differing rates of proliferation with the R175H mutation exhibiting the highest rate. Application of NSC319726 significantly decreases the proliferation rate and appears to successfully refold the R175H mutant to a WT conformation. The R248Q mutation exhibited morphological change suggestive of the epithelial to mesenchymal transition associated with increased metastatic capacity. Preliminary data suggest that HDACi affect among these cell lines in conjunction with NSC 319726 and SCH 529074 treatment. In conclusion, HDACi treatment may be contraindicated while treatment with HDACi may have great benefit in tumors which are WT or null for p53 protein expression.
Citation Format: Brianna Flores, Elizabeth E. Hull. Oncogenic properties and response to HDAC inhibitor treatment of H1299 cells expressing GOF p53 mutants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 556.
Abstract 5563: Kinetically-controlled release of blocking molecules for the targeted enhancement of therapeutic activity in antibody-cytokine fusion proteins
Authors: Ongaro Tiziano , Bigatti Martina , Sladojevich Filippo , Donckele Etienne , Villa Alessandra Micaela , Neri Dario 
Published: August 2018

Abstract
Cytokines are able to mediate a potent anticancer activity but have significant side effects that prevent dose escalation to therapeutically-active regimens. Targeting the cytokines to the site of disease helps to improve their therapeutic index while decreasing associated toxicities. However, peak concentrations in blood are still associated with side-effects. We have developed a novel technology (termed “CORK Technology”), which consists in masking the undesired activity of a cytokine in circulation. The “cork” can be either an antibody fragment or a small molecule, which specifically binds to the cytokine thus preventing the interaction with its receptor. Once the complex accumulates in the tumor, the cork dissociate from the cytokine allowing it to exert its function. Capitalizing on the fact that the kinetic dissociation constant koff of the complex is identical in different species, this technology can be easily translated from mouse to man with comparable results. In this poster we describe the experimental implementation of CORK Technology to improve the therapeutic index of the clinical stage L19-IL2 (L19 is an antibody fragment specific to the alternatively-spliced EDB domain of fibronectin, a marker of tumor angiogenesis). Two classes of IL2 inhibitors were discovered and characterized: (i) a fully human scFv fragment, and (ii) a small organic ligand, featuring a modified methylindole moiety. Both types of agents reduced IL2 activity in vitro, were able to dissociate from the cognate cytokine in a kinetically-tuned process and allowed the administration of the L19-IL2 fusion protein at higher doses, both in normal and in tumor-bearing mice. The technology is applicable to other cytokine payloads and facilitates the development of targeted cytokine products with “activity on demand” (i.e., with increased activity at the tumor site, promoting an activation and proliferation of tumor-resident lymphocytes). Albeit still in its infancy, this elegant approach provides promising results and a strong rationale to further investigate this therapeutic power of the CORK Technology.
Citation Format: Tiziano Ongaro, Martina Bigatti, Filippo Sladojevich, Etienne Donckele, Alessandra Micaela Villa, Dario Neri. Kinetically-controlled release of blocking molecules for the targeted enhancement of therapeutic activity in antibody-cytokine fusion proteins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5563.
Abstract 557: Aberrant methylation of tumor-suppressor genes in pediatric myelodysplastic syndrome/acute myeloid leukemia
Authors: Shimada Akira , Kanzaki Hirotaka , Ishida Hisashi , Matsubara Takehiro , Aoe Michinori 
Published: August 2018

Abstract
Introduction: Not only somatic mutations, but also epigenetic modifications in acute myeloid leukemia (AML) are estimated to have a pivotal role in leukemogenesis and it could be a therapeutic target. Especially, aberrant methylation of the promotor region of tumor suppressor genes (TSGs) were the causative events in leukemogenesis, however, there was only limited information in pediatric myelodysplastic syndrome (MDS) and AML. Materials and Methods: We analyzed the aberrant methylation of promotor region of 25 TSGs in pediatric 7 low grade MDS, 4 advanced MDS and 22 AML patients by FAB classification by Methylation-Specific Multiplex Ligation-dependent Probe Amplification (MS-MLPA) method (10 Male, 12 female, 0-14 years old, median 6 years ols). Simultaneously, detection of SNVs, In/del, and copy number variants were also analyzed by target sequence of more than 150 leukemia related genes. Especially, specific chimeras were analyzed in each patient. Results: Total 12/22(54.5%) patients had more than one methylated TSGs (number of methylated TSGs was 0-5 in each patient, median 1). More than 20% of patients had methylated TSGs including CDKN2B, CADM1, CDH13 and ESR1. Especially, there was a specific methylation pattern of TSGs, for example, all (4/4) t(8;21) patients had CDH13 methylation, 3/4 (75%) patients with inv(16) had ESR1 mutation and normal karyotype did not. Normal control samples, complete remission samples, and low grade MDS samples were not completely methylated. All advanced MDS patients had 1 or 2 methylated TSGs. Simultaneously, several leukemogenic genes were mutated such as GATA1, IKZF1, KRAS, KIT, FLT3, SH2B3, PIK3CD, PU.1, SMARC1, ALK, etc. Several genes were deleted such as CTCF, RB1, SRP72, ATM, NF1, U2AF1 etc. Discussion: In adult MDS, the increased number of methylated TSGs correlated to the development of AML and the poor prognosis. In this study, a few TSGs were methylated as the adult study (Hess CJ., Leuk Lymphoma 2008), furthermore, many genes related to epigenetic modification such as ASXL1, TET2 and EZH2 were not mutated in this study. Recently, anti-methylation drug were used in adult MDS/AML, larger study will be needed for adjusted use of epigenetic modifier in pediatric MDS/AML.
Citation Format: Akira Shimada, Hirotaka Kanzaki, Hisashi Ishida, Takehiro Matsubara, Michinori Aoe. Aberrant methylation of tumor-suppressor genes in pediatric myelodysplastic syndrome/acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 557.
Abstract 560: Identification of a novel MUTYH mutation in non-small cell lung cancer
Authors: Fong Alvin Hong-Wai , Lau Eunice Yuen-Ting , Cheung William Ka-Chun , Cho William Chi-Shing 
Published: August 2018

Abstract
Introduction: Lung cancer is the leading cause of death from cancer in Hong Kong and worldwide. Nearly 80-85% of lung cancers are diagnosed with non-small cell lung cancer (NSCLC). Treatment strategies can be refined according to the distinct difference of NSCLC molecular profiling among different ethnic populations. Moreover, oncogenic driver mutations are closely linked to NSCLC in non-smokers and young people. Therefore, the urge of finding pathogenic mutations is inevitable. This study aims to discover novel mutations in NSCLC patients in Hong Kong by next-generation sequencing and characterize the clinical significance of these mutations. Methods: In order to identify mutations, DNA was purified from 6 pairs of lung tumor-normal tissues from 2 stage I adenocarcinoma (LUAD), 2 stage III LUAD and 2 stage I squamous cell carcinoma (LUSC) patients. Samples were sequenced by targeted sequencing with the TOMA OS-Seq 130 cancer gene panel. Sequence alignment and variant calling were performed by combining TOMA Stratus and in-house pipelines. Results: The mean aligned reads exceeded 14 million and the mean coverage of target region was over 1000X. MUTYH deletion was found in 66.7% (4/6) of the patients. Data from The Cancer Genome Atlas (TCGA) revealed that MUTYH deletion is significantly associated with poorer disease-free survival (DFS) (p=0.0063) and overall survival (p=0.022) in LUAD patients. TCGA data also showed that MUTYH copy number correlates with gene expression (r=0.473) and LUAD patients with MUTYH mRNA overexpression have better DFS (p=0.0205). However, such correlations were not observed in LUSC patients. MUTYH is a DNA glycosylase which involves in the base excision repair and it repairs oxidative DNA damage by preventing G:C to T:A transversion. Numerous studies indicated that biallelic mutations in MUTYH cause MUTYH-associated polyposis and increase the lifetime risk of colorectal cancer. MUTYH mutations could be associated with increased risk of endometrial and breast cancer. Conclusion: To elucidate the clinical significance of MUTYH in LUAD, an independent cohort will be sequenced to validate the primary result. Immunohistochemistry, RT-qPCR and functional assays will be performed to examine the protein expression, the gene expression and the functional role. All these findings suggested that MUTYH deletion may play a crucial role in LUAD and potentially lead to the development of biomarker and therapeutic target.
Citation Format: Alvin Hong-Wai Fong, Eunice Yuen-Ting Lau, William Ka-Chun Cheung, William Chi-Shing Cho. Identification of a novel MUTYH mutation in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 560.
Abstract 5651: Achieving simultaneous improvements in workflow and multiplexing in whole-slide tissue imaging
Authors: Natan Michael 
Published: August 2018

Abstract
With very high spatial and biological complexity, tumor micro-environments present a significant
characterization challenge, which is only heightened by the need to image entire sections of cancer
tissue on many different samples. A variety of techniques offer very high levels of multiplexing, but
always fail on either speed requirements (incredibly long times required to image a whole slide) or on
compatibility issues (expensive, hard-to-operate CapEx not suitable for high-throughput CLIA operation).
Ultivue has developed a platform reagent technology (InSituPlex™) that simultaneously enables whole-
slide higher multiplexing by immunofluorescence AND complete compatibility with existing
instrumentation.
The InSituPlex technology comprises five key foundational elements. First, short unique DNA barcodes
are covalently attached to each primary antibody (Ab). These conjugates are purified and functionally
characterized in tissue for optimal staining specificity. Importantly, all of this work is done in advance by
Ultivue. Second, tissue samples are stained in a single step. Third, all the DNA sequences attached to
targets (via primary Ab binding) are simultaneously amplified, allowing for detection of less abundant
markers e.g. PD-1, PDL-1 etc. Fourth, complementary DNA sequences each with different, covalently-
attached fluorescent labels (“imager strands”) are simultaneously hybridized to the amplified DNA on
the targets. All these wet chemistry steps are carried out in walkaway mode using commercially
available auto-stainers. The samples are then imaged using a standard, whole-slide multi-color
fluorescence imaging system. Finally, in an optional fifth step, the imager strands are gently removed
via an enzymatic dehybridzation- with complete retention of antigenicity- to enable higher multiplexing
via additional rounds of hybridization/imaging.
The InSituPlex reagent technology offers many advantages for cancer research over current approaches:
• the ability to detect 5, 10, or more targets simultaneously via whole-slide imaging on an each
and every sample, with no loss in antigenicity;
• the ability to leverage existing auto-stainers and existing fluorescent microscopes with
Ultivue's reagent kits to carry out high-throughput analyses of multiple cancer
biomarkers; and
• the ability to design custom biomarker panels that leverage Ultivue's unique barcoding
capability and infrastructure.
This poster will elaborate on each step of the technology, and provide multiple examples of data
acquired using different biomarker panels and different cancer tissue types.
Citation Format: Michael Natan. Achieving simultaneous improvements in workflow and multiplexing in whole-slide tissue imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5651.
Abstract 5657: Use of a novel immunofluorescence multiplexing technology, InSituPlex™, for the simultaneous detection of immune cells in multiple cancer types
Authors: Downing Sean , Patel Katir , Buell Jamie , Hebert Courtney 
Published: August 2018

Abstract
Introduction: The field of immuno-oncology has enthusiastically adopted multiplexed
immunohistochemistry (IHC) techniques to establish the spatial relationships between various
immune cells in tumor biology. Multiplexing enables researchers to gain a deeper understanding
and insight into the tumor microenvironment. Unfortunately, many of the multiplexing
technologies currently utilized in the immuno-oncology field face a number of challenges. These
challenges include complicated and difficult assay optimizations for high-level multiplexing and
the need of specialized imaging instrumentation. In addition, harsh stripping methods and
irreversible staining techniques compromise the integrity of precious tissue samples that ultimately
can no longer be used for additional forms of testing. InSituPlex™ is a new method of multiplexed
IHC that relies on the detection of a unique DNA barcode conjugated to primary antibodies. This
technology removes the need to perform multiple, harsh stripping methods to perform multiplexed
IHC and allows for higher order of multiplexing in less time than currently available multiplexing
techniques, all the while maintaining tissue integrity for use in downstream analyses.
Methods: InSituPlex was used to perform a multiplexed IHC assay on 5 samples from 4 tumor
types (breast, lung, colon, and melanoma). The assay consisted of the following markers: CD4,
CD8, CD20, CD68, PD1, Ki67, FoxP3, and a tumor marker; pan-cytokeratin (CK) for breast,
colon, and lung carcinomas and Sox10 for melanoma. Staining was performed using the Leica
BOND RX autostainer, imaging was performed on various platforms including the Leica VERSA
whole slide scanner, and image analysis was performed using HALO from Indica Labs.
Data: All markers were detected utilizing the InSituPlex technology across all tumor types. Data
indicates a range of phenotypes for infiltrating immune cells in tumor types from highly inflamed
to “immune deserts”. The panel provided for analysis of many phenotypic subtypes, (e.g.,
CD4+/PD1+, CD8+/Ki67+, and Ki67+/CK+), cell densities, proliferative indexes, and spatial
analysis (e.g., CD8+ to tumor cells).
Conclusion: InSituPlex technology is proficient in maintaining tissue integrity and detecting a
range of immune cell phenotypes in multiple tumor types. InSituPlex can be implemented by any
lab possessing a standard fluorescent microscope and does not rely on the purchase of, nor access
to, more expensive platforms.
Citation Format: Sean Downing, Katir Patel, Jamie Buell, Courtney Hebert. Use of a novel immunofluorescence multiplexing technology, InSituPlex™, for the simultaneous detection of immune cells in multiple cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5657.