bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 869: Leveraging a novel analysis pipeline for outcomes predictions from routine MRIs
Authors: Vadmal Vachan , Waite Kristin , Barnholtz-Sloan Jill S. 
Published: September 2020

Abstract
There is a desperate need for approaches that allow us to use routinely gathered clinical and imaging data to make outcomes predictions for patients. The acquisition of MRI images forms a standard part of clinical care for cancer patients, especially for malignant brain tumor patients. As these digital MRI scans are performed regularly, the associated digital MRI data also grows and can form the basis for longitudinal assessment of disease and prediction of clinical outcomes. However, standard modalities are coupled with non-standard modalities in most cases (some of which is institution specific), making it difficult to organize and standardize these images for analysis. In addition, for a rare cancer such as malignant brain tumors, multi-institutional collaborations are necessary in order to have appropriate power for analyses, thereby complicating the issues around organization and standardization of images for analysis. In addition, there are likely to be discrepancies among data formats intra-institutionally. To address these shortcomings and to expedite the research process, we developed a general digital MRI analysis pipeline that is able to organize messy data, automatically preprocess, segment, extract features, and produce results that are ready for statistical analysis and discovery. Such a pipeline with modular segments for major stages in the process is beneficial to investigators who are analyzing MRI data and hope to save time from the tedium of organization and data management. With a focus on efficiency, extensibility, and reproducibility, the tools that form this pipeline also aim to increase the accessibility of complex imaging analysis to a wider audience by leveraging artificial intelligence. While pipelines exist in the literature, most are not focused on clinical MRI images of brain tumors and quickly become deprecated as software dependencies change, resulting in outdated and potentially buggy software. Our pipeline implements the latest Python version using object-oriented principles, employing PEP 8 style, and is optimized to run on modern hardware thus ensuring extensibility. The pipeline itself runs intuitively via the command line interface (CLI) that requires minimal input parameters to perform its subtasks but will have the option of accepting other parameters. We showcase features of this new MRI analysis pipeline, using malignant brain tumors as an exemplar, given their disproportionate contribution to cancer morbidity and mortality.
Citation Format: Vachan Vadmal, Kristin Waite, Jill S. Barnholtz-Sloan. Leveraging a novel analysis pipeline for outcomes predictions from routine MRIs [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 869.
Abstract 908: BRAF inhibition and nanoparticle-delivered cytokine therapy for melanoma: A novel rational combined approach
Authors: Romano Gabriele , Liang Roger , Francesca Paradiso , Miller John , Taraballi Francesca , Costello James , Kwong Lawrence 
Published: September 2020

Abstract
Although the advent of BRAF inhibitors plus MEK inhibitors has revolutionized BRAF-mutant melanoma therapy, most patients relapse within 16 months due to the persistence of minimal residual disease (MRD), a key obstacle in cancer therapy. In our inducible genetically engineered mouse model (iBIP), doxycycline withdrawal results in BRAFV600E extinction causing tumors to shrink, but not completely disappear, achieving a status of MRD. Time-course microarray analysis revealed a set of immune hallmarks with acute and strong initial activation after BRAFV600E extinction, then a decrease through to MRD, suggesting that the MRD might be immune suppressive/evasive.
Systems biology analysis pinpointed the family of interferon inducible chemokines CXCL9/10/11 as central players in the orchestration of the process: CXCL9/10/11 are strongly induced within 8 hours of BRAFV600E extinction, but dissipate just prior to MRD, paralleling the more general immune signature. Data obtained in human samples and in other immunocompetent mouse models also show both a strong CXCL9/10/11 induction after BRAF inhibition and an immune evasive/suppressive microenvironment after eventual tumor relapse. Our preliminary data indicates resident macrophages as the main population responsible for CXCL9/10/11 production.. These data led us to hypothesize that sustaining CXCL9/10/11 expression might support superior tumor immune infiltration and activation to neutralize or eradicate the MRD.
In a pilot study, we have observed significant tumor rejection in vivo with combined BRAF extinction plus intratumoral recombinant CXCL9 (rCXCL9) therapy in immunocompetent mice, which suggests that CXCL9 can therapeutically convert immunologically “cold” MRD back to “hot”. In order to improve the pharmacokinetics of cytokine therapy, we are currently developing a nanoparticle-based delivery that extends stability and half-life of rCXLC9 in vitro, with in vivo experiments as the next step. In this work, we utilized a confluence of in silico and in vivo data to guide the rational identification of a molecularly-driven cancer treatment based on immune drivers with predicted molecular synergy.
Citation Format: Gabriele Romano, Roger Liang, Paradiso Francesca, John Miller, Francesca Taraballi, James Costello, Lawrence Kwong. BRAF inhibition and nanoparticle-delivered cytokine therapy for melanoma: A novel rational combined approach [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 908.
Abstract 913: Defining melanoma patients unresponsive to single agent anti-PD-1 therapy but responsive to combination anti-PD-1 + anti-CTLA-4 therapy
Authors: Edwards Jarem J. , da Silva1 Inês Pires , Ferguson Angela , Johansson Peter , Conway Jordan , Attrill Grace , Saw Robyn P.M , Thompson John F. , Menzies Alexander M. , Palendira Umaimainthan , Long Georgina V. , Scolyer Richard A. , Wilmott James S. 
Published: September 2020

Abstract
Background: A proportion of patients that fail single agent anti-PD-1 therapy will subsequently receive and respond to combination anti-PD-1 and anti-CTLA-4 immunotherapy. The clinical and biological characteristics of these patients remain poorly defined and as such there are presently no reliable validated biomarkers to distinguish patients requiring the addition of anti-CTLA-4 in the context of anti-PD-1 therapy.
Clinical cohort and methods: We performed RNA sequencing, immunofluorescence-IHC, and multiparameter image-mass cytometry (IMC) on formalin-fixed paraffin embedded (FFPE) tumors at baseline and post anti-PD-1 therapy from n=15 stage IV melanoma patients who failed anti-PD-1 therapy and went on to receive combination immunotherapy (7 non-responders; 8 responders).
Results: Tumor pathological parameters including TIL and neutrophil densities, fibrosis, necrosis and mitotic rates identified were not different between responders and non-responders. While T-reg, cytotoxic CD8 and CD39+ resident CD8 T cells densities were not significantly different, the proportion of TCF7+ CD8 T cells was significantly higher at baseline (p=0.01) and in all tumor samples (p=0.007) in responders compared to non-responders. RNA differential gene expression analysis revealed higher expression of cancer testis antigens (CTAs) in responding patient tumors. Hierarchical clustering of differentially expressed genes separated responding patients from non-responding patients.
Conclusions: The proportion of TCF7+ CD8 T cells and the presence of melanoma cancer testis antigens may be a predictive biomarker of response to combination immunotherapy in patients failing anti-PD-1 monotherapy but requires further validation.
Citation Format: Jarem J. Edwards, Inês Pires da Silva1, Angela Ferguson, Peter Johansson, Jordan Conway, Grace Attrill, Robyn P.M Saw, John F. Thompson, Alexander M. Menzies, Umaimainthan Palendira, Georgina V. Long, Richard A. Scolyer, James S. Wilmott. Defining melanoma patients unresponsive to single agent anti-PD-1 therapy but responsive to combination anti-PD-1 + anti-CTLA-4 therapy [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 913.
Abstract 92: Increasing TTFields treatment efficacy by targeting G2 cell cycle checkpoint
Authors: Slangen Paul , van Geldorp Mariska , de Gooijer Mark , van Tellingen Olaf , Borst Gerben 
Published: September 2020

Abstract
Introduction; Tumor Treating Fields (TTFields) is a novel non-invasive anticancer treatment modality utilizing alternating electric fields. TTFields is FDA approved for glioblastoma patients after demonstrating a 5 months increase in overall survival, and for unresectable mesothelioma patients after the STELLAR trial showed an overall survival of 18 months without increasing the toxicity. While the effectiveness of TTFields is initially attributed to the effects of TTFields during cell division, studies are ongoing analysing its interphase effects and impact on the tumor (micro)environment. Our aim is to further exploit the working mechanism of TTFields by analysing its effect on the cell cycle and identify targets to increase its efficacy.
Material and Methods; To analyse the effect of TTFields on the cell cycle, A172 glioblastoma cells were synchronized in S-phase by double thymidine block. Six hours post-release, cells were subjected to TTFields treatment (200kHz; 4,5V/cm). Cell cycle analysis was performed by flow cytometry (PI, α-phospho-histone H3Ser10). Efficacy of combination strategies were tested in 3 different glioblastoma cells lines (A172, U251 and SNB-19). Efficacy was quantified by colony formation assay (CFA) testing the cell reproductive death after treatment (i.e. only viable cells after treatment are replated to analyse the colony forming capacity).
Results: TTFields treatment of synchronized A172 cells showed that TTFields causes an accumulation of cells in G2 phase and delayed entry into mitosis with less than 1% of the cells in mitosis 4 hours after TTFields exposure (versus 5% of mitotic cells in the control arm, p&lt;0.001). This arrest can be abrogated by Wee1 inhibition (AZD1775) increasing the mitotic population to more than 35% at 4 hours after TTFields exposure (p&lt;0.001). To test the efficacy of targeting the G2 checkpoint during TTFields treatment, cells were treated with TTFields and a Wee1 (AZD1775, PD0166285) or Chk1 (AZD7762) inhibitor for 72 hours and then replated for CFA. We observed an impressive synergistic effect between TTFields and any of these G2 cell cycle interfering drugs in all three cell lines (p&lt;0.001).
Conclusion: The underlying mechanism of the G2 checkpoint activation and the synergistic effect of TTFields plus G2 checkpoint targeting agents is subject of ongoing research. By any means, the combination of TTFields and G2 checkpoint targeting agents causes a synergistic treatment effect and is a very promising strategy.
Citation Format: Paul Slangen, Mariska van Geldorp, Mark de Gooijer, Olaf van Tellingen, Gerben Borst. Increasing TTFields treatment efficacy by targeting G2 cell cycle checkpoint [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 92.
Abstract 94: Pla2g4a: A new cell cycle related gene in patients with non-M3/NPM1 wildtype acute myeloid leukemia
Authors: Bai Hansong , Ming Zeng 
Published: September 2020

Abstract
In this study, we aimed to explore and validate the prognostic value of PLA2G4A expression in patients with non-M3/NPM1 wildtype (WT) acute myeloid leukemia (AML) using two independent datasets. Data from the Cancer Genome Atlas-Acute Myeloid Leukemia (TCGA-LAML) and the Therapeutically Applicable Research to Generate Effective Treatments (TARGET)-AML were used to assess the prognostic value PLA2G4A in NPM1-WT AML cases. A single-cell RNA-seq dataset that included 96 AML cells from a recurrent AML case was used to check the correlation between PLA2G4A expression and the functional state of AML cells. Results showed that non-M3 AML cases had significantly increased PLA2G4A expression compared to normal peripheral blood samples. Multivariate analysis showed that high PLA2G4A expression was independently associated with shorter OS in 97 non-M3/NPM1-WT AML cases in TCGA-LAML (HR: 1.932, 95%CI: 1.092-3.419, p=0.024). The prognostic value was validated based on 128 non-M3/NPM1-WT AML cases in TARGET-AML (HR: 1.894, 95%CI: 1.065-3.369, p=0.030). Single-cell RNA-seq data suggested that PLA2G4A expression was positively correlated with cell cycle progression of AML cells. Therefore, PLA2G4A expression might serve as an independent prognostic marker in OS in patients with non-M3/NPM1 WT AML. Its upregulation might confer malignant phenotype of AML cells at least partly by promoting cell cycle progression. Future molecular studies are required to explore other molecular pathways involved.
Citation Format: Hansong Bai, Zeng Ming. Pla2g4a: A new cell cycle related gene in patients with non-M3/NPM1 wildtype acute myeloid leukemia [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 94.
Abstract 949: Anti-cancer activity by photoimmunotherapy is driven by adaptive immune responses and vaccinates the host against the tumor
Authors: De Magalhaes Filho C. Daniel , Hsu Michelle A. , Okamura Stephanie M. , Gitnick Dany , Solis Estela , Fong Jerry J. , Garcia-Guzman Miguel 
Published: September 2020

Abstract
INTRODUCTION: Photoimmunotherapy (PIT) is an investigational anti-cancer treatment platform utilizing cell-targeted antibodies conjugated to the IR700 (IRDye 700DX®) light-excitable dye. Upon illumination with non-thermal red light, target cells bound with antibody-conjugates undergo rapid necrosis. Previous work demonstrated that PIT induces features of immunogenic cell death of tumor cells and ignites an immune response against the tumor. In these preclinical studies, we investigated the extent to which the immune response contributes to the in vivo anti-cancer activity using syngeneic cancer models.
METHODS: PIT treatment was applied to a panel of mouse and human cancer cell lines targeted by their respective antigen-binding conjugate in vitro, and the release of damage-associated molecular patterns (DAMPs) was measured from the cell supernatant. To determine the contribution of the immune response to PIT anti-cancer activity, PIT treatment was applied to immunocompetent animals with antibody-mediated CD8 T cell depletion, or blockade of CD40-CD40L axis concurrent with tumor implant or PIT treatment. To determine whether the immunogenic properties of PIT treatment induce vaccinal effects, immunocompetent animals were inoculated with in vitro PIT-treated cancer cells, and then challenged with live tumor cells in the contralateral flank one week later.
RESULTS: Cancer cells treated with PIT released significant amounts of immunogenic cell death markers including DAMPs such as ATP and Annexin A1. The anti-cancer activity of PIT treatment in immunocompetent animals was inhibited when 1) pre-existing immunity was abrogated by blockade of the CD40-CD40L interaction at time of tumor implant, and 2) CD8 T cells were depleted from the animals. Applying CD40-CD40L blockade concurrent with PIT treatment partially abrogated anti-cancer activity. When animals were inoculated with cancer cells treated by PIT ex vivo, tumor rejection was achieved in 8 out of 9 animals when challenged with live tumor cells on the contralateral flank.
CONCLUSIONS: Cancer treatment by PIT induces necrotic and immunogenic cell death resulting in local and systemic immune response. These preclinical data indicate that adaptive immune responses induced by PIT treatment drive the anti-cancer effects and can also provide vaccinal effects due to the release of DAMPs and cancer antigens.
Citation Format: C. Daniel De Magalhaes Filho, Michelle A. Hsu, Stephanie M. Okamura, Dany Gitnick, Estela Solis, Jerry J. Fong, Miguel Garcia-Guzman. Anti-cancer activity by photoimmunotherapy is driven by adaptive immune responses and vaccinates the host against the tumor [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 949.
Abstract 953: Herpes simplex virus thymidine kinase/ganciclovir-mediated apoptotic tumor cells induce anti-tumor immunity
Authors: Umegaki Sho , Shirota Hidekazu , Ishioka Chikashi 
Published: September 2020

Abstract
Immune cells can recognize tumor antigen and elicit an adaptive immune response against tumor cells. It has been reported that apoptotic or necrotic death of tumor cells releases tumor antigen stimulating anti-tumor immunity. However, the immune responses against apoptotic tumor cells in vivo are poorly understood. To investigate whether apoptotic tumor cells affect anti-tumor immunity, local immune responses in tumor were evaluated by induction of apoptotic tumor cells with herpes simplex virus thymidine kinase (HSVtk)/ ganciclovir (GCV) system. HSVtk gene transduced tumor cells were resulted in apoptosis in vitro. Administration of GCV triggered apoptosis in HSVtk transfected tumor cells in vivo and regressed the tumor. Comprehensive gene expression analysis of the bulk tumor showed that IFNγ and IL-12 were upregulated. CD8+ T cells were increased in the treatment group compared to the control group. The tumor regression by induction of GCV-triggered apoptosis was inhibited by anti-CD8 depleting antibody. These findings indicate that apoptotic tumor cells induce CD8+ T cell-dependent anti-tumor immunity.
Citation Format: Sho Umegaki, Hidekazu Shirota, Chikashi Ishioka. Herpes simplex virus thymidine kinase/ganciclovir-mediated apoptotic tumor cells induce anti-tumor immunity [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 953.
Abstract CT114: Pharmacokinetic analysis of navitoclax in combination with sorafenib in patients with relapsed or refractory solid organ tumors
Authors: Koubek Emily J. , Costello Brian A. , Yin Jun , McGovern Renee M. , Buhrow Sarah A. , Schoon Renee A. , Strand Carrie A. , Jiang Yixing , Borad Mitesh J. , Takebe Naoko , Kaufmann Scott H. , Adjei Alex A. , Reid Joel M. 
Published: September 2020

Abstract
Prior in vitro work in the human hepatoma cell lines Huh7 and HEP3B indicated that combination treatment of the BH3 mimetic, navitoclax, and the multi-kinase inhibitor, sorafenib, was more effective at inducing apoptosis than either compound alone. This current study was part of a phase I clinical trial to determine the maximum tolerated dose of concurrent navitoclax and sorafenib treatment in patients with relapsed or refractory solid organ tumors and sought to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of both agents in combination. Cleavage of cytokeratin 18 by caspase 3 was used as a biomarker for therapy-induced activation of apoptosis to determine if combination treatment results in an increase in apoptosis as previously observed in in vitro work. PK were assessed in 26 patients (ages 32 - 80) enrolled in a phase I clinical trial (NCT02143401). 150 mg of oral navitoclax was administered once daily for a seven day run-in (beginning Day -7) prior to 150 mg (Dose level 1) or 200 mg (Dose level 2) navitoclax concomitant treatment with 400 mg of twice daily oral sorafenib (Day 1). Samples for pharmacokinetic analysis were obtained on Day -7 and Day 1 prior to dosing and at 1, 2, 4, 8-12, and 24 hours post dosing. PK parameters were estimated by noncompartmental analysis using Phoenix® WinNonlin® Version 6.4. To examine the PD of both agents in combination, cytokeratin 18 cleavage was quantified by ELISA after the 7-day navitoclax run-in and on Day 2 or 4 and Day 8 of navitoclax and sorafenib combination treatment. PK estimates of maximum concentration, exposure, volume of distribution, and clearance for navitoclax on Day -7 and Day 1 were not significantly different, indicating a lack of navitoclax accumulation. Finally, no correlation was found between navitoclax exposure and apoptosis as indicated by cytokeratin-18 cleavage. This work was supported by the NCI Cancer Center Support Grant P30 CA15083 and NCI Experimental Therapeutics Phase I Grant UM1 CA186686.
Citation Format: Emily J. Koubek, Brian A. Costello, Jun Yin, Renee M. McGovern, Sarah A. Buhrow, Renee A. Schoon, Carrie A. Strand, Yixing Jiang, Mitesh J. Borad, Naoko Takebe, Scott H. Kaufmann, Alex A. Adjei, Joel M. Reid. Pharmacokinetic analysis of navitoclax in combination with sorafenib in patients with relapsed or refractory solid organ tumors [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 CT114.