tbuckley/cabot-search huggingface dataset:
Abstract IA25: Modeling cancer in the CRISPR era
Authors: Andrea Ventura
Journal: Cancer Research (2020)

Abstract Chromosomal rearrangements are common cancer-associated mutations that often result in the generation of therapeutically actionable gene fusions. Unfortunately, until recently this class of mutations has proved challenging to recapitulate using conventional gene-targeting methods. To overcome this limitation, we have recently developed a CRISPR-based strategy to model a broad range of chromosomal rearrangements, including inversions, deletions, translocations, and tandem duplications (Maddalo et al., 2014). Since this strategy can be used to induce the desired chromosomal rearrangement in somatic cells—ex vivo or directly in vivo—of adult animals, it enables the rapid and cost-effective generation of novel mouse models of human cancer. As proof of concept, we have applied this strategy to generate a novel model of EML4-ALK driven lung adenocarcinoma, and to show that a novel gene fusion observed in a few human gliomas is a potent oncogenic driver and therapeutic target (Cook et al., 2017; Maddalo et al., 2014; Ventura, Dow, 2018). In my presentation, I will discuss how my group is using these novel technologies, as well as conventional gene-targeting methods, to recapitulate the genetic complexity of human cancers in vivo. I will present new and unpublished models of pediatric brain cancers driven by BRAF gene fusions we have recently generated using in vivo and ex vivo CRISPR-mediated chromosomal engineering and show how we are using these models to test novel therapeutic strategies and to gain insights into the molecular pathogenesis of human cancers. References: Cook PJ, Thomas R, Kannan R, de Leon ES, Drilon A, Rosenblum MK, Scaltriti M, Benezra R, Ventura A. Somatic chromosomal engineering identifies BCAN-NTRK1 as a potent glioma driver and therapeutic target. Nat Commun 2017;8:15987. Maddalo D, Manchado E, Concepcion CP, Bonetti C, Vidigal JA, Han YC, Ogrodowski P, Crippa A, Rekhtman N, de Stanchina E, et al. (2014). In vivo engineering of oncogenic chromosomal rearrangements with the CRISPR/Cas9 system. Nature 2014;516: 423-27. Ventura A, Dow LE. (2018). Modeling cancer in the CRISPR era. Annu Rev Cancer Biol 2018;2: 111-31. Citation Format: Andrea Ventura. Modeling cancer in the CRISPR era [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA25.
Reply to Problematic methodology in a systematic review and meta-analysis of DecisionDx-Melanoma
Authors: Bradley N. Greenhaw, Kyle R. Covington, Sarah J. Kurley, Yildiray Yeniay, Nhat Anh Cao, Kristen M. Plasseraud, Robert W. Cook, Eddy C. Hsueh, Brian R. Gastman, Maria L. Wei
Journal: Journal of the American Academy of Dermatology (2020)
Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial
Authors: Michael G Ison, Simon Portsmouth, Yuki Yoshida, Takao Shishido, Melissa Mitchener, Kenji Tsuchiya, Takeki Uehara, Frederick G Hayden
Journal: The Lancet Infectious Diseases (2020)
Quality and Safety in Healthcare, Part LXXIII
Authors: Jay A. Harolds
Journal: Clinical Nuclear Medicine (2020)

Abstract Disruptive behavior in the healthcare system is costly because it has an adverse effect on patient outcomes, staff morale, and referrals to a healthcare organization, and it increases staff turnover. A small proportion of medical providers exhibit disruptive behavior, but those individuals may exhibit this behavior frequently in some healthcare institutions so that this type of conduct is not uncommonly there. Each healthcare institution should have policies and procedures to address disruptive behavior and decrease the frequency of this type of conduct.
AB1110 QUANTUM BLUE® RAPID TDM ASSAY STANDARDIZATION HIGHLY CORRELATES WITH WHO INTERNATIONAL STANDARD FOR INFLIXIMAB
Authors: E. Keller, P. Spies, F. Frei, V. Eckhardt, T. Schuster, M. Schneider
Journal: Annals of the Rheumatic Diseases (2020)

Background: Therapeutic drug monitoring of RA patients under anti-TNF therapy is based on trough level determination of the drug. Rapid assays and multiple ELISAs are available that measure anti-TNF biologics. An international standard is required to improve comparability among different assays. Recently, WHO introduced a series of anti-TNF standards for etanercept, adalimumab and infliximab. This is the first step for achieving common standardisation of assays available on the market. Objectives: The aim of the study was to evaluate the correlation of the WHO standard with BÜHLMANN Quantum Blue® Infliximab standardization and to compare spiking recovery in three commercially available infliximab ELISAs and one infliximab rapid test. Methods: Calibration curves were generated with BÜHLMANN calibrators and with calibrators made from WHO international standard for infliximab (NIBSC 16/170). Twenty-six serum samples, covering a concentration range from 0.5 µg/mL to 19 µg/mL, were analyzed with both calibration curves and compared by Bland-Altman and Passing-Bablok analysis. Furthermore, recovery of six serum samples spiked with WHO international standard for infliximab was determined in Theradiag LISA TRACKER Infliximab (a), Grifols/Progenika Promonitor-IFX (b), Immundiagnostik IDKmonitor Infliximab drug level (c) and BÜHLMANN Quantum Blue® Infliximab (d). Spiking recovery experiments were performed according to Westgard 2008. Results: The sample values gained with BÜHLMANN calibrators showed an excellent correlation with values gained with the WHO international standard for infliximab as calibrator. Passing-Bablok regression analysis revealed a slope of 0.96 and correlation coefficient (R) of 0.99. Bland-Altman analysis revealed a mean difference in the obtained values of less than five percent. Regarding spiking recovery analysis, all tests exhibit an excellent mean recovery of 101% (85-114%; a), 99% (91-105%; b); 101% (95-107%; c) and 94% (88-100%, d). Conclusion: Current standardization of Quantum Blue® Infliximab rapid test correlates very well with the WHO international standard for infliximab (NIBSC 16/170). Spiking recovery was highly comparable for ELISAs and the Quantum Blue® Infliximab assay. This rapid test represents a unique and modern analytical method, for fast time-to-result and simplicity of usage in a more patient near medical environment. References: [1]Westgard, James. (2008). Basic Method Validation. Disclosure of Interests: None declared
Reimagining healthcare after covid-19: a new normal for medicine
Authors: Mayur Lakhani, Sonam Lakhani, Priyanka Lakhani
Journal: BMJ (2020)

Godlee discusses the long road ahead after covid-19.1 Is this an opportunity to reimagine healthcare and forge a “new normal” for medicine?

After the most extraordinary few weeks, WB Yeats’s memorable line comes to mind: “All changed, changed utterly.” Normally complex changes such as virtual care and major service reconfigurations have occurred at breathtaking pace.2 Traditional barriers, institutional inertia, …
Cancer in pregnancy: Trends and research
Authors: L. F. McKain, J. D. Albano, M. Desai
Journal: Journal of Clinical Oncology (2009)

e20720 Background: Treatment advances for some cancers have allowed reproductive opportunities that would not have otherwise been possible. Optimal cancer treatment in pregnancy balances maternal needs with concerns for the developing fetus, often relying upon case report and retrospective study data which are subject to confounding factors. Study objectives were to estimate trends in cancer incidence during pregnancy and to describe current research methodology. Methods: The number and rate of pregnancies affected by cancer in 1990 and 2004 were estimated by applying age-specific incidence data from the Surveillance, Epidemiology, and End Results Program to pregnancy data from the National Center for Health Statistics for women 15–44 years. In addition, public trials registries were searched for actively enrolling studies related to “cancer in pregnancy.” Investigators were contacted for detail regarding methodology and descriptive statistics tabulated. Results: The incidence of cancer complicated pregnancies has increased overall between 1990 and 2004 from 1/1,560 to 1/1,180 pregnancies, and individually for breast, melanoma, and thyroid cancers. Seven studies actively enrolling pregnant patients with cancer were identified. Six studies are observational registries, two of which prospectively study specific drug therapies. Three enroll patients receiving care at single institutions whereas the others allow open-enrollment. Three studies focus on breast cancer during pregnancy including the only interventional study. Both maternal and pediatric outcomes are of interest. Conclusions: The shift in the distribution of pregnancies towards older women coupled with an overall increased incidence of cancer puts more women at risk of having a pregnancy complicated by cancer. Current studies are few and dominated by observational registries which maximize the eligible study population through open enrollment. Registries can efficiently provide outcome and follow-up data for this special population but have limited ability to assess effectiveness of specific treatment regimens. Oncologists must recognize the trend in the incidence of cancer in pregnancy and become stakeholders in the process of contributing to ongoing research by engaging their patients in existing studies and initiating new projects. [Table: see text]
Abstract IA13: Tracking and targeting colorectal cancer evolution
Authors: Alberto Bardelli
Journal: Clinical Cancer Research (2020)

Abstract When metastatic cancers are challenged with targeted agents, almost invariably a subset of cells insensitive to the drug emerges. As a result, in most instances, targeted therapies are only transiently effective in patients. Strategies to prevent or overcome resistance are therefore essential to design the next generation of clinical trials. How can we overcome the near certainty of disease recurrence following treatment with targeted agents? Addressing this question means considering as a target not “only” individual oncogenes but also the evolving nature of human tumors. We used colorectal cancer (CRC) as a model system to test the hypothesis that by understanding tumors’ evolution, the emergence of drug resistance can be controlled. We find that clonal dynamics can be monitored in real time in the blood of patients, and liquid biopsies can be used to intercept the emergence of resistant clones before relapses are clinically manifest. We discovered that a multistep clonal evolution process driven by progressive increases in drug fitness underlies the development of resistance in cells and patient avatars. To have long-term efficacy, the use of targeted therapies must take into account the continuous evolution of cancer cells, that is to say, therapies must adapt to tumor evolution. One possibility is to anticipate the changes the tumors will make. For example, by knowing in advance how CRC cells overcome resistance to EGFR blockade, we devised further rounds of therapy. These findings became the bases of clinical trials aimed at targeting cancer evolution and exploiting liquid biopsies to monitor the emergence of drug resistance and to design further lines of therapies. Citation Format: Alberto Bardelli. Tracking and targeting colorectal cancer evolution [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr IA13.
Clinicopathologic predictors of the 21-gene assay in a Hispanic cohort
Authors: A. Khan, C. Rodriguez, Y. E. Tovar, B. Rajabi, Z. D. Mulla, M. N. Hakim
Journal: Journal of Clinical Oncology (2009)

e22209 Background: The 21-gene recurrence score (RS) assay became commercially available (Oncotype DX) in January 2005. It is used to predict the likelihood of distant recurrence in women with estrogen-receptor (ER)-positive, lymph node-negative invasive breast cancer treated with adjuvant tamoxifen. We aimed to identify clinicopathologic predictors of an elevated recurrence score in a group of women with invasive breast cancer living in a predominantly Hispanic population on the Texas-Mexico border. Methods: A retrospective cohort study of 60 consecutive patients with primary ER-positive, lymph node-negative invasive breast cancer who had an Oncotype DX assay performed by Genomic Health, Inc. on paraffin-embedded tumor between March 2006 and November 2008. ER, PR and HER-2 was performed by immunohistochemistry. Patients were classified as low RS (&lt;18), intermediate RS (18–30), or high RS (≥31). Ordinal logistic regression was used to calculate odds ratios (OR) for an increasing RS. Patient age and tumor pathological features were documented in each group. There was no selection bias in ordering the assay. Results: 95% of the cohort was Hispanic. Average age was 55.5 years. 29 patients (48%) had a low RS, 15 (25%) had an intermediate RS, while 16 (27%) had a high RS. HER-2 was amplified in 8 patients (13%). HER-2 positivity was strongly associated with a high RS (p&lt;0.0001). Tumor grade and Ki-67 proliferative index were correlated with one another in a positive fashion (weighted kappa=0.46, p&lt;0.05) and in univariate analyses both factors were significant predictors of a higher RS: tumor grade 3 vs. 1 OR=26.6 (p&lt;0.0001) and Ki-67 proliferative index high vs. low OR=6.59 (p=0.0033). After adjustment, neither OR was significant. A negative progesterone receptor (PR) status was a strong risk factor for a higher RS (adjusted OR=21.64, p=0.0002). Univariate and multivariate ORs for higher RS for invasive ductal vs. invasive lobular carcinoma were, respectively, 4.3 (p=0.051) and 2.23 (p=0.4). Conclusions: Initially, a tumor grade of 3 and a high Ki-67 proliferative index were strong risk factors for a higher RS. However, after controlling for multiple factors, neither tumor grade nor Ki-67 proliferative index had an impact on RS in this predominantly Hispanic cohort. No significant financial relationships to disclose.
EULAR provisional recommendations for the management of rheumatic and musculoskeletal diseases in the context of SARS-CoV-2
Authors: Robert BM Landewé, Pedro M Machado, Féline Kroon, Hans WJ Bijlsma, Gerd R Burmester, Loreto Carmona, Bernard Combe, Massimo Galli, Laure Gossec, Annamaria Iagnocco, John D Isaacs, Xavier Mariette, Iain McInnes, Ulf Mueller-Ladner, Peter Openshaw, Josef S Smolen, Tanja A Stamm, Dieter Wiek, Hendrik Schulze-Koops
Journal: Annals of the Rheumatic Diseases (2020)

The provisional EULAR recommendations address several aspects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus, and the disease caused by SARS-CoV-2, COVID-19 and are meant for patients with rheumatic and musculoskeletal diseases (RMD) and their caregivers. A task force of 20 members was convened by EULAR that met several times by videoconferencing in April 2020. The task force finally agreed on five overarching principles and 13 recommendations covering four generic themes: (1) General measures and prevention of SARS-CoV-2 infection. (2) The management of RMD when local measures of social distancing are in effect. (3) The management of COVID-19 in the context of RMD. (4) The prevention of infections other than SARS-CoV-2. EULAR considers this set of recommendations as a 'living document' and a starting point, which will be updated as soon as promising new developments with potential impact on the care of patients with RMD become available.
Aetiology of acute febrile illness in children in a high malaria transmission area in West Africa
Authors: B. Kaboré, A. Post, P. Lompo, J.D. Bognini, S. Diallo, B.T.D. Kam, J. Rahamat-Langendoen, H.F.L. Wertheim, F. van Opzeeland, J.D. Langereis, M.I. de Jonge, H. Tinto, J. Jacobs, A.J. van der Ven, Q. de Mast
Journal: Clinical Microbiology and Infection (2020)

ObjectivesAreas with declining malaria transmission in sub-Saharan Africa have recently witnessed important changes in the aetiology of childhood acute febrile illness (AFI). We describe the aetiology of AFI in a high malaria transmission area in rural Burkina Faso.MethodsIn a prospective hospital-based diagnostic study, children aged 3 months to 15 years with AFI were recruited and assessed using a systematic diagnostic protocol, including blood cultures, whole blood PCR on a selection of bacterial pathogens, malaria diagnostics and a multiplex PCR on nasopharyngeal swabs targeting 21 viral and 4 bacterial respiratory pathogens.ResultsA total of 589 children with AFI were enrolled from whom an infectious disease was considered in 575 cases. Acute respiratory tract infections, malaria and invasive bacterial infections (IBI) accounted for 179 (31.1%), 175 (30.4%) and 75 (13%) of AFI cases respectively; 16 (21.3%) of IBI cases also had malarial parasitaemia. A viral pathogen was demonstrated from the nasopharynx in 157 children (90.7%) with respiratory tract symptoms. Of all children with viral respiratory tract infections, 154 (92.4% received antibiotics, whereas no antibiotic was provided in 13 (17%) of IBI cases.ConclusionsViral respiratory infections are a common cause of childhood AFI in high malaria transmission areas, next to malaria and IBI. These findings highlight the importance of interventions to improve targeted treatment with antimicrobials. Most patients with viral infections received antibiotics unnecessarily, while a considerable number with IBI did not receive antibiotics.
AB1257 SCREENING FOR IMMUNOGLOBULIN A ANTIBODY REACTIVITY IN EARLY AXIAL SPONDYLOARTHRITIS IDENTIFIES NOVEL ANTIGENIC TARGETS
Authors: P. Vandormael, D. Quaden, P. Ruytinx, J. Janssens, J. Vanhoof, P. Geusens, V. Somers
Journal: Annals of the Rheumatic Diseases (2020)

Background: Although autoantibodies are not generally considered to be a hallmark of axial spondyloarthritis (axSpA), increasing evidence suggests the presence of autoantibodies in a subset of axSpA patients. Most of these described antibodies are of the immunoglobulin G (IgG) isotype while other antibody isotypes are less well studied. Antibodies of the IgA isotype can be of interest due to the strong link between gut inflammation and spondyloarthropathies. Objectives: The aim of this study was to identify and characterize novel IgA isotype (auto)antibodies specific for early axSpA patients. Methods: An axSpA cDNA phage display library, representing the antigenic repertoire from axSpA hip synovium, was constructed and screened for reactivity with IgA antibodies in plasma of early axSpA patients ( n=10 ). Using enzyme-linked immunosorbent assays (ELISA), antibody reactivity against 173 identified targets was initially determined in pooled plasma of early axSpA patients (n=60) and healthy controls (HC, n=30 ), collected at Hasselt University. Antigenic targets that showed increased IgA reactivity in axSpA plasma pools were further validated in individual plasma samples of early axSpA patients ( n=79 ) and HC ( n=101 ). Results: We identified 10 novel Hasselt University (UH) axSpA peptide targets with increased IgA antibody reactivity in pooled axSpA plasma. At present, validation of 8 UH-axSpA-IgA peptide targets in individual plasma samples revealed antibody reactivity against at least one of these targets in 32% of early axSpA patients (25/79) compared to 26% in HC (31/101, p=0.4082 ). By combining the 3 UH-axSpA-IgA peptides with the highest positive likelihood ratio (LR+) into a panel, an increased overall specificity of 90% (10/101) could be achieved, with an associated sensitivity of 24% (19/79, p=0.0138 ) resulting in a LR+ of 2.4. Antibody reactivity testing of the remaining 2 UH-axSpA-IgA peptide targets is currently ongoing. Conclusion: The increased reactivity of IgA (auto)antibodies against several novel antigenic peptide targets underscores the role of the humoral immune response in axSpA, and might indicate a potential link with mucosal inflammation. IgA antibody reactivity against these novel peptide targets will be further validated in independent cohorts of early axSpA patients as well as in patients with chronic low back pain. Disclosure of Interests: Patrick Vandormael: None declared, Dana Quaden: None declared, Pieter Ruytinx: None declared, Joyce Janssens: None declared, Johan Vanhoof: None declared, Piet Geusens Grant/research support from: Pfizer, Abbott/Abbvie, Janssen, Celgene, Lilly, Amgen, MSD, UCB, Will, Roche, BMS, Novartis, Sanofi, Consultant of: Pfizer, Abbott/Abbvie, Janssen, Celgene, Lilly, Amgen, MSD, UCB, Will, Roche, BMS, Novartis, Sanofi, Veerle Somers Grant/research support from: Research grant from Pfizer and BMS
Abstract PHA01: Modeling the tissue-specific oncogenesis of mutant RAS
Authors: Amanda R. Moore, Lisa McGinnis, Shiva Malek
Journal: Cancer Research (2020)

Abstract RAS mutations are highly prevalent in tumors, especially those of the lung, colon, skin, and pancreas. The tissues in which these tumors arise are enriched for specific RAS isoform and codon preferences. For example, mutations in KRAS are prevalent in lung, colon, and pancreas, while NRAS mutations are predominantly found in melanoma. Additionally, mutations in KRAS predominantly occur at codons 12 and NRAS mutations at codon 61. Independent of the RAS isoform, the mutated codon contributes to distinct biochemical differences, with codon 61 mutations largely viewed as more biochemically active than codon 12 mutations. Previous RAS-mutant genetically engineered mouse (GEM) models resembled the tissue specificity observed in patients. In the colon, expression of KrasG12D but not NrasG12D induced colonic hyperplasia. While in melanocytes, the expression of NrasQ61R, but not NrasG12D, led to melanoma development. Given these data, we developed RAS-mutant GEM models to identify the tissues susceptible to RAS mutations and the differences among these animal models. To achieve this, we generated four conditional knockin GEM models to directly compare Kras and Nras mutations in codons 12 and 61; G12D and Q61R. To robustly determine the effects of mutant expression across a wide range of tissues, we utilized the ubiquitous and temporally expressed Cre, Rosa26-CreERT2. Following the induction of recombination by tamoxifen treatment, we observed rapid mortality in Kras-mutant animals. KrasQ61R mice survived to a median of 13 days while KrasG12D mice survived to a median of 22 days post-tamoxifen. However, the Nras-mutant mice have extended survival. While ongoing, these survival data suggest tissues acutely sensitive to Kras-mutant expression can tolerate or are resistant to Nras-mutant expression. When comparing the two Kras conditional knockin GEM models, we found expression of KrasG12D and KrasQ61R drove hyperproliferation in both lung and colon tissues to varying degrees and different tissue types in the colon. For instance, we observe colonic hyperplasia in KrasG12D mice and polypoid hyperplasia in KrasQ61R mice. Interestingly, the hematopoietic cells were exquisitely sensitive to expression of KrasQ61R, and these animals rapidly developed acute myeloid leukemia leading to death. These data illustrate how the strength of the constitutive activation of RAS proteins drives differential tumorigenesis. We plan to further our understanding of the tissue-specific tumorigenesis of mutant-RAS proteins by comparing the Kras- and Nras-mutant GEM models. This abstract is also being presented as Poster A01. Citation Format: Amanda R. Moore, Lisa McGinnis, Shiva Malek. Modeling the tissue-specific oncogenesis of mutant RAS [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr PHA01.