bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-14-06: Prepectoral direct to implant reconstruction following nipple sparing mastectomy using the TiLOOP bra pocket
Authors: Thill Marc , van Haasteren Viviane , Kelling Katharina 
Published: March 2020

Abstract
Aim: Evaluation of safety, cosmetic outcome and patients satisfaction following nipple sparing mastectomy with prepectoral direct to implant reconstruction using the TiLOOP® Bra Pocket.
Background: TiLOOP® Bra Pocket is a new surgical tool consisting of a large-pore, non-absorbable synthetic mesh made from titanized monofilament polypropylene thread. It is used for immediate prepectoral implant reconstruction to fix the implant on the pectoralis major muscle and to avoid implant rotation.
Material and methodes: Between October 2017 and February 2019, 57 patients underwent nipple sparing mastectomy in the certified breast cancer centre, at the AGAPLESION Markus Hospital, Frankfurt, Germany. Data was collected in a prospective registry. All of the patients underwent a prepectoral direct to implant reconstruction using the new TiLOOP® Bra Pocket. We present the first analysis of this prospective unicentric registry. To measure and to analyse the cosmetic outcome and patients’ satisfaction, the BREAST-Q questionnaire was used, an established modular questionnaire to assess patient reported outcome (PRO).
Results: All of the 57 patients were available for postoperative analysis. In 35/57 (61%) of the cases a seroma occured and was worth to be punctured. The median number of punctures was 4. The volume was 70 ml in average. Seven patients had a postoperative hematoma and had to undergo another surgical procedure. Three patients developed a skin necrosis or severe wound healing problem due to bad quality of the soft tissue and skin mantle and had to undergo implant explantation. One patient suffered from implant infection but could be treated conservatively. The analysis of patients’ reported outcome via the BREAST-Q resulted in a high satifaction rate regarding the cosmetic outcome.
Conclusion: Direct to implant reconstruction with prepectoral implant position by using the TiLOOP® Bra Pocket is a very promising surgical approach. In comparison to a subpectoral implant reconstruction it reduces the duration of surgery, avoids a jumping breast phenomenon and causes less postoperative pain, moreover, it leeds to a high patient satisfaction rate and shows a moderate complication rate. Follow up of our patients will continue. The next analysis will be done after 24 months.
Citation Format: Marc Thill, Viviane van Haasteren, Katharina Kelling. Prepectoral direct to implant reconstruction following nipple sparing mastectomy using the TiLOOP bra pocket [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-14-06.
Abstract A10: The MACSimaTM platform enables high-content imaging for characterization and classification of glioblastoma multiforme
Authors: Reiß Sandy , Tomiuk Stefan , Leyendeckers Heike , Kollet Jutta , Drewes Jan , Brück Wolfgang , Jungblut Melanie , Bosio Andreas 
Published: March 2020

Abstract
Glioblastoma multiforme (GBM), a highly malignant, incurable brain tumor of the primary central nervous system, was subclassified into different subsets. Here, we introduce the new MACSimaTM technology that uses iterative fluorescent staining, image acquisition, and signal erasure with multiple fluorochrome-conjugated antibodies per cycle. We have used this technology to categorize glioblastomas according to the published classification schemes and to identify new glioblastoma-specific markers. Glioblastoma xenografts derived from primary tumors were dissociated into single cells and analyzed by flow cytometry for the expression of cell surface markers, including 371 directly conjugated antibodies. A ranking by percentage of positive cells and staining index was performed, which resulted in a selection of 96 markers for the characterization of primary glioblastoma with the imaging platform MACSimaTM. Sections of primary tumor were fixed with acetone and each sample was exposed to 96 fluorescent labeled antibodies through cycles of antibody reaction, image acquisition, and signal deletion as well as DAPI counterstaining. 2D image stacks were analyzed for antigen quantification and pattern recognition at the level of single pixels or segmented cells. To divide glioblastomas into oligodendrocyte precursors (OPC), differentiated oligodendrocytes (DOC), astrocytic mesenchymals (AsMes) or mixed subtypes, and peritoneal, neuronal, classical or mesenchymal subtypes, we used the detection of previously published markers such as PDGFRα, Olig2, p16, p53, CD44, Nestin, Podoplanin, GFAP, MET, Hes-1, and EGFR. Established antigens such as EGFRvIII, HER2, or IL-13Rα2, some of which were already used in chimeric antigen receptor T cells (CAR T) studies, showed broad inter- and intratumor heterogeneity of expression. Finally, segmentation, clustering, and correlation analysis enabled the identification of new markers that could be used for a more robust classification of glioblastomas and could serve as new potential candidates for targeted immunotherapies. In summary, analysis with the imaging platform MACSimaTM shows a high heterogeneity of protein expression in glioblastomas, together with the ability to classify tumors more deeply and identify new markers that allow selective detection of tumor cells for their potential use in immunotherapy.
Citation Format: Sandy Reiß, Stefan Tomiuk, Heike Leyendeckers, Jutta Kollet, Jan Drewes, Wolfgang Brück, Melanie Jungblut, Andreas Bosio. The MACSimaTM platform enables high-content imaging for characterization and classification of glioblastoma multiforme [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A10.
Abstract A101: Single-cell analysis reveals the pivotal role of the innate immune compartment in aCTLA-4 antitumor response
Authors: Yofe Ido , Jelinski Adam , Solomon Isabelle , Landsberger Tomer , de Massy Marc Robert , Peggs Karl , Quezada Sergio , Amit Ido 
Published: March 2020

Abstract
Immunotherapies have revolutionized and continue to revolutionize cancer patient care; however, much of our understanding of the mechanism of action of these therapies is currently limited. The accumulation of regulatory T cells (Tregs) in the tumor hampers antitumor activity and correlates with bad prognosis in several human cancers. Anti-CTLA-4 monoclonal antibodies (mAbs) have been extensively studied, and their activity depends both on the blockade of the CTLA-4 coinhibitory molecule, as well as the intratumoral depletion of Tregs, increasing effector cell abundance, and favoring tumor rejection. Fc-gamma receptor (FcgR) coengagement has been proven to be important for the action of aCTLA-4, in addition to its Treg-depleting activity via antibody-dependent cellular cytotoxicity (ADCC); however, it is unclear what are the cellular changes involved. We therefore wished to dissect the differences between aCTLA-4 mIgG1, an antibody that only blocks the CTLA-4 receptor, and aCTLA-4 mIgG2a, which has a dual activity of both blocking the receptor and depleting Tregs. To address this, we performed single-cell RNA-seq of infiltrating leukocytes from tumors in mice treated with aCTLA-4 mIgG1, mIgG2a, or left untreated (UT). This high-resolution comparison revealed unique cellular profiles generated by each treatment. While the blocking-only mIgG1 was similar to UT, mIgG2a with ADCC effector function demonstrated major changes. Tumors in mIgG2a treated mice showed an immediate decline of immune suppressive macrophages, and the emergence of proinflammatory monocytes, as well as NK cells and naive CD8 T cells. In addition, mIgG2a-treated mice displayed a gradual increase of CD4 T-cell subsets throughout treatment. Finally, a vast tissue repair signature was observed in later time points of aCTLA-4 mIgG2a treatment, comprising MRC1+ macrophages, neutrophils, and myeloid-derived suppressor cells (MDSCs), while CD8 T-cell abundance declined. In summary, our findings provide an in-depth view of the differences in mechanisms of action between an aCTLA-4 blocking mAb and an optimized blocking-depleting mAb, underscoring how FcgRs coengagement leads to enhanced antitumor response via the innate immune compartment.
Citation Format: Ido Yofe, Adam Jelinski, Isabelle Solomon, Tomer Landsberger, Marc Robert de Massy, Karl Peggs, Sergio Quezada, Ido Amit. Single-cell analysis reveals the pivotal role of the innate immune compartment in aCTLA-4 antitumor response [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A101.
Abstract A104: A stochastic model of tumor-immune evasion predicts sustained coevolution and tumor antigen downregulation
Authors: George Jason T. , Levine Herbert 
Published: March 2020

Abstract
The dynamical interaction between a growing cancer population and the adaptive immune system generates diverse evolutionary trajectories that ultimately result in tumor clearance or immune escape. Here we create a simple mathematical model of T-cell recognition of tumor-associated antigens. We show that declines in T-cell turnover declines explain differences in early incidence data for almost all cancer types. Fitting the model to evolutionary data argues in favor of substantial and sustained immune pressure exerted on a developing tumor, suggesting that measured incidence is a small proportion of all cancer initiation events. Extending our model to account for the number of distinct tumor antigens, we solve for the optimal cancer evasion strategy and demonstrate that such a population-level strategy predicts that the accumulation rate of cancer mutations is a reflection of the tumor microenvironment and determined by the balance of cancer evasion costs and host recognition rate. We apply our framework to combination drug therapy and quantify the difference in predicted efficacy of combination therapy vs. sequential monotherapy. More generally, this framework has significant implications for understanding drug resistance in the face of an adaptive threat.
Citation Format: Jason T. George, Herbert Levine. A stochastic model of tumor-immune evasion predicts sustained coevolution and tumor antigen downregulation [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A104.
Abstract A108: Identification of distinct fibroblast populations with unique roles in PDAC progression and tumor immunity
Authors: Darpolor J. Kebbeh , Zheng Xiaofeng , Yang Sujuan , McAndrews Kathleen M. , Carstens Julienne L. , Phillips Patricia E. , Sugimoto Hikaru , De Sampaio Pedro Correa , Wu Chia-Chin , LeBleu Valerie S. , Kalluri Raghu 
Published: March 2020

Abstract
The desmoplastic reaction in pancreatic ductal adenocarcinomas (PDAC) involves a significant accumulation of immune cells and fibroblasts. Although carcinoma-associated fibroblasts (CAFs) have been associated with immune suppression and immunotherapy resistance in PDAC mouse models, some studies have shown immune-promoting and tumor-suppressing roles of CAFs. The functional diversity of carcinoma-associated fibroblasts (CAFs) remains largely unknown, and identification of immune-regulating subsets would have a substantial impact in augmentation of immunotherapy efficacy. Employing histology, FACs, multiplex immunohistochemistry, single-cell RNA sequencing (sc-RNA-seq), and genetically engineered mouse models, we demonstrate that SMA+ cells are a dominant CAF population in PDAC with tumor-restraining properties (TS-CAFs), as opposed those of the FAP+ CAFs, which demonstrate tumor-promoting activity (TP-CAFs). Analysis of bulk tumor depleted of either TS-CAFs or TP-CAFs showed that TS-CAFs predominantly modulate extracellular matrix (ECM) production, facilitate cell-ECM adhesion, and regulate adaptive immunity, while TP-CAFs exhibit a lineage that is skewed towards a proinflammatory, chemokine-secreting phenotype. Further, scRNA-Seq analyses demonstrate that CAFs share distinct gene expression profiles characteristic of lymphocytic and myeloid lineages. Together our data distinguish two populations of CAFs, one that is tumor suppressing with roles in ECM remodeling and another that is tumor promoting with roles in cytokine production, both with immune-modulating capabilities. Collectively, our study identifies a complex network of functionally heterogeneous fibroblasts during PDAC progression with significant immunotherapeutic implication.
Citation Format: J. Kebbeh Darpolor, Xiaofeng Zheng, Sujuan Yang, Kathleen M. McAndrews, Julienne L. Carstens, Patricia E. Phillips, Hikaru Sugimoto, Pedro Correa De Sampaio, Chia-Chin Wu, Valerie S. LeBleu, Raghu Kalluri. Identification of distinct fibroblast populations with unique roles in PDAC progression and tumor immunity [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A108.
Abstract A12: Inhibition of protease-activated receptor 4 (PAR4) suppresses C4a-induced invasion of lung cancer cells in vitro
Authors: Wang Hongbin , Xiong Lingxin , Wang Zhibin , Wang Yuanyuan , Xu Ling , Zhang Weidong 
Published: March 2020

Abstract
It has been well established that chronic inflammation can cause neoplasm development and cancer cell dissemination. The complement system, an essential component of innate immunity, contains some of the most powerful proinflammatory molecules upon its activation. Recent studies have demonstrated that complement activation components, anaphylatoxins C3a and C5a, can regulate the fate of cancer cells through direct or regulatory effects on cancer cells or immune system. C4a (77 aa) is released from complement component C4 upon the activation of the classical and lectin pathways of the complement system. Our recent study provided the data that C4a acts as an untethered ligand for G protein-coupled receptors, protease activated receptor 1 (PAR1) and PAR4. It is still unclear whether C4a generates any effects on cancer cells through binding to its receptors. In our present study, we want to determine the effect of C4a on the invasive ability of lung cancer cells in vitro, which is supposed to be correlated with lung cancer cell metastasis in vivo. First, we checked the levels of C4a in the plasma from patients of different stages of lung cancer, and our results revealed that the plasma level of C4a from stage IV lung cancer patients is significantly higher than that from stage I lung cancer patients, suggesting C4a might be involved in the metastasis of late-stage lung cancer. In addition, our in silico analysis of data from lung adenocarcinoma and squamous cell carcinoma patients using Kalpan-Meier Plotter online database revealed a negative correlation between PAR4 expression and the overall survival and progression-free survival. Moreover, our in vitro transwell invasion experiments demonstrated that C4a could significantly enhance lung cancer cell invasion in a concentration-dependent fashion, and the blockade of PAR4 by its specific antagonist (ML354) significantly inhibited C4a-induced lung cancer cell invasion in vitro. Our data provide the direct evidence that complement activation fragment C4a induces lung cancer cell invasion through acting on its receptor PAR4, suggesting that targeting PAR4 as a therapeutic intervention might be beneficial for impeding cancer cell metastasis in late-stage lung cancer patients.
Citation Format: Hongbin Wang, Lingxin Xiong, Zhibin Wang, Yuanyuan Wang, Ling Xu, Weidong Zhang. Inhibition of protease-activated receptor 4 (PAR4) suppresses C4a-induced invasion of lung cancer cells in vitro [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A12.
Abstract A18: Investigating CDK4/6 inhibition in triple-negative breast cancer
Authors: Guo Qiuchen , Goreczny Gregory J. , Maynard Adam , Spasic Milos , McAllister Sandra S. 
Published: March 2020

Abstract
The purpose of our study is to investigate the immunologic effects of CDK4/6 inhibitors in triple-negative breast cancer (TNBC), a highly aggressive breast cancer subtype for which there are no targeted therapies. CDK4/6 inhibitors, including the recently FDA approved abemaciclib, show promising response rates in patients with advanced stage hormone receptor-positive (HR+) breast cancer. Our previous report established that CDK4/6 inhibitors promote antitumor immunity by inducing tumor cell antigen presentation by activating tumor endogenous retroviral elements, which induce type III interferon production and MHC-I upregulation (Goel, DeCristo, et al., Nature 2017). In addition, CDK4/6 inhibitors decrease T regulatory cell proliferation without affecting cytotoxic CD8 T-cell numbers. TNBC has been considered a poor candidate for CDK4/6 inhibitor therapy, as tumors often lose Rb protein expression, which is critical for CDK4/6 inhibitor-induced cell cycle arrest. However, reports show around 50%-70% TNBC still has intact RB. We found murine and human TNBC cell lines that express Rb to varying extents and decrease proliferation in vitro in response to abemaciclib. In our preclinical model of TNBC, abemaciclib induced tumor regression. Consistent with previous findings, TNBC tumor cells upregulated MHC-I upon abemaciclib treatment, suggesting increased antigen presentation. Tumor cell-surface PD-L1 was also increased with abemaciclib both in vitro and in vivo, as assessed by flow cytometry and RT-qPCR. These results are encouraging, since a recent trial evaluating αPD-L1 therapy (atezolizumab) reported enhanced progression-free survival in patients with PD-L1+ tumors. These data suggest the potential efficacy of CDK4/6 inhibitors in combination with αPD-L1 in the treatment of TNBC, as we previously reported in our Her2+ model. Abemaciclib also increased total CD8+ and CD4+ T cells and decreased PD1+ CD8 and CD4 cells in the spleen. Furthermore, total numbers of naive CD8+ and CD4+ T cells increased with abemaciclib treatment in the spleen, suggesting a favorable antitumor systemic immunologic effect. CDK4/6 inhibitors might therefore show efficacy in treating TNBC. Deeper analysis of the mechanisms involved in regulating PD-L1 and enhancing naive T cells should enable us to evaluate combination therapies using CDK4/6 inhibitors for this particularly deadly breast cancer subtype.
Citation Format: Qiuchen Guo, Gregory J. Goreczny, Adam Maynard, Milos Spasic, Sandra S. McAllister. Investigating CDK4/6 inhibition in triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A18.
Abstract A30: Combined IDO inhibitor and OX40L-armed-oncolytic-adenovirus therapy improves survival in murine glioblastoma
Authors: Nguyen Teresa T. , Shin Dong Ho , Jiang Hong , Lang Frederick , Gomez-Manzano Candelaria , Fueyo Juan 
Published: March 2020

Abstract
Glioblastoma diagnoses associate with upregulation of the immunosuppressive indoleamine-2,3-dioxygenase (IDO) enzyme, which correlates with poor prognoses. IDO inhibitors are immunometabolic adjuvants that can reverse protumor immunosuppression through increasing effector T-cell metabolism. To further stimulate antitumor T-cell activation, the OX40L-armed-oncolytic-adenovirus (Delta-24-RGDOX) can be used, which has shown to induce immune mechanisms that activate antitumor cytotoxic properties of T cells. Thus, we hypothesized that combining IDO inhibitors and Delta-24-RGDOX synergizes to produce a therapeutic effect in glioblastoma. In this study, we used a syngeneic glioblastoma orthotopic immunocompetent model to test the efficacy of combining Delta-24-RGDOX and an IDO inhibitor (1MT or indoximod). Delta-24-RGDOX treatment resulted in a significant survival benefit compared to the control groups (mean survival, 46.5 vs. 38.5 days, P=0.02). Interestingly, the combination of Delta-24-RGDOX and 1MT produced a higher percentage of long-term survivors compared to single therapy with Delta-24-RGDOX (50% vs. 20%, P=0.03). Moreover, when these long-term glioblastoma survivors were rechallenged with the same glioblastoma cells, we observed 100% survival, indicating the establishment of immune memory by the combination therapy. Furthermore, functional studies showed a significant increase in antitumor activity of splenocytes from glioblastoma-bearing combination-treated mice compared to Delta-24-RGDOX-treated mice (P=0.009). Additionally, immunophenotyping by flow cytometry revealed that glioblastoma-bearing combination-treated mice yielded the highest levels of PD-1/TIM-3/CD8+ T cells compared to all other treatment groups and decreased levels of immune-tolerant populations, including regulatory T cells and myeloid-derived suppressor cells, compared to Delta-24-RGDOX-only treated mice, and correlated with complete tumor elimination. Most importantly, these data support the use of immunometabolic adjuvants combined with virotherapy as a treatment for glioblastoma to improve its dismal outcomes.
Citation Format: Teresa T. Nguyen, Dong Ho Shin, Hong Jiang, Frederick Lang, Candelaria Gomez-Manzano, Juan Fueyo. Combined IDO inhibitor and OX40L-armed-oncolytic-adenovirus therapy improves survival in murine glioblastoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A30.