tbuckley/cabot-search huggingface dataset:
Abstract 17277: Apixaban Use in Patients With Atrial Fibrillation With Bioprosthetic Valves: Insights From ARISTOTLE
Authors: Sean D Pokorney, Meena P Rao, Daniel M Wojdyla, Bernard J Gersh, Renato D Lopes, Basil S Lewis, Michael Hanna, Alvaro Avezum, Lars Wallentin, John H Alexander, Christopher B Granger
Journal: Circulation (2015)

Background: The package insert for apixaban recommends against its use for stroke prevention in patients with atrial fibrillation (AF) with prosthetic heart valves. There are no published data on the use of apixaban in patients with AF with bioprosthetic valves. This analysis provides preliminary exploratory data on the safety and efficacy of apixaban in these patients. Methods: The ARISTOTLE trial randomized patients with AF to apixaban versus warfarin, and patients with a history of bioprosthetic valve replacement were eligible for inclusion in the trial. In this secondary analysis, baseline characteristics of patients with bioprosthetic valves were compared between apixaban and warfarin patients using Wilcoxon tests for continuous variables and chi-square tests for categorical variables. Unadjusted endpoints were compared between randomized treatments using a Cox regression model. With data collection on these valve patients ongoing, this interim report represents 82 of 260 patients with a history of valve surgery from ARISTOTLE. Results: Among 82 patients with bioprosthetic valves, 41 patients each were in the apixaban and warfarin arms. The patients had a median age of 78 years (vs. 70 years in overall trial), 18% had prior stroke (vs. 19% in overall trial), and 41% had concomitant aspirin use (vs. 31% in overall trial). Other than a higher rate of hypertension in the warfarin arm (98% vs. 81%, p=0.03), there were no statistically significant differences in baseline characteristics between the two groups. There were few events in patients with bioprosthetic valves. There were 2 stroke events, and there were no statistically significant differences between the apixaban and warfarin groups for major bleeding, stroke/systemic embolism, all-cause death, or cardiovascular death (Table). Conclusions: Among the small number of patients in ARISTOTLE with bioprosthetic valves, there were few events with similar event rates in both the apixaban and warfarin groups.
Comparative effectiveness of everolimus versus chemotherapies among post-menopausal women with HR+/HER2- metastatic breast cancer: A retrospective chart review of community oncology practices in the US.
Authors: Nanxin Li, Yanni Hao, Jipan Xie, Peggy L. Lin, Valerie Koo, Erika Ohashi, Eric Qiong Wu
Journal: Journal of Clinical Oncology (2015)

e11520 Background: Everolimus-based therapies (EVE) and chemotherapies (CT) are commonly used to treat post-menopausal women with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) metastatic breast cancer (mBC). This study compared key effectiveness outcomes between these treatments in a real-world setting. Methods: This retrospective chart review examined a nationwide sample of post-menopausal HR+/HER2- mBC women in community-based oncology practices. Patients were required to have received EVE or CT (index therapy) for mBC between July 1, 2012 and April 15, 2013, after failure of a non-steroidal aromatase inhibitor. Overall survival (OS), progression-free survival (PFS), and time on treatment (TOT), all measured from index therapy initiation, were compared between patients initiated EVE and those initiated CT using Kaplan-Meier analysis and Cox proportional hazards model adjusting for baseline characteristics. Results: A total of 234 and 137 patients received EVE and CT, respectively, were selected. At baseline, EVE treated patients were older, more likely to be white, and had lower proportion of liver, lung, and any visceral metastases, as well as fewer metastatic sites and lower tumor volume compared to CT treated patients. Multivariable-adjusted Cox model results showed that EVE was associated with significantly longer OS [hazard ratio (HR) = 0.37, 95% confidence interval (CI): 0.22 – 0.63], PFS (HR = 0.70, 95% CI = 0.50 – 0.97), and TOT (HR = 0.34, 95% CI: 0.25 - 0.45) than CT. When further adjusted by interaction between line of therapy and treatment arms, HRs ranged from 0.30 to 0.45 for OS, 0.56 to 0.86 for PFS, and 0.29 to 0.53. Conclusions: Our study showed that treatment with EVE was associated with significantly longer OS, PFS, and TOT compared with CT, in post-menopausal HR+/HER2- mBC patients.
Abstract MS2-1: MS2-1 Targeting the ATR checkpoint in cancer therapy
Authors: L Zou
Journal: Cancer Research (2017)

Abstract Rémi Buisson1, Michael S. Lawrence2, Cyril H. Benes1 &amp; Lee Zou1,3 1. Massachusetts General Hospital Cancer Center &amp; Harvard Medical School, Boston, MA. 2. Broad Institute of Harvard and MIT, Cambridge, MA. 3. Department of Pathology, Massachusetts General Hospital &amp; Harvard Medical School, Boston, MA. Recent cancer genomics studies have revealed that the mutation signatures of APOBEC3A/B are commonly detected in several cancer types, such as bladder, breast, head and neck cancers, lung adenocarcinoma, and lung squamous cell carcinoma. APOBEC3A/B are members of the APOBEC family of cytosine deaminases. While APOBEC3 proteins are important for the innate immunity against viral infection, they are not expressed in normal tissues. When APOBEC3A/B are aberrantly expressed in cancer cells, they become potent “mutators”, which may promote genomic instability and contribute to tumor evolution. Interestingly, recent studies have suggested that APOBEC3A/B may act during DNA replication. However, whether the APOBEC3A/B activity in cancer cells induces DNA replication stress, and whether this activity creates a vulnerability in cancer cells that can be exploited therapeutically, remains unknown. In this study, we show that APOBEC3A imposes a unique type of mutator-driven DNA replication stress, and that the ATR kinase plays a crucial role in antagonizing this stress. APOBEC3A expression activates ATR during DNA replication through UNG2-generated abasic sites. Surprisingly, ATR inhibition in APOBEC3A-expressing cells results in a drastic surge of abasic sites at replication forks, revealing an ATR-mediated feedback loop countering the action of APOBEC3A during replication. Mechanistically, ATR inhibition unleashes APOBEC3A-driven ssDNA accumulation at replication forks, which propagates the substrate of APOBEC3A and ultimately drives cells into replication catastrophe. In a panel of cancer cell lines, ATR inhibitor selectively induces replication catastrophe in those harboring high APOBEC3A/B activity, showing that the APOBEC3A/B activity in cancer cells confers susceptibility to ATR inhibition. Together, these results suggest that the unique APOBEC-driven replication stress in cancer cells may offer a new opportunity for ATR-targeted therapy. Citation Format: Zou L. MS2-1 Targeting the ATR checkpoint in cancer therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr MS2-1.
The Type of Enteropathy Is a Prognostic Factor in Enteropathy-Associated T-Cell Lymphoma.
Authors: Marie-Olivia Chandesris, Georgia Malamut, Virginie Verkarre, Bertrand Meresse, Gabriel Rahmi, Elizabeth Macintyre, Nicole Brousse, Nadine Cerf-Bensussan, Christophe Cellier, Olivier Hermine
Journal: Blood (2009)
Phase II study of bevacizumab plus irinotecan and carboplatin for recurrent WHO grade 3 malignant gliomas with no prior bevacizumab failure.
Authors: Annick Desjardins, James J Vredenburgh, Katherine B. Peters, Stevie Threatt, James Emmett Herndon, John Howard Sampson, Allan H. Friedman, Henry S. Friedman, David A. Reardon
Journal: Journal of Clinical Oncology (2012)

2095^ Background: No standard treatment exists for recurrent WHO grade 3 malignant glioma patients. Bevacizumab (BV) with irinotecan has significant anti-tumor activity for recurrent glioblastoma. Carboplatin has anti-glioma activity and can potentiate the cytotoxicity of irinotecan. We evaluated the progression-free survival (PFS) of BV in combination to irinotecan and carboplatin in recurrent WHO grade 3 malignant gliomas, as well as its safety. Methods: Adult patients with measurable recurrent WHO grade 3 malignant glioma, ≥12 weeks after radiation therapy, ≥4 weeks after chemotherapy, with adequate organ function, KPS ≥70%, no prior failure or grade ≥3 toxicity to the agents, and no contraindications to BV were eligible for study. Patients received BV at 10 mg/kg with irinotecan on days 1 and 15 of a 28-day cycle. The dose of irinotecan was 125 mg/m2 for patients not on enzyme inducing anti-epileptics (EIAEDs) and 340 mg/m2 for patients on EIAEDs. All patients received carboplatin at an AUC of 4 on day 1 of each cycle. MRIs were obtained every 8 weeks. Results: As planned, 39 WHO grade III malignant glioma patients were enrolled on study. Median age was 47 (range, 26-71). At a median follow up of 14 months, the 6-month PFS is 69% and the median PFS is 11 months. A median of 8 cycles were given. Seven patients completed the planned course of treatment (12 cycles) with hypometabolic PET scan and nine patients remain on study. Fifteen patients came off study due to disease progression and eight due to toxicity. As of 1/25/2012, 22 patients are still alive and 17 have died. Grade 3-4 toxicities included: neutropenia (grade 3, n=12; grade 4, n= 1), thrombocytopenia (grade 3, n=6; grade 4, n=4), nausea (grade 3, n=7), diarrhea (grade 3, n=2), deep venous thrombosis (grade 3, n=2), febrile neutropenia (grade 3, n=1; grade 4, n=1), fatigue (grade 3, n=8; grade 4, n=1), cerebral infarction (grade 4, n=3), intracranial hemorrhage (grade 4, n=1), posterior reversible encephalopathy syndrome (grade 3, n=1). Conclusions: The combination of bevacizumab, irinotecan and carboplatin for WHO grade 3 malignant glioma patients is effective and with no more than expected toxicity.
Abstract #1109: The signaling pathway PAR1-PAFR-MCAM/MUC18 links inflammation with melanoma metastasis
Authors: Vladislava Melnikova, Krishnakumar Balasubramanian, Andrey Dobroff, Gabriel Villares, Maya Zigler, Hua Wang, Janet Price, Alan Schroit, Menashe Bar-Eli
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

The development of tumor metastasis comprises a complex cascade of events that involves multiple intercellular interactions. Cellular and molecular pathways that regulate platelet activation, blood coagulation, and inflammation are critical players in tumor growth and metastasis. In particular, thrombin and platelet activating factor (PAF), through the activity of their specific G-protein-coupled receptors, act as putative mediators of tumor growth, angiogenesis, and metastasis. Surprisingly little is known about their mechanism(s) of action. Here, we demonstrate a novel signaling axis whereby the activation of Protease-Activated Receptor 1 (PAR1) regulates melanoma cell adhesion to endothelial cells, diapedesis, and lung metastasis via PAF receptor-mediated expression of the Melanoma Cell Adhesion Molecule MCAM/MUC18, thus linking the inflammatory microenvironment with melanoma metastasis. Indeed, in A375SM and C8161-c9 metastatic melanoma cells, silencing of PAR1 with small hairpin RNA resulted in downregulation of expression of PAFR and a decrease in PAF production. Silencing of either PAR1 or PAFR expression abrogated expression of MCAM/MUC18, a critical marker of homo- and heterotypic adhesion in melanoma. Overexpression of PAFR led to restoration of MCAM/MUC18 expression in PAR1shRNA cells, suggesting that PAFR acts downstream of PAR1. PAR1 silencing resulted in a loss of MCAM/MUC18 promoter activity, which was associated with the decreased binding and activity of CREB. Silencing of PAR1 or CREB also induced stronger in vivo binding of EGR1 and inhibition of Sp1 binding to MCAM/MUC18 promoter. Furthermore, silencing of PAR1 resulted in dramatic inhibition of melanoma cell adhesion and migration over the Human Dermal Microendothelial Cells (HDMECs), as well as a decreased retention of melanoma cells in lungs of nude mice after tail vein injection. Silencing MCAM/MUC18 produced similar non-metastatic phenotype. However, while melanoma cell adhesion to HDMECs, diapedesis and retention in lungs were rescued upon overexpression of PAFR in PAR1shRNA cells, only adhesion was rescued by overexpression of MCAM/MUC18. This suggested that in addition to MCAM/MUC18, other downstream targets of PAR1/PAFR signaling axis were required for metastatic dissemination of melanoma cells. Indeed, RT-PCR analysis in PAR1shRNA and PAFRshRNA cells revealed that PAR1 and PAFR modulate expression of the MMP-2 and VEGF, which are known to increase tumor cell invasiveness, vascular permeability, and metastatic dissemination into lungs. Overall, our results suggest that PAR1 and PAFR are critical targets for intervention with melanoma metastasis.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1109.
Outcome of Elderly Frail Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Prospectively Identified by Comprehensive Geriatric Assessment (CGA). Results From a Study of the Intergruppo Italiano Linfomi (IIL)
Authors: Francesco Merli, Stefano Luminari, Giuseppe Rossi, Caterina Mammi, Luigi Marcheselli, Isabel Alvarez, Alessandra Tucci, Caterina Stelitano, Fiorella Ilariucci, Maurizio Musso, Luca Baldini, Alberto Fragasso, Annalisa Chiappella, Massimo Federico
Journal: Blood (2010)
Cost utility analysis of a randomized radiation therapy trial among patients with one to three brain metastases.
Authors: Anna Likhacheva, Lincy S. Lal, Eric L. Chang, Paul D. Brown, John Michael Swint
Journal: Journal of Clinical Oncology (2014)

2077 Background: Two common options for the treatment of 1-3 brain metastases (BM) are whole brain radiotherapy with stereotactic radiosurgery boost (WBRT+SRS) and stereotactic radiosurgery alone (SRS). These two approaches entail differences in efficacy, neurocognitive toxicity and cost. Currently, there is an absence of evidence contrasting these two strategies both in terms of effectiveness and cost in a randomized setting. Methods: A randomized single institution trial tested the difference between outcomes and utilities among patients with 1-3 BM receiving WBRT+SRS or SRS alone. Patients receiving SRS alone could undergo salvage SRS or WBRT. Between 2001 and 2007, 58 patients were randomized to one of two arms. Another 42 patients refused the assigned treatment at randomization but were still followed prospectively. Institutional costs were utilized and adjusted using the Consumer Price Index. Overall survival (OS) was estimated by the Kaplan-Meier method. Utility score was derived using a time trade-off method. Cost per life-years saved and cost per quality-adjusted life-year (QALY) saved were calculated. Results: OS and utility scores in the SRS alone group were significantly higher than SRS+WBRT group among randomized patients (p=0.005 and p=0.05) while neither metric was statistically different in the non-randomized cohort (p=0.72 and p=0.5). The incremental cost effectiveness ratios (ICER) of SRS alone over WBRT+SRS were $47201, $74,560, and $56,455 per QALY for randomized patients, non-randomized patients and all patients, respectively. Sensitivity analysis demonstrated that the likelihood of having 1 versus 2-3 BM had the highest impact on ICER. Conclusions: The degree of cost effectiveness for SRS alone, as estimated by patient level costs in a prospective study, varied with whether the patients were randomized or chose their own treatment. Nonetheless, SRS alone for 1-3 brain metastases is a reasonable option from the payor perspective in all populations.
Indoxyl sulfate induces platelet hyperactivity and contributes to chronic kidney disease–associated thrombosis in mice
Authors: Ke Yang, Changhong Du, Xinmiao Wang, Fengju Li, Yang Xu, Song Wang, Shilei Chen, Fang Chen, Mingqiang Shen, Mo Chen, Mengjia Hu, Ting He, Yongping Su, Junping Wang, Jinghong Zhao
Journal: Blood (2017)
Abstract B61: Intratumoral oxygen gradients mediate sarcoma cell invasion
Authors: Daniel M. Lewis, Kyung Min Park, T.S. Karin Eisinger-Mathason, Celeste Simon, Sharon Gerecht
Journal: Cancer Research (2017)

Abstract Hypoxia is a critical factor in the progression and metastasis of many cancers including soft tissue sarcomas. Frequently, oxygen (O2) gradients develop in tumors as they grow beyond their vascular supply leading to heterogeneous areas of O2 depletion. Here we report the impact of hypoxic O2 gradients on sarcoma cell invasion and migration. O2 gradient measurements showed that large sarcoms mouse tumors (&amp;gt;300mm3) contain a severely hypoxic core (≤0.1% pO2) whereas smaller tumors possessed hypoxic gradients throughout the tumor mass (0.1%-6% pO2). To analyze tumor invasion, we utilized O2-controllable hydrogels to recreate the physio-pathological O2 levels in vitro. Small tumor grafts encapsulated in the hydrogels revealed increased invasion that was both faster and extended over a longer-distance in the hypoxic hydrogels compared to nonhypoxic hydrogels. To accurately model the effect of the O2 gradient, we examined individual sarcoma cells embedded in the O2-controllable hydrogel. We observed that hypoxic gradients guide sarcoma cell motility and matrix remodeling through HIF1α activation. We further found that in the hypoxic gradient, individual cells migrate more quickly, across longer distances, and in the direction of increasing O2 tension. Treatment with minoxidil, inhibitor of hypoxia-induced sarcoma metastasis, abrogated cell migration and matrix remodeling in the hypoxic gradient. Overall, we show that O2 acts as a 3D physico-tactic agent during sarcoma tumor invasion and propose the O2-controllable hydrogels as a predictive system to study early stages of the metastatic process and therapeutic targets. Citation Format: Daniel M. Lewis, Kyung Min Park, T.S. Karin Eisinger-Mathason, Celeste Simon, Sharon Gerecht. Intratumoral oxygen gradients mediate sarcoma cell invasion. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B61.
Sudden hearing loss in a melanoma patient on pembrolizumab: an etiology not to be omitted in the differential diagnosis
Authors: Marc-Elie Nader, Jeffrey N. Myers, Paul W. Gidley
Journal: Journal for ImmunoTherapy of Cancer (2017)

Immune checkpoint inhibitors have emerged as a promising therapeutic option for metastatic cancers. However, they have been associated with inflammatory adverse reactions in various organ systems. A recent article reported a case of sudden bilateral hearing loss that occurred in a patient with metastatic melanoma being treated with pembrolizumab. The authors attributed that complication to an autoimmune reaction secondary to the treatment. This commentary discusses the importance of considering the diagnosis of leptomeningeal metastasis in patients with metastatic melanoma who present with new cranial nerve deficits.
Cabozantinib in hepatocellular carcinoma: results of a phase 2 placebo-controlled randomized discontinuation study
Authors: R.K. Kelley, C. Verslype, A.L. Cohn, T.-S. Yang, W.-C. Su, H. Burris, F. Braiteh, N. Vogelzang, A. Spira, P. Foster, Y. Lee, E. Van Cutsem
Journal: Annals of Oncology (2017)

BackgroundCabozantinib, an orally bioavailable inhibitor of tyrosine kinases including MET, AXL, and VEGF receptors, was assessed in patients with hepatocellular carcinoma (HCC) as part of a phase 2 randomized discontinuation trial with nine tumor-type cohorts.Patients and methodsEligible patients had Child-Pugh A liver function and ≤1 prior systemic anticancer regimen, completed ≥4 weeks before study entry. The cabozantinib starting dose was 100 mg daily. After an initial 12-week cabozantinib treatment period, patients with stable disease (SD) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 were randomized to cabozantinib or placebo. The primary endpoint of the lead-in stage was objective response rate (ORR) at week 12, and the primary endpoint of the randomized stage was progression-free survival (PFS).ResultsAmong the 41 HCC patients enrolled, the week 12 ORR was 5%, with 2 patients achieving a confirmed partial response (PR). The week 12 disease control rate (PR or SD) was 66% (Asian subgroup: 73%). Of patients with ≥1 post-baseline scan, 78% had tumor regression, with no apparent relationship to prior sorafenib therapy. Alpha-fetoprotein (AFP) response (>50% reduction from baseline) occurred in 9 of the 26 (35%) patients with elevated baseline AFP and ≥1 post-baseline measurement. Twenty-two patients with SD at week 12 were randomized. Median PFS after randomization was 2.5 months with cabozantinib and 1.4 months with placebo, although this difference was not statistically significant. Median PFS and overall survival from Day 1 in all patients were 5.2 and 11.5 months, respectively. The most common grade 3/4 adverse events, regardless of attribution, were diarrhea (20%), hand-foot syndrome (15%), and thrombocytopenia (15%). Dose reductions were utilized in 59% of patients.ConclusionsCabozantinib has clinical activity in HCC patients, including objective tumor responses, disease stabilization, and reductions in AFP. Adverse events were managed with dose reductions.Trial registration numberNCT00940225.
Bortezomib in Combination with Epirubicin, Dexamethasone and Thalidomide Is a Highly Effective Regimen for Multiple Myeloma
Authors: Shuqing Lü, Jianmin Wang, Xiaoqian Xu, Xiong Ni, Huiying Qiu, Yi He, Bin Wang, Chongmei Huang, Jianmin Yang
Journal: Blood (2008)
CELL INTERACTIONS BETWEEN HISTOINCOMPATIBLE T AND B LYMPHOCYTES
Authors: Toshiyuki Hamaoka, David P. Osborne, David H. Katz
Journal: The Journal of Experimental Medicine (1973)

The adoptive transfer of 2,4-dinitrophenyl(DNP)-keyhole limpet hemocyanin(KLH)-primed lymphocytes into a heavily irradiated allogeneic recipient permits the development of a secondary anti-DNP antibody response to DNP-bovine gamma globulin(BGG) whether or not the irradiated allogeneic host possesses BGG-specific helper T cells. This "allogeneic effect" has been demonstrated to result from the capacity of residual, apparently radioresistant, T cells in the irradiated host to exert an active effect on the transferred histoincompatible B lymphocytes. This conclusion derives from two corroborative experiments. In the first, an allogeneic effect was shown to occur on DNP-primed F(1) spleen cells that had been adoptively transferred to irradiated parental recipients; the second experiment demonstrated the development of an allogeneic effect on anti-theta-treated, DNP-specific donor cells transferred to irradiated allogeneic hosts. These results emphasize the extreme caution required in designing and interpreting experiments that may involve adoptive cell transfers into histoincompatible hosts, and illustrate why such models are unsuitable for investigation of the question of physiologic cooperative interactions between T and B lymphocytes. Suitable approaches are described in the accompanying paper.
Subject Index Vol. 75, 2006
Authors: Chiara Brombin, Ernesto Caffo, J. Wiltink, P. Bech, H.V. Hansen, L.V. Kessing, C. Faravelli, C. Ravaldi, E. Truglia, T. Zucchi, F. Cosci, V. Ricca, Johann F. Kinzl, Katharina Hauer, Christian Traweger, Ingrid Kiefer, Chiara Ruini, Carlotta Belaise, A. Dippel, M. Szczepanski, R. Thiede, Yi-Ching Lu, M.E. Beutel, Giovanni A. Fava, Silvana Grandi, Stefania Fabbri, Naike Panattoni, Elisabetta Gonnella, Isaac Marks, Nina Rieckmann, Matthew M. Burg, William Gerin, William F. Chaplin, Lynn Clemow, Karina W. Davidson, Johan Denollet, Jacqueline J. Strik, Richel Lousberg, Adriaan Honig, Bih-Ching Shu, Yong-Yuan Chang, For-Wey Lung, Boudewijn van Houdenhove, Victor I. Spoormaker, Jan van den Bout
Journal: Psychotherapy and Psychosomatics (2006)