tbuckley/cabot-search huggingface dataset:
Abstract 1053: Highly characterized patient-derived PDX breast cancer collection for preclinical efficacy studies
Authors: Michele Melton
Journal: Cancer Research (2018)

Abstract We have acquired a world-class collection of highly characterized patient-derived breast cancer models (PDX) from Washington University, St. Louis, MO (1). We have established growth curves for 17 of these lines, 6 ER+, 2 HER2+ and 4 triple-negative (TNBC) models beyond what was originally published. Continued characterization of these models is ongoing in our lab to ensure the integrity of the models is being maintained over multiple rounds of propagation. Short tandem repeat (STR) analysis, sequencing, quantitative RTPCR and Western blots were run to confirm genotypic and phenotypic fidelity of many of these model. To further characterize these models, RNA samples have been run using NanoString PanCancer gene expression analysis with 770 genes from 13 cancer-associated pathways including: MAPK, STAT, PI3K, RAS, Cell Cycle, Apoptosis, Hedgehog, Wnt, DNA Damage Control, transcription regulation, chromatin modification and TGF-β. Results: These data sets show that we have maintained the integrity of the WHIM PDX models over several passages in mice and provided confidence in the use of these models for preclinical efficacy studies. Reference: 1. Li et al., Cell Reports 2013;4:1116-30. Citation Format: Michele Melton. Highly characterized patient-derived PDX breast cancer collection for preclinical efficacy studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1053.
Abstract 2195: Temporal and spatial dynamics of metastatic colonization revealed by 26 rapid-autopsy tumor biopsies from a TNBC patient
Authors: Xiaomeng Huang, Yi Qiao, Samuel W. Brady, Adam Cohen, Andrea H. Bild, Gabor T. Marth
Journal: Cancer Research (2018)

Abstract Metastatic breast cancer is an advanced-stage disease in which the cancer cells have spread to distant organs. To understand the patterns of metastatic colonization in a patient who presented with aggressive disease, we have collected tumor biopsies at initial diagnosis, at mastectomy necessitated by the patient's relapse, twenty-six metastatic tumors across seven organs and two normal tissue control skin biopsies via a rapid autopsy procedure within hours after the patient's death. All biopsy samples were subjected to 60X Illumina whole genome sequencing. Our analysis revealed extensive chromosomal changes including amplifications, deletions, LOH and translocations, as well as known driver mutations in RB1, TP53, and PTEN in all tumor samples. We used the CNV and LOH data to reconstruct the phylogenetic relationships among the tumor samples. We used the somatic SNV allele frequencies in copy number-normal regions to refine these phylogenetic relationships, and to establish the evolution of the tumor at the subclonal level across different metastatic sites, with an extension of our SubcloneSeeker algorithm. Our analysis reveals the lung as the first metastatic site. In fact, this invasion occurred before relapse at the primary site in the breast, indicating early metastatic escape. This initial invasion was followed by distinct waves of massive metastatic expansion, beginning with the abdominal organs, then the lymph nodes, brain and bones. As the initial invasion, each metastatic wave involved other distinct sites in the lungs, these sites serving as incubators where subclones further evolved prior to seeding new metastatic sites. Finally, we see clear evidence for metastatic “recolonization” where such further evolved subclones invaded already established, earlier metastatic sites. The high number of biopsied sites in this study, 30 in all, allowed us to reconstruct the evolution of the aggressive disease in our patient with unprecedented resolution, and to identify characteristic patterns of metastatic colonization. If confirmed in additional, similarly high resolution datasets, these patterns will lead to better understanding of the metastatic process, and guide effective clinical intervention. Citation Format: Xiaomeng Huang, Yi Qiao, Samuel W. Brady, Adam Cohen, Andrea H. Bild, Gabor T. Marth. Temporal and spatial dynamics of metastatic colonization revealed by 26 rapid-autopsy tumor biopsies from a TNBC patient [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2195.
Combined Analysis of Asthma Safety Trials of Long-Acting β<sub>2</sub>-Agonists
Authors: William W. Busse, Eric D. Bateman, Arthur L. Caplan, H. William Kelly, Paul M. O’Byrne, Klaus F. Rabe, Vernon M. Chinchilli
Journal: New England Journal of Medicine (2018)

Safety concerns regarding long-acting β2-agonists (LABAs) in asthma management were initially identified in a large postmarketing trial in which the risk of death was increased. In 2010, the Food and Drug Administration (FDA) mandated that the four companies marketing LABAs for asthma perform prospective, randomized, controlled trials comparing the safety of combination therapy with a LABA plus an inhaled glucocorticoid with that of an inhaled glucocorticoid alone in adolescents (12 to 17 years of age) and adults. In conjunction with the FDA, the manufacturers harmonized their trial methods to allow an independent joint oversight committee to provide a final combined analysis of the four trials.
Avelumab plus axitinib vs sunitinib as first-line treatment of advanced renal cell carcinoma: Phase 3 study (JAVELIN Renal 101).
Authors: Toni K. Choueiri, Brian I. Rini, James M. G. Larkin, Georg A. Bjarnason, Gwenaelle Gravis, Howard Gurney, Jae-Lyun Lee, Daniel Keizman, John B. A. G. Haanen, Yoshihiko Tomita, Hirotsugu Uemura, Laurence Albiges, Manuela Schmidinger, Michael B. Atkins, Mariangela Mariani, Michael Shnaidman, Alessandra di Pietro, Robert J. Motzer
Journal: Journal of Clinical Oncology (2017)

TPS4594 Background: The combination of a checkpoint inhibitor with an anti-VEGF agent is a promising treatment strategy for advanced renal cell carcinoma (aRCC). Avelumab is a fully human IgG1 anti–PD-L1 antibody with clinical activity in aRCC and other tumor types (eg, Apolo et al. ASCO 2016; Gulley et al. ECC 2015). Axitinib is an anti-VEGF receptor tyrosine kinase inhibitor approved for second-line treatment of aRCC (Rini et al. Lancet 2011) that has also shown clinical activity as a first-line (1L) therapy (Hutson et al. Lancet Oncol 2013). In an ongoing phase 1b study in treatment-naïve patients (pts) with aRCC, avelumab + axitinib administered at standard monotherapy doses showed a tolerable safety profile and encouraging antitumor activity (Larkin et al. ESMO 2016). JAVELIN Renal 101 is a randomized, multicenter, phase 3 study (NCT02684006) comparing avelumab + axitinib vs sunitinib in pts with treatment-naïve aRCC. Methods: The primary objective is to demonstrate superiority of avelumab + axitinib vs sunitinib in prolonging progression-free survival (PFS) in the 1L treatment of pts with aRCC. Eligibility criteria include: aRCC with a clear cell component, ECOG PS ≤1, no prior systemic therapy for advanced disease, and measurable disease per RECIST v1.1. Approximately 583 pts will be randomized 1:1 and stratified based on ECOG PS (0 vs 1) and region (US vs Canada/Europe vs rest of the world). Pts receive either avelumab 10 mg/kg IV Q2W + axitinib 5 mg orally BID continuously (cycle length 6 weeks) or sunitinib 50 mg orally once daily for 4 weeks followed by 2 weeks off. Treatment is discontinued for unacceptable toxicity or if any other criteria for withdrawal are met. Pts may continue treatment beyond progression (RECIST v1.1) if investigator-assessed clinical benefit is achieved and treatment is well tolerated. PFS is assessed by blinded central review. Secondary efficacy assessments include overall survival, objective response, disease control, duration of response, and time to response. Safety, PK, and biomarker analyses will also be performed. The trial is currently active at 103 sites across 12 countries and as of Feb 2017, more than 40% of patients have been enrolled. Clinical trial information: NCT02684006.
Efficacy of gemcitabine with erlotinib in rash-positive patients selected according to eligibility for FOLFIRINOX.
Authors: Michael Haas, Stefan Hubert Boeck, Jens T. Siveke, Michael Schenk, Markus Lerch, Karel Caca, Jens Freiberg-Richter, Ludwig Fischer von Weikersthal, Frank Kullmann, Anke C. Reinacher-Schick, Martin Fuchs, Thomas Jens Ettrich, Stephan Kanzler, Volker Kunzmann, Stephan Kruger, Benedikt Westphalen, Swantje Held, Volker Heinemann
Journal: Journal of Clinical Oncology (2017)

4108 Background: The efficacy and safety of gemcitabine + erlotinib has not yet been defined prospectively in patients (pts) with metastatic pancreatic cancer (mPC) selected according to the inclusion criteria defined by Conroy et al. for FOLFIRINOX (e. g. ECOG 0-1, age &lt; 75, bilirubin &lt; 1.5xULN). Methods: In this German phase II trial, 150 pts with histologically confirmed mPC were recruited between July 2012 and July 2015 in 20 centers. If pts showed skin rash of any grade within 4 weeks after start of treatment with gemcitabine (1000 mg/m 2 weekly) and erlotinib (100 mg daily), this regimen was continued; rash-negative pts were switched to FOLFIRINOX. The primary study endpoint was the 1-year survival rate in rash-positive pts (hypothesis: ≥40%). Results: Ninety pts who were under treatment with gemcitabine + erlotinib for 4 weeks developed skin rash of any grade: the 1-year survival rate in those pts positive for skin rash was 40.0% (95%CI 29.8-50.9); median overall survival (OS) counted from day of first treatment was 10.1 months (mo) (95%CI 9.0-12.5), progression-free survival (PFS) 3.9 mo (95%CI 3.5-4.9), objective response rate (ORR) and disease control rate (DCR) were 21% and 64%, respectively. Median treatment duration with gemcitabine+erlotinib was 3.7 mo (Range 0.7-17.5). In rash-negative pts who were switched to FOLFIRINOX after 4 weeks of gemcitabine + erlotinib (n = 28) the 1-year survival rate was 46.4% (95%CI 27.5-66.1), median OS 10.6 mo (95%CI 6.6-13.6), median PFS 5.2 mo (95%CI 2.3-7.9) and the corresponding ORR and DCR rates were 29 and 54%, respectively. The rate of salvage therapy was 53% after gemcitabine+erlotinib, mostly consisting of 5-FU-based schemas (42 % 5-FU/folinic acid + irinotecan or oxaliplatin, 38% FOLFIRINOX) and 43% after FOLFIRINOX (all pts received gemcitabine, 67% in combination with nab-paclitaxel). In the Intention To Treat (ITT) population (n = 145) OS was 9.7 mon (95%CI 7.8-10.9). Conclusions: In rash-positive pts deemed fit for FOLFIRINOX first-line treatment with gemcitabine + erlotinib appears effective achieving a one-year-survival rate of 40%. Early switch to FOLFIRINOX was an effective strategy in rash-negative patients. Clinical trial information: NCT01729481.
Risk of Myocardial Infarction in Anticoagulated Patients With Atrial Fibrillation
Authors: Christina Ji-Young Lee, Thomas Alexander Gerds, Nicholas Carlson, Anders Nissen Bonde, Gunnar Hilmar Gislason, Morten Lamberts, Jonas Bjerring Olesen, Jannik Langtved Pallisgaard, Morten Lock Hansen, Christian Torp-Pedersen
Journal: Journal of the American College of Cardiology (2018)
The Effect of Addition of Calcium Phosphate Particles to Hydrogel‐Based Composite Materials on Stiffness and Differentiation of Mesenchymal Stromal Cells toward Osteogenesis
Authors: Kshama S. Sen, Daniela F. Duarte Campos, Marius Köpf, Andreas Blaeser, Horst Fischer
Journal: Advanced Healthcare Materials (2018)

Abstract The stiffness of a hydrogel has a significant role on the mechanical stability of a scaffold. However, the stiffness of pure hydrogels can be tuned only within a limited range. Herein, it is hypothesized that the range of hydrogel stiffness can be greatly increased by the addition of calcium phosphate particles and that such composites promote the osteogenic differentiation of human mesenchymal stem cells (hMSCs). Beta‐tricalcium phosphate (β‐TCP) particles are incorporated at concentrations of 0.5 and 5 mg mL −1 into various agarose and agarose–collagen blends. These composites are characterized with respect to stiffness, viscosity, degradation, cell morphology, viability, and osteogenesis. The osteogenic hMSCs in less stiff composites with 0.5 mg mL −1 β‐TCP show the highest alkaline phosphatase expression compared to blends without β‐TCP and stiffer composites with 5 mg mL −1 β‐TCP. Quantitative polymerase chain reaction also shows higher expression of ALP, RUNX2, and collagen I by hMSCs in less stiff composites with 0.5 mg mL −1 β‐TCP compared to blends without β‐TCP and stiffer composite blends. It is concluded that by addition of calcium phosphate to specific hydrogels the stiffness can be tuned in a desired range and thus the osteogenic differentiation of embedded hMSCs can be better controlled and adjusted compared to pure hydrogels.
Exogenous/Endogenous‐Triggered Mesoporous Silica Cancer Nanomedicine
Authors: Bowen Yang, Yu Chen, Jianlin Shi
Journal: Advanced Healthcare Materials (2018)

Abstract Recent advances in nanomedicine‐based theranostic platforms have catalyzed the generation of new theranostic modalities for pathological abnormalities, such as cancer. Mesoporous silica–based nanomedicines, which feature unique physicochemical properties and specific applicability, are extensively explored for numerous oncological applications. Due to the well‐defined morphology, specific surface area, and pore volume, mesoporous silica nanoparticle (MSN)‐based theranostic platforms have provided unprecedented opportunities for the development of next‐generation cancer nanomedicine. However, current understanding on the underlying mechanisms of how these feasible theranostic platforms interact with exogenous/endogenous triggers and how this unique responsiveness for optimized cancer therapy can be taken advantage of is still preliminary. In this progress report, efforts are made to give a comprehensive overview of the development of MSN‐based “smart” theranostic platforms, from exogenous physical irradiation–triggered platforms for localized therapy to endogenous biological stimulus–triggered platforms for tumor microenvironment responsiveness. It is highly expected that these elaborately fabricated MSN‐based nanoformulations will play an indispensable role in the efficient cancer therapy based on their high therapeutic outcome and reduced side effects.
Advanced in vitro models of vascular biology: Human induced pluripotent stem cells and organ-on-chip technology
Authors: Amy Cochrane, Hugo J. Albers, Robert Passier, Christine L. Mummery, Albert van den Berg, Valeria V. Orlova, Andries D. van der Meer
Journal: Advanced Drug Delivery Reviews (2018)

The vascular system is one of the first to develop during embryogenesis and is essential for all organs and tissues in our body to develop and function. It has many essential roles including controlling the absorption, distribution and excretion of compounds and therefore determines the pharmacokinetics of drugs and therapeutics. Vascular homeostasis is under tight physiological control which is essential for maintaining tissues in a healthy state. Consequently, disruption of vascular homeostasis plays an integral role in many disease processes, making cells of the vessel wall attractive targets for therapeutic intervention. Experimental models of blood vessels can therefore contribute significantly to drug development and aid in predicting the biological effects of new drug entities. The increasing availability of human induced pluripotent stem cells (hiPSC) derived from healthy individuals and patients have accelerated advances in developing experimental in vitro models of the vasculature: human endothelial cells (ECs), pericytes and vascular smooth muscle cells (VSMCs), can now be generated with high efficiency from hiPSC and used in 'microfluidic chips' (also known as 'organ-on-chip' technology) as a basis for in vitro models of blood vessels. These near physiological scaffolds allow the controlled integration of fluid flow and three-dimensional (3D) co-cultures with perivascular cells to mimic tissue- or organ-level physiology and dysfunction in vitro. Here, we review recent multidisciplinary developments in these advanced experimental models of blood vessels that combine hiPSC with microfluidic organ-on-chip technology. We provide examples of their utility in various research areas and discuss steps necessary for further integration in biomedical applications so that they can be contribute effectively to the evaluation and development of new drugs and other therapeutics as well as personalized (patient-specific) treatments.
Determination of Tumor Margins with Surgical Specimen Mapping Using Near-Infrared Fluorescence
Authors: Rebecca W. Gao, Nutte T. Teraphongphom, Nynke S. van den Berg, Brock A. Martin, Nicholas J. Oberhelman, Vasu Divi, Michael J. Kaplan, Steven S. Hong, Guolan Lu, Robert Ertsey, Willemieke S.F.J. Tummers, Adam J. Gomez, F. Christopher Holsinger, Christina S. Kong, Alexander D. Colevas, Jason M. Warram, Eben L. Rosenthal
Journal: Cancer Research (2018)

For many solid tumors, surgical resection remains the gold standard and tumor-involved margins are associated with poor clinical outcomes. Near-infrared (NIR) fluorescence imaging using molecular agents has shown promise for in situ imaging during resection. However, for cancers with difficult imaging conditions, surgical value may lie in tumor mapping of surgical specimens. We thus evaluated a novel approach for real-time, intraoperative tumor margin assessment. Twenty-one adult patients with biopsy-confirmed squamous cell carcinoma arising from the head and neck (HNSCC) scheduled for standard-of-care surgery were enrolled. Cohort 1 (n = 3) received panitumumab-IRDye800CW at an intravenous microdose of 0.06 mg/kg, cohort 2A (n = 5) received 0.5 mg/kg, cohort 2B (n = 7) received 1 mg/kg, and cohort 3 (n = 6) received 50 mg. Patients were followed 30 days postinfusion and adverse events were recorded. Imaging was performed using several closed- and wide-field devices. Fluorescence was histologically correlated to determine sensitivity and specificity. In situ imaging demonstrated tumor-to-background ratio (TBR) of 2 to 3, compared with ex vivo specimen imaging TBR of 5 to 6. We obtained clear differentiation between tumor and normal tissue, with a 3-fold signal difference between positive and negative specimens (P < 0.05). We achieved high correlation of fluorescence intensity with tumor location with sensitivities and specificities >89%; fluorescence predicted distance of tumor tissue to the cut surface of the specimen. This novel method of detecting tumor-involved margins in surgical specimens using a cancer-specific agent provides highly sensitive and specific, real-time, intraoperative surgical navigation in resections with complex anatomy, which are otherwise less amenable to image guidance.Significance: This study demonstrates that fluorescence can be used as a sensitive and specific method of guiding surgeries for head and neck cancers and potentially other cancers with challenging imaging conditions, increasing the probability of complete resections and improving oncologic outcomes. Cancer Res; 78(17); 5144-54. ©2018 AACR.
Abstract 18459: Outcomes of Pediatric Heart Failure Related Hospitalizations in Canada:2004-2013
Authors: Gitanjali P Mansukhani, Sunjidatul Islam, Andrew S Mackie, Padma Kaul, Paul F Kantor
Journal: Circulation (2016)

Introduction:  Heart failure (HF) in children is an important cause of morbidity and mortality with frequent hospitalizations. We sought to describe the prevalence, causes and outcomes of heart failure hospitalizations (HFH) in Canada during a contemporary 10-year time frame and compare the Canadian experience with the U.S experience.   Methods:  All HFH with heart failure as a primary or secondary diagnosis between 2004 and 2013 in patients    Results:  A total of 4,693 HFH occurred among 3,523 children, with annual number of hospitalizations ranging from 435 to 559 (7-10 HFH/100,000 children). Infants were the most commonly affected age group (73.6% of all admissions). Congenital heart disease (CHD), cardiomyopathy, and acquired heart disease were associated with 76.1%, 10.5% and 4.2% of HFH respectively. Ventricular septal defect was the most common CHD lesion (33%). Median length of stay (LOS) for all HFH was 10.7 days (IQR 4.1 - 28.7) and was highest in the 0-30 day age group at 21.7 days (IQR 8.1 - 46.6). The in-hospital mortality rate was 8.8%, with the majority of deaths occurring during the index hospitalization. Extra-corporeal life support (ECLS), ventricular assist-device implantation (VAD) and cardiac transplantation occurred in 2.4%, 0.7% and 1.9% respectively. 31.5% of HFH had cardiac surgery and/or catheterization. For patients discharged alive, the cumulative 30-day readmission rate was 12.5%.   Conclusions:  Pediatric HFHs in Canada are a high-risk event with a significant risk for death and early readmission after discharge. Canadian data shares some similarities with that of the U.S with few pertinent differences. Infants remain the most commonly affected group with CHD seen in the majority of the HFH. ECLS, VAD and cardiac transplant including crude hospital mortality rates are similar in both jurisdictions. HFH rates are lower in Canada as compared to U.S (7-10 v/s 14.5-17.9 per 100,000 children/year). Over the ten-year study period, the annual hospitalization rate has declined significantly in Canada by 3% per year, which differs from the United States where the hospitalizations have remained constant.
Abstract 14365: The Role of Alcohol Abuse and Tobacco Use in the Incidence of Early Acute Coronary Syndrome
Authors: Hassan Alkhawam, Raef Madanieh, Mariya Fabisevich, Robert Sogomonian, Mohammed El-Hunjul, Abed Madanieh, Joseph J Lieber, Timothy J Vittorio
Journal: Circulation (2015)

Objective: To investigate the synergistic role of alcohol abuse/dependence and tobacco use in the early incidence of ACS. Methods: A retrospective chart analyses of 8076 patients diagnosed with ACS between 2000 to 2014, defined by ICD-9 codes for acute MI, alcohol abuse/dependence and tobacco use. Average age of ACS was calculated for the general population. Patients were then divided into 4 subgroups based on alcohol abuse/dependence and tobacco use status as follows: non-alcoholic non-smokers, non-alcoholic smokers, alcoholic non-smokers and alcoholic smokers. Results: The mean age of our 8076 ACS patients population was ~59.5 (95% CI 59.2-59.8). Patients with history of alcohol abuse/dependence appeared to develop ACS ~8.7 years younger than their non-alcoholic counterparts. When tobacco use is incorporated as a risk factor, those with both alcohol abuse/dependence and tobacco use seemed to develop ACS ~5 years earlier than those with history of either alone, and ~20 years earlier when compared to those with neither alcohol abuse/dependence nor tobacco use. (Table 1 summarizes mean age of ACS incidence in our study subgroups) Conclusion: Alcohol abuse/dependence appears to be a risk factor for earlier ACS. In our population, the average age of ACS incidence in alcoholic patients was significantly earlier than non-alcoholic patients. Furthermore, alcoholic patients who also used tobacco developed ACS at an even younger age when compared to those who had history of either alcohol abuse/dependence or tobacco use alone, suggesting a possible synergistic effect of these two risk factors in developing early ACS. Healthcare intervention in this population through screening, counseling and education regarding alcohol abuse/dependence and smoking cession is warranted to reduce early ACS morbidity and mortality.