tbuckley/cabot-search huggingface dataset:
Cost Effectiveness of Interval Cytoreductive Surgery With Hyperthermic Intraperitoneal Chemotherapy in Stage III Ovarian Cancer on the Basis of a Randomized Phase III Trial
Authors: Simone N. Koole, Christiaan van Lieshout, Willemien J. van Driel, Evi van Schagen, Karolina Sikorska, Jacobien M. Kieffer, Jules H. Schagen van Leeuwen, Henk W.R. Schreuder, Ralph H. Hermans, Ignace H. de Hingh, Jacobus van der Velden, Henriette J. Arts, Leon F.A.G. Massuger, Arend G. Aalbers, Victor J. Verwaal, Koen K. Van de Vijver, Neil K. Aaronson, Harm van Tinteren, Gabe S. Sonke, Wim H. van Harten, Valesca P. Retèl
Journal: Journal of Clinical Oncology (2019)

In the randomized open-label phase III OVHIPEC trial, the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery (CRS) improved recurrence-free and overall survival in patients with stage III ovarian cancer. We studied the cost effectiveness of the addition of HIPEC to interval CRS in patients with ovarian cancer.We constructed a Markov health-state transition model to measure costs and clinical outcomes. Transition probabilities were derived from the OVHIPEC trial by fitting survival distributions. Incremental cost-effectiveness ratio (ICER), expressed as euros per quality-adjusted life-year (QALY), was calculated from a Dutch societal perspective, with a time horizon of 10 years. Univariable and probabilistic sensitivity analyses were conducted to evaluate the decision uncertainty.Total health care costs were €70,046 (95% credibility interval [CrI], €64,016 to €76,661) for interval CRS compared with €85,791 (95% CrI, €78,766 to €93,935) for interval CRS plus HIPEC. The mean QALY in the interval CRS group was 2.12 (95% CrI, 1.66 to 2.64 QALYs) and 2.68 (95% CrI, 2.11 to 3.28 QALYs) in the interval CRS plus HIPEC group. The ICER amounted to €28,299/QALY. In univariable sensitivity analysis, the utility of recurrence-free survival and the number of days in the hospital affected the calculated ICER most.On the basis of the trial data, treatment with interval CRS and HIPEC in patients with stage III ovarian cancer was accompanied by a substantial gain in QALYs. The ICER is below the willingness-to-pay threshold in the Netherlands, indicating interval CRS and HIPEC is cost effective for this patient population. These results lend additional support for reimbursing the costs of treating these patients with interval CRS and HIPEC in countries with comparable health care systems.
Abstract 1853: Association of IDH genes with prostate cancer progression and their regulation by the androgen receptor
Authors: Kevin Gonthier, Raghavendra TK Poluri, Cindy Weidmann, Etienne Audet-Walsh
Journal: Cancer Research (2019)

Abstract A primary function of the prostate is to synthesize and secrete high levels of citrate by way of a unique metabolic profile regulated by the androgen receptor (AR). Prostate cancer (PCa) is an androgen-dependent disease that is characterized by early reprogramming of citrate metabolism. Accordingly, mutations of the isocitrate dehydrogenase genes IDH1 and IDH2, which are key enzymes involved in the regulation of cellular citrate levels, have been demonstrated as important oncogenic events in several cancer types, including in about 3% of all PCa cases. However, if IDH1 and other IDH isoforms are associated with PCa progression as well as the regulatory factors controlling their expression remain mostly unknown. Across the human cancer spectrum, PCa appears to be the cancer type with the highest expression of IDH1, with levels even higher than common cancers associated with IDH1 mutations such as gliomas. Using publicly available datasets and quantitative PCR, we showed that IDH1 is the predominant IDH isoform expressed in PCa cells. In PCa, the androgen receptor was found to regulate several IDH isoforms in both in vitro and in vivo models of PCa, predominantly positively regulating IDH1. Chromatin immunoprecipitation experiments confirmed the recruitment of AR at several regulatory regions of IDH1 and IDH2. IDH1 and other IDH isoforms were shown to be significantly altered during PCa progression, which is consistent with a reprogramming of citrate metabolism in PCa. In addition, modulation of IDH expression significantly altered PCa cell proliferation and metabolism. Overall, our study indicates that IDH gene regulation is associated with PCa progression and that AR plays a significant role in the regulation of IDH genes. Citation Format: Kevin Gonthier, Raghavendra TK Poluri, Cindy Weidmann, Etienne Audet-Walsh. Association of IDH genes with prostate cancer progression and their regulation by the androgen receptor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1853.
Retrospective study of Regorafenib versus Trifluridine/Tipiracil efficacy in chemorefractory metastatic colorectal cancer patients: a single Italian institution real-life clinical data
Authors: P. Vitale, N. Zanaletti, P. Vitiello, e. martinelli, D. Ciardiello, V. De Falco, E. Giunta, L. Poliero, M. Terminiello, C. Borrelli, V. Caputo, G. Arrichiello, G. Martini, N. Stefania, V. Famiglietti, C. Cardone, F. Ciardiello, T. Troiani
Journal: Annals of Oncology (2019)
10 minute consultation: Newly diagnosed hypothyroidism
Authors: H U Rehman, T A Bajwa
Journal: BMJ (2005)

A 46 year old woman has returned to you for the results of blood tests. Two weeks earlier she had complained of increasing tiredness, constipation, dry skin, and weight gain. Thyroid function tests at her previous consultation showed concentrations of free thyroxine (T4) of 7 nmol/l and of thyroid stimulating hormone (TSH) of 38 mU/l. Her mother had Graves' disease and was treated with radioiodine ablation.
Abstract 2383: The molecular binding mechanism of tislelizumab, an investigational anti-PD-1 antibody, is differentiated from pembrolizumab and nivolumab
Authors: Yingcai Feng, Yuan Hong, Hanzi Sun, Bo Zhang, Hongfu Wu, Kang Li, Xuesong (Mike) Liu, Ye Liu
Journal: Cancer Research (2019)

Abstract Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor expressed by activated T, B, and NK cells, which interacts with its ligand PD-L1/L2 to inhibit T-cell proliferation and effector functions such as tumor cell killing and cytokine production. Two anti-PD-1 antibodies approved by the FDA, pembrolizumab and nivolumab, have shown efficacy in many cancer types, nevertheless there are some indications where limited efficacy is observed. Tislelizumab (BGB-A317), an investigational anti-PD-1 antibody, has demonstrated significant clinical activity (85.7% ORR, including 61.4% CR) in relapsed/refractory classical Hodgkin’s lymphoma (R/R cHL). Additionally, tislelizumab is being studied in global pivotal trials in a number of malignancies, including non-small cell lung cancer, hepatocellular carcinoma, and esophageal squamous cell carcinoma. However, how tislelizumab binds to PD-1 has yet to be shown, particularly in comparison to pembrolizumab and nivolumab. Here we report the co-crystal structure of PD-1 extracellular domain and the Fab of tislelizumab. Tislelizumab interacts with IgV-like domain of PD-1 with an interface area of 1112 Å2. Structure-guided mutagenesis of PD-1 and surface plasmon resonance were performed to compare the binding of tislelizumab, pembrolizumab and nivolumab to mutant and wild type PD-1. The dissociation rate (kd) of tislelizumab from wild type PD-1 is about 100-fold and 50-fold slower than that of pembrolizumab and nivolumab, respectively. Gln75, Thr76, Asp77 and Arg86 on PD-1 are critical epitopes for tislelizumab, but mutation of them showed little effect on binding of PD-1 to pembrolizumab and nivolumab. Both the co-crystal structure and mutagenesis study identified the unique epitopes of tislelizumab that correlate to the extremely slow-off property of tislelizumab after binding to PD-1. In conclusion, we observed that tislelizumab is differentiated from pembrolizumab and nivolumab by its unique binding epitopes as well as binding kinetics. Citation Format: Yingcai Feng, Yuan Hong, Hanzi Sun, Bo Zhang, Hongfu Wu, Kang Li, Xuesong (Mike) Liu, Ye Liu. The molecular binding mechanism of tislelizumab, an investigational anti-PD-1 antibody, is differentiated from pembrolizumab and nivolumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2383.
Abstract 1496: Novel hCD3e mouse models for preclinical pharmacology studies of therapeutic bi-specific antibodies
Authors: Jie Xiang, Yanan Li, Yuelei Shen, Yanan Guo
Journal: Cancer Research (2019)

Abstract Recently it has been demonstrated that T cell-mediated immunotherapy is an attractive treatment strategy for various diseases. For this therapeutic approach, the CD3 complex is one of the key targets to modulate T cell activation; however, in many instances we cannot directly evaluate antibody candidates in mice because the monoclonal antibodies specific to human CD3 cannot cross-react to mouse endogenous CD3. In order to overcome the current model limitation, we have generated CD3e-extracellular domain KI mice for anti-human CD3e bispecific antibody in vivo efficacy evaluation. In this model, the mouse CD3e extracellular domain was replaced by human CD3e. We used conventional mouse ES/HR technology to knock-in human CD3e genomic DNA from the 3’ end of exon 2 to the 5’ end of exon7 to replace murine exon 2-exon 6. CD3e is one of four subunits of the CD3 co-receptor, which plays an important role in the immune response, associating with the T cell receptor (TCR) to couple antigen recognition to intracellular signal transduction, leading to T cell activation. We have characterized our B-hCD3e mice with the following features: 1.Mouse CD3e+ cells were detected in the wildtype C57BL/6 mice, while human CD3e+ cells were only detected in the homozygous B-hCD3e mice. 2.T cell development was normal in B-hCD3e homozygous mice. 3.T cell subtypes in the spleen, thymus, lymph nodes, and PBMC in B-hCD3e mice were similar and comparable to that in wildtype C57BL/6 mice. 4.Normal in vitro T cell proliferation and cytokine production were found in anti-hCD3e antibody treated humanized B-hCD3e mice 5.Mouse anti-PD-1 antibody can significantly repress the growth of MC38 tumor cells engrafted on B-hCD3e mice, suggesting that T cells in B-hCD3e mice are functionally normal 6.Treatment of B-hCD3e mice with anti-human CD3e antibody OKT leads to T cell depletion, resulting in more aggressive tumor growth. Furthermore, efficacy and toxicity evaluation of CD3e based bispecific antibodies in B-hCD3e mice are ongoing. Based on our data from extensive phenotypical analyses of B-hCD3e mice, we believe this novel humanized CD3e mouse model will be very useful for in vivo efficacy studies of CD3- mediated therapy, especially anti-CD3e bi-specific antibodies. Citation Format: Jie Xiang, Yanan Li, Yuelei Shen, Yanan Guo. Novel hCD3e mouse models for preclinical pharmacology studies of therapeutic bi-specific antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1496.
Pro-Inflammatory State of MGUS and Myeloma Patients Presenting with a Monoclonal Immunoglobulin Specific for an Infectious Pathogen
Authors: Adrien Bosseboeuf, Delphine Feron, Sophie Allain-Maillet, Nicolas Mennesson, Cathy Charlier, Anne Tallet, Francois Girodon, Laurent Garderet, Cédric Rossi, Denis Caillot, Philippe Moreau, Pierre Weigel, Eric Piver, Edith Bigot-Corbel, Jean Harb, Sylvie Hermouet
Journal: Blood (2017)
Abstract 3693: GLIS1 can replace MYC to generate induced pluripotent stem cells from ovarian cancer cells
Authors: S Bindhya, C Sidhanth, S Krishnapriya, R P. Nagare, M Garg, T S. Ganesan
Journal: Cancer Research (2019)

Abstract Ovarian cancer is the most common cause of mortality among gynecological cancers, despite advances in treatment. Recurrence is common and is due to development of drug resistance. One of the reasons for drug resistance is the persistence of cancer stem cells. To understand the role of CSCs, it is essential to capture and propagate cells continuously in culture. Reprogramming cancer cells to induced pluripotent stem cells (iPSCs) is an approach to achieve this. An ovarian cancer cell line, PEO4 (high grade serous adenocarcinoma), was initially reprogrammed into iPSCs using the classical four factors OCT4, SOX2, KLF4 and MYC (OSKM) using STEMCCA by lentivirus transduction. Embryonic stem cell (ESC)-like bodies appeared between 8 to 15 days post-transduction. Morphology of the colonies resembled that of ESC colonies with defined border and tightly-packed cells. Two individual clones were further characterized. The reprogrammed PEO4-OSKM-iPSCs expressed alkaline phosphatase and pluripotency markers, NANOG, OCT4, SSEA4, TRA-1-60 and TRA-1-81 by immunofluorescence. Further, reverse-transcriptase-polymerase chain reaction (RT-PCR) analysis showed expression of the pluripotency markers NANOG, SOX2, OCT4, TERT, NESTIN, DMNT, DPPA4 in PEO4-OSKM-iPSC which were absent in the parental PEO4 cells. PEO4-OSKM-iPSC cells could be differentiated in vitro with appropriate growth factors into ectodermal, mesodermal and endodermal lineages. MYC was replaced with GLIS1 in the lentiviral cassette and PEO4 cells were able to be transformed to iPSCs. The transfection efficiency was two fold better with OCT4-SOX2-KLF4-GLIS1 with larger colonies. Individual iPSC colonies expressed all pluripotency markers and were able to differentiate into all 3 lineages. Characterization of iPSC cells for expression of cell surface markers specific for serous adenocarcinoma, showed that CD133, EPHA1, CD44 and LGR5 were expressed. Cell viability assays demonstrated that IC50 of cisplatin in parental PEO4 cells (15uM) was less as compared to iPSC cells (32uM) (p&amp;lt;0.03) and similarly, IC50 of paclitaxel was less in parental PEO4 (17 uM) as compared to iPSC cells (27 uM) (p&amp;lt;0.02). These results demonstrate for the first time that an ovarian cancer cell line derived from a patient with high grade serous adenocarcinoma can be reprogrammed. Further, GLIS1 can successfully replace MYC as a transcription factor to generate induced pluripotent stem cells. Citation Format: S Bindhya, C Sidhanth, S Krishnapriya, R P. Nagare, M Garg, T S. Ganesan. GLIS1 can replace MYC to generate induced pluripotent stem cells from ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3693.
A phase II study of myeloablative allogeneic hematopoietic stem cell transplantation (aHSCT) for acute lymphoblastic leukemia (ALL) in older patients using fludarabine and total body irradiation (Flu/TBI).
Authors: Omer Hassan Jamy, Donna E. Salzman, Antonio Di Stasi, Racquel Innis-Shelton, Costa Luciano, Lawrence S. Lamb, Shin Mineishi, Ayman A. Saad
Journal: Journal of Clinical Oncology (2019)

TPS7069 Background: Older adults with ALL have poor survival outcomes. Although aHSCT can be curative when used as consolidation after complete remission (CR), advanced age, limited performance status, and comorbidities are risk factors for increased non-relapse mortality (NRM) after myeloablative aHSCT. The 1-year disease free survival (DFS) for patients ≥ 40 years who receive an aHSCT for ALL is often estimated to be 40-50%. Previous studies have demonstrated the efficacy of TBI-based regimens in adults with ALL when combined with cyclophosphamide (Cy). Reduced intensity conditioning for ALL patients has fallen out of favor due to high relapse rate forfeiting the benefit of reduced NRM. High-dose Cy is, however, associated with cardiac, hemorrhagic and hepatic toxicities. Fludarabine (Flu) has emerged as a safer substitute of Cy (e.g. Flu/Bu replacing Bu/Cy) with favorable toxicity profile. Given the efficacy of TBI-based regimens in ALL, we hypothesized that a myeloablative regimen of Flu/TBI (12 Gy) is almost as effective as Cy/TBI 12 Gy in older adults with ALL undergoing aHSCT, but with less NRM confering survival benefit over Cy/TBI 12 Gy. Methods: This study is a single center, single-arm phase II clinical trial of Flu 40 mg/m 2 IV daily (days -7 to -4) and TBI 2 Gy X2 (days -3 to -1) as myeloablative conditioning for older adults (≥40 years old) or younger adults with significant comorbidities with ALL. Patients aged 40-65 years with ALL in CR, KPS ≥ 70, adequate organ function, and having HLA-matched sibling or unrelated donor will be eligible. The primary endpoint of the study is 1-year DFS post-transplant. Secondary endpoints include 1-year overall survival (OS), incidence and severity of acute and chronic GVHD, immune reconstitution and regimen related toxicity. The study has just finished accrual (January 2019) enrolling a total of 16 patients. This number of patients was pre-determined to give a probability ≤ 0.05 of concluding that the 1-year DFS rate exceeds 45%, and a probability of at least 0.80 of concluding that the 1-year DFS rate exceeds 45% (expecting 1-year DFS of 75%). Clinical trial information: NCT01991457.
Glucose Control in the Perioperative Period
Authors: Thomas E. Finucane
Journal: JAMA (2019)

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Abstract 4140: Discovery and characterization of novel highly potent A2A adenosine receptor antagonists for cancerimmunotherapy
Authors: Kyungik Lee, Seungah Jun, EunYoung Byun, Hosun Lee, Yongtaek Lee, MiJin Moon, Yu-Yon Kim, Hyun Jeong Kang, YoungGil Ahn, YoungHoon Kim, Kwee Hyun Suh
Journal: Cancer Research (2019)

Abstract Introduction: Extracellular adenosine produced at high concentrations within the tumor micro-environment (TME) and suppresses immune function via inhibition of immune cell activation. Targeting adenosine receptors has emerged as a novel method to activate anti-tumor immunity. In particular, A2A adenosine receptor (A2AR), one of the G-protein-coupled-receptors, exhibits immunosuppressive functions. Herein, we suggest novel A2AR antagonist lead compounds as a highly potent antagonist of A2AR for immunotherapy. Materials and Methods: Novel A2AR antagonist lead compounds were designed using CADD and synthesized as the active biologic inhibitory compound. The protein preparation and molecular docking were performed using Glide (Schrödinger). A radioligand binding assay was performed to evaluate the affinities of A2AR Antagonists for the human adenosine A2AR. The potencie of A2AR antagonists were determined by cAMP assay in HEK293-hA2AR cells and cAMP-mediated pCREB assay in human CD8+ T cells from whole blood. In vivo CT26 and MC38 syngeneic tumor models were used to assess the therapeutic effect of A2AR antagonists. Results: A2AR antagonist lead compounds showed strong binding affinities toward human A2AR. They also potently inhibited the NECA-mediated production of intracellular cAMP in HEK293 cells expressing human A2AR. Elevated intracellular cAMP following A2AR activation results in the phosphorylation of CREB (cAMP response element-binding protein). A2AR antagonist lead compounds treatment inhibited pCREB in NECA-stimulated HEK293-hA2AR and human CD8+ T cells. A2AR antagonist lead compounds inhibited tumor growth of mouse syngeneic tumor models as a single agent and combination with anti-PD-L1. In combination with anti-PD-L1, A2AR antagonist lead compounds had remarkable antitumor activities in multiple mouse tumor models, including restoration of immune responses in models that incompletely responded to anti-PD-L1 monotherapy. Conclusion: These results showed the potencies of A2AR antagonist lead compounds with high capability of A2AR inhibition. Blockade of the adenosine signaling pathway may be vital for enhancing anti-tumor responses in solid tumors that show an incomplete response to anti-PD-L1 therapy. A2AR antagonist lead compounds demonstrate a novel approach to anti-cancer immunotherapy. Citation Format: Kyungik Lee, Seungah Jun, EunYoung Byun, Hosun Lee, Yongtaek Lee, MiJin Moon, Yu-Yon Kim, Hyun Jeong Kang, YoungGil Ahn, YoungHoon Kim, Kwee Hyun Suh. Discovery and characterization of novel highly potent A2A adenosine receptor antagonists for cancerimmunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4140.
DNA-Dependent Protein Kinase Drives Prostate Cancer Progression through Transcriptional Regulation of the Wnt Signaling Pathway
Authors: Vishal Kothari, Jonathan F. Goodwin, Shuang G. Zhao, Justin M. Drake, Yi Yin, S. Laura Chang, Joseph R. Evans, Kari Wilder-Romans, Kristina Gabbara, Emanuela Dylgjeri, Jonathan Chou, Grace Sun, Scott A. Tomlins, Rohit Mehra, Kristen Hege, Ellen H. Filvaroff, Edward M. Schaeffer, R. Jeffrey Karnes, David A. Quigley, Dana E. Rathkopf, Housheng H. He, Corey Speers, Daniel E. Spratt, Luke A. Gilbert, Alan Ashworth, Arul M. Chinnaiyan, Ganesh V. Raj, Karen E. Knudsen, Felix Y. Feng
Journal: Clinical Cancer Research (2019)

Protein kinases are known to play a prominent role in oncogenic progression across multiple cancer subtypes, yet their role in prostate cancer progression remains underexplored. The purpose of this study was to identify kinases that drive prostate cancer progression.