bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3298: Eosinophilia and improved survival in non-hematologic malignancies treated with immune checkpoint inhibitors
Authors: Mitchell Jasmine L. , Moyers Justin , Cao Huynh 
Published: September 2020

Abstract
Background
Immune checkpoint inhibitors (ICI) have become a mainstay treatment of a variety of advanced malignancies, prolonging survival. There are no serologic markers to predict response to ICI, but some small series have suggested eosinophilia predicts improved survival.
Methods
This is an IRB approved single-center retrospective observational study including all patients (n= 80) from 2014-2019 who received ICI for non-hematologic malignancies at Loma Linda University Medical Center. Data were collected via chart review. Clinically significant increase of absolute eosinophil count was defined as a count &gt; 0.5 bil/L on at least two occasions during treatment. Kaplan-Meier survival estimates were used to estimate overall survival.
Results
In non-small cell lung cancer (n= 35), patients with eosinophilia (n=5) had no death events compared to the median survival of 17.6 months in those without eosinophilia (p = 0.02). Similarly, in patients with renal cell carcinoma (n=11), those with eosinophilia (n=2) had no death events while the median survival for those without was 16.9 months (p= 0.24). In the metastatic melanoma cohort (n=9), those with eosinophilia (n= 5) had a median overall survival of 45.4 vs 9.9 months in those without (p= 0.02).
Conclusions
In both NSCLC and metastatic melanoma, eosinophilia during ICI therapy was associated with significantly increased overall survival, while in RCC there was a trend towards improved survival. Interestingly, there were no death events in those with eosinophilia in either NSCLC or RCC cohorts.
Citation Format: Jasmine L. Mitchell, Justin Moyers, Huynh Cao. Eosinophilia and improved survival in non-hematologic malignancies treated with immune checkpoint inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3298.
Abstract 33: Epidemiology and clinicopathology of T-cell intravascular lymphoma (TIVL): Making the case for extra-nodal NK-T cell lymphoma-angiotropic type as a provisional entity
Authors: Haddad Philip A. , Gallagher Kevin , Hammoud Dalia 
Published: September 2020

Abstract
TIVL is a rare and often aggressive NK/T-cell lymphoma characterized by the presence of neoplastic lymphocytes that are restricted to the lumen of small vessels. It comprises 8-10% of all IVL. By the time a diagnosis is made, TIVL tends to be widely disseminated across multiple extra-nodal sites with frequent catastrophic consequences. In order to study the demographic characteristics, presentation and progression patterns, survival, and prognostic factors, we constructed a database that pooled cases between 1986 and 2019. Kaplan-Meier survival curves were constructed. Cox proportional-hazards model and Log-rank tests were used to assess the influence of demographic and clinical factors on survival. A total of 81 patients with confirmed TIVL were identified. The median age was 53 (17-87) years with a peak incidence between ages 50 and 60. There was a slight male predominance with a male to female ratio of 1.5. Comprising 43% of reported cases, Asians were the most afflicted ethnic group. Skin (71%) was the most common site involved with TIVL followed by CNS (23%), and pulmonary and bone marrow involvement (8% each). The median overall survival of the whole group was 7 months. Sex and age did not seem to affect survival rates. When compared to supportive care, chemotherapy significantly improved survival (HR:0.15, p&lt;0.0001). Skin only involvement had the highest survival rates whereas CNS and pulmonary involvement had the worst. When skin only involvement was associated with constitutional symptoms survival rates significantly declined. In a multivariate analysis, skin only involvement (HR:0.43, p=0.009) and not receiving treatment (HR:3.45, p=0.001) continued to have a significant association with survival. CD56+, CD30-, and TCR clonality each seems to adversely impact survival. However, they were of borderline non-statistical significance. Only the detection of EBER in the sample was found to significantly impact survival in a negative manner (p=0.016). Our results indicate that TIVL is an NK/T cell entity with distinct angiotropic pathology and aggressive clinical behavior and often poor outcomes. TIVL's B-cell counterpart is already recognized by the WHO lymphoma classification as a separate B-cell entity. It is our hope that these results serve as the basis for establishing Extra-Nodal NK/T Cell Lymphoma-Angiotropic Type as a provisional entity in order to further study and characterize this rare disease.
Citation Format: Philip A. Haddad, Kevin Gallagher, Dalia Hammoud. Epidemiology and clinicopathology of T-cell intravascular lymphoma (TIVL): Making the case for extra-nodal NK-T cell lymphoma-angiotropic type as a provisional entity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 33.
Abstract 3320: Humanized NSG-Tg(Hu-IL15) mice support preclinical immune-oncology efficacy for testing of NK cells based immunology
Authors: Yao Li-Chin , Cheng Mingshan , Cai Danying , Shultz Leonard D. , Keck James G. 
Published: September 2020

Abstract
The JAX® Onco-Hu® platform utilizes humanized mice engrafted with tumors to enable in vivo investigation of the interactions between the human immune system and human cancer. A major avenue of our investigation is to generate humanized mouse models containing a more complete human hematopoietic system and robust innate immune cell population. Nature killer (NK) cells are important players of innate defense against cancerous cells by a number of mechanisms, including antibody-dependent cell mediated cytotoxicity (ADCC). To overcome limited NK cell development in humanized NSG™ mice, we have developed NSG-Tg(Hu-IL15) mice constitutively expressing human IL15 in a physiological level. Following CD34+ HSC-engraftment of NSG-Tg(Hu-IL15) mice, significantly higher levels of human NK cells are detectable in peripheral blood as compared to NSG mice and the engraftment is stable for over six months. Levels of circulating human CD45+ cells, CD3+ T cells, and CD33+ myeloid cells are similar between the HSC-engrafted NSG-Tg(Hu-IL15) and NSG mice. Minimal baseline activation of NK cells is detected in the spleen and peripheral blood. Previously we have described that the human NK cells developing in HSC-engrafted NSG-Tg(Hu-IL15) mice are functional and can lyse the NK-sensitive target cells K562 by in vitro cytotoxicity assay. We also showed that NK cells directly limited growth of a PDX melanoma xenograft and NK cell depletion by antibody blockage largely abrogated the delayed PDX growth. Here we extended these observations by evaluating tumor growth of multiple PDX and CDX models in humanized NSG-Tg(Hu-IL15) mice. We found that not all tumors were able to grow and for those that grew some spontaneous regression might still occur. In ex vivo experiments NK cells in the PBMCs isolated from humanized NSG-Tg(Hu-IL15) mice could be activated by Her2+ human cancer cells in the presence of anti-human H2 antibody (Trastuzumab). Furthermore we showed in vivo that humanized NSG-Tg(Hu-IL15) mice mediated efficient ADCC against Daudi B lymphoma cells using anti-human CD20 antibody (Rituximab). Administration of rituximab resulted in significant tumor growth inhibition as measured by both tumor volume and tumor weight. Together these data demonstrate that HSC-engrafted NSG-Tg(Hu-IL15) mice support enhanced development of functional human NK cells and that this mouse model enables preclinical evaluation of NK cell-targeted cancer immunotherapy in vivo.
Citation Format: Li-Chin Yao, Mingshan Cheng, Danying Cai, Leonard D. Shultz, James G. Keck. Humanized NSG-Tg(Hu-IL15) mice support preclinical immune-oncology efficacy for testing of NK cells based immunology [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3320.
Abstract 3348: Exogenous DNA upregulates DUOX2 expression in pancreatic cancer via activation of the cGAS-STING signaling pathway
Authors: Wang Stephen L. , Wu Yongzhong , Antony Smitha , Juhasz Agnes , Meitzler Jennifer , Jiang Goujian , Dahan Iris , Lu Jiamo , Roy Krishnendu , Doroshow James 
Published: September 2020

Abstract
Dual oxidase 2 (DUOX2) is a transmembrane protein that produces hydrogen peroxide in the extracellular environment, mediates innate immunity at mucosal surfaces, contributes to chronic inflammation-related tissue injury and angiogenesis, and can promote the initiation of epithelial-derived cancers. In pancreatic adenocarcinomas (PDAC), the composition of the tumor microbiome significantly affects patient outcomes. However, it remains unclear how microbes in the tumor microbiome affect PDAC on a cellular level. In recent years, the cGAS-STING signaling pathway has been identified as a crucial mediator of anti-viral defense by recognizing the presence of DNA in the cytosol and subsequently producing Type I interferons (IFNs) as well as a host of other anti-viral genes. Using Western blot and qPCR, we show that the introduction of exogenous DNA into the cytosol significantly upregulates DUOX2 expression in human PDAC cells after activating cGAS-STING signaling. Expression of DUOX2 occurs most strongly 2 days post-transfection of DNA, while cGAS-STING signaling is activated within hours. Treatment of BxPC-3 cells with exogenous cyclic GMP-AMP (cGAMP) for 24 hrs increases DUOX2 expression in a concentration-dependent manner, suggesting the necessity of cGAS activity for DUOX2 induction. Furthermore, Western analysis of phospho-NF-κB p65 in BxPC-3 cells demonstrates activation of NF-κB that mirrors the time-dependent induction of DUOX2. In CFPAC-1 cells, another PDAC line, Jak-Stat signaling is activated along with the components of cGAS-STING. These data suggest that DNA-induced DUOX2 upregulation in PDAC cells may be mediated in a cell context-specific fashion, beyond the canonical components of the cGAS-STING pathway. Upregulation of DUOX2 by exogenous DNA is not observed in colon cancer cell lines. In summary, these data suggest that extracellular DNA could contribute to a DUOX2-induced, H2O2-mediated pro-inflammatory milieu that specifically contributes to the pathogenesis of PDAC, in part through activation of the cGAS-STING pathway.
Citation Format: Stephen L. Wang, Yongzhong Wu, Smitha Antony, Agnes Juhasz, Jennifer Meitzler, Goujian Jiang, Iris Dahan, Jiamo Lu, Krishnendu Roy, James Doroshow. Exogenous DNA upregulates DUOX2 expression in pancreatic cancer via activation of the cGAS-STING signaling pathway [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3348.
Abstract 3379: Cancer dependency signatures for line of sight genomic alterations in squamous cell lung cancer yield rational targets
Authors: Ahdesmäki Miika , Armenia Joshua , Bulusu Krishna , Sidders Ben , Dry Jonathan , McDermott Ultan 
Published: September 2020

Abstract
The Cancer Dependency Map Portal enables combined analyses of genomic and phenomic data such as genomic alterations and CRISPR gene dependencies but focuses on single genes or cell lines. This is well suited for verifying previously generated hypotheses such as the dependency of cells on PRMT5 in the setting of loss of function mutations in MTAP. To identify additional actionable de-novo vulnerabilities in-silico, we refined the genomic status of 1000 cell lines by 1. focusing on variants (driver mutations and copy number alterations) that have higher prevalence in a given cancer type in TCGA and 2. reclassifying variants as actionable only if they cause loss of function in known tumour suppressor genes or gain of function in oncogenes. This gives a clear line of sight, a more manageable set of variants and is analogous to Mendelian randomization. This approach was applied to lung squamous cell carcinoma to form a binary event matrix for the shortlisted genes and copy number alterations across a panel of lung squamous cell lines. For each of the variants, we used machine learning approaches to define a dependency signature from CRISPR dependencies for the matching cell lines that distinguish altered vs non-altered cell lines. The top ranking dependencies were further examined for biological relevance and potential toxicity, yielding novel targets to follow up on. The approach generalises well and can be applied to any other cancers with unmet needs.
All data in this study was derived from public databases.
By combining TCGA cancer specific prevalent genomic alterations in tumor suppressor and oncogenes we drew clear line of sight and associated these alterations to CRISPR based vulnerabilities. This yielded a manageable set of alterations, and for each of these we identified a set of essential genes/pathways to use in machine learning. These signatures were further refined by biological enrichment, targetability and toxicity in order to build a process for rational novel target ID generation.
Citation Format: Miika Ahdesmäki, Joshua Armenia, Krishna Bulusu, Ben Sidders, Jonathan Dry, Ultan McDermott. Cancer dependency signatures for line of sight genomic alterations in squamous cell lung cancer yield rational targets [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3379.
Abstract 3380: Predicting the effects of small molecules on transcriptome of cancer cell lines using deep learning
Authors: Jeon Junhyeok , Lee Sang Mi , Lee GaRyoung , Kim Hyun Uk 
Published: September 2020

Abstract
Developing a computational model that can predict the effects of small molecules on biological status of a cell can be very useful for various applications, including candidate drug compound screening and toxicity testing in silico. In this study, we developed a deep learning model that predicts the effects of small molecules on gene expression levels of a cell. This deep learning model takes two inputs: the structure of a chemical, presented in SMILES, and a protein sequence encoded by a gene of interest. The model processes these two input data using a fingerprinting method for the input chemical structure and a convolutional neural network for the input protein sequence. As a result, the model predicts whether a given molecule upregulates or downregulates a gene of interest where the molecule and gene are both provided as inputs. The deep learning model was developed by using so called L1000 profiles covering gene expression levels of various cancer cell lines under a large number of perturbation conditions [1]. L1000 is a cost-effective transcriptome technology that can accurately infer the expression levels of 9,196 genes on the basis of expression levels of 978 ‘landmark' genes that are directly measured. In this study, the deep learning model was developed for three different cancer cell lines, HA1E (kidney), HCC515 (lung), and HEPG2 (liver), by using L1000 profiles covering expression levels of the landmark genes individually perturbed with 5,213 molecules for the HA1E cell line, 5,171 molecules for the HCC515, and 3,529 for HEPG2. The deep learning models developed in this study will be useful for a wide range of studies that examine the effects of small molecules, for example in drug development and toxicity testing. [1] Subramanian et al. A next generation connectivity map: L1000 platform and the first 1,000,000 profiles. Cell 171, 1437-1452 (2017)
Citation Format: Junhyeok Jeon, Sang Mi Lee, GaRyoung Lee, Hyun Uk Kim. Predicting the effects of small molecules on transcriptome of cancer cell lines using deep learning [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3380.
Abstract 3394: Brisk walking and hepatocellular carcinoma risk in US men and women
Authors: Luo Xiao , Yang Wanshui , Ma Yanan , Simon Tracey , Meyerhardt Jeffrey , Meyerhardt Jeffrey , Meyerhardt Jeffrey , Chan Andrew , Giovannucci Edward , Zhang Xuehong 
Published: September 2020

Abstract
Emerging evidence indicates a potential beneficial effect of vigorous physical activity on hepatocellular carcinoma (HCC) by improving energy balance, immune response, and insulin sensitivity. However, the association between moderate physical activity, such as brisk walking, and the risk of HCC remains largely unknown. Two prospective cohorts of 77,535 women from the Nurses' Health Study and 44,779 men from the Health Professionals Follow-up Study were included. Weekly time spent on brisk walking and other physical activity were updated biennially. The Cox proportional hazard regression model was used to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95%CIs). After an average 23.1-year follow-up, a total of 138 incident HCC cases were identified. In the multivariable-adjusted model, engaging in brisk walking was significantly associated with a lower risk of HCC (over 1 hour/week vs. non-brisk walking; HR: 0.44, 95%CI: 0.27-0.70; Ptrend&lt;0.001). Further adjustment for body mass index (BMI) and type 2 diabetes (T2D) yielded similar results (HR: 0.51; 95%CI: 0.31-0.83; Ptrend=0.006). The association between brisk walking and HCC risk was generally consistent across all subgroups, including age, BMI, T2D, smoking status, aspirin use, and alcohol consumption (all P&gt;0.05 for interaction). In conclusion, brisk walking was associated with a significantly lower risk of developing HCC among US men and women. If confirmed, brisk walking might serve as a feasible way for some individuals for HCC primary prevention.
Citation Format: Xiao Luo, Wanshui Yang, Yanan Ma, Tracey Simon, Jeffrey Meyerhardt, Jeffrey Meyerhardt, Jeffrey Meyerhardt, Andrew Chan, Edward Giovannucci, Xuehong Zhang. Brisk walking and hepatocellular carcinoma risk in US men and women [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3394.
Abstract 3417: A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: The small bowel tumor cohort
Authors: Chae Young Kwang , Othus Megan , Patel Sandip Pravin , Zalupski Mark , Kasi Anup , Khalil Maged , Kalyan Aparna , Polite Blase , Fenton Sarah , Gurung Sewan , McLeod Christine M. , Giles Francis , Chen Helen X. , Sharon Elad , Mayerson Edward , Plets Melissa , Ryan Christopher W. , Blanke Charles D. , Kurzrock Razelle 
Published: September 2020

Abstract
Background: The potential therapeutic benefits of checkpoint inhibitors and their application to many different tumor types has been a key factor in the advancement of medical oncology since their first approval for metastatic melanoma in 2011. However, their efficacy in rare tumor types remains to be seen. This paper presents the results of combination therapy with both anti-CTLA and anti-PD-1 in the small bowel cohort of SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART).
Methods: This study is designed as a prospective, open-label, multicenter phase 2 clinical trial of ipilimumab (1mg/kg intravenously every 6 weeks) plus nivolumab (240mg intravenously every 2 weeks) in rare tumors. Here we report the outcomes from patients diagnosed with small bowel cancer (SBC). The primary endpoints included overall response rate (ORR) (RECIST v1.1) (complete response (CR) and partial responses (PR)); progression-free survival (PFS), overall survival (OS), stable disease &gt;6 months, and toxicity were the secondary endpoints.
Results: Twenty five patients were registered to the cohort and twenty three received therapy. The duodenum was the primary site of origin in 52% (N=11), 14% (N=3) arose in the ileum and 14% (N=3) arose in the jejunum. The primary site of origin was unknown in 19% (N=4). The overall response rate was 8% (CR, 4%, N= 1; PR, 4%, N= 1). The median PFS was 2 months; 6-month OS was 48% and median OS 6 months. The most common toxicities were diarrhea and fatigue (both 17%) followed by dyspnea (13%) with diarrhea, increased bilirubin, colitis and elevated lipase (all 4.3%) as the most common grade 3-5 immune-related adverse events.
Conclusions: Combination therapy with ipilimumab plus nivolumab in small bowel tumors resulted in an overall response rate of 8% with one partial and one complete response in twenty three treated patients.
Citation Format: Young Kwang Chae, Megan Othus, Sandip Pravin Patel, Mark Zalupski, Anup Kasi, Maged Khalil, Aparna Kalyan, Blase Polite, Sarah Fenton, Sewan Gurung, Christine M. McLeod, Francis Giles, Helen X. Chen, Elad Sharon, Edward Mayerson, Melissa Plets, Christopher W. Ryan, Charles D. Blanke, Razelle Kurzrock. A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: The small bowel tumor cohort [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3417.