tbuckley/cabot-search huggingface dataset:
Abstract 12806: A Speckle-tracking Echocardiographic Multi-layer LV Global Strain Study to Evaluate Specific Compensation Mechanisms to Maintain Cardiac Function in Subjects With Hypertrophied LV Myocardium
Authors: Koya Ozawa, Nobusada Funabashi, Hiroyuki Takaoka, Yoshio Kobayashi
Journal: Circulation (2015)

Introduction: A novel transthoracic echocardiography (TTE) technique enables multi-layer measurement of left ventricular (LV) endocardial and epicardial layer myocardial strain. Hypothesis: There may be compensation mechanisms to maintain cardiac function in subjects with hypertrophied LV myocardium. To evaluate mechanisms in hypertrophied LV myocardium in subjects with preserved LV ejection fraction (LVEF) using multi-layer TTE analysis. Methods: A total of 105 subjects with preserved LVEF (41 hypertrophic cardiomyopathy subjects (31 male; 62±15 yr), 40 with severe aortic stenosis (19 male; 74±5 yr; transaortic maximum velocity 4.8±0.6m/s; aortic valve area index 0.46±0.12cm2/m2), and 24 controls (12 male; 54±18 yr)) underwent TTE (Vivid E9). Apical 4-, 2-, and 3-chamber GLS views and parasternal short axis GCS views at mitral valve level, papillary muscle, and apex were acquired. Strain measurements (absolute values) of endocarial and epicardial layers were performed. Results: Correlation coefficients (CC) between inter ventricular septum thickness in end diastole (IVSTd) and endocardial and epicardial GLS were -0.62, and -0.60 for apical 4 chamber, -0.60, and -0.62 for 2 chamber, and -0.58, and -0.57 for 3 chamber views, and -0.64, and -0.64 for averaged, respectively. GLS values showed significant negative correlation with degree of LV hypertrophy. CC between IVSTd and GCS values of endocardial and epicardial layer were -0.17, and -0.42 for mitral valve, -0.17, and -0.38 for papillary muscle, -0.15, and -0.37 for apex levels, respectively. GCS degree of correlation with IVSTd was &lt; GLS, especially in endocardial layer. GCS values of endocardial layer did not significantly correlate with IVSTd for all levels. Conclusions: GLS and GCS decrease proportionally with increase in degree of LV hypertrophy. Degree of decrement of GCS was smaller than with GLS, especially in endocardial layer. This may be a compensation mechanism to maintain cardiac function.
Advax augments B and T cell responses upon influenza vaccination via the respiratory tract and enables complete protection of mice against lethal influenza virus challenge
Authors: Jasmine Tomar, Harshad P. Patil, Gustavo Bracho, Wouter F. Tonnis, Henderik W. Frijlink, Nikolai Petrovsky, Rita Vanbever, Anke Huckriede, Wouter L.J. Hinrichs
Journal: Journal of Controlled Release (2018)

Administration of influenza vaccines via the respiratory tract has potential benefits over conventional parenteral administration, inducing immunity directly at the site of influenza exposure as well as being needle free. In this study, we investigated the suitability of Advax™, a stable particulate polymorph of inulin, also referred to as delta inulin, as a mucosal adjuvant for whole inactivated influenza vaccine (WIV) administered either as a liquid or dry powder formulation. Spray freeze-drying produced Advax-adjuvanted WIV powder particles in a size range (1-5 μm) suitable for inhalation. The physical and biological characteristics of both WIV and Advax remained unaltered both by admixing WIV with Advax and by spray freeze drying. Upon intranasal or pulmonary immunization, both liquid and dry powder formulations containing Advax induced significantly higher systemic, mucosal and cellular immune responses than non-adjuvanted WIV formulations. Furthermore, pulmonary immunization with Advax-adjuvanted WIV led to robust memory B cell responses along with an increase of lung localization factors i.e. CXCR3, CD69, and CD103. A less pronounced but still positive effect of Advax was seen on memory T cell responses. In contrast to animals immunized with WIV alone, all animals pulmonary immunized with a single dose of Advax-adjuvanted WIV were fully protected with no visible clinical symptoms against a lethal dose of influenza virus. These data confirm that Advax is a potent mucosal adjuvant that boosts vaccine-induced humoral and cellular immune responses both in the lung and systemically with major positive effects on B-cell memory and complete protection against live virus. Hence, respiratory tract immunization, particularly via the lungs, with Advax-adjuvanted WIV formulation as a liquid or dry powder is a promising alternative to parenteral influenza vaccination.
Discovery and Characterization of Dual Inhibitors of MDM2 and NFAT1 for Pancreatic Cancer Therapy
Authors: Wei Wang, Jiang-Jiang Qin, Sukesh Voruganti, Bhavitavya Nijampatnam, Sadanandan E. Velu, Ke-He Ruan, Ming Hu, Jianwei Zhou, Ruiwen Zhang
Journal: Cancer Research (2018)

Overexpression and activation of the murine double minute 2 (MDM2) or nuclear factor of activated T cells 1 (NFAT1) oncoproteins frequently occur in pancreatic cancer. Most MDM2 inhibitors under development target MDM2-p53 binding and have little or no effect on cancers without functional p53, including pancreatic cancer. Some available compounds indirectly inhibit NFAT1 activity by interfering with calcineurin activity, but there are currently no specific inhibitors against NFAT1. Here we performed a high-throughput virtual and cell-based screening to yield a lead compound (MA242) that can directly bind both MDM2 and NFAT1 with high affinity, induce their protein degradation, and inhibit NFAT1-mediated transcription of MDM2 As a result of this binding, MA242 decreased cell proliferation and induced apoptosis in pancreatic cancer cell lines regardless of p53 status. MA242 alone or in combination with gemcitabine inhibited pancreatic tumor growth and metastasis without any host toxicity. Our data indicate that targeting both MDM2 and NFAT1 represents a novel and effective strategy to treat pancreatic cancer.Significance: These findings suggest that pharmacological inhibition of both MDM2 and NFAT1 is a promising strategy for the treatment of pancreatic cancer, even in tumors lacking functional p53. Cancer Res; 78(19); 5656-67. ©2018 AACR.
Compliance with guidelines and factors associated with ordering the 21-gene breast cancer assay.
Authors: Valentina I. Petkov, Nadia Howlader, Kathleen Cronin, Allison W. Kurian, Lynne Penberthy
Journal: Journal of Clinical Oncology (2016)

6552 Background: The 21-gene Recurrence Score result estimates the likelihood of distant recurrence and predicts the benefit of chemotherapy in early stage, hormonal receptor positive (HR+), HER2 negative (HER2-) invasive breast cancer. It has been recommended by oncology practice guidelines since 2008. We evaluated compliance with guidelines and factors associated with ordering the test at the population level using Surveillance Epidemiology and End Results (SEER) data. Methods: We augmented manually collected Oncotype DX results from SEER with all test results from Genomic Health Clinical Laboratory for cancer cases diagnosed 2004-2012. Patients were eligible for this analysis of test ordering practices if diagnosed between 2010 and 2012 with node negative, hormone receptor positive, HER2 negative invasive breast cancer, and met the NCCN guideline criteria for 21-gene assay testing during the study period. Logistic regression was used to identify demographic and tumor characteristics associated with testing. Results: A total of 31,790 (42%) of 75,366 eligible patients had the 21-gene assay ordered. Univariate and multivariate analysis indicated that there were many factors that significantly influenced the proportion of tests ordered. In multivariable analysis, significant factors that were associated with test ordering included, age, race, socioeconomic status, marital status, insurance, geographic location, tumor grade, tumor size (p-value < 0.01 for each covariate) . The large magnitude of the variation in test ordering by age, geographic area, and tumor size are illustrated in the univariate results in the Table. Conclusions: Despite guideline recommendations important demographic and socioeconomic factors are associated with testing in node negative breast cancer, suggesting important disparities in who receives the test. Understanding these disparities may help improve patient care and outcomes by increased awareness and targeted interventions. Most Commonly Tested Groups Least Commonly Tested Groups Age 45-54 60% Age 75+ 11% Married 48% Widowed 21% Grade 2 45% Grade 1 37% 11-20 mm 49% 6-10 mm 33% New Jersey 55% California 35%
A 12 multigene NGS panel to characterize molecular biotypes in endometrial cancer.
Authors: Ignacio Romero, Raquel López Reig, Antonio Fernandez-Serra, Zaida Garcia-Casado, Cristina Zorrero, Carmen Illueca, Andres Poveda, Jose Antonio Lopez-Guerrero
Journal: Journal of Clinical Oncology (2018)

5591 Background: The Cancer Genome Atlas (TCGA) study for endometrial carcinomas (EC) defined four prognostic molecular biotypes based on POLE status, Microsatellite instability (MSI) and Copy Number (CN) analysis. The aim of this study was to develop a prognostic EC molecular classifier, based on the analysis of a small multi-gene NGS panel, as a tool that supports the therapeutic decision making for EC patients. Methods: Serous (S) and endometrioid (E) EC (stages I, II and III from FIGO 2009) were identified from a prospective EC database of 187 patients. DNA from FFPE blocks was obtained and sequenced following the NGS TruSeq Custom Amplicon low input (Illumina) protocol interrogating a 12 multi-gene panel, including: POLE, PTEN, TP53, ARID1A, ARID5B, FBXW7, PPP2R1A, CTCF, CTNNB1, RPL22, PIKRCA y PIK3R1. MSI analysis was carried out using eight specific microsatellite markers. Random Forest classification algorithm (RFA) including the NGS results of the 12-gene panel, histology, stage and grade was developed from TCGA EC data. Validation was performed in our independent cohort of EC cases. Results: A total of 96 cases (13 S and 83 E) fulfilled histology, stage and DNA quality assessment criteria for the analysis. Most of the cases were Stage I (77); stage II and III being 2 and 17 respectively. Median age at diagnosis was 62 years (36-87) with a median follow-up of 33 months (2– 88). A RFA to classify patients in the four EC molecular biotypes was developed using a training set from TCGA EC dataset. The accuracy of this RFA (99 %) was confirmed in an independent set of the TCGA cohort, and then independently validated in our series with the following results by biotype: POLE, 17/96 (17.7 %); MSI-H, 15/96 (15.6 %); CN High (CNH), 22/96 (22.9 %); and CN Low (CNL), 42/96 (43.7 %). Progression-free and Overall survival analysis revealed that POLE and CNH biotypes constitute the best and worst prognostic groups respectively (PFS, p = 0.038; OS, p = 0.029). Conclusions: We have defined a prognostic model to classify EC molecular biotypes on the basis of the analysis of a 12 multi-gene NGS panel; which could be easily implemented as molecular diagnostic tool.
Hypomethylating agent (HMA) treatment as a bridge to allogeneic hematopoietic cell transplantation (HCT) for relapsed/refractory acute myeloid leukemia (RR-AML).
Authors: Michael Richard Grunwald, Danielle Boselli, Lauren M. Bohannon, Michael Keith Alister Zimmerman, Jing Ai, Thomas Gregory Knight, Brittany K. Ragon, Dragos Plesca, Jigar S. Trivedi, Belinda Rene Avalos, Edward Alan Copelan, James Thomas Symanowski, Jonathan Michael Gerber
Journal: Journal of Clinical Oncology (2018)

7033 Background: Outcomes for patients (pts) with RR-AML are poor, with limited treatment options. Salvage HMA therapy has been explored for RR-AML but is often considered palliative. We examined response and survival in RR-AML pts treated with HMA therapy, including HCT rates and outcomes. Methods: All RR-AML pts initiated on HMAs at our institution between August 2013 and August 2017 were analyzed. Overall response rate (ORR) included complete remission (CR), CR with incomplete platelet recovery (CRp), CR with incomplete count recovery (CRi), and hematologic remission (defined by neutrophils > 1000/µL, platelets > 100k/µL, transfusion independence, and no peripheral blasts). We assessed the number of pts receiving HCT and their outcomes. Overall survival (OS) was estimated by Kaplan-Meier method. Log rank test was used for comparisons. Results: Fifty RR-AML pts received HMAs. Median age at HMA start was 58 years (range, 24-81); 54% of pts were male. NCCN risk categories at diagnosis were 14% favorable, 32% intermediate, and 54% unfavorable. FLT3-ITD mutations were present in 21% of pts, FLT3-TKD in 10%, and NPM1 in 31%. Most pts (72%) received azacitidine; 28% received decitabine. Concomitant with their HMA, 28% of pts received lenalidomide, and 16% (all FLT3-ITD) received sorafenib. Cytoreduction with hydroxyurea or cyclophosphamide was given to 20%. Among 37 evaluable pts, ORR was 57%. For the entire 50 pt cohort, ORR was 42%; median OS was 9.5 months. There was no correlation between survival and NCCN risk at diagnosis (p = 0.98) or at the start of HMA (p = 0.85). Most pts (84%) had received 1 prior line of therapy, while 16% had received 2 lines. Pts naïve to HMAs had OS superior to those with previous HMA exposure (median OS, 13.0 vs. 5.3 months; p = 0.02). Following HMA therapy, 14 pts (28%) underwent HCT. In this group with a median follow-up of 19.2 months, 1-year OS was 100%, and 2-year OS 78%. Conclusions: HMA therapy for RR-AML can yield response and survival rates comparable to other, more toxic therapies. Additionally, HMAs can be used to bridge RR-AML pts to HCT, with encouraging outcomes. These results warrant validation in a large prospective study.
ICONIC: Biologic and clinical activity of first in class ICOS agonist antibody JTX-2011 +/- nivolumab (nivo) in patients (pts) with advanced cancers.
Authors: Timothy Anthony Yap, Howard A. Burris, Shivaani Kummar, Gerald Steven Falchook, Russell Kent Pachynski, Patricia LoRusso, Scott S. Tykodi, Geoffrey Thomas Gibney, Justin F. Gainor, Osama E. Rahma, Tanguy Y. Seiwert, Funda Meric-Bernstam, Mariela A. Blum Murphy, Jennifer Keating Litton, Ellen Michelle Diament Hooper, Heather Anne Hirsch, Christopher Harvey, Myles Clancy, Ty McClure, Margaret K. Callahan
Journal: Journal of Clinical Oncology (2018)

3000 Background: ICOS is a costimulatory molecule expressed on the surface of activated T cells. JTX-2011 is an ICOS agonist designed to stimulate CD4 T effector (T eff) cells and deplete intratumoral T regulatory (Treg) cells. Preclinical efficacy was seen with mouse JTX-2011 monotherapy (mono) and combination (combo) with anti-PD-1 in ICOS+ tumors. Methods: Relapsed/refractory cancer pts received escalating doses of JTX-2011 mono or combo with nivo in Phase 1 (P1), and the recommended P2 dose (RP2D) in P2, based on safety, target engagement (TE), immunophenotyping and cytokines. P2 gastric (GC) and triple negative breast (TNBC) combo cohorts completed enrollment. ICOS was assessed by IHC in archival (arch) and fresh pre-treatment tumor biopsies (bx) or by flow in peripheral blood. Results: 164 pts had ≥1 dose of JTX-2011; 71 P1 (40 mono, 31 combo); 93 P2 (25 mono, 68 combo) including 7 GC mono, 24 GC and 16 TNBC combo. Pts ≥3 prior therapies: 57% GC mono, 48% GC combo, 56% TNBC combo. JTX-2011 RP2D: 0.3mg/kg q3w mono and combo with nivo 240 mg q3w. DLTs: raised AST/ALT and pleural effusion at 1 mg/kg mono. At 0.3mg/kg: TE > 70% sustained through 3wks; no substantial change in # of peripheral T eff or Tregs; dose dependent increase in IFN-γ at 1-6 hrs. P2 adverse events (AEs): drug-related G3-4 8% mono, 13% combo; immune-related 4% mono, 21% combo; infusion related 12% mono, 19% combo. Of 13 GC combo pts with paired arch and fresh bx, 6 were ICOS hi on both, 5 changed from low to hi. Of 7 TNBC combo pts with paired bx, 5/7 archival were ICOS hi, 4/7 fresh were ICOS hi. RECIST antitumor activity: JTX-2011 mono: 1/7 partial response (PR) in GC; 2/5 stable disease (SD) in P1 TNBC. JTX-2011 combo: 2 PRs (0.1, 0.3mg/kg) and 2 ongoing SD in 19 P1/2 GC; 1 PR in 15 P2 TNBC. Of 17 evaluable pts, 4 had emergence of peripheral CD4 T cell ICOS hi subsets during JTX-2011 therapy, including 1 PR mono, 2 PR combo and 1 SD; none were seen in pts with progressive disease. Conclusions: JTX-2011 mono and combo with nivo were well tolerated with antitumor responses in heavily pre-treated GC and TNBC pts. Emergence of peripheral blood CD4 ICOS hi T cell subsets may be a surrogate biomarker of response. Further trials of JTX-2011 are planned. Clinical trial information: NCT02904226.
A pilot trial of anti-KIR antibody with or without 5-azacitidine for myelodysplastic syndrome.
Authors: Fevzi Firat Yalniz, Naval Guastad Daver, Steven Mitchell Kornblau, Maro Ohanian, Gautam Borthakur, Courtney Denton Dinardo, Marina Konopleva, Jan Andreas Burger, Yvonne Gasior, Sherry Pierce, Hagop M. Kantarjian, Guillermo Garcia-Manero
Journal: Journal of Clinical Oncology (2018)

7067 Background: Experimental and clinical data suggest that enhancement of NK cell activity by a surrogate of KIR blockage improves the outcomes in myeloid malignancies. Lirilumab (LIRI) is a human IgG4 monoclonal antibody that blocks KIR/HLA-C interaction and augments NK cell activity. We designed a phase 2 study to evaluate the safety and efficacy of LIRI as a single agent and in combination with 5-Azacitidine (AZA) in patients (pts) with myelodysplastic syndrome (MDS). Methods: Adult pts with MDS of any risk who had not received prior therapy with a hypomethylating agent, adequate performance status (ECOG ≤ 2) and organ function were included. Lower risk MDS pts (low and intermediate-1 by IPSS) were given LIRI at the dose of 3 mg/kg in every 4 weeks. Higher risk MDS pts received AZA at the dose of 75 mg/m2 on days 1-7 in combination with LIRI 3 mg/kg on day 7 of 28 day cycle. Responses were evaluated on day 28 of course 1 and afterwards every 3 months or as indicated according to IWG-2006 criteria. Results: A total of 10 pts including 8 with higher and 2 with lower risk MDS were enrolled. The median age was 70 years (range, 50-84) and 40% of pts had complex cytogenetics. All pts had baseline next generation sequencing and frequently identified mutations included TP53 (n = 5), TET2 (n = 3) and NRAS (n = 2). The median follow up was 5 months (range, 3-15) and pts received a median of 4 (range, 2-13) and 9 (range, 5-14) cycles of treatment with AZA plus LIRI and single agent LIRI, respectively. Two pts achieved complete remission (CR), 5 marrow CR and 3 had stable disease. Two achieved cytogenetic CR (20%) and 4 had hematologic improvement. Reasons for study discontinuation included disease progression (n = 4), stem cell transplantation (n = 3) and toxicities (myocarditis, non-therapy related, n = 1). The median duration of CR/mCR responses were 3 months (range, 1-5). Grade 3/4 toxicities included 3 episodes of neutropenic infections, 2 pneumonia, 2 infectious colitis and 1 elevated bilirubin. Nine serious adverse events reported of which 6 possibly related to LIRI. Conclusions: LIRI either as a single as well as in combination with AZA was well tolerated in pts with MDS. A large scale multicenter study is warranted to confirm our findings. Clinical trial information: 02599649.
Demographic variation of Ki67 and its relation with prognosis in triple-negative breast cancer: A single-center pilot project.
Authors: Mashrafi Ahmed, Tahmina Begum
Journal: Journal of Clinical Oncology (2012)

e11539 Background: Ki-67 is a proliferation marker expressed during cell cycle. ASCO does not recommend this biomarker to be done routinely in breast cancer. As triple negative breast cancer lacks all the ASCO recommended biomarkers (estrogen, progesterone and HER-2 gene), non-recommended markers may carry significant prognostic value in different demographic population. Methods: A retrospective chart review was conducted on patients who were diagnosed with triple negative breast cancer at Saint Joseph Hospital, Chicago from 2005 to 2010. We analyzed the data for Ki67 value among age group, race, menstrual status, tumor histology, stage, treatment given and outcome of the treatment. The data was obtained from medical record, cancer registry and department of pathology. Results: Only 35 cases were found retrospectively. The mean age was 55.6 year. Nearly 47% were African American, 38% White and rest was other races. Most of the cases (71%) were post-menopausal. The average follow-up was 214 days with nearly 62% patients remained disease free, 21% suffered from relapse but alive and 18% died from relapse. The analysis of data is presented here in tabulated form. Conclusions: In our study, we could not reach to statistical significance mostly due to small size of the population. Being a rare subtype of breast cancer, a single center data analysis is not sufficient. This pilot study will encourage us to go for a large scale study involving multi-center or cancer registry data of the state of Illinois. [Table: see text] [Table: see text] [Table: see text] [Table: see text] [Table: see text]
Circulating Let-7 as a prognostic factor and potential agent to detect accelerated reproliferation during radiotherapy in lung cancer.
Authors: Xiaolin Li, Xindong Sun, Haiyan Zeng, Wanlong Li, Peng Xie, Jinming Yu
Journal: Journal of Clinical Oncology (2016)

e23098 Background: The mainstay treatment for small cell lung cancer (SCLC) and advanced non-small cell lung cancer (NSCLC) has being chemoradiotherapy. Accelerated reproliferation during radiation is an important factor resulting in radiotherapy failure. The identification of strategies that accurately reflect accelerated reproliferation during radiation would help in determining radiotherapy strategy, thus implement individualized treatment and improve long-term survival of patients. Methods: Patients of lung cancer were enrolled from Shandong Cancer Hospital & Institute in China from March 2014 to January 2016. All patients received concurrent or sequential chemo-radiotherapy, or radiotherapy only. Peripheral blood was obtained before treatment and every week during radiotherapy, and then separated for serum. Quantitative real-time polymerase chain reaction (PCR) was utilized to detect the sequential expression level of let-7 in serum. Results: Twenty-four consecutive consenting patients were enrolled into this study. There was a strong correlation between serum let-7 and tissue Ki-67 before treatment (r = − 0.593, P = 0.020). Patients with high level of baseline serum let-7 had significantly better OS (100% : 58.3%, P = 0.036) than patients with low level of baseline serum let-7. For those patients with relatively low expression level of serum let-7 before radiotherapy, there was a peak of expression levels at the time point of week 4 during radiotherapy. For those patients with relatively high expression level of serum let-7 before radiotherapy, the expression levels were downregulated at the early stage of radiotherapy. Conclusions: Serum let-7 is a prognostic factor, and could reflect the proliferation of tumor tissue reliably in lung cancer. Initial accelerated proliferation may exist in patients with relatively slow proliferation before radiotherapy, and late course accelerated reproliferation may exist in patients with relatively fast proliferation before radiotherapy.