tbuckley/cabot-search huggingface dataset:
Evaluation of the sensitivity of RAS mutation detection of the Idylla platform in comparison to the OncoBEAM RAS CRC assay.
Authors: Anna Vivancos, Enrique Aranda, Manuel Benavides, Elena Elez, A. Gomez, Marta Toledano, Martina Alvarez, M Rosario Chica Parrado, Vanesa García-Barberán, Eduardo Diaz-Rubio
Journal: Journal of Clinical Oncology (2018)

592 Background: Accurate detection of RAS mutations in metastatic colorectal cancer (mCRC) patients is of high clinical importance for therapy selection as RAS detection methods lacking sensitivity may lead to poor patient outcomes. Liquid biopsy has emerged as a viable alternative to individualize the management and treatment of mCRC patients. However, there is a current need to cross-compare the performance of liquid biopsy platforms. The OncoBEAM RAS dPCR assay offers highly sensitive RAS mutation detection in clinical practice, achieving &gt; 90% concordance when compared to results obtained by tumor mutation testing. The Idylla platform offers a highly-automated qPCR platform for RAS mutation testing of tissue samples, and has shown potential for liquid biopsy. The objective of this study was to provide a head-to-head comparison of the sensitivity of OncoBEAM and Idylla for KRAS mutation detection in plasma from mCRC patients. Methods: Plasma samples from 92 mCRC patients determined to be KRAS-positive using OncoBEAM were re-tested using Idylla. Samples with mutant allelic fractions (MAF) below 5% were selected for analysis. The positive percent agreement (PPA) of KRAS mutation results was compared for replicate samples analyzed by OncoBEAM and Idylla. Results: So far, Idylla detected KRAS mutations in 63 out of 92 (68.4%) OncoBEAM KRAS-positive plasma samples. Categorization of results based on MAF% revealed distinct differences in sensitivity between the two technologies. Conclusions: OncoBEAM demonstrated significantly greater sensitivity for plasma detection of RAS mutations than Idylla. Moreover, these data identify a “gray zone” below 1% MAF where Idylla fails to identify RAS-positivity in patient plasma samples. These findings serve as a reminder that liquid biopsy assays with diminished sensitivity may lack the dynamic range to provide accurate and timely RAS mutational status information to properly guide highly individualized anti-EGFR therapy and chemotherapy treatment decisions that may benefit patient outcomes. [Table: see text]
Primary Care Practitioners’ Perceptions of Electronic Consult Systems
Authors: Michelle S. Lee, Kristin N. Ray, Ateev Mehrotra, Paul Giboney, Hal F. Yee, Michael L. Barnett
Journal: JAMA Internal Medicine (2018)

<h3>Importance</h3> Safety-net health systems across the country are implementing electronic consult (eConsult) systems in which primary care practitioners (PCPs) submit all requests for specialty assistance electronically to be reviewed and discussed with specialists. Evidence suggests that eConsult systems can make significant improvements in specialty access, but the outcomes of these systems for frontline PCPs is poorly understood. <h3>Objective</h3> To understand PCP perceptions of the results of eConsult initiation on PCP workflow, specialist access, and patient care. <h3>Design, Setting, and Participants</h3> Qualitative interviews were conducted from December 1, 2016, to April 15, 2017, with 40 safety-net PCPs in Los Angeles County who use the Los Angeles County Department of Health Services (DHS) eConsult system. Interviewees were recruited to include diversity in PCP type, practice setting, and employer (DHS employed vs DHS affiliated). Participants were interviewed about their perceptions of clinical workflow, access to specialists, relationships with specialists, and referral decision making. <h3>Main Outcomes and Measures</h3> Perceptions of the results of eConsult, including positive and negative themes and remaining perceived gaps in specialty care. <h3>Results</h3> Of the 40 participants, 27 (68%) were women; 24 (60%) PCPs performed 5 or more eConsults per week. Primary care practitioners' perceptions of eConsult clustered around 4 main themes: access and timeliness of specialty care, shift of work to PCPs, relationships with specialists, and eConsult interface issues. Many PCPs praised the improved timeliness of specialist input with eConsult, as well as the added clinical and educational value of dialogue with specialists, particularly compared with the limitations of the prior referral process. However, PCPs also consistently perceived that eConsult shifted some of the work of specialty care to them. Many PCPs believed that this extra burden was worth the effort given the benefits of eConsult, such as improved timeliness of care and ability to manage specialty conditions. In contrast, others were frustrated by the increased administrative burden, broadened clinical responsibility, and restructuring of specialty care delivery. <h3>Conclusions and Relevance</h3> While associated with improved specialty care access, eConsult systems simultaneously created new challenges for PCPs, such as an increased burden of work in providing specialty care. Primary care practitioners varied in their enthusiasm for these workflow changes with diverging perceptions of the same processes. Our findings provide insights on challenges future primary care transformation efforts may face.
ACELARATE: A phase III, open label, multicentre randomised clinical study comparing Acelarin (NUC-1031) with gemcitabine in patients with metastatic pancreatic carcinoma.
Authors: Daniel H. Palmer, Paul J. Ross, Paul Silcocks, William Greenhalf, Olusola Olusesan Faluyi, Yuk Ting Ma, Jonathan Wadsley, Charlotte Louise Rawcliffe, Juan W. Valle, John P. Neoptolemos
Journal: Journal of Clinical Oncology (2018)

TPS537 Background: Single agent gemcitabine still remains an appropriate choice for patients with metastatic pancreatic adenocarcinoma who are not suitable for combination therapy. Known resistance factors, such as low hENT1 and dCK, and CDA overexpression limit gemcitabine’s efficacy. NUC-1031 (Acelarin), is designed to overcome this resistance and deliver significantly higher intracellular levels of the active agent, dFdCTP, than gemcitabine. In Phase I studies Acelarin has shown activity in a range of metastatic cancers, including pancreatic, biliary and ovarian cancers. This Phase III study is designed to show superiority of Acelarin over gemcitabine in patients unsuitable for combination chemotherapy. Methods: To date, 85 patients have been randomised in this multicentre, Phase III study comparing Acelarin with gemcitabine first-line in patients with metastatic pancreatic adenocarcinoma. Patients must have a Performance Status of 0-2 and be unsuitable for combination chemotherapy. To detect a hazard ratio of 0.705 between the two arms, 270 events must be obtained from 328 patients, assuming a median survival of 6 months in the control arm. Currently, pts are being recruited at 27 centres. Patients receive either 825mg/m 2 Acelarin or 1000mg/m 2 gemcitabine on Day 1, 8 and 15 of a 28-day cycle until disease progression. The primary outcome measure is Overall Survival. Secondary outcome measures include Progression Free Survival, Response Rate, Disease Control Rate and Toxicity. Translational research will explore the use of biomarkers for predictive benefit of Acelarin over gemcitabine. Clinical trial information: ISRCTN16765355.
Multiple admissions for acetaminophen overdose: Acetaminophen frequent fliers, a new entity?
Authors: Edward Yang, Lan Peng, William M. Lee
Journal: Hepatology (2018)

1Division of Digestive and Liver Diseases 2Department of PathologyUT Southwestern Medical Center at DallasDallasTX *ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO: William M. Lee, M.D., F.A.C.P., F.A.A.S.L.D. Division of Digestive and Liver Diseases, UT Southwestern Medical Center at Dallas 5959 Harry Hines Blvd., Ste 420 Dallas, TX 75390‐8887 E‐mail: [email protected] Tel: +1‐214‐645‐6111
Acid-sensitive hybrid polymeric micelles containing a reversibly activatable cell-penetrating peptide for tumor-specific cytoplasm targeting
Authors: Baoqiang Tang, Jennica L. Zaro, Yan Shen, Qian Chen, Yinglan Yu, Pingping Sun, Yanqi Wang, Wei-Chiang Shen, Jiasheng Tu, Chunmeng Sun
Journal: Journal of Controlled Release (2018)
High Variability in Lymph Node Counts Among an International Cohort of Pathologists: Questioning the Scientific Validity of Node Counts
Authors: John P. Sherbeck, Lili Zhao, Richard W. Lieberman
Journal: Journal of the National Comprehensive Cancer Network (2018)

Background: The enumeration of lymph nodes (LNs) from surgical specimens plays a critical role in the staging of patients with cancer. LN count (LNC) can affect prognosis, staging, adequacy of resection, and/or eligibility for clinical trials. However, there is no standard method for counting LNs. Most studies in the literature site the pathology report as the source of LN data, without discussion of the counting criteria. Patients and Methods: Four microscopic slides from separate pelvic LN dissections were digitally scanned and uploaded with their gross descriptions to an online library and an online survey. Respondents were asked how many LNs they would count per slide as part of a staging procedure. The survey was distributed to an international cohort of pathologists. Results: A total of 122 surveys were returned: 79 from practicing pathologists and 43 from residents/fellows. There was no statistical difference between the groups. All slides showed significant individual variability. The LNC range for each slide was as follows: slide 1, 1-3; slide 2, 0-13; slide 3, 1-8; slide 4, 1-11. The intraclass correlation (ICC) for all responders was 0.26 (95% CI, 0.05<ICC<0.74), which demonstrates a very low agreement among individuals. Although there is a small amount of literature assessing causes of variability in counts, nearly all focus on different techniques at the grossing bench. Our study is the largest prospective assessment of LNC by an international cohort of pathologists. We have demonstrated tremendous variation in the number of LNs pathologists report for a given slide, thus significantly altering how many total LNs are counted. This calls into question the clinical utility of node counts, as well as their use as a quality indicator. Conclusions: LNC is subject to tremendous interpathologist variation, which has a significant clinical and research impact. Consensus in pathologic handling and microscopic enumeration of LNs is essential.
185P Retrospective study of tumour responses and toxicities associated with anti-PD1 antibody therapy in elderly cancer patients (&gt;75yo) in comparison to patients ≤75yo with metastatic non-small cell lung cancer
Authors: L.C. Chong, N. Corsini, J. Hogan-Doran, M. Brown
Journal: Journal of Thoracic Oncology (2018)
MIR-708 promotes phagocytosis to eradicate T-ALL cells by targeting CD47
Authors: Wei Huang, Wen-Tao Wang, Ke Fang, Zhen-Hua Chen, Yu-Meng Sun, Cai Han, Lin-Yu Sun, Xue-Qun Luo, Yue-Qin Chen
Journal: Molecular Cancer (2018)

Immunoevasion is a hallmark of cancer progression, and immune checkpoint blockade has emerged as a promising strategy for cancer treatment. microRNAs (miRNAs) are important negative regulators of gene expression in the immune system. Here, we demonstrate that miR-708 regulates CD47, a transmembrane protein that inhibits phagocytosis in T cell acute lymphoblastic leukemia. miR-708 directly targeted CD47 through binding to 3'UTR and is inversely correlated with CD47 expression. Functional studies showed that restoration of miR-708 expression in the T-ALL cell line is sufficient to promote phagocytosis by macrophages in the absence or presence of the anti-CD47 antibody to eradicate T-ALL cells, and inhibited tumor engraftment in vivo. Together, our findings suggest that miR-708 is a key negative regulator of CD47 and may serve as an attractive candidate for immunotherapy of T-ALL.
Surveillance to Track Progress Toward Polio Eradication — Worldwide, 2016–2017
Authors: Tracie J. Gardner, Ousmane M. Diop, Jaume Jorba, Smita Chavan, Jamal Ahmed, Abhijeet Anand
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Global efforts to eradicate polio began in 1988, and four of the six World Health Organization (WHO) regions currently have achieved poliofree certification. Within the remaining two regions with endemic poliomyelitis (African and Eastern Mediterranean), Afghanistan, Nigeria, and Pakistan have never interrupted transmission of wild poliovirus (WPV). The primary means of detecting poliovirus transmission is surveillance for acute flaccid paralysis (AFP) among children aged <15 years, combined with collection and testing of stool specimens for detection of WPV and vaccine-derived polioviruses (VDPVs)* in WHO-accredited laboratories within the Global Polio Laboratory Network (GPLN) (1,2). AFP surveillance is supplemented by environmental surveillance for polioviruses in sewage from selected locations. Genomic sequencing of isolated polioviruses enables the mapping of transmission by time and place, assessment of potential gaps in surveillance, and identification of the emergence of VDPVs (3). This report presents poliovirus surveillance data from 2016-2017, with particular focus on six countries in the Eastern Mediterranean Region (EMR) and 20 countries in the African Region (AFR) that reported WPV or circulating VDPVs (cVDPVs) during 2011-2017. Included in the 20 AFR countries are the three most affected by the 2014-2015 Ebola virus disease (Ebola) outbreak (Guinea, Liberia, and Sierra Leone), even though only one (Guinea) reported WPV or cVDPVs during the surveillance period. During 2017, a total of 14 (70%) of the 20 AFR countries and five (83%) of the six EMR countries met both surveillance quality indicators at the national level; however, provincial-level variation was seen. Surveillance strengthening activities are needed in specific countries of these regions to provide evidence supporting ultimate certification of the interruption of poliovirus circulation.
Implementation of Transcatheter Aortic Valve Replacement in France
Authors: Virginia Nguyen, Morgane Michel, Helene Eltchaninoff, Martine Gilard, Christel Dindorf, Bernard Iung, Elias Mossialos, Alain Cribier, Alec Vahanian, Karine Chevreul, David Messika-Zeitoun
Journal: Journal of the American College of Cardiology (2018)
Analysis of the newly defined immune checkpoints in pancreatic cancer.
Authors: Satoshi Wada
Journal: Journal of Clinical Oncology (2017)

109 Background: Pancreatic cancer has not been improved with the five-year survival rate for more than 10 years, which is a refractory cancer of poor prognosis. Development of novel therapeutic agents has been desired, because the standard chemotherapy has not been satisfied yet. Anti-tumor immunotherapy is expected for less burden on the patient in recent years. However, it is limited by multiple tolerogenic mechanisms related to the tumor, the host immune system, and the tumor microenvironment. Therefore satisfactory results are not obtained in the clinical trials for several vaccinations. In this experiment, we focused on negative co-signaling molecules, especially immune checkpoints. The purpose of the present study was to investigate the relationship between the expression of immune checkpoints and clinico-pathological findings, including prognosis in pancreatic cancer patients. Methods: We enrolled 81 patients (52 men and 29 women; age range: 36-84 years) with pancreatic cancer who underwent curative resection with lymphadenectomy at Gunma University Hospital and Saiseikai Maebashi Hospital (Maebashi, Japan) between 2000 and 2011. Patients who had undergone palliative resection, preoperative chemotherapy and radiation therapy were excluded from this study. Furthermore, none of the patients enrolled in this study had synchronous or metachronous cancer in other organs. Results: Immunohistochemical staining of immune checkpoints in primary pancreatic tissue was performed. Patients with high B7-H4 expression had a significantly poorer prognosis than those with low B7-H4 expression. It was also seen in B7-H3 expression in this experiment. Furthermore, in analysis for the expression of CD8, IFN-γ and FOXP3, patients with high FOXP3 expression had a significantly poorer prognosis than those with low FOXP3 expression. Conclusions: The B7-h3 and B7-H4 are negative co-stimulatory molecules and a novel prognostic marker related to the T-cell mediated immune response. It’s pathway may be a molecular target for controlling tumor progression in patients with pancreatic cancer.
CXCL12γ Promotes Metastatic Castration-Resistant Prostate Cancer by Inducing Cancer Stem Cell and Neuroendocrine Phenotypes
Authors: Younghun Jung, Frank C. Cackowski, Kenji Yumoto, Ann M. Decker, Jingcheng Wang, Jin Koo Kim, Eunsohl Lee, Yugang Wang, Jae-Seung Chung, Amy M. Gursky, Paul H. Krebsbach, Kenneth J. Pienta, Todd M. Morgan, Russell S. Taichman
Journal: Cancer Research (2018)

There is evidence that cancer stem-like cells (CSC) and neuroendocrine behavior play critical roles in the pathogenesis and clinical course of metastatic castration-resistant prostate cancer (m-CRPC). However, there is limited mechanistic understanding of how CSC and neuroendocrine phenotypes impact the development of m-CRPC. In this study, we explored the role of the intracellular chemokine CXCL12γ in CSC induction and neuroendocrine differentiation and its impact on m-CRPC. CXCL12γ expression was detected in small-cell carcinoma of metastatic tissues and circulating tumor cells from m-CRPC patients and in prostate cancer cells displaying an neuroendocrine phenotype. Mechanistic investigations demonstrated that overexpression of CXCL12γ induced CSC and neuroendocrine phenotypes in prostate cancer cells through CXCR4-mediated PKCα/NFκB signaling, which promoted prostate tumor outgrowth, metastasis, and chemoresistance
Effect of MMP9 inhibition on effector T-cell responses in a PD1-axis refractory model.
Authors: Victoria Smith, Vladi Juric, Amanda Mikels-Vigdal, Chris O'Sullivan, Maria Kovalenko, Jeremiah Degenhardt, Peng Yue, Venkataraman Sriram
Journal: Journal of Clinical Oncology (2017)

104 Background: Matrix metalloproteinase 9 (MMP9) acts via diverse mechanisms to promote tumor growth and metastasis, and is a key component of the immune-suppressive myeloid inflammatory milieu. We developed a monoclonal antibody (AB0046) that inhibits murine MMP9 and assessed its mechanism of action in immunocompetent mice as a single agent, or in combination with a murine anti-PDL1 antibody. Methods: An orthotopic, syngeneic tumor model (NeuT), which models MMP9-positive myeloid infiltrate, was utilized for efficacy and pharmacodynamic studies involving RNA and T cell receptor (TCR) sequencing, and flow cytometry. Enzymatic analyses were performed on T cell chemoattractant CXCR3 ligands (CXCL9, CXCL10, and CXCL11) which were subsequently evaluated in chemotaxis assays. Results: Anti-MMP9 treatment alone or in combination with an anti-PDL1 antibody decreased primary tumor growth as compared to IgG control-treated animals (56% vs 335% tumor growth increase, p = 0.0005) or anti-PDL1 alone. Profiling of tumors by RNA sequencing revealed that inhibition of MMP9 resulted in elevated expression of genes associated with immune cell activation pathways (Hallmark Interferon Gamma Response, FDR p &lt; 0.001). Treatment with anti-MMP9 and anti-PDL1 antibodies decreased TCR clonality, with evidence of a more diverse TCR repertoire (p = 0.005). Immunophenotyping of tumor-associated T cells by flow cytometry showed that anti-MMP9 and anti-PDL1 co-treatment promoted a 2.8-fold increase in CD3+ cells in tumors (p = 0.01), which was associated with an increase in CD4+ T cells (3.2-fold increase; p = 0.006) and CD8+ T cells (2.8-fold increase; p = 0.013). In contrast, anti-MMP9 and combination treatment resulted in a decrease in tumor-associated regulatory T cells (CD25+ FoxP3+ cells, p = 0.04). MMP9 cleavage of T cell chemoattractant ligands in vitro rendered them functionally inactive for recruitment of activated primary human effector T cells. Conclusions: Inhibition of MMP9 reduces tumor burden and promotes cytotoxic T cell infiltration in a PD1-axis refractory mouse model. The combination of nivolumab and GS-5745, a humanized anti-MMP9 inhibitory antibody, is currently being evaluated in gastric cancer (NCT02864381).
Immune priming by stereotactic body radiation: Dosimetric characteristics.
Authors: Serguei A. Castaneda, Sunjay A Shah, David Huang, Jennifer Sims-Mourtada, Firas Mourtada
Journal: Journal of Clinical Oncology (2017)

85 Background: A systemic immune response to tumors after stereotactic body radiation therapy (SBRT) has been observed. The role of radiation dosimetry variables in priming an immune response is not well characterized. Methods: We analyzed radiation dosimetry variables in a patient with metastatic melanoma receiving pembrolizumab for about 1 year prior to concurrent use with Cyberknife SBRT for a symptomatic lesion in the right lower lobe of the lung. The patient received 50 Gy in 5 fractions prescribed to the 74% isodose line (using a Monte Carlo dose calculation) and developed a systemic immune response three months after this intervention. Results: We observed priming of the immune system as man ifested by radiological and clinical responses in non-irradiated cervical lymph nodes and a new persistent FDG-avid lesion on PET scan located in the base of the tongue. Given the concern for a new malignancy, the patient underwent hemi tongue base glossectomy; interestingly, this surgical specimen showed tonsillar mucosa with reactive lymphoid hyperplasia without evidence of tumor. Upon review of the CyberKnife SBRT plan, we identified that the planning target volume (PTV) was atypically under covered to 89.9% and also had a relatively high value of gross tumor volume (GTV) conformity index (CI) of 2.1. In our experience with CyberKnife plans for lung lesions, usually the PTV coverage is more than 95% and the GTV CI is less than 1.5. Other dosimetry variables had more typical values, including GTV coverage of 99.9%, PTV CI of 1.1, and both GTV and PTV homogeneity index of 1.4. Conclusions: Relatively low PTV coverage and high GTV CI were associated with immune system priming in a well-documented case of systemic responses in non-irradiated pathological and normal tissues, in the setting of concurrent immunotherapy and SBRT. Further studies are warranted to confirm this association.
Care in Chronic Obstructive Lung Disease (CAROL): a randomised trial in general practice
Authors: Stefan Markun, Thomas Rosemann, Kaba Dalla-Lana, Claudia Steurer-Stey
Journal: European Respiratory Journal (2018)

Disease management of chronic obstructive pulmonary disease (COPD) is complex and shortcomings in general practice care for COPD are common. A care bundle is a disease management aid used as a reminder and for steering specific elements of care. Our objectives were to test whether a COPD care bundle delivered to general practitioners (GPs) and practice assistants increases the implementation of key elements of COPD care.The study was a cluster-randomised clinical trial, with 1:1 randomisation of GPs and a 1-year follow-up. The intervention introduced a COPD care bundle and aimed at enhancing collaboration between GPs and practice assistants. The control group continued usual care. The primary outcome measure was the composite score from nine key elements of COPD care measured at the patient level.We enrolled 35 GPs and 216 patients with a median age of 69 years, 59% female, 69% Global Initiative for Chronic Obstructive Lung Disease group A or B. After 1 year, the between-group difference in change of the primary outcome measure was +2.2 (95% CI +1.5- +2.9) in favour of the intervention group. The intervention was associated with significantly higher implementation rates in seven out of nine key elements of care.Disease management using a COPD care bundle increased the implementation of key elements of COPD care in general practice.