tbuckley/cabot-search huggingface dataset:
Safely Identifying Emergency Department Patients With Acute Chest Pain for Early Discharge
Authors: Simon A. Mahler, Kristin M. Lenoir, Brian J. Wells, Gregory L. Burke, Pamela W. Duncan, L. Douglas Case, David M. Herrington, Jose-Franck Diaz-Garelli, Wendell M. Futrell, Brian C. Hiestand, Chadwick D. Miller
Journal: Circulation (2018)

Background: The HEART Pathway (history, ECG, age, risk factors, and initial troponin) is an accelerated diagnostic protocol designed to identify low-risk emergency department patients with chest pain for early discharge without stress testing or angiography. The objective of this study was to determine whether implementation of the HEART Pathway is safe (30-day death and myocardial infarction rate &lt;1% in low-risk patients) and effective (reduces 30-day hospitalizations) in emergency department patients with possible acute coronary syndrome. Methods: A prospective pre-post study was conducted at 3 US sites among 8474 adult emergency department patients with possible acute coronary syndrome. Patients included were ≥21 years old, investigated for possible acute coronary syndrome, and had no evidence of ST-segment–elevation myocardial infarction on ECG. Accrual occurred for 12 months before and after HEART Pathway implementation from November 2013 to January 2016. The HEART Pathway accelerated diagnostic protocol was integrated into the electronic health record at each site as an interactive clinical decision support tool. After accelerated diagnostic protocol integration, ED providers prospectively used the HEART Pathway to identify patients with possible acute coronary syndrome as low risk (appropriate for early discharge without stress testing or angiography) or non-low risk (appropriate for further in-hospital evaluation). The primary safety and effectiveness outcomes, death, and myocardial infarction (MI) and hospitalization rates at 30 days were determined from health records, insurance claims, and death index data. Results: Preimplementation and postimplementation cohorts included 3713 and 4761 patients, respectively. The HEART Pathway identified 30.7% as low risk; 0.4% of these patients experienced death or MI within 30 days. Hospitalization at 30 days was reduced by 6% in the postimplementation versus preimplementation cohort (55.6% versus 61.6%; adjusted odds ratio, 0.79; 95% CI, 0.71–0.87). During the index visit, more MIs were detected in the postimplementation cohort (6.6% versus 5.7%; adjusted odds ratio, 1.36; 95% CI, 1.12–1.65). Rates of death or MI during follow-up were similar (1.1% versus 1.3%; adjusted odds ratio, 0.88; 95% CI, 0.58–1.33). Conclusions: HEART Pathway implementation was associated with decreased hospitalizations, increased identification of index visit MIs, and a very low death and MI rate among low-risk patients. These findings support use of the HEART Pathway to identify low-risk patients who can be safely discharged without stress testing or angiography. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02056964.
Abstract 18301: The Prognostic Utility of Dihomo-gamma-linolenic Acid (dgla) in Patients With Acute Coronary Heart Disease
Authors: Dennis W Nilsen, Hildegunn Aarsetoey, Volker Pønitz, Trygve Brugger-Andersen, Harry Staines, William S Harris, Heidi Grundt
Journal: Circulation (2017)

Introduction: We previously investigated the prognostic utility of red blood cell (RBC) n-3 fatty acids (FAs) in survivors of an acute myocardial syndrome (ACS) but found no relationship with all-c...
Abstract LB-188: Breast cancer immunotherapy using magnetized HSV1716
Authors: Haider AL-Janabi, Joe Conner, Faith Howard, Stuart Hunt, Zainab Taher, Sarah Staniland, Munitta Muthana
Journal: Cancer Research (2019)

Abstract Background: Oncolytic viruses (OV) are encouraging new immunotherapies for cancer. OVs, replicate in cancer cells inducing immunogenic cell death (ICD) and activating antitumor immunity. To date, clinical use has focused on intratumoral delivery due to concerns over inadequate tumor targeting following systemic administration. We hypothesize that magnetizing OVs and magnetic guidance strategies will improve systemic delivery by protecting the viruses from inactivating immune mechanisms and non-specific adsorption. Methods: To investigate this, we synthesized and characterized complexes of magnetized oncolytic herpes simplex virus (HSV1716) co-assembled with biocompatible magnetic nanoparticles (MAG) derived from magnetotactic bacteria (AMB-1) to give MAG-HSV1716 complexes. Characterization of the physical, chemical and oncolytic potential of our MAG-HSV1716 was performed. The safety and efficacy of our nanomedicine in combination with magnetic guidance strategies were also assessed in vivo. Results: Stable MAG-HSV1716 complexes of ~160nm diameter successfully infected human and murine breast cancer cells in a dose-dependent manner, and induced tumor oncolysis. Following MAG-HSV1716 infection a significant increase in viral replication (ICP0, gB, ICP8), ICD (HMGB1, CALR, ATP) and apoptotic (CASP 3, CASP8, FASL) signals were detected. Intravenous delivery of MAG-HSV1716 resulted in reduced tumour burden in the presence of magnetic guidance (MAG-HSV1716 448.3mm³ vs. HSV1716 670.6mm³; p ≤ 0.05, n=6-9 mice/group) and an increase in tumor-infiltrating T-cells, NK cells and neutrophils. Furthermore, MAG-HSV1716 were protective in the presence of neutralizing Abs both in vitro and in vivo. Conclusion: This study indicates that magnetizing HSV1716 results in viral protection from neutralizing antibodies and in combination with magnetic guidance reduces tumor burden and induces anti-tumor immunity. Citation Format: Haider AL-Janabi, Joe Conner, Faith Howard, Stuart Hunt, Zainab Taher, Sarah Staniland, Munitta Muthana. Breast cancer immunotherapy using magnetized HSV1716 [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 LB-188.
Clinicopathologic features of multiple phyllodes tumors of the breast.
Authors: Fumi Yoshidaya, Naoki Hayashi, Atsushi Yoshida, Hiroshi Yagata, Hiroko Tsunoda, Koyu Suzuki, Seigo Nakamura, Hideko Yamauchi
Journal: Journal of Clinical Oncology (2013)

1126 Background: Phyllodes tumor of the breast is one of the rare neoplasm accounting for 0.3-0.5% of all breast tumors. It is difficult to diagnose the histological type of phyllodes tumors preoperatively by radiological and even pathological findings. The aim of this study is to clarify the clinicopathological features of phyllodes tumors. Methods: We retrospectively reviewed records from 116 patients with phyllodes tumors who underwent surgery between 2003 and 2011. We determined the clinicopathological characteristics, including the presense of multiple lesions and the type of surgical procedure, of each histological type of phyllodes tumors which were classified as benign, borderline, and malignant. Results: The median follow-up time was 23.3 months. Benign phyllodes tumors were presented in 91 patients (78.4 %), borderline were in 17 patients (14.6 %), and malignant were in 8 patients (6.9 %). Ten patients (8.6 %) had multiple phyllodes tumors; 9 for ipsilateral and one for bilateral breasts. One hundred two patients underwent lumpetcomy and 14 patients underwent mastectomy. No patients received chemotherapy or radiation therapy. Noteworthy, all multiple tumors were diagnosed histologically benign. The median age at operation were 41 years (range, 12-72 years) for benign tumors, 44 years (26-67 years) for borderline, and 47 years (39-60 years) for malignant. The size of malignant tumors was significantly large (a median, 11.3 cm; range, 6-27 cm) compared to benign (a median, 4.4 cm; range 1-21 cm) and borderline (a median, 4.7cm; range 1-16 cm) (p = 0.001, and 0.03, respectively). Local recurrence developed in 14 of the 91 patients (15.4 %) with benign, 2 of the 17 patients (11.8 %) with borderline, and 2 of the 8 patients (25 %) with malignant tumors. Four patients (50 %) with malignant tumors but none with benign and borderline developed distant metastasis. Of the 4 patients, 3 had undergone mastectomy and one had lumpetcomy for initial treatment. No benign and borderline tumor had malignant change when tumors recurred. Conclusions: Our new findings indicated that multiple phyllodes tumors may be histologically benign. Furthermore, patients with benign or borderline phyllodes tumors had good prognosis regardless of surgical procedure.
Abstract 2779: miR-142-3p as a regulator of RAC1 and a prognostic factor in melanoma
Authors: Adriana T. Cruz, Júlia A. Morata, Ana C. Monteiro, Ana Luísa P. Ayub, Roseli S. Soares, André Fujita, Fernando Andrade, Victor Tron, Miriam G. Jasiulionis
Journal: Cancer Research (2019)

Abstract In order to identify miRNAs able to distinguish melanoma patients with good or poor prognosis, the expression profile of a panel of miRNAs evaluated in primary melanoma samples from 65 patients was compared to clinicopathological data from these patients (Breslow’s depth, mitotic counts, metastasis progression and survival). The miR-142-3p was identified as presenting at least 2-fold reduced expression in melanoma samples from patients with poor prognosis for 3 of 4 clinical parameters analyzed compared to melanoma samples from patients with good prognosis. The miR-142-3p expression was validated by RT-qPCR in primary human melanoma samples, confirming a significant lower expression in melanoma patients with poor prognosis compared to those with good prognosis. Searching for miR-142-3p mRNA targets in melanoma, the gene expression profile was analyzed by gene microarrays in a wild type and miR-142-3p overexpressing melanoma cell line. RAC1, ITGB8 e GNB2 were found as potential targets of this miRNA. Protein expression analyses in melanoma cell lines overexpressing the miR-142-3p reinforced the regulation of RAC1 by this miRNA. Functional assays showed that the overexpression of miR-142-3p leads to a reduced migratory ability compared to control cells, indicating its role in cell migration process. Finally, multivariate COX analyses demonstrated that high levels of RAC1 and reduced levels of miR-142-3p predict poor progression-free survival of melanoma patients, revealing these molecules as potential prognostic biomarkers for melanoma patients. Supported by FAPESP, CNPQ and CAPES Short title: miR-142-3p as a prognostic factor in melanoma Note: This abstract was not presented at the meeting. Citation Format: Adriana T. Cruz, Júlia A. Morata, Ana C. Monteiro, Ana Luísa P. Ayub, Roseli S. Soares, André Fujita, Fernando Andrade, Victor Tron, Miriam G. Jasiulionis. miR-142-3p as a regulator of RAC1 and a prognostic factor in melanoma [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 2779.
Multimorbidity patterns and their association with survival in a large national cohort of older veterans with multiple myeloma.
Authors: Nathanael Fillmore, Clark DuMontier, David Cheng, Diana Cirstea, Sarvari Yellapragada, Saiju Pyarajan, Nhan Do, Dae Kim, Gregory A. Abel, Mary T. Brophy, Jane A. Driver, Nikhil C. Munshi
Journal: Journal of Clinical Oncology (2019)

8033 Background: The majority of older adults carry two or more chronic conditions (multimorbidity). Although comorbidity in multiple myeloma (MM) has often been described with comorbidity counts, the impact of multimorbidity clusters has yet to be investigated. Methods: In a national cohort of 7815 patients aged ≥60 years diagnosed with and treated for MM in Veterans Affairs Healthcare System, we extracted 53 chronic conditions from claims in the 3 years preceding diagnosis using the Centers of Medicare and Medicaid Services-defined chronic and disabling conditions. We performed latent class analysis to identify patterns of multimorbidity that coexisted with MM at diagnosis. We then assessed whether these multimorbidity patterns were associated with survival in 5992 non-transplanted patients initially treated with either doublet or triplet chemotherapy regimens, adjusting for MM stage, sociodemographic factors, and prognostic lab values. Results: Mean follow up time was 3.1 years (SD, 2.6). We identified 6 multimorbidity clusters at the time of MM diagnosis: minimal disease (1302 patients, 16.7%), cardiovascular disease (2011, 25.7%), diabetes and complications (1820, 23.3%), psychiatric and substance use disorders (931, 11.9%), chronic lung disease (759, 9.7%), and multisystem impairment (992, 12.7%). In patients initially treated with doublet or triplet chemotherapy, survival varied across multimorbidity patterns (p &lt; 0.001); patients with minimal disease had the best survival (median survival [MS] = 4.5 years, 5-year survival = 47.5%), and patients with multisystem impairment had the worst (MS = 2.4 years, 5-year survival = 24.3%). After adjustment for covariates, patients with clusters of chronic lung disease (HR = 1.40 [1.22-1.60]), psychiatric and substance use (HR = 1.57 [1.37-1.79]), and multisystem impairment (HR = 1.71 [1.50-1.94]) had higher hazards of death than patients with minimal disease. Conclusions: We found higher-impact and lower-impact multimorbidity clusters among older veterans with newly-diagnosed MM treated with chemotherapy. Unique combinations of chronic diseases may interact with MM itself to drive differences in mortality.
Final results of the randomized phase II VOLFI trial (AIO- KRK0109): mFOLFOXIRI + Panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild-type metastatic colorectal cancer (mCRC)
Authors: M. Geissler, A. Tannapfel, A. Reinacher-Schick, U. Martens, J. Ricke, J. Riera-Knorrenschield, S. Kanzler, S. Held, V. Heinemann, T. Seufferlein, D. Modest
Journal: Annals of Oncology (2019)
Abstract 2803: CSF-1 receptor-mediated macrophage depletion can induce immunomodulatory resistance mechanisms in murine tumor models
Authors: Sarah A. O'Brien, Katarzyna Skrzypczynska, Jessica Orf, Brian Belmontes, Hong Tan, Daniel Lu, Ian Driver, Jackson Egen
Journal: Cancer Research (2019)

Abstract Tumor associated macrophages (TAMs) are present within the stroma of most solid tumors where they can act to inhibit immune responses and promote disease progression through expression of immunosuppressive factors and modulation of tumor stroma. Tumor immunotherapies aimed at depletion of TAMs, for instance through the use of blocking antibodies against the CSF1 receptor (CSF1R), have been widely explored, with multiple studies demonstrating that blocking TAM function can inhibit tumor growth/metastasis and stimulate anti-tumor immunity. In order to further dissect the functions of TAM populations and define conditions under which antiCSF1R immunotherapy may have benefit, we evaluated the effect of antiCSF1R treatment on multiple subcutaneous murine tumor models with varying dosing parameters. Despite robust macrophage depletion, some tumor models, such as Renca renal cell adenocarcinoma, showed only a modest change in tumor volume and minimal effector T cell recruitment or activation in response to anti-CSF1R therapy. Comprehensive flow cytometry-based immunophenotyping and single-cell RNA sequencing on immune cells isolated from antiCSF1R and isotype control-treated Renca tumors revealed shifts in gene expression patterns related to vascular remodeling, hypoxic responses, and enhanced regulatory T cell activity. These studies indicate macrophage depletion may, under some conditions, result in compensatory anti-tumor immune responses that could limit the clinical benefit of this therapeutic approach. Citation Format: Sarah A. O'Brien, Katarzyna Skrzypczynska, Jessica Orf, Brian Belmontes, Hong Tan, Daniel Lu, Ian Driver, Jackson Egen. CSF-1 receptor-mediated macrophage depletion can induce immunomodulatory resistance mechanisms in murine tumor models [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 2803.
Real-world guideline application in the management of pancreatic cancer patients: the Italian GARIBALDI study
Authors: M. Reni, F. Bergamo, L. Cavanna, M. Spada, M. Ghidini, E. Giommoni, E. Maiello, F. Artioli, G. Cardellino, V. Torri, M. Cinquini, V. Giugliano, C. Pinto
Journal: Annals of Oncology (2019)
A phase Ib/II study of oral nanatinostat (N) and valganciclovir (VG) in subjects with Epstein-Barr virus (EBV)-associated lymphomas.
Authors: Pierluigi Porcu, Bradley Haverkos, Elizabeth Brem, Anusha Vallurupalli, Tatyana Feldman, Onder Alpdogan, Jonathan Edward Brammer, Locke Johnson Bryan, Stefan K. Barta, Sebastian Obrzut, Hao Shen, Rosemary Rochford, Robert A. Baiocchi, Corey Casper, John Gutheil, Robert McRae, Preston Daniels, Marshelle Smith Warren, Ivor Royston, Douglas V. Faller
Journal: Journal of Clinical Oncology (2019)

7551 Background: Nanatinostat (N; VRx-3996) is a Class I-selective oral hydroxamate histone deacetylase (HDAC) inhibitor active against HDAC 1-3, but not HDAC 6. N induces expression of EBV thymidine kinase (TK, BXLF1) and protein kinase (PK, BGLF4) in EBV+ lymphomas. This study examines if N+VG results in tumor sensitization to antivirals (i.e., VG) and impacts EBV-induced T-cell exhaustion. Methods: The study employs a 3+3 design with expansion in patients (pts) with relapsed/refractory EBV+ lymphomas (EBER-ISH). Objectives: Maximal Tolerated Dose (MTD), Recommended Phase 2 Dose (RP2D), and efficacy. Primary endpoint: safety. Secondary endpoints: PK, response rate. Exploratory endpoints: PBMC histone H3 acetylation (Ac), quantitative plasma EBV DNA (pEBVd), and immune biomarkers. Responses (investigator-assessed and centrally-reviewed) are based on the Lugano Classification. Early safety and efficacy data are reported. Results: As of 10-Jan-2019, 15 pts (4F/11M, median age 60 yrs [19-79]) were enrolled with a median of 2 prior therapies and various lymphoma subtypes. Cohort 1 (N 10 mg BID/VG 900 mg BID) exceeded MTD (DLTs: leukopenia, neutropenia and thrombocytopenia). PK demonstrated ~2-fold higher N exposure compared to a prior study. VG levels were consistent with published data. Doses were reduced in Cohort 2 (N 5 mg BID/VG 450 mg BID) with no DLTs to date and 3 active pts. Most non-hematologic treatment-related AEs (TRAEs) were G1-2. Most G3+ TRAEs were hematologic (neutropenia, leukopenia, thrombocytopenia). Increases in creatinine occurred early and responded to reductions in VG. Among 7 evaluable pts, 4 responses were seen (2 CR, 2 PR) in PTLD, DLBCL, AITL, and plasmablastic lymphoma. Two pts had SD, and 1 PD. Of 8 pts with detectable baseline pEBVd, 7 demonstrated a reduction (median -54% [17 to -83%]). PBMC H3 Ac levels, multi-cytokine expression panel, and functional assessments in CD8+ T cells are in progress. Conclusions: N+VG appears well-tolerated at 5 mg and 450 mg BID, respectively with hematologic DLTs in a higher dose cohort. Responses are observed at all doses in both B and T cell lymphomas, with reductions in pEBVd levels and changes in T cell functionality. A RP2D will be defined prior to dose expansion. Clinical trial information: NCT03397706.
Abstract 2187: Tryptophan Metabolism Plays a Central Role in Immunosuppression
Authors: Sandaruwan Geeganage, Lillian Sams, James Henry, Frank Dorsey, Kenneth Roth, Alexander Nikolayev, Karim Benhadji, Raymond Gilmour, Ana Cerezo, Sandra Peregrina, Gloria Martínez-del Hoyo, Ramón Campos-Olivas, Juan Manuel Funes, Laura Diezma, Susana Velasco-Miguel
Journal: Cancer Research (2019)

Abstract Tryptophan metabolism plays a central role in immunosuppression through the local depletion of tryptophan with the concomitant production and accumulation of kynurenine, both of which are immunosuppressive. Indoleamine 2,3-dioxygenase 1 (IDO1), a heme-dependent enzyme, catalyzes the initial and rate-limiting step of the kynurenine pathway. Tumor cells selectively upregulate IDO1 as an immune-evasion mechanism either through intrinsic expression of IDO1, or in response to IFN-γ, a cytokine secreted by immune cells during an active immune response. In addition to the immuno-suppressive role of IDO1 and kynurenine, we investigated their additional roles in tumor cells. Here we describe an NMR-based readout assay for IDO1 activity, in which we are able to trace the extra- and intracellular destination of the single tryptophan carbon groups. This assay allowed us to detect contribution of the tryptophan catabolism to purine synthesis in tumor cells, and suggested further roles of tryptophan catabolism in tumors, apart from kynurenine production, that contribute to the modulation of tumor growth. We detected the incorporation of labeled tryptophan carbon units in intracellular purine pools. Our highly potent, orally available, and CNS penetrant small molecule inhibitor of IDO1 (LY3381916) inhibits this incorporation of tryptophan-derived one carbon units into purines in vitro and in vivo. This activity leads to pre-clinical efficacy and may be an added advantage of inhibiting IDO1 in cancer. Citation Format: Sandaruwan Geeganage, Lillian Sams, James Henry, Frank Dorsey, Kenneth Roth, Alexander Nikolayev, Karim Benhadji, Raymond Gilmour, Ana Cerezo, Sandra Peregrina, Gloria Martínez-del Hoyo, Ramón Campos-Olivas, Juan Manuel Funes, Laura Diezma, Susana Velasco-Miguel. Tryptophan Metabolism Plays a Central Role in Immunosuppression [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 2187.