tbuckley/cabot-search huggingface dataset:
Efficacy of fulvestrant (F) ± anastrozole (A) in highly endocrine-sensitive (HES) and moderately endocrine-sensitive (MES) advanced breast cancer (BC): A retrospective study.
Authors: Ziad U. Khan, Rita S. Mehta
Journal: Journal of Clinical Oncology (2016)

e12022 Background: High-dose For F+A is associated with improvement in survival as compared to A, in patients (pts) with advanced hormone receptor-positive BC, as shown in S0226 and FIRST trials. The benefit is most notable in pts with HES disease. We performed a retrospective analysis of pts treated with F±A at our institution. Methods: We reviewed charts of 169 pts with advanced BC. 117 pts received F±A either as treatment, or as maintenance following chemotherapy. 94/117(80%) pts received high-dose F, 50% (58/117) received F+A, 49/117 (42%) received high-dose F+A, rest loading dose F. Pts with visceral and brain metastases were not excluded. PS ranged from 0-2. Primary endpoint was to compare outcomes in pts with HES and MES disease. HES disease was defined as either no prior exposure to or progression ≥ 12 months of endocrine or chemotherapy completion, and the rest as MES disease (1-5 lines of prior therapy). Kaplan-Meir survival curves were constructed. Log-rank and multivariate Cox proportional-hazards models were used to compare differences among the groups. Results: Median Progression-free survival (PFS) was 24 months for pts with HES disease (n = 43), and 9 months for pts with MES disease (n = 74; HR: 2.6; 95% CI: 1.7-3.9, p = < 0.0001). Median Overall survival (OS) was 65 months for pts with HES, and 31 months for MES disease (HR 2; 95% CI: 1.2-3.3, p = 0.012). Six pts discontinued F±A. In univariate analysis, PFS was significantly different in pts with HES vs. MES and visceral vs. non-visceral disease, and oligo vs. diffuse metastasis. Prior Tamoxifen use, F±A as treatment or maintenance, and HER2 status were not significant factors. HES vs. MES and visceral vs. non-visceral disease remained significant in multivariate analysis. Conclusions: Patients with advanced BC will receive multiple lines of treatment, and the use of mostly high-dose For F+A affords patients an extended time on endocrine treatment. Survival outcomes are promising compared to historical controls. While endocrine sensitivity is a continuum, given the two-fold difference in survival among HES and MES cohorts, the current definition of HES and MES should be prospectively validated.
SAT0160 Immunogenicity of biosimilars for the treatment of inflammatory rheumatic diseases: a review from confirmatory clinical trials
Authors: F Araújo, J Gonçalves, JE Fonseca
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> The assessment of immunogenicity is mandatory during the comparability exercise of biosimilar candidate drugs, as even small structural differences can potentially elicit antidrug antibodies (ADA) and affect efficacy and safety. <h3>Objectives</h3> To review the incidence of ADA and neutralizing ADA (nADA) in confirmatory clinical trials of biosimilar drugs approved for the treatment of inflammatory rheumatic conditions in the European and North-American markets; to review the type of assays used for this purpose; to compare the incidence of ADA with historical data from reference biotechnological drugs. <h3>Methods</h3> We performed a literature search in the Medline database and hand searched EULAR and ACR meeting abstracts to identify phase I and III confirmatory clinical trials of biosimilar drugs for the treatment of rheumatic conditions approved in the European and North-American markets. Open-label extensions involving biological switch were not included. All outcomes regarding immunogenicity were extracted (ADA, nADA and type of immunogenicity assays). <h3>Results</h3> We screened 255 articles by title and abstract and 7 publications fulfilled our inclusion criteria. Three meeting abstracts were also included. Six studies assessed infliximab biosimilars (CT-P13 and SB2), three studies assessed etanercept biosimilars (SB4 and GP2015) and one study assessed an adalimumab biosimilar (ABP 501). All but two concerned phase III trials and seven were performed on rheumatoid arthritis patients. All biosimilars had comparable immunogenicity profiles in respect to their reference drugs, except for the etanercept biosimilar SB4, which presented significantly less ADA when compared to reference etanercept (0.7% vs 13.1% at 24 weeks and 1.0% vs 13.2% at 52 weeks, p&lt;0.001 for both). As expected, infliximab had the highest incidence of ADA; the proportion of ADA in studies of infliximab and adalimumab was higher when compared to historical data. Only 4 studies reported nADA, which were highest in the infliximab biosimilar CT-P13 54-week study in ankylosing spondylitis patients. Electrochemiluminescence immunoassay was the preferred method to measure ADA. Table 1 summarizes the main findings in the included studies. <h3>Conclusions</h3> Currently approved biosimilars for the treatment of rheumatic diseases have comparable immunogenicity profiles in respect to their reference drugs. The discrepancy in ADA between SB4 and reference etanercept did not correlate with efficacy or safety and did not preclude biosimilarity, according to the regulatory agencies. The higher proportion of ADA compared to historical data may be explained by the greater sensitivity of current immunogenicity assays, such as electrochemiluminescence. <h3>Disclosure of Interest</h3> None declared
Targeting AXL and mTOR Pathway Overcomes Primary and Acquired Resistance to WEE1 Inhibition in Small-Cell Lung Cancer
Authors: Triparna Sen, Pan Tong, Lixia Diao, Lerong Li, Youhong Fan, Jennifer Hoff, John V. Heymach, Jing Wang, Lauren Averett Byers
Journal: Clinical Cancer Research (2017)

Purpose: Drugs targeting DNA repair and cell-cycle checkpoints have emerged as promising therapies for small-cell lung cancer (SCLC). Among these, the WEE1 inhibitor AZD1775 has shown clinical activity in a subset of SCLC patients, but resistance is common. Understanding primary and acquired resistance mechanisms will be critical for developing effective WEE1 inhibitor combinations.Experimental Design: AZD1775 sensitivity in SCLC cell lines was correlated with baseline expression level of 200 total or phosphorylated proteins measured by reverse-phase protein array (RPPA) to identify predictive markers of primary resistance. We further established AZD1775 acquired resistance models to identify mechanism of acquired resistance. Combination regimens were tested to overcome primary and acquired resistance to AZD1775 in in vitro and in vivo SCLC models.Results: High-throughput proteomic profiling demonstrate that SCLC models with primary resistance to AZD1775 express high levels of AXL and phosphorylated S6 and that WEE1/AXL or WEE1/mTOR inhibitor combinations overcome resistance in vitro and in vivo Furthermore, AXL, independently and via mTOR, activates the ERK pathway, leading to recruitment and activation of another G2-checkpoint protein, CHK1. AZD1775 acquired resistance models demonstrated upregulation of AXL, pS6, and MET, and resistance was overcome with the addition of AXL (TP0903), dual-AXL/MET (cabozantinib), or mTOR (RAD001) inhibitors.Conclusions: AXL promotes resistance to WEE1 inhibition via downstream mTOR signaling and resulting activation of a parallel DNA damage repair pathway, CHK1. These findings suggest rational combinations to enhance the clinical efficacy of AZD1775, which is currently in clinical trials for SCLC and other malignancies. Clin Cancer Res; 23(20); 6239-53. ©2017 AACR.
Changes in the tumor glucose-uptake measured by 18F-FDG PET with two weeks of single-agent cetuximab in localized squamous cell carcinoma of the esophagus.
Authors: Kathrin Philipp-Abbrederis, Ken Herrmann, Ambros Beer, Alexander Hapfelmeier, Christian Peschel, Florian Lordick
Journal: Journal of Clinical Oncology (2013)

e15042 Background: Cetuximab (CET), an antibody directed against epidermal growth factor receptor (EGFR) has proved efficacy in squamous cell cancer (SCC) of the head and neck in vitro and in vivo by enhancing the activity of chemo- and radiotherapy. The aim was to investigate the early metabolic response in esophageal SCC induced by single agent CET. Methods: Patients with cT3 Nx esophageal SCC received single agent CET for two weeks (400mg/m2 i. v. d -15 followed by 250mg/m2 d -8) before entering a neoadjuvant dose escalation protocol of weekly cetuximab plus weekly oxaliplatin (starting dose level 45mg/m²; d1,8,15,22,29), plus 5-FU cont. i.v. (starting dose level 180mg/m²/d; d1-5, 8-12, 15-19, 22-26, 29-33) and radiotherapy (45Gy cumulative dose; 1.8Gy/d). Surgery was scheduled 4-6 weeks after chemoradiation (CRT). Tumor FDG uptake was assessed by PET at baseline, two weeks after start of CET and two weeks after start of CRT. Standard uptake values (SUV) of the two response PETs were compared with SUVs measured at baseline and correlated with the histopathological response data. Results: 11 patients are assessable for metabolic and histopathological response. Decreases in the SUVs two weeks after the start of CET compared with baseline SUV ranged from -16% to -70% (median -24%) and from 0% to -72% (median -39%) two weeks after start of CRT. Three patients were classified as complete histopathological responders. One patient had a subtotal (&lt;10% residual tumor) and three patients a moderate response (10-50% residual tumor). No histopathological response was seen in 4 patients. We found an association between FDG uptake decreases both after single agent CET and after two weeks of CRT and a favourable histopathological response with no statistical significance due to the low number of cases. Conclusions: This study shows that single agent CET can lead to a marked and early decrease in tumor glucose uptake. Our findings suggest that there may be an association between the early decrease in FDG uptake during CET monotherapy, indicating a growth dependency of some tumors from the EGFR signal pathway. These preliminary observations require confirmation in a larger patient cohort. Clinical trial information: 2006-001097-24.
CCND1 Mutations Increase Protein Stability and Promote Ibrutinib Resistance in Mantle Cell Lymphoma
Authors: Atish Ranjan Mohanty, Natalie Sandoval, Manasi Das, Hesham M. Amin, Guido Marcucci, Raju Pillai, Dennis D Weisenburger, Steven T. Rosen, Lan Pham, Vu N. Ngo
Journal: Blood (2016)
Comprehensive Functional Characterization of Germline ETV6 Variants Associated with Inherited Predisposition to Acute Lymphoblastic Leukemia in Children
Authors: Rina Nishii, Rebekah Baskin, Takaya Moriyama, Keito Hoshitsuki, Monika L. Metzger, Gang Wu, Meenakshi Devidas, Wenjian Yang, Paige Tedrick, Emily Quinn, Julie M. Gastier-Foster, Elizabeth Raetz, Eric Larsen, Paul L. Martin, W. Paul Bowman, Naomi Winick, Masatoshi Takagi, Ching-Hon Pui, William E. Evans, Jinghui Zhang, Mary V. Relling, Stephen P. Hunger, Charles Mullighan, Mignon L. Loh, Kim E. Nichols, Jun J. Yang
Journal: Blood (2016)
Abstract P079: Cardiac Contractility in Response to Isoproterenol from Gravin Knockout (AKAP12) Mice
Authors: Bradley McConnell, Xing Yin, Zhitao Li, Cori Wijaya, Andrea Diaz, Muhammad Siddiqui, Abeer Rabaha'h, Ashley Guillory, Wei Dong Ga
Journal: Circulation Research (2011)

Gravin (AKAP12), one of the A-Kinase-Binding-Proteins (AKAPs), serves as a scaffold protein linking β 2 -adrenergic receptor (β 2 -AR), phosphatase 2B and several kinases including Protein Kinase A (PKA) and Protein Kinase C (PKC). The presence of gravin facilitates signal transduction of β 2 -AR and thus affects cardiac excitation-contraction coupling. We previously showed decreased cardiac hypertrophy, increased contractility and decreased arrhythmias in gravin-KO mice, following chronic β-AR stimulation. This response was associated with enhanced [Ca 2+ ] i homeostasis. Here, we test whether cardiac contraction is also affected in gravin knock-out (gravin-KO) mice. Trabeculae or small papillary muscles from the right ventricles were mounted between a force transducer and a motor arm, and superfused with K-H solution (pH 7.4) at room temperature. Developed force increased as external Ca 2+ ([Ca 2+ ] o ) was raised from 1 to 10 mM in both gravin-KO and wide-type (WT) muscles. Developed force and intracellular Ca 2+ transient (Ca 2+ i ) increased in a dose dependent manner as [Ca 2+ ] o was raised. Gravin-KO muscles had lower Ca 2+ i at any given [Ca 2+ ] o , but had similar force at [Ca 2+ ] o &gt;4.0 mM; at higher [Ca 2+ ] o s, developed forces was significantly lower. Isoproterenol (ISO, 0.05-200nM) increased force and Ca 2+ i in both groups of muscles. However, force and Ca 2+ i started to blunt in gravin-KO muscle at higher ISO doses and became significantly lower at ISO does &gt;50 nM. Both force and Ca 2+ i were lower at a given rest interval in gravin-KO muscles with no changes in recirculation fraction (RF). These results show that gravin-KO muscles maintain their response to both Ca 2+ and ISO with reduced capacity at higher doses, and to rest potentiations with lower magnitudes, but with no changes in recirculation fraction of Ca 2+ through the sarcoplasmic reticulum (SR). These findings suggest: (1) gravin-KO muscles may likely have smaller Ca 2+ content in the SR; (2) gravin plays an important modulatory role in the argumentation of force by Ca 2+ and β 2 -AR stimulation; (3) at physiological [Ca 2+ ] o , gravin-KO increases myofilament Ca 2+ responsiveness. Ongoing experiments are focused on changes myofilament Ca 2+ responsiveness in gravin-KO mice.
Individuals with sickle cell disease have a significantly greater vasoconstriction response to thermal pain than controls and have significant vasoconstriction in response to anticipation of pain
Authors: Maha Khaleel, Mammen Puliyel, Payal Shah, John Sunwoo, Roberta M. Kato, Patjanaporn Chalacheva, Wanwara Thuptimdang, Jon Detterich, John C. Wood, Jennie Tsao, Lonnie Zeltzer, Richard Sposto, Michael C. K. Khoo, Thomas D. Coates
Journal: American Journal of Hematology (2017)

The painful vaso-occlusive crises (VOC) that characterize sickle cell disease (SCD) progress over hours from the asymptomatic steady-state. SCD patients report that VOC can be triggered by stress, cold exposure, and, pain itself. We anticipated that pain could cause neural-mediated vasoconstriction, decreasing regional blood flow and promoting entrapment of sickle cells in the microvasculature. Therefore, we measured microvascular blood flow in the fingers of both hands using plethysmography and laser-Doppler flowmetry while applying a series of painful thermal stimuli on the right forearm in 23 SCD patients and 25 controls. Heat pain applied to one arm caused bilateral decrease in microvascular perfusion. The vasoconstriction response started before administration of the thermal pain stimulus in all subjects, suggesting that pain anticipation also causes significant vasoconstriction. The time delay between thermal pain application and global vasoconstriction ranged from 5 to 15.5 seconds and increased with age (P < .01). Although subjective measures, pain threshold and pain tolerance were not different between SCD subjects and controls, but the vaso-reactivity index characterizing the microvascular blood flow response to painful stimuli was significantly higher in SCD patients (P = .0028). This global vasoconstriction increases microvascular transit time, and may promote entrapment of sickle cells in the microvasculature, making vaso-occlusion more likely. The rapidity of the global vasoconstriction response indicates a neural origin that may play a part in the transition from steady-state to VOC, and may also contribute to the variability in VOC frequency observed in SCD patients.
Computer-aided reading of tuberculosis chest radiography: moving the research agenda forward to inform policy
Authors: Faiz Ahmad Khan, Tripti Pande, Belay Tessema, Rinn Song, Andrea Benedetti, Madhukar Pai, Knut Lönnroth, Claudia M. Denkinger
Journal: European Respiratory Journal (2017)

Key gaps limit the evidence base for computer-aided reading of TB on CXR. We describe a research agenda to fill them http://ow.ly/JkmQ30cynWR
ACC/AHA 2007 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery
Authors: Lee A. Fleisher, Joshua A. Beckman, Kenneth A. Brown, Hugh Calkins, Elliott L. Chaikof, Kirsten E. Fleischmann, William K. Freeman, James B. Froehlich, Edward K. Kasper, Judy R. Kersten, Barbara Riegel, John F. Robb, Sidney C. Smith, Alice K. Jacobs, Cynthia D. Adams, Jeffrey L. Anderson, Elliott M. Antman, Christopher E. Buller, Mark A. Creager, Steven M. Ettinger, David P. Faxon, Valentin Fuster, Jonathan L. Halperin, Loren F. Hiratzka, Sharon A. Hunt, Bruce W. Lytle, Rick Nishimura, Joseph P. Ornato, Richard L. Page, Barbara Riegel, Lynn G. Tarkington, Clyde W. Yancy
Journal: Journal of the American College of Cardiology (2007)
Poor Prognosis Indicated by Venous Circulating Tumor Cell Clusters in Early-Stage Lung Cancers
Authors: Vasudha Murlidhar, Rishindra M. Reddy, Shamileh Fouladdel, Lili Zhao, Martin K. Ishikawa, Svetlana Grabauskiene, Zhuo Zhang, Jules Lin, Andrew C. Chang, Philip Carrott, William R. Lynch, Mark B. Orringer, Chandan Kumar-Sinha, Nallasivam Palanisamy, David G. Beer, Max S. Wicha, Nithya Ramnath, Ebrahim Azizi, Sunitha Nagrath
Journal: Cancer Research (2017)

Early detection of metastasis can be aided by circulating tumor cells (CTC), which also show potential to predict early relapse. Because of the limited CTC numbers in peripheral blood in early stages, we investigated CTCs in pulmonary vein blood accessed during surgical resection of tumors. Pulmonary vein (PV) and peripheral vein (Pe) blood specimens from patients with lung cancer were drawn during the perioperative period and assessed for CTC burden using a microfluidic device. From 108 blood samples analyzed from 36 patients, PV had significantly higher number of CTCs compared with preoperative Pe (
HDAC1 Upregulation by NANOG Promotes Multidrug Resistance and a Stem-like Phenotype in Immune Edited Tumor Cells
Authors: Kwon-Ho Song, Chel Hun Choi, Hyo-Jung Lee, Se Jin Oh, Seon Rang Woo, Soon-Oh Hong, Kyung Hee Noh, Hanbyoul Cho, Eun Joo Chung, Jae-Hoon Kim, Joon-Yong Chung, Stephen M. Hewitt, Seungki Baek, Kyung-Mi Lee, Cassian Yee, Minjoo Son, Chih-Ping Mao, T.C. Wu, Tae Woo Kim
Journal: Cancer Research (2017)

Abstract Cancer immunoediting drives the adaptation of tumor cells to host immune surveillance. Immunoediting driven by antigen (Ag)-specific T cells enriches NANOG expression in tumor cells, resulting in a stem-like phenotype and immune resistance. Here, we identify HDAC1 as a key mediator of the NANOG-associated phenotype. NANOG upregulated HDAC1 through promoter occupancy, thereby decreasing histone H3 acetylation on K14 and K27. NANOG-dependent, HDAC1-driven epigenetic silencing of cell-cycle inhibitors CDKN2D and CDKN1B induced stem-like features. Silencing of TRIM17 and NOXA induced immune and drug resistance in tumor cells by increasing antiapoptotic MCL1. Importantly, HDAC inhibition synergized with Ag-specific adoptive T-cell therapy to control immune refractory cancers. Our results reveal that NANOG influences the epigenetic state of tumor cells via HDAC1, and they encourage a rational application of epigenetic modulators and immunotherapy in treatment of NANOG+ refractory cancer types. Cancer Res; 77(18); 5039–53. ©2017 AACR.
Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial
Authors: Georgina V Long, Victoria Atkinson, Jonathan S Cebon, Michael B Jameson, Bernie M Fitzharris, Catriona M McNeil, Andrew G Hill, Antoni Ribas, Michael B Atkins, John A Thompson, Wen-Jen Hwu, F Stephen Hodi, Alexander M Menzies, Alexander D Guminski, Richard Kefford, Benjamin Y Kong, Babak Tamjid, Archana Srivastava, Anna J Lomax, Mohammed Islam, Xinxin Shu, Scot Ebbinghaus, Nageatte Ibrahim, Matteo S Carlino
Journal: The Lancet Oncology (2017)
Unique radiological features of two cases of primary pulmonary diffuse large B-cell lymphoma
Authors: Yuu Saitoh, Ayae Ohnishi-Amemiya, Michiyo Asano, Yuko Tanaka, Seiichiro Yoshizawa, Hiroaki Fujimoto, Yoshikazu Itoh, Naoya Nakamura, Kazuma Ohyashiki
Journal: Thorax (2017)

Radiographic infiltration of the lungs by malignant lymphoma is often observed, with a reported frequency of approximately 25%. On the other hand, primary pulmonary lymphoma (PPL) is very rare. According to previous reports, PPL was observed in only 3% of patients with extranodal lymphoma, and in less than 1% of patients with non-Hodgkin's lymphoma. Most cases of PPL (58%–87%) are marginal zone lymphomas of the mucosa-associated lymphoid tissue (MALT) type.1 However, primary lung diffuse large B-cell lymphoma (DLBCL) is rare (10%).2 Here we present two cases of primary lung DLBCL displaying unique imaging.

### Case 1

A 56-year-old woman complaining of dyspnoea and fever was admitted to our hospital. Consolidation in the bilateral upper fields on chest radiological examination and multiple pulmonary nodules on CT were the only abnormalities detected by radiography (Figure 1A).

Upper and lower endoscopy showed no evidence of gastrointestinal cancer. A trans-bronchial lung biopsy (TBLB) was subsequently performed for histopathological analysis. Haematoxylin and eosin staining of tissue sections showed diffuse and monotonous proliferation of large round cells, in the form of sheets within interstitial lung tissue (Figure 1B). Immunohistochemical staining demonstrated that the …