tbuckley/cabot-search huggingface dataset:
Abstract 5695: Induction of lymphangiogenesis in breast cancer enhances responsiveness to immunotherapies
Authors: Peyman Hosseinchi, Aslan Mansurov, Léa Maillat, Lambert Potin, Gavin Fujimori, Jeffrey A. Hubbell, Melody A. Swartz
Journal: Cancer Research (2020)

Abstract Growth and remodeling of tumor-associated lymphatics, termed lymphangiogenesis, has been known to increase metastasis rate in cancer patients. However, a recent study from our group has shown that tumor-associated lymphatics can improve anti-tumor immunity in melanoma upon treatment with immunotherapies. The role of lymphangiogenesis in shaping anti-tumor immune responses in breast cancer, however, remains unexplored. Furthermore, recently approved checkpoint inhibitor immunotherapies have had limited success in breast cancer patients. A better understanding of the role of tumor-associated lymphatics in shaping anti-tumor immune responses could lead to more informed decisions when treating breast cancer patients with immunotherapies. In this study, we investigated the role of induced tumor lymphangiogenesis in modulating responsiveness to different immunotherapies in a murine triple-negative mammary carcinoma model. Spontaneously metastatic 4T1 tumor cells were transduced to over-express the pro-lymphangiogenic growth factor VEGF-C (VC) to induce tumor lymphangiogensis in vivo. Flow cytometry and immunohistochemistry analyses confirmed that VEGF-C over-expressing tumors have an increase in tumor-associated lymphatics than control ones. Higher infiltrations of conv CD4 T cells and macrophages were observed in lymphangiogenic 4T1 tumors. Lymphangiogenic tumors treated with aPD-1 and aCTLA-4 checkpoint inhibitors, or an agonist of the Stimulator of Interferon Genes (STING) pathway, showed improved responsiveness to the therapy compared to the control tumors, as indicated by a reduced tumor growth rate. Moreover, positive correlations between VEGF-C expression and CD4 T cell and macrophage gene expressions were observed in primary human triple-negative breast tumor samples from The Cancer Genome Atlas (TCGA). In conclusion, our study shows that increase in tumor-associated lymphatics in triple-negative breast cancer enhances responsiveness to immunotherapies. Citation Format: Peyman Hosseinchi, Aslan Mansurov, Léa Maillat, Lambert Potin, Gavin Fujimori, Jeffrey A. Hubbell, Melody A. Swartz. Induction of lymphangiogenesis in breast cancer enhances responsiveness to immunotherapies [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 5695.
COVID-19: risk accumulation among biologically and socially vulnerable older populations
Authors: Amaia Calderón-Larrañaga, Serhiy Dekhtyar, Davide L. Vetrano, Tom Bellander, Laura Fratiglioni
Journal: Ageing Research Reviews (2020)

Emerging data show that the health and economic impacts of COVID-19 are being disproportionately borne by individuals who are not only biologically, but also socially vulnerable. Based on preliminary data from Sweden and other reports, in this paper we propose a conceptual framework whereby different factors related to biological and social vulnerability may explain the specific COVID-19 burden among older people. There is already some evidence showing large social disparities in the prevention, treatment, prognosis and/or long-term consequences of COVID-19. The remaining question is to what extent these affect older adults specifically. We provide the rationale to address this question with scientific methods and proper study designs, where the interplay between individuals' biomedical status and their social environment is the focus. Only through interdisciplinary research integrating biological, clinical and social data will we be able to provide new insights into the SARS-CoV-2 pandemic and inform actions aimed at reducing older adults' vulnerability to COVID-19 or other similar pandemics in the future.
Rucaparib in Men With Metastatic Castration-Resistant Prostate Cancer Harboring a<i>BRCA1</i>or<i>BRCA2</i>Gene Alteration
Authors: Wassim Abida, Akash Patnaik, David Campbell, Jeremy Shapiro, Alan H. Bryce, Ray McDermott, Brieuc Sautois, Nicholas J. Vogelzang, Richard M. Bambury, Eric Voog, Jingsong Zhang, Josep M. Piulats, Charles J. Ryan, Axel S. Merseburger, Gedske Daugaard, Axel Heidenreich, Karim Fizazi, Celestia S. Higano, Laurence E. Krieger, Cora N. Sternberg, Simon P. Watkins, Darrin Despain, Andrew D. Simmons, Andrea Loehr, Melanie Dowson, Tony Golsorkhi, Simon Chowdhury
Journal: Journal of Clinical Oncology (2020)

BRCA1 or BRCA2 (BRCA) alterations are common in men with metastatic castration-resistant prostate cancer (mCRPC) and may confer sensitivity to poly(ADP-ribose) polymerase inhibitors. We present results from patients with mCRPC associated with a BRCA alteration treated with rucaparib 600 mg twice daily in the phase II TRITON2 study.We enrolled patients who progressed after one to two lines of next-generation androgen receptor-directed therapy and one taxane-based chemotherapy for mCRPC. Efficacy and safety populations included patients with a deleterious BRCA alteration who received ≥ 1 dose of rucaparib. Key efficacy end points were objective response rate (ORR; per RECIST/Prostate Cancer Clinical Trials Working Group 3 in patients with measurable disease as assessed by blinded, independent radiology review and by investigators) and locally assessed prostate-specific antigen (PSA) response (≥ 50% decrease from baseline) rate.Efficacy and safety populations included 115 patients with a BRCA alteration with or without measurable disease. Confirmed ORRs per independent radiology review and investigator assessment were 43.5% (95% CI, 31.0% to 56.7%; 27 of 62 patients) and 50.8% (95% CI, 38.1% to 63.4%; 33 of 65 patients), respectively. The confirmed PSA response rate was 54.8% (95% CI, 45.2% to 64.1%; 63 of 115 patients). ORRs were similar for patients with a germline or somatic BRCA alteration and for patients with a BRCA1 or BRCA2 alteration, while a higher PSA response rate was observed in patients with a BRCA2 alteration. The most frequent grade ≥ 3 treatment-emergent adverse event was anemia (25.2%; 29 of 115 patients).Rucaparib has antitumor activity in patients with mCRPC and a deleterious BRCA alteration, but with a manageable safety profile consistent with that reported in other solid tumor types.
AB0043 EFFECT OF IN VIVO HYDROXYCHLOROQUINE AND EX VIVO ANTI-BDCA2 TREATMENT ON PDC IFNα PRODUCTION FROM PATIENTS AFFECTED WITH CUTANEOUS LUPUS ERYTHEMATOSUS
Authors: Agnes Gardet, Alex Pellerin, Christie-Ann Mccarl, Rohan Diwanji, Wenting Wang, Douglas Donaldson, Nathalie Franchimont, Victoria Werth, Dania Rabah
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> BIIB059 (aka 24F4A) is a monoclonal antibody that targets BDCA2, an inhibitory receptor expressed on pDCs. Plasmacytoid dendritic cells (pDCs) are a major source of Type-I Interferon (IFN-I), which is considered to be a key pathogenic driver in Cutaneous Lupus Erythematosus (CLE). Recent results from a Phase I clinical trial suggest that BIIB059 may ameliorate skin lesions in CLE patients. BIIB059 is currently evaluated in Phase II clinical trial for CLE with or without SLE. <h3>Objectives:</h3> Given that Hydroxychloroquine (HCQ), a widely-used CLE therapy, and BIIB059 are both able to inhibit pDC-derived IFN-I production; this study aimed to determine whether BIIB059 would show an additional inhibitory effect on pDC response after <i>ex-vivo</i> or <i>in-vivo</i> treatment with HCQ. <h3>Methods:</h3> The effect of BIIB059 on pDC-derived IFNα was measured from peripheral blood mononuclear cells (PBMC) either from healthy donors in presence or absence of HCQ or from CLE patients clinically exposed to various levels of HCQ. TLR7, TLR7/8, and TLR9 agonists (ssRNA, R848, and,CpG-A) were used for pDC stimulation. <h3>Results:</h3> PDCs were the only producers of IFNα in response to CpG-A, R848, and ssRNA stimulation in PBMC cultures. CLE patients with high blood HCQ levels showed lower <i>ex-vivo</i> pDC responses to CpG-A, but not R848 or ssRNA. In contrast, BIIB059 reduced the amount of IFNα produced by pDCs from CLE patients in response to all TLR agonists, irrespective of the blood HCQ level. This effect was observed in patients with low or high blood IFN signature and in patients with or without concomitant SLE diagnosis. <h3>Conclusion:</h3> Clinically-relevant HCQ concentrations partially inhibit the pDC response to TLR9 and weakly affect the response to TLR7/8 stimulation. BIIB059 robustly inhibits pDC responses even in the presence of HCQ, highlighting its unique potential to disrupt pDC disease relevant biology, which could provide additional therapeutic benefit for CLE patients. <h3>Disclosure of Interests:</h3> Agnes Gardet Shareholder of: Biogen, Employee of: Biogen, Alex Pellerin Shareholder of: Biogen, Employee of: Biogen, Christie-Ann McCarl Shareholder of: Biogen, Employee of: Biogen, Rohan Diwanji Shareholder of: Biogen, Employee of: Biogen, Wenting Wang Shareholder of: Biogen, Employee of: Biogen, Douglas Donaldson Shareholder of: Biogen, Employee of: Biogen, NATHALIE FRANCHIMONT Shareholder of: owner of BIOGEN shares/stocks, Employee of: BIOGEN employee, Victoria Werth: None declared, Dania Rabah Shareholder of: Employee and shareholder of Biogen, Employee of: Biogen
COVID-19 infection in hematopoietic cell transplantation: age, time from transplant and steroids matter
Authors: Ankur Varma, Satyajit Kosuri, Celalettin Ustun, Uroosa Ibrahim, Jonathan Moreira, Michael R. Bishop, Sunita Nathan, Jayesh Mehta, Daniel Moncayo, Joseph Heng, Keren Osman, Kehinde U. A. Adekola
Journal: Leukemia (2020)
Abstract 12558: Treatment of Limb Ischemia Using Hydrogels With Tunable Mechanical Properties for Endothelial Cell Transplantation
Authors: Mahdis Shayan, Riley Suhar, Abbygail Foster, Sarah C Heilshorn, Ngan F Huang
Journal: Circulation (2019)

Introduction: Peripheral arterial disease (PAD) affects over 8 million people in the US. It is associated with narrowing the peripheral arteries and restricts the blood flow to peripheral limbs. Ce...
Compliance Phenotypes in Early Acute Respiratory Distress Syndrome before the COVID-19 Pandemic
Authors: Rakshit Panwar, Fabiana Madotto, John G. Laffey, Frank M. P. van Haren
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: A novel model of phenotypes based on set thresholds of respiratory system compliance (Crs) was recently postulated in context of coronavirus disease (COVID-19) acute respiratory distress syndrome (ARDS). In particular, the dissociation between the degree of hypoxemia and Crs was characterized as a distinct ARDS phenotype.Objectives: To determine whether such Crs-based phenotypes existed among patients with ARDS before the COVID-19 pandemic and to closely examine the Crs–mortality relationship.Methods: We undertook a secondary analysis of patients with ARDS, who were invasively ventilated on controlled modes and enrolled in a large, multinational, epidemiological study. We assessed Crs, degree of hypoxemia, and associated Crs-based phenotypic patterns with their characteristics and outcomes.Measurements and Main Results: Among 1,117 patients with ARDS who met inclusion criteria, the median Crs was 30 (interquartile range, 23–40) ml/cm H2O. One hundred thirty-six (12%) patients had preserved Crs (≥50 ml/cm H2O; phenotype with low elastance ["phenotype L"]), and 827 (74%) patients had poor Crs (<40 ml/cm H2O; phenotype with high elastance ["phenotype H"]). Compared with those with phenotype L, patients with phenotype H were sicker and had more comorbidities and higher hospital mortality (32% vs. 45%; P < 0.05). A near complete dissociation between PaO2/FiO2 and Crs was observed. Of 136 patients with phenotype L, 58 (43%) had a PaO2/FiO2 < 150. In a multivariable-adjusted analysis, the Crs was independently associated with hospital mortality (adjusted odds ratio per ml/cm H2O increase, 0.988; 95% confidence interval, 0.979–0.996; P = 0.005).Conclusions: A wide range of Crs was observed in non–COVID-19 ARDS. Approximately one in eight patients had preserved Crs. PaO2/FiO2 and Crs were dissociated. Lower Crs was independently associated with higher mortality. The Crs–mortality relationship lacked a clear transition threshold.
Acute Myeloid Leukemia and Myelodysplastic Syndromes with <i>TP53</i> Aberrations — A Distinct Stem Cell Disorder
Authors: Heinz Sill, Armin Zebisch, Detlef Haase
Journal: Clinical Cancer Research (2020)

Abstract The tumor suppressor p53 exerts pivotal roles in hematopoietic stem cell (HSC) homeostasis. Mutations of the TP53 gene have recently been described in individuals with clonal hematopoiesis conferring substantial risk of developing blood cancers. In patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), TP53 aberrations—mutations, deletions, and a combination thereof—are encountered at a constant frequency of approximately 10%. These aberrations affect HSCs transforming them into preleukemic stem cells, pinpointing their central role in leukemogenesis. AML and MDS with TP53 aberrations are characterized by complex chromosomal aberrations. Respective patients experience a dismal long-term outcome following treatment with both intensive and nonintensive regimens including novel agents like venetoclax combinations or even allogeneic HSC transplantation. However, according to the 2016 WHO classification, AML and MDS with TP53 aberrations are still regarded as separate disease entities. On the basis of their common biological and clinical features, we propose to classify AML and MDS with TP53 aberrations as a single, distinct stem cell disorder with a unique genetic make-up, comparable with the WHO classification of “AML with recurrent genetic abnormalities.” This approach will have implications for basic and translational research endeavors, aid in harmonization of current treatment strategies, and facilitate the development of master trials targeting a common deleterious driver event.
Abstract 6673: B7-H3-targeted 4-1BB activation potentiates CD8 T cell-dependent antitumor immunity without systemic toxicity
Authors: Gihoon You, Yangsoon Lee, Yeon-Woo Kang, Han Wook Park, Kyeongsu Park, Jaeho Jung, Seung-Woo Lee
Journal: Cancer Research (2020)

Abstract 4-1BB is a costimulatory receptor on activated T and NK cells, and the stimulation of 4-1BB by the natural ligand or agonistic mAb enhances cellular proliferation and effector functions. Immunotherapy targeting 4-1BB has been tested for cancer patients; however, dose-limiting toxicities of 4-1BB agonists restrict further clinical development. B7-H3 (CD276) is overexpressed on the cell surface of multiple cancers and tumor-associated endothelial cells, yet barely on healthy adult tissues. To restrict 4-1BB stimulation activity in tumors, we have developed an FcγR-binding null bispecific IgG1 antibody consisting of B7-H3-targeting IgG and two anti-4-1BB single-chain variable fragments. The B7-H3x4-1BB bispecific antibody (B5x1D8) shows a potent in vitro T cell costimulatory activity in the presence of B7-H3 on the tumor cells. B5x1D8 rapidly accumulates in B7-H3-overexpressing tumors compared to 4-1BB agonistic mAb. B5x1D8 elicits a 4-1BB-dependent anti-tumor response in three different B7-H3-overexpressing murine tumor models. More importantly, in contrast to 4-1BB mAb, B5x1D8 does not induce any observable systemic abnormalities. Treatment of B5x1D8 increases the density, cytokine production, and proliferation of CD8 T cells in the tumor. Characterization of TILs indicates that B5x1D8 increases the number of PD-1+TIM-3+ “terminal effector” CD8 T cells for eliminating tumor cells. Furthermore, a combination of B5x1D8 and immune checkpoint blockade (ICB), anti-PD1, synergistically inhibits tumor growth. The human 4-1BB-targeting bispecific antibody also induces B7-H3-dependent 4-1BB costimulation and inhibits tumor growth in human 4-1BB transgenic mice. In sum, our data suggest that the B7-H3x4-1BB bispecific antibody represents an alternative form of IgG-based 4-1BB agonistic mAb for effective and safe cancer immunotherapy against B7-H3 positive cancers as monotherapy and combination therapy with other immunotherapy, like ICB. Citation Format: Gihoon You, Yangsoon Lee, Yeon-Woo Kang, Han Wook Park, Kyeongsu Park, Jaeho Jung, Seung-Woo Lee. B7-H3-targeted 4-1BB activation potentiates CD8 T cell-dependent antitumor immunity without systemic toxicity [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 6673.
Comparison of molecular testing strategies for COVID-19 control: a mathematical modelling study
Authors: Nicholas C Grassly, Margarita Pons-Salort, Edward P K Parker, Peter J White, Neil M Ferguson, Kylie Ainslie, Marc Baguelin, Samir Bhatt, Adhiratha Boonyasiri, Nick Brazeau, Lorenzo Cattarino, Helen Coupland, Zulma Cucunuba, Gina Cuomo-Dannenburg, Amy Dighe, Christl Donnelly, Sabine L van Elsland, Richard FitzJohn, Seth Flaxman, Keith Fraser, Katy Gaythorpe, Will Green, Arran Hamlet, Wes Hinsley, Natsuko Imai, Edward Knock, Daniel Laydon, Thomas Mellan, Swapnil Mishra, Gemma Nedjati-Gilani, Pierre Nouvellet, Lucy Okell, Manon Ragonnet-Cronin, Hayley A Thompson, H. Juliette T Unwin, Michaela Vollmer, Erik Volz, Caroline Walters, Yuanrong Wang, Oliver J Watson, Charles Whittaker, Lilith Whittles, Xiaoyue Xi
Journal: The Lancet Infectious Diseases (2020)

WHO has called for increased testing in response to the COVID-19 pandemic, but countries have taken different approaches and the effectiveness of alternative strategies is unknown. We aimed to investigate the potential impact of different testing and isolation strategies on transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Tocilizumab for severe COVID-19 pneumonia
Authors: Salvatore Piano, Roberto Vettor, Paolo Angeli, G Arcidiacono, D Benfaremo, S Bettini, BM Bonora, G Bucca, A Cattelan, L Cerruti, A Dalbeni, V Framba, A Gabrielli, CG Gambino, F Ghirardini, U Gnudi, MM Luchetti, A Mantovani, S Mareso, M Marini, A Martini, M Mattioli, L Mucci, GP Perna, F Presotto, C Sensi, R Serra, F Soliani, R Stupia, E Vettore, M Zoncapè
Journal: The Lancet Rheumatology (2020)
Bubble Bubble, Senescent Cells Are a Cauldron of Tumor Trouble
Authors: Christopher D. Wiley
Journal: Cancer Research (2020)

Abstract Senescent cells release a mélange of factors that drive multiple forms of pathology, including cancer aggressiveness. In this issue of Cancer Research, Han and colleagues show that small extracellular vesicles (sEV), membrane-enclosed bubbles that carry signaling molecules, from senescent stromal cells can promote tumorigenesis and multidrug resistance in prostate or breast cancer cells. They find that loss of SIRT1 activity drives senescence-associated sEV release, and treatment with a SIRT1 agonist prevented this effect. This adds another mechanism by which senescent cells can promote tumorigenesis and offers another activity of senescent cells that might be targeted to limit the spread of cancer. See related article by Han et al., p. 3383
Identification of proteins associated with development of metastasis from cutaneous squamous cell carcinomas (cSCCs) via proteomic analysis of primary cSCCs*
Authors: A. Shapanis, C. Lai, S. Smith, G. Coltart, M. Sommerlad, J. Schofield, E. Parkinson, P. Skipp, E. Healy
Journal: British Journal of Dermatology (2020)

Cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers capable of metastasizing. Proteomic analysis of cSCCs can provide insight into the biological processes responsible for metastasis, as well as future therapeutic targets and prognostic biomarkers.To identify proteins associated with development of metastasis in cSCC.A proteomic-based approach was employed on 105 completely excised, primary cSCCs, comprising 52 that had metastasized (P-M) and 53 that had not metastasized at 5 years post-surgery (P-NM). Formalin-fixed, paraffin-embedded cSCCs were microdissected and subjected to proteomic profiling after one-dimensional (1D), and separately two-dimensional (2D), liquid chromatography fractionation.A discovery set of 24 P-Ms and 24 P-NMs showed 144 significantly differentially expressed proteins, including 33 proteins identified via both 1D and 2D separation, between P-Ms and P-NMs. Several differentially expressed proteins were also associated with survival in SCCs of other organs. The findings were verified by multiple reaction monitoring on six peptides from two proteins, annexin A5 (ANXA5) and dolichyl-diphosphooligosaccharide-protein glycosyltransferase noncatalytic subunit (DDOST), in the discovery group and validated on a separate cohort (n = 57). Increased expression of ANXA5 and DDOST was associated with reduced time to metastasis in cSCC and decreased survival in cervical and oropharyngeal cancer. A prediction model using ANXA5 and DDOST had an area under the curve of 0·93 (confidence interval 0·83-1·00), an accuracy of 91·2% and higher sensitivity and specificity than cSCC staging systems currently in clinical use.This study highlights that increased expression of two proteins, ANXA5 and DDOST, is significantly associated with poorer clinical outcomes in cSCC.
Abstract LB-254: The effectiveness of healthcare professional training on the legal issues impacting individuals diagnosed with cancer to improve patient quality of life
Authors: Joanna Morales, Monica Bryant
Journal: Cancer Research (2020)

Abstract A cancer diagnosis may carry with it a variety of legal issues, including insurance coverage, government benefits, and consumer rights. These legal issues can cause people unnecessary worry, confusion, and stress, and can be overwhelming. The Insurance and Finance Intensive is focused on providing healthcare professionals tools to proactively identify the presence of cancer-related legal, health insurance, and financial issues facing their patients. Additionally, the training helps health care professionals to offer referrals to appropriate legal and related resources, once those issues are identified. Oncology healthcare professionals participated in an eight-hour comprehensive training. Attendees were provided with substantive information about cancer-related legal issues, such as identifying health insurance options, navigating disability insurance and appeals, and managing finances. A follow-up survey was sent to all past intensive attendees to measure the effectiveness of the training and to address any lingering questions and difficult case studies. Ninety-four percent of survey respondents strongly agreed or agreed that the information provided by the training helped them reduce the stress and anxiety of their patients and their families. Ninety-two percent of survey respondents strongly agreed or agreed that the information provided by the training improved the quality of life of their patients and their families. The Insurance &amp; Finance Intensive successfully provided health care professionals with valuable information on the practical and legal issues that impact individuals diagnosed with cancer. It is recommended that more healthcare professionals participate in this training to improve the quality of life of their patients beyond diagnosis. Citation Format: Joanna Morales, Monica Bryant. The effectiveness of healthcare professional training on the legal issues impacting individuals diagnosed with cancer to improve patient quality of life [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 LB-254.