tbuckley/cabot-search huggingface dataset:
ClarIDHy: A phase 3 multicenter randomized double-blind study of AG-120 versus placebo in patients with non-resectable or metastatic cholangiocarcinoma with an IDH1 mutation.
Authors: Ghassan K. Abou-Alfa, Juan W. Valle, Robin Kate Kelley, Lipika Goyal, Rachna T. Shroff, Milind M. Javle, Mitesh J. Borad, James M. Cleary, Anthony B. El-Khoueiry, Johanna C. Bendell, Teresa Mercade Macarulla, Arndt Vogel, Christopher Korth, Liewen Jiang, Camelia Gliser, Bin Wu, Samuel V. Agresta, Shuchi Sumant Pandya, Andrew X. Zhu
Journal: Journal of Clinical Oncology (2018)

TPS545 Background: Advanced cholangiocarcinoma (CC) is a life-threatening disease with limited effective chemotherapy options. Mutations in isocitrate dehydrogenase 1 (mIDH1) occur in 13–15% of CC cases, and up to 25% of intrahepatic CC cases, leading to epigenetic and genetic changes that promote oncogenesis via production of the oncometabolite 2-hydroxyglutarate (2-HG). AG-120 (ivosidenib), a first-in-class oral mIDH1 inhibitor, displayed a favorable safety profile and clinical activity in a phase 1 study enrolling 73 mIDH1 CC patients who had received ≥1 prior systemic regimen. As of 10 Mar 2017, 4/73 (5%) had a partial response and 41/73 (56%) stable disease. Progression free survival (PFS) rates at 6 months and 12 months were 38.5% and 20.7%, respectively. The 500 mg once daily dose level of AG-120 was selected for further development in mIDH1 CC. Methods: ClarIDHy is a global, phase 3, multicenter, double-blind, randomized (2:1) study of AG-120 (500 mg once daily) vs. matched placebo in 186 mIDH1 CC patients (ClinicalTrials.gov NCT02989857). Key eligibility criteria: non-resectable or metastatic CC, documented mIDH1 by central laboratory testing, ECOG performance status 0–1, measurable disease (RECIST v1.1), documented disease progression after ≤2 prior systemic therapies in the advanced setting including at least 1 gemcitabine- or 5-fluorouracil-containing regimen, and no prior mIDH inhibitor therapy. Crossover from placebo to AG-120 will be allowed at time of radiographic disease progression. Primary endpoint: PFS assessed by independent radiologists. Secondary endpoints: safety, tolerability, overall response rate (RECIST 1.1), overall survival, pharmacokinetic/pharmacodynamic analyses, and quality of life (EORTC QLQ-C30 and QLQ-BIL21 scales). An independent data monitoring committee will monitor the data during study conduct. The ClarIDHy study is currently activated at participating sites in the US, UK, EU, and S. Korea. R eused with permission from the American Society of Clinical Oncology (ASCO). This abstract was accepted and previously presented at the 2017 ASCO Annual Meeting. All rights reserved. Clinical trial information: NCT02989857.
Malignant Abnormalities in Male <i>BRCA</i> Mutation Carriers
Authors: Roy Mano, Shlomit Tamir, Inbal Kedar, Ofer Benjaminov, Jack Baniel, Tzlil Tabachnik, David Margel
Journal: JAMA Oncology (2018)

There were no differences between arms among the secondary outcomes (Table ).There were 18 serious adverse events: 8 in patients receiving ketamine and 10 in patients receiving placebo.Common adverse events were cognitive disturbance, dizziness, fatigue, nausea, and somnolence.Discussion | This trial reports that ketamine was equivalent to placebo for cancer-related neuropathic pain.Findings enhance previous work 4 by examining ketamine in cancerrelated neuropathic pain.There may be subgroups of patients for whom ketamine is helpful, such as those with central sensitization.A limitation of the present study was that we did not specifically select patients with clinical evidence of central sensitization, for whom it is reasonable to hypothesize a more specific analgesic target for ketamine.Future studies that examine ketamine in chronic neuropathic pain should focus on patients with central sensitization, which can be established by a bedside test.This approach would be congruent with preclinical knowledge and would address an important remaining unanswered question.
Association of minimally invasive colorectal resection with elevated levels of plasma B7 homolog 1 (B7-H1) during the first month after surgery and effect on immune suppression and growth of residual metastases.
Authors: Hmc Shantha Kumara, Erica Pettke, Carl S Winkler, Sandhu K Jaspreet, Xiaohong Yan, Cekic Vesna, Nipa Dilip Gandhi, Richard L Whelan
Journal: Journal of Clinical Oncology (2018)

602 Background: The co-stimulatory molecule B7 homolog 1 (B7-H1) is a ligand for PD-1 which is an immunoinhibitory receptor of activated lymphocytes. PD-1 expression is upregulated on tumor infiltrating lymphocytes (TILs), and B7-H1 expressed on cancer cells may inhibit T-cell activation and proliferation. B7-H1 is also expressed on endothelial (EC) and intestinal epithelial cells as well as activated macrophages. B7H1 in EC is rapidly induced by IFN-gamma and TNF. B7-H1 silencing with siRNA inhibits tumor cell proliferation/invasion. B7H1 expression in keratinocytes (KC) directly downregulates CD8(+) T-cell effector function via PD-1 binding at sites of inflammation. Shed B7-H1 can be found in the blood. Surgery’s impact on plasma B7H1 levels is unknown. This study’s purpose was to evaluate plasma B7H1 levels during the first month after MICR for colorectal (CRC). Methods: MICR CRC patients in an IRB approved data/plasma bank with adequate plasma available were eligible. Clinical and pathological data were reviewed. Blood samples were collected preoperatively (PreOp) and at 6 post-operative (Postop) time points (POD 1, 3, 7-13, 14-20, 21-27, 28-41). B7-H1 levels were analyzed in duplicate using ELISA. The Wilcoxon test was used for analysis. Results: 88 CRC patients who had a MICR met inclusion criteria (28% rectal and 62% colon lesions). The mean PreOp B7-H1 level was 51.9±20.9 pg/ml. Significantly elevated mean plasma levels were noted on POD1 (64.9±24.2 pg/ml, n = 86, p = &lt; 0.0001), POD3 (67.3±24.6 pg/ml, n= 72, p = &lt; 0.0001), POD7-13 (69.2±22.6 pg/ml, n = 65, p = &lt; 0.0001), POD14-20 (72.5±28.9 pg/ml, n=23,p=0.001), POD 21-27 (79.4±66.6 pg/ml, n = 13, p = 0.001), and on POD 28-41 (56.3 ±22.7 pg/ml, n = 20, p =0.02), when compared to PreOp levels. Conclusions: Plasma B7-H1 levels are elevated for over a month after MICR for CRC. The etiology of the early increase may be the acute inflammatory response whereas late elevations may be related to wound healing-related tissue remodeling. Elevated plasma B7-H1 may suppress TIL’s which may result in increased tumor growth. Further studies are warranted.
120P Optimal chemotherapy regimen for concurrent chemo-radiotherapy of locally advanced unresectable stage III non-small cell lung cancer (NCSLC)
Authors: N. Jokhadze, I. Kiladze, L. Katselashvili, M. Kacharava, N. Jankarashvili, I. Zumbadze, N. Kalandarishvili, T. Melkadze, E. Gogua
Journal: Journal of Thoracic Oncology (2018)
Proposed Chaoyang vascular classification for superior mesenteric-portal vein invasion, resection, and reconstruction in patients with pancreatic head cancer during pancreaticoduodenectomy – A retrospective cohort study
Authors: Jiqiao Zhu, Xianliang Li, Jiantao Kou, Jun Ma, Lixin Li, Hua Fan, Ren Lang, Qiang He
Journal: International Journal of Surgery (2018)
211P First analysis of a real-world study to explore the character and treatment outcome of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) on non-small cell lung cancer (NSCLC) with brain metastases (BM)
Authors: H. Zhang, L. Liu, C. Zhang, N. Zhang, H. Su, Y. Song, J. Min
Journal: Journal of Thoracic Oncology (2018)
Verification of the analytical performance of a molecular diagnostic for response to anti-PD1 therapy on the nCounter Dx Analysis System.
Authors: Brett Wallden, Irena Pekker, Simina Popa, Naeem Dowidar, Celine Ngouenet, Amy Sullivan, Patrick Danaher, Afshin Mashadi-Hossein, Mingdong Liu, Matthew John Marton, Sean Ferree, James Justin Storhoff
Journal: Journal of Clinical Oncology (2017)

8 Background: Pembrolizumab is a humanized anti-PD1 antibody that is approved for use in advanced melanoma, recurrent or metastatic head and neck squamous cell carcinoma, and metastatic non-small-cell lung cancer. It has also shown clinical activity in a number of other tumor types in clinical trials, but there is need for a precise and accurate test that can identify patients most likely to benefit from therapy. We have previously described the development and analytical performance of a NanoString RNA expression clinical trial assay, referred to here as the Tumor Inflammation Signature (TIS) assay, which is being evaluated as a patient enrichment biomarker in multiple solid tumor types for treatment with pembrolizumab. Here we describe additional performance data and analytical verification of reproducibility from tissue and RNA input range in multiple tumor types. Methods: Linearity and specificity were assessed with single targets or pools of in vitro transcribed RNAs with sequences matching the 18 biomarker and 10 normalization gene probe targets. The verification of the previously reported analytical precision from RNA and reproducibility from tissue was performed using independent samples from 11 tumor types. The biological variability of the signature within a patient sample was evaluated by testing multiple core punches from formalin fixed paraffin embedded (FFPE) tissue blocks. Results: The TIS assay’s measurement of the 28 genes was linear across a wide dynamic range ( ≥ 4 logs) and was highly specific with &lt; 1% cross reactivity between probes. The assay was verified across the specified RNA input range with &gt; 90% concordance at the low end (50ng) of the RNA input range. The total standard deviation of the anti-PD1 Predictor Score from tissue was verified as &lt; 5% of the signature score range and &gt; 90% concordance in biomarker high/low categorization within the biological replicates. Conclusions: The analytical performance of the NanoString TIS assay was verified to be robust. The assay is well suited for decentralized clinical testing and is currently under investigation to identify responders to anti-PD1 therapy in multiple tumor types in several clinical studies.
169P Nephrotoxicity of pemetrexed maintenance in patients with advanced NSCLC: Two cohort studies
Authors: S. Visser, J. Huisbrink, N. Van 'T Veer, J. Van Toor, T. Van Boxem, N. Van Walree, B. Stricker, J. Aerts
Journal: Journal of Thoracic Oncology (2018)
Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia
Authors: Luis A. Carvajal, Daniela Ben Neriah, Adrien Senecal, Lumie Benard, Victor Thiruthuvanathan, Tatyana Yatsenko, Swathi-Rao Narayanagari, Justin C. Wheat, Tihomira I. Todorova, Kelly Mitchell, Charles Kenworthy, Vincent Guerlavais, D. Allen Annis, Boris Bartholdy, Britta Will, Jesus D. Anampa, Ioannis Mantzaris, Manuel Aivado, Robert H. Singer, Robert A. Coleman, Amit Verma, Ulrich Steidl
Journal: Science Translational Medicine (2018)

The tumor suppressor p53 is often inactivated via its interaction with endogenous inhibitors mouse double minute 4 homolog (MDM4 or MDMX) or mouse double minute 2 homolog (MDM2), which are frequently overexpressed in patients with acute myeloid leukemia (AML) and other cancers. Pharmacological disruption of both of these interactions has long been sought after as an attractive strategy to fully restore p53-dependent tumor suppressor activity in cancers with wild-type p53. Selective targeting of this pathway has thus far been limited to MDM2-only small-molecule inhibitors, which lack affinity for MDMX. We demonstrate that dual MDMX/MDM2 inhibition with a stapled α-helical peptide (ALRN-6924), which has recently entered phase I clinical testing, produces marked antileukemic effects. ALRN-6924 robustly activates p53-dependent transcription at the single-cell and single-molecule levels and exhibits biochemical and molecular biological on-target activity in leukemia cells in vitro and in vivo. Dual MDMX/MDM2 inhibition by ALRN-6924 inhibits cellular proliferation by inducing cell cycle arrest and apoptosis in cell lines and primary AML patient cells, including leukemic stem cell-enriched populations, and disrupts functional clonogenic and serial replating capacity. Furthermore, ALRN-6924 markedly improves survival in AML xenograft models. Our study provides mechanistic insight to support further testing of ALRN-6924 as a therapeutic approach in AML and other cancers with wild-type p53.
U.S. Food and Drug Administration Precertification Pilot Program for Digital Health Software: Weighing the Benefits and Risks
Authors: Theodore T. Lee, Aaron S. Kesselheim
Journal: Annals of Internal Medicine (2018)

In 2017, the U.S. Food and Drug Administration (FDA) announced a new program for software classified as a medical device. The Digital Health Software Precertification (Pre-Cert) Program is designed to expedite regulatory review for companies that demonstrate quality and organizational excellence in software development. Although Pre-Cert is intended to promote the worthy goals of access and innovation in digital health, many questions have been raised. In particular, Pre-Cert may reduce incentives for developers to study the safety and effectiveness of their software products before patients start to rely on them. Although postmarket surveillance can mitigate risks of these products, the FDA does not have as much authority after a product's widespread use to enforce data collection deadlines. Pre-Cert may also create confusion for patients and physicians, who may believe that marketed products were subject to rigorous study.
Development of a novel T-cell immunotherapy targeting HEATR1.
Authors: Robson Grando Dossa, Tanya Cunningham, Marie Bleakley
Journal: Journal of Clinical Oncology (2017)

149 Background: Allogeneic hematopoietic stem cell transplantation (HCT) often cures acute leukemia. However leukemic relapse remains a major cause of HCT failure, and patients with post-HCT relapse have a very poor prognosis. We are developing T cell immunotherapies targeting leukemia-associated minor histocompatibility (H) antigens to manage post-HCT relapse. Because the presentation of minor H antigens is HLA-restricted, a panel of hematopoietic-restricted, leukemia-associated minor H antigens is required to enable the development of broadly applicable minor H antigen targeted immunotherapy. We previously discovered a HLA- B*0801-restricted, leukemia-associated minor H antigen, HEATR1. We showed that HEATR1-specific T cells can specifically kill leukemic blasts and prevent engraftment in a murine model, implying that this minor H antigen is expressed in leukemic stem cells. We have now developed immunotherapy targeting HEATR1 using genetically modified T cells. Methods: We isolated a HEATR1-specific T cell clone from the peripheral blood of a normal donor and sequenced its T cell receptor (TCR). The TCR was codon-optimized and cysteine-modified to maximize expression in T cells and reduce the risk of mispairing with endogenous TCR chains, then cloned into a multicistronic lentiviral vector (LV). Primary CD8 + T cells were transduced with the HEATR1 TCR LV and evaluated with a range of assays. Results: The HEATR1-specific T cell clone specifically killed B8 + HEATR1 + primary leukemia. Similarly, CD8 + HEATR1 TCR-transduced T cells killed target cells pulsed with HEATR1 peptide (ISKERAEAL), but not the allelic variant control peptide (ISKERAGAL), and specifically killed cell lines that endogenously present the HEATR1 minor H antigen. HEATR1-transduced T cells also secrete cytokines and proliferate in response to HEATR1 + but not HEATR1 - cells. Conclusions: We have demonstrated that HEATR1-specific T cell clone and HEATR1 TCR-transduced T cells can kill HEATR1 + cells. If the safety and efficacy of HEATR1 TCR immunotherapy is confirmed in further preclinical studies, development of phase I clinical studies will be warranted and may ultimately provide a new option for management of relapse after HCT.
Inhibiting Fibronectin Attenuates Fibrosis and Improves Cardiac Function in a Model of Heart Failure
Authors: Iñigo Valiente-Alandi, Sarah J. Potter, Ane M. Salvador, Allison E. Schafer, Tobias Schips, Francisco Carrillo-Salinas, Aaron M. Gibson, Michelle L. Nieman, Charles Perkins, Michelle A. Sargent, Jiuzhou Huo, John N. Lorenz, Tony DeFalco, Jeffery D. Molkentin, Pilar Alcaide, Burns C. Blaxall
Journal: Circulation (2018)

Background: Fibronectin (FN) polymerization is necessary for collagen matrix deposition and is a key contributor to increased abundance of cardiac myofibroblasts (MFs) after cardiac injury. We hypothesized that interfering with FN polymerization or its genetic ablation in fibroblasts would attenuate MF and fibrosis and improve cardiac function after ischemia/reperfusion (I/R) injury. Methods: Mouse and human MFs were used to assess the impact of the FN polymerization inhibitor (pUR4) in attenuating pathological cellular features such as proliferation, migration, extracellular matrix deposition, and associated mechanisms. To evaluate the therapeutic potential of inhibiting FN polymerization in vivo, wild-type mice received daily intraperitoneal injections of either pUR4 or control peptide (III-11C) immediately after cardiac surgery for 7 consecutive days. Mice were analyzed 7 days after I/R to assess MF markers and inflammatory cell infiltration or 4 weeks after I/R to evaluate long-term effects of FN inhibition on cardiac function and fibrosis. Furthermore, inducible, fibroblast-restricted, FN gene–ablated (Tcf21 MerCreMer ; Fn flox ) mice were used to evaluate cell specificity of FN expression and polymerization in the heart. Results: pUR4 administration on activated MFs reduced FN and collagen deposition into the extracellular matrix and attenuated cell proliferation, likely mediated through decreased c-myc signaling. pUR4 also ameliorated fibroblast migration accompanied by increased β1 integrin internalization and reduced levels of phosphorylated focal adhesion kinase protein. In vivo, daily administration of pUR4 for 7 days after I/R significantly reduced MF markers and neutrophil infiltration. This treatment regimen also significantly attenuated myocardial dysfunction, pathological cardiac remodeling, and fibrosis up to 4 weeks after I/R. Last, inducible ablation of FN in fibroblasts after I/R resulted in significant functional cardioprotection with reduced hypertrophy and fibrosis. The addition of pUR4 to the FN-ablated mice did not confer further cardioprotection, suggesting that the salutary effects of inhibiting FN polymerization may be mediated largely through effects on FN secreted from the cardiac fibroblast lineage. Conclusions: Inhibiting FN polymerization or cardiac fibroblast gene expression attenuates pathological properties of MFs in vitro and ameliorates adverse cardiac remodeling and fibrosis in an in vivo model of heart failure. Interfering with FN polymerization may be a new therapeutic strategy for treating cardiac fibrosis and heart failure.
Concurrent BRAF/MEK Inhibitors in <i>BRAF</i> V600–Mutant High-Grade Primary Brain Tumors
Authors: Karisa C. Schreck, Andrew Guajardo, Doris D.M. Lin, Charles G. Eberhart, Stuart A. Grossman
Journal: Journal of the National Comprehensive Cancer Network (2018)

BRAF V600 mutations are being identified in patients with primary brain tumors more often as molecular testing becomes widely available. Targeted treatment with BRAF inhibitors has been attempted in individual cases with some responses, whereas others showed no response or developed resistance. Preclinical work suggests that gliomas could be more responsive to the concurrent use of BRAF and MEK inhibition for MAP kinase pathway suppression. This report presents 2 cases of malignant brain tumors with BRAF V600E mutations that were resistant to radiation and temozolomide, and reports on their response to targeted treatment with the BRAF and MEK inhibitors dabrafenib and trametinib. One patient with an anaplastic pleomorphic xanthoastrocytoma experienced a partial response for 14 months, demonstrated by progressive tumor shrinkage and clinical improvement; however, this was followed by clinical and radiographic progression. The patient with glioblastoma continued to have stable disease after 16 months of treatment. These cases are encouraging in a disease that urgently needs new treatments. Further work is necessary to understand response rates, duration, and survival in primary brain tumors.
Abstract 16021: Quality of Layperson Bystander Cardiopulmonary Resuscitation During Real Life Out-of-hospital Cardiac Arrest
Authors: Tore Gyllenborg, Asger Granfeldt, Freddy Lippert, Ingunn S Riddervold, Fredrik Folke
Journal: Circulation (2016)

Background:  Out-of-hospital cardiac arrest (OHCA) is a leading cause of death. Early basic life support increases survival, however the effect is dependent on the quality of cardiopulmonary resuscitation (CPR). While bystander CPR quality primarily has been investigated in controlled, simulated cardiac arrest scenarios, limited is known about CPR quality by laypersons in real life OHCA.   Aim:  To describe the quality of bystander CPR based on information from automated external defibrillator (AED) CPR process data during OHCA and to evaluate the results compared with the 2015 American Heart Association Resuscitation Guidelines.   Methods:  All cases of public OHCA in the Capital Region of Denmark where an AED (ZOLL AED Plus®) was used for bystander CPR prior to ambulance arrival was included. We included 86 cases with at least one continuous full minute of data. Data was analyzed for the initial 10 minutes of CPR using RescueNet™ Code Review 5.71 that calculates compression rate (CR), depth (CD) and fraction (CF) delivered for each minute of CPR.   Results:  Median analysis period was 4 min [2;7]. The initial rhythm was shockable in 47% (n=40) of cases.  Bystanders compressed with a mean CR of 104 min -1  (SD15), a CD of 5.0 cm (SD 1.4) and a CF of 58% (SD 16). Mean CR was within the range of 100-120 min -1  in 51% (n=43), below in 36% (n=31) and above in 11% of all cases (n=11). CD was between 5-6 cm in 35% (n=30), below in 46% (n=39) and above in 19 % of cases (n=16). CF was below the recommended 60% in 50% of cases (n=43).  During the entire resuscitation period a median of 40 % [IQR 0;75] of total resuscitation time CR was 100-120 min -1 , whereas CD was between 5-6 cm in 14% [IQR 0;50] of the time. Pauses due to defibrillation had a median length of 27 seconds [IQR 22;30]. The duration of pre-shock pauses were 19 seconds [IQR 17;21] while the prompted pre-shock pause was 15 seconds [IQR 14;18].   Conclusion:  Bystanders using AEDs with real time audio feedback in OHCA are able to perform quality CPR. However, only in 40% of the total resuscitation period did bystanders perform chest compressions at the recommended rate and 14% of the resuscitation period for compression depth. Furthermore, none of the pre-shock pauses where below recommended 10 seconds, in part due to the prompted pre-shock pause of 15 seconds.
Association of disrupted circadian rhythmicity with mood disorders, subjective wellbeing, and cognitive function: a cross-sectional study of 91 105 participants from the UK Biobank
Authors: Laura M Lyall, Cathy A Wyse, Nicholas Graham, Amy Ferguson, Donald M Lyall, Breda Cullen, Carlos A Celis Morales, Stephany M Biello, Daniel Mackay, Joey Ward, Rona J Strawbridge, Jason M R Gill, Mark E S Bailey, Jill P Pell, Daniel J Smith
Journal: The Lancet Psychiatry (2018)