tbuckley/cabot-search huggingface dataset:
National lung cancer screening utilization trends in the Veterans Health Administration.
Authors: Jennifer A. Lewis, Jason Denton, Michael E. Matheny, Christopher G. Slatore, Amelia W Maiga, Eric Grogan, Pierre P. Massion, Robert H. Sherrier, Robert S. Dittus, Laura Keohane, Christianne L. Roumie, Sayeh Nikpay
Journal: Journal of Clinical Oncology (2019)

6547 Background: Low-dose CT (LDCT) is an effective means for early lung cancer detection, but is often underutilized. An estimated 900,000 Veterans are eligible for lung cancer screening. We are the first to describe national lung cancer screening utilization trends in the Veterans Health Administration (VHA). Methods: We assembled a retrospective cohort of patients within the VHA’s Observational Medical Outcomes Partnership (OMOP) Common Data Model who underwent lung cancer screening. LDCT scans with Common Procedure Terminology (CPT) codes G0297 or 71250 from January 1, 2011 to May 31, 2018 were eligible for inclusion. We further selected exams described as “lung cancer screening,” “screening,” or “LCS.” We used descriptive statistics with frequencies and medians to calculate the total exams per Veteran and evaluate utilization trends over time and by region. Results: At initial screening, Veterans had a median age of 66 (IQR 61, 70), 95% were male, 76% Caucasian. From January 1, 2011 to May 31, 2018, 75 VHA facilities performed 129,363 LDCT exams for lung cancer screening; 87,950 (68%) initial and 41,413 (32%) subsequent exams. Screening has increased over time (226 in 2011-2012; 7848 in 2013-2014; 41,225 in 2015-2016; 80,064 in 2017 until May 31, 2018) in all regions. Providers in primary care/internal medicine (56%), family medicine (16%), pulmonology (6%), oncology (0.3%), other specialties (21%) ordered screening exams. Conclusions: Lung cancer screening with low-dose CT within the VHA increased over time within all geographic regions. Future strategies aimed at the Veteran, provider, and healthcare system levels are needed to increase lung cancer screening utilization among eligible Veterans. [Table: see text]
IMpassion130: updated overall survival (OS) from a global, randomized, double-blind, placebo-controlled, Phase III study of atezolizumab (atezo) + <i>nab-</i>paclitaxel (nP) in previously untreated locally advanced or metastatic triple-negative breast cancer (mTNBC).
Authors: Peter Schmid, Sylvia Adams, Hope S. Rugo, Andreas Schneeweiss, Carlos H. Barrios, Hiroji Iwata, Veronique Dieras, Volkmar Henschel, Luciana Molinero, Stephen Y. Chui, Amreen Husain, Eric P. Winer, Sherene Loi, Leisha A. Emens
Journal: Journal of Clinical Oncology (2019)

1003 Background: IMpassion130 evaluated atezo (anti–PD-L1) + nP vs placebo + nP in 1L mTNBC. The primary PFS analysis found that atezo + nP significantly improved PFS in intent-to-treat (ITT) and PD-L1+ pts vs placebo + nP, with efficacy driven by the PD-L1+ population. At that time, the 1st interim OS analysis was conducted (Schmid, NEJM 2018). Here we report the 2nd interim OS analysis. Methods: Eligible pts had histologically documented locally advanced or mTNBC, ECOG PS 0-1 and tumor tissue for PD-L1 testing. Pts were randomized 1:1 to IV atezo 840 mg or placebo on d1 and d15 + nP 100 mg/m 2 on d1, d8 and d15 of each 28-d cycle until progression (stratification factors: prior taxanes, liver metastases, PD-L1 on tumor-infiltrating immune cells [IC]). RECIST 1.1 PFS (in ITT and PD-L1+ pts) and OS (tested in ITT and, if significant, PD-L1+ pts) were co-primary endpoints. Results: OS data are shown (Table). As of data cutoff (Jan 2, 2019), 9% of pts in the atezo + nP arm and 3% in the placebo + nP arm were still on treatment. Statistical significance was not demonstrated in ITT pts, but a 7.0-month improvement in median OS was observed in PD-L1+ pts with atezo + nP (25.0 mo) vs placebo + nP (18.0 mo; HR, 0.71 [95% CI: 0.54, 0.93]). A 4.5-mo safety update (Schneeweiss, ASCO 2019, submitted) showed that atezo + nP remained tolerable. Conclusions: The 2nd IMpassion130 interim OS analysis was consistent with the 1st analysis, confirming clinically meaningful OS benefit with atezo + nP in previously untreated PD-L1+ mTNBC. Clinical trial information: NCT02425891. [Table: see text]
KRAS mutation and microsatellite instability in colorectal cancer: Screening pattern and mutational landscape across the US.
Authors: Johannes Uhlig, Stacey Stein, Jill Lacy, Hyun S. Kim
Journal: Journal of Clinical Oncology (2019)

e15138 Background: To assess screening patterns for KRAS mutation and microsatellite instability (MSI), associated mutational prevalence in colorectal cancer (CRC), and whether mutational screening affects survival. Methods: Patients with adenocarcinoma of the colon, sigmoid, and rectum were included from the 2010-2015 National Cancer Database. Socioeconomic, geographic and cancer factors were correlated with screening patterns. Propensity score matching was used to account for confounding. Overall survival was assessed in the matched cohort via Cox proportional hazards models. Results: 371,669 patients were included, of which 113,197 (30.4%) were screened: n=63,967 for MSI, n=33,319 for KRAS, and n=15,911 for MSI + KRAS. Younger patients with private insurance, high income locally advanced and metastatic sigmoid CRC treated at academic centers in Middle Atlantic and New England states were more likely to be screened. MSI was more prevalent among older female Caucasians from East South Central and Middle Atlantic States. KRAS mutation showed no significant discrepancies according to patient age or US geography, but was more prevalent among female African Americans. KRAS mutation was associated with locally advanced and metastatic CRC. MSI was more common in localized, non-metastatic CRC. Distinct mutational patterns were evident among primary CRC sites, with highest mutation rates in cecum/appendix and ascending colon (table). In the propensity score matched cohort with balanced distribution of confounders (n=157,678), mutational screening was not associated with overall survival (HR=1.012, 95% CI: 0.99-1.03, p=0.15). MSI versus MSS did not significantly influence patients´ overall survival (matched cohort n=26,014, HR=1.00, 95% CI: 0.96-1.05, p=0.88). Kras mutation versus wildtype showed decreased overall survival after accounting for confounders (matched cohort n=28,084, HR=1.11, 95% CI: 1.07-1.15, p&lt;0.001). Conclusions: Testing for MSI and Kras mutation in CRC shows distinct patterns across the US, but does not influence outcomes. Decreased overall survival is observed in those patients with Kras mutation versus wildtype. [Table: see text]
cfDNA for accurate determination of RAS and BRAF mutations using OncoBEAM liquid biopsy in metastatic colorectal cancer patients: Results of the real-world multicentric ColoBEAM study.
Authors: Alexandre Harle, Celine Gavoille, Olivier Bouche, Meher Ben Abdelghani, Jérôme Edouard Plaza, Aurélien Lambert, Dominique Spaeth, Axelle Boudrant, François Ghiringhelli, Anne-Laure Villing, Christophe Borg, Marie Rouyer, Marie Husson, Pauline Gilson, Fabienne Polet, Frederick S. Jones, Dan Edelstein, Florian Baumard, Julia Salleron, Jean-Louis Merlin
Journal: Journal of Clinical Oncology (2019)

3542 Background: Determination of KRAS, NRAS ( RAS) and BRAF mutations is a standard of care for the management of patients with metastatic colorectal cancer (mCRC). RAS mutations are well characterized resistance biomarkers to anti-EGFR antibodies and BRAF V600 mutations indicate poor prognosis. Tissue biopsy has traditionally been used to determine RAS and BRAF status, but liquid biopsy analysis of circulating tumor DNA (ctDNA) has demonstrated utility as a less invasive tool to expedite molecular testing results to the clinic. The ColoBEAM study reports the performance of plasma mutation testing in a real-life prospective series of 278 patients across 8 centers. Methods: Plasma derived ctDNA was prepared from 20mL blood samples prospectively collected from mCRC patients who had not received chemotherapy in the prior 15 days. ctDNA was centrally assessed using OncoBEAM and results compared to those obtained by routine analysis of tissue. Both tissue and blood samples with discrepant RAS results were blindly reassessed with OncoBEAM. Results: Of 278 patients enrolled, 202 blood samples were available for OncoBEAM testing. RAS and BRAF V600E mutations were detected in tissue in 132/202 (65.4%) and 4/198 (2.0%) patients, respectively. Analysis of the first ctDNA sample as compared to tissue DNA resulted in a kappa coefficient (κ) of 0.52 [0.41 – 0.63] and accuracy of 75.2% (65.1% sensitivity; 94.3% specificity). OncoBEAM testing of a second sample resulted (κ) of 0.66 [0.56 - 0.76] and accuracy of 83.2% (77.3% sensitivity; 94.3% specificity). Of the 4 samples with a BRAF V600E mutation in tumor tissue 2 were detected in blood. In the subgroup of patients with liver metastasis (n=136), accuracy was 88.2% (87.4% sensitivity; 90.2% specificity) for RAS and BRAF status with (κ) of 0.73 [0.61 – 0.86]. In a subgroup of chemotherapy naïve patients with liver metastasis (n=49), accuracy was 91.8% (93.3% sensitivity; 89.5% specificity) for RAS and BRAF status with (κ) of 0.83 [0.67 – 0.99]. Conclusions: The results of the ColoBEAM study confirm plasma ctDNA as a credible surrogate marker to tissue DNA for RAS and BRAF status assessment and may be incorporated as a first-line theragnostic assessment. New testing on a second sample for wild-type status demonstrated 91.8% concordance between blood and tissue. Clinical trial information: NCT02751177.
Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis
Authors: Chen Wei, Chaogang Yang, Shuyi Wang, Dongdong Shi, Chunxiao Zhang, Xiaobin Lin, Qing Liu, Rongzhang Dou, Bin Xiong
Journal: Molecular Cancer (2019)

Tumor-associated macrophages (TAMs) are major components of tumor microenvironment that frequently associated with tumor metastasis in human cancers. Circulating tumor cell (CTC), originating from primary tumor sites, is considered to be the precursors of tumor metastasis. However, the regulatory mechanism of TAMs in CTC-mediated tumor metastasis still remains unclear. Immunohistochemical staining was used to detect the macrophages infiltration (CD68 and CD163), epithelial–mesenchymal transition (EMT) markers (E-cadherin and Vimentin) expression in serial sections of human colorectal cancer (CRC) specimens. Then, the correlations between macrophages infiltration and clinicopathologic features, mesenchymal CTC ratio, and patients' prognosis were analyzed. A co-culture assay in vitro was used to evaluate the role of TAMs on CRC EMT, migration and invasion, and ELISA, luciferase reporter assay and CHIP were performed to uncover the underlying mechanism. Furthermore, an in vivo model was carried out to confirm the effect of TAMs on mesenchymal CTC-mediated metastasis. Clinically, CD163+ TAMs infiltrated in invasive front was associated with EMT, mesenchymal CTC ratio, and poor prognosis in patients with CRC. CRC–conditioned macrophages regulated EMT program to enhance CRC cells migration and invasion by secreting IL6. TAMs-derived IL6 activated the JAK2/STAT3 pathway, and activated STAT3 transcriptionally inhibited the tumor suppressor miR-506-3p in CRC cells. miR-506-3p, a key miRNA regulating FoxQ1, was downregulated in CRC cells, resulting in increased FoxQ1 expression, which in turn led to the production of CCL2 that promoted macrophage recruitment. Inhibition of CCL2 or IL6 broke this loop and reduced macrophage migration and mesenchymal CTC-mediated metastasis, respectively. Our data indicates that TAMs induce EMT program to enhance CRC migration, invasion, and CTC-mediated metastasis by regulating the JAK2/STAT3/miR-506-3p/FoxQ1 axis, which in turn leads to the production of CCL2 that promote macrophage recruitment, revealing a new cross-talk between immune cells and tumor cells in CRC microenvironment.
Comprehensive evaluation of structural variation detection algorithms for whole genome sequencing
Authors: Shunichi Kosugi, Yukihide Momozawa, Xiaoxi Liu, Chikashi Terao, Michiaki Kubo, Yoichiro Kamatani
Journal: Genome biology (2019)

Structural variations (SVs) or copy number variations (CNVs) greatly impact the functions of the genes encoded in the genome and are responsible for diverse human diseases. Although a number of existing SV detection algorithms can detect many types of SVs using whole genome sequencing (WGS) data, no single algorithm can call every type of SVs with high precision and high recall.We comprehensively evaluate the performance of 69 existing SV detection algorithms using multiple simulated and real WGS datasets. The results highlight a subset of algorithms that accurately call SVs depending on specific types and size ranges of the SVs and that accurately determine breakpoints, sizes, and genotypes of the SVs. We enumerate potential good algorithms for each SV category, among which GRIDSS, Lumpy, SVseq2, SoftSV, Manta, and Wham are better algorithms in deletion or duplication categories. To improve the accuracy of SV calling, we systematically evaluate the accuracy of overlapping calls between possible combinations of algorithms for every type and size range of SVs. The results demonstrate that both the precision and recall for overlapping calls vary depending on the combinations of specific algorithms rather than the combinations of methods used in the algorithms.These results suggest that careful selection of the algorithms for each type and size range of SVs is required for accurate calling of SVs. The selection of specific pairs of algorithms for overlapping calls promises to effectively improve the SV detection accuracy.
The Influence of Type 2 Diabetes–Associated Factors on Type 1 Diabetes
Authors: Maria J. Redondo, Carmella Evans-Molina, Andrea K. Steck, Mark A. Atkinson, Jay Sosenko
Journal: Diabetes Care (2019)

Current efforts to prevent progression from islet autoimmunity to type 1 diabetes largely focus on immunomodulatory approaches. However, emerging data suggest that the development of diabetes in islet autoantibody–positive individuals may also involve factors such as obesity and genetic variants associated with type 2 diabetes, and the influence of these factors increases with age at diagnosis. Although these factors have been linked with metabolic outcomes, particularly through their impact on β-cell function and insulin sensitivity, growing evidence suggests that they might also interact with the immune system to amplify the autoimmune response. The presence of factors shared by both forms of diabetes contributes to disease heterogeneity and thus has important implications. Characteristics that are typically considered to be nonimmune should be incorporated into predictive algorithms that seek to identify at-risk individuals and into the designs of trials for disease prevention. The heterogeneity of diabetes also poses a challenge in diagnostic classification. Finally, after clinically diagnosing type 1 diabetes, addressing nonimmune elements may help to prevent further deterioration of β-cell function and thus improve clinical outcomes. This Perspectives in Care article highlights the role of type 2 diabetes–associated genetic factors (e.g., gene variants at transcription factor 7-like 2 [TCF7L2]) and obesity (via insulin resistance, inflammation, β-cell stress, or all three) in the pathogenesis of type 1 diabetes and their impacts on age at diagnosis. Recognizing that type 1 diabetes might result from the sum of effects from islet autoimmunity and type 2 diabetes–associated factors, their interactions, or both affects disease prediction, prevention, diagnosis, and treatment.
Osteoclast‐Derived Autotaxin, a Distinguishing Factor for Inflammatory Bone Loss
Authors: Sacha Flammier, Olivier Peyruchaud, Fanny Bourguillault, François Duboeuf, Jean‐Luc Davignon, Derek D. Norman, Sylvie Isaac, Hubert Marotte, Gabor Tigyi, Irma Machuca‐Gayet, Fabienne Coury
Journal: Arthritis & Rheumatology (2019)

The severity of rheumatoid arthritis (RA) correlates directly with bone erosions arising from osteoclast (OC) hyperactivity. Despite the fact that inflammation may be controlled in patients with RA, those in a state of sustained clinical remission or low disease activity may continue to accrue erosions, which supports the need for treatments that would be suitable for long-lasting inhibition of OC activity without altering the physiologic function of OCs in bone remodeling. Autotaxin (ATX) contributes to inflammation, but its role in bone erosion is unknown.ATX was targeted by inhibitory treatment with pharmacologic drugs and also by conditional inactivation of the ATX gene Ennp2 in murine OCs (ΔATXCtsk ). Arthritic and erosive diseases were studied in human tumor necrosis factor-transgenic (hTNF+/- ) mice and mice with K/BxN serum transfer-induced arthritis. Systemic bone loss was also analyzed in mice with lipopolysaccharide (LPS)-induced inflammation and estrogen deprivation. Joint inflammation and bone erosion were assessed by histology and micro-computed tomography. The role of ATX in RA was also examined in OC differentiation and activity assays.OCs present at sites of inflammation overexpressed ATX. Pharmacologic inhibition of ATX in hTNF+/- mice, as compared to vehicle-treated controls, significantly mitigated focal bone erosion (36% decrease; P < 0.05) and systemic bone loss (43% decrease; P < 0.05), without affecting synovial inflammation. OC-derived ATX was revealed to be instrumental in OC bone resorptive activity and was up-regulated by the inflammation elicited in the presence of TNF or LPS. Specific loss of ATX in OCs from mice subjected to ovariectomy significantly protected against the systemic bone loss and erosion that had been induced with LPS and K/BxN serum treatments (30% reversal of systemic bone loss [P < 0.01]; 55% reversal of erosion [P < 0.001]), without conferring bone-protective properties.Our results identify ATX as a novel OC factor that specifically controls inflammation-induced bone erosions and systemic bone loss. Therefore, ATX inhibition offers a novel therapeutic approach for potentially preventing bone erosion in patients with RA.
Abstract 10737: Does the Evidence Support a Radial Approach in Non-ST Elevation Acute Coronary Syndromes?
Authors: Peter L Amaduzzi, Edina Cenko, Sasko Kedev, Oliver Kalpak, Goran Stankovic, Zorana Vasiljevic, Marija Vavlukis, Marialuisa Scarpone, Monireh Rajabi, Sasa Pavasovic, Olivia Manfrini, Davor Milicic, Akos Koller, Lina Badimon, Raffaele Bugiardini
Journal: Circulation (2018)

Introduction: Trans-radial access (TRA) for PCI has been consistently shown to reduce mortality and bleeding complications compared with trans-femoral access (TFA) in pts with STEMI. On the contrar...
Abstract #1529: The Egr1 target Toe1 interacts with p53 to modulate its transactivation
Authors: Sabina Sperandio, Saverio Tardito, Aleksandra Surzycki, Martin Latterich, Ian de Belle
Journal: Cancer Research (2009)

The TOE1 gene was discovered as a target of the Egr1 transcription factor that participates in cell growth regulation through the upregulation of p21 and a cell cycle delay at the G2/M phase. We report here that TOE1 is able to bind to the p53 tumor suppressor protein, specifically interacting with the C terminal tetramerization domain of p53. We have further characterized this interaction through determination of binding kinetics using nanoporous optical interferometry and demonstrated that this interaction is capable of enhancing the transcriptional activity of p53-dependent gene targets. These results suggest a mechanistic role for TOE1 as a co-regulator of p53.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1529.
Cruising for a Diagnosis
Authors: Faith T. Fitzgerald
Journal: Annals of Internal Medicine (2019)

On Being a Doctor4 June 2019Cruising for a DiagnosisFaith T. Fitzgerald, MDFaith T. Fitzgerald, MDUniversity of California, Davis, Sacramento, California (F.T.F.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M19-0194 Audio Reading - “Cruising for a Diagnosis” Audio. Virginia Hood, MD, reads “Cruising for a Diagnosis” by Faith T. Fitzgerald, MD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Many years ago, San Francisco had a program where ambulances (then unkindly called “boozer cruisers”) would set out at night to pick up people on the street. They were mostly alcoholics found collapsed on the sidewalk, huddled in doorways, staggering into traffic, or otherwise clearly unable to care for themselves. They would then be brought to Mission Emergency, the emergency room at San Francisco General Hospital. There, they were triaged by the ER medical resident, deloused (that is, dipped into the Cuprex bathtub) if necessary, and given cots in the men's area. Each was hooked up to a “yellow bottle” ... Author, Article, and Disclosure InformationAffiliations: University of California, Davis, Sacramento, California (F.T.F.)Corresponding Author: Faith T. Fitzgerald, MD, UC Davis Medical Center, C/O Division of General Medicine, 4150 V Street, Suite 2400, Sacramento, CA 95817; e-mail, [email protected]edu. PreviousarticleNextarticle Advertisement Audio Reading - “Cruising for a Diagnosis” Audio. Virginia Hood, MD, reads “Cruising for a Diagnosis” by Faith T. Fitzgerald, MD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics 4 June 2019Volume 170, Issue 11Page: 810KeywordsAlcoholicsAlcoholsAmbulancesCoffeeMethylene bluePatientsReflexesTriageVitamins ePublished: 4 June 2019 Issue Published: 4 June 2019 Copyright & PermissionsCopyright © 2019 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...