tbuckley/cabot-search huggingface dataset:
Clinical and phylogenetic factors affecting the detection of genomic variants in circulating cell-free DNA for patient with primary breast cancer.
Authors: Yidong Zhou, Yaping Xu, Yuhua Gong, Yanyan Zhang, Yaping Lu, Changjun Wang, Ru Yao, Peng Li, Yanfang Guan, Xuefeng Xia, Ling Yang, Xin Yi, Qiang Sun
Journal: Journal of Clinical Oncology (2018)

e12600 Background: Noninvasive circulating cell-free DNA (cfDNA) detection has been applied to predict relapse and prognosis of breast cancer. However, most of studies were about pts with multi-lines treatment, and systematic evaluation of cfDNA from primary breast cancer (PBC) was still absent. This study aim to comprehensively assess the cfDNA detection and explore the factors affecting the release of tumor-derived variants in PBC pts. Methods: 71 females initially diagnosed with PBC were enrolled. Treatment-naive peripheral blood, and paired tumor tissue from surgical resection/fine-needle aspiration (FNA) were obtained. Target-capture deep sequencing with a panel covering 1021 genes was performed to detect somatic variants. Clonality of variants was analyzed using PyClone with Bayesian algorithm. Results: 226 somatic variants were detected in tumor DNA of 70 pts (98.59%), and 114 somatic variants were detected in cfDNA of 48 pts (67.61%). Significant correlation was found between mutant frequencies of genes in tumor DNA and cfDNA (R2 = 0.9532, p < 0.0001). 94 tumor-derived variants could be detected in cfDNA of 43 pts, and similar enrichment of functions and pathways for mutated genes was present in tumor specific and overlapped variants. TNM stage (p = 0.026), individual N stage (p < 0.001), hormone receptor (HR) status (p = 0.001) and molecular subtypes (p = 0.002) could independently predicted the positive detection of tumor-derived variants in cfDNA. The maximal variant allele frequency (MVAF) of cfDNA was significantly higher in pts with stage IV (p = 0.0136) and T3/T4 stage (p = 0.0085). Clonal variants in tumor DNA were much easier to be detected in cfDNA than subclonal variants (84.62% vs. 48.75%). Conclusions: Profiling tumor-derived variants in cfDNA is a promising method to assess mutational profile, and PBC pts with advanced stage and positive HR status are more likely to benefit from cfDNA sequencing. Clinical trial information: NCT02797652.
Phase 3 randomized study of adjuvant anastrozole (A), exemestane (E) or letrozole (L) with or without tamoxifen (T) in postmenopausal women with hormone-responsive (HR) breast cancer. The FATA-GIM3 trial
Authors: S. De Placido, C. Gallo, M. De Laurentiis, G. Bisagni, G. Arpino, M.G. Sarobba, F. Riccardi, A. Russo, L. Del Mastro, A. Cogoni, F. Cognetti, S. Gori, A. Frassoldati, D. Amoroso, L. Laudadio, L. Moscetti, F. Montemurro, F. Nuzzo, P. Carlini, F. Perrone
Journal: Annals of Oncology (2017)
Abstract 8885: C1q-induced Activation of Wnt Signaling Triggers Hypertensive Arterial Remodeling
Authors: Tomokazu Sumida, Atsuhiko T Naito, Ichiro Shiojima, Issei Komuro
Journal: Circulation (2012)

Hypertension is the leading risk factor of many cardiovascular diseases, and the structural remodeling of arteries in response to elevated blood pressure (hypertensive arterial remodeling) contributes to the end-organ damage associated with hypertension. The signaling mechanism that initiates hypertensive arterial remodeling remains elusive. Here we show that complement C1q-induced activation of Wnt signaling plays a critical role in arterial remodeling associated with hypertension. In the early phase of hypertension, proliferation of vascular smooth muscle cells (VSMCs) and activation of canonical Wnt signaling in VSMCs were observed, and inhibition of canonical Wnt signaling suppressed hypertension-induced VSMC proliferation. Complement C1q was highly expressed in macrophages recruited to the vessel wall following blood pressure elevation, and depletion of macrophages attenuated hypertension-induced VSMC proliferation and activation of canonical Wnt signaling in VSMCs. Furthermore, both C1s inhibition and C1qa gene deletion suppressed activation of canonical Wnt signaling in VSMCs and VSMC proliferation in the early phase of hypertension, and prevented subsequent structural arterial remodeling in the chronic phase. Our findings collectively suggest that macrophage-derived C1q triggers hypertensive arterial remodeling through activation of canonical Wnt signaling in VSMCs. Inhibition of C1q-induced Wnt signal activation may be a novel therapeutic strategy to reduce cardiovascular complications in patients with hypertension.
Metabolic status of BRCA1 mutation carriers.
Authors: Olga Ivanov, Aileen Caceres, Nicole Lee Centers, Karen Wiercinski, Courtney Krants, Cynthia Buffington
Journal: Journal of Clinical Oncology (2018)

e12545 Background: BRCA1 not only plays an important role as a cell cycle regulator and DNA damage repair protein in breast and ovarian tissue but also acts as a regulator of metabolic function in a wide variety of tissues, including human skeletal muscle. Therefore, mutations in BRCA1 may not only increase the risk for specific cancers but also for metabolic disorders. Presently, there is limited data regarding the effects of BRCA 1 mutation on metabolic status. In this study, we examine the metabolic profiles of BRCA1 mutation carriers. Methods: The study population included 27 BRCA1 female mutation carriers and 29 age- and weight-matched unaffected controls with no family history of ovarian/breast cancer. Study measures included: a metabolic profile (total cholesterol, LDL, HDL, triglyceride, fasting blood glucose, HbA1c), anthropometrics (BMI, body composition), and self-reported information pertaining to demographics, BRCA1 testing, menopausal status, cancer history, previous surgeries, current marital status, parity, health status, physical activity, sleep, and the use of alcohol, tobacco, and caffeine. Results: We found no significant differences between the BRCA1 and control groups for anthropometrics, glycemic status, triglyceride and HDL-cholesterol. However, total- and LDL-cholesterol were significantly (p < 0.001) higher for the BRCA1 mutation carriers than for their non-affected controls, i.e. total cholesterol = 222.1 ±10.0 vs. 176.7±6.3; LDL = 131.1±8.9 vs. 91.6±5.7, respectively. The increased cholesterol levels of the BRCA1 mutation carriers did not occur secondary to 1) lifestyle (physical activity, sleep, alcohol/tobacco use), 2) health/medications, or 3) menopausal status. Multiple modeling analyses found that none of study variables (measured, categorical, self-reported) were significant predictors of the elevated cholesterol of BRCA1 mutation carriers. Conclusions: The results of the study suggest that a BRCA1 mutation may adversely affect lipid metabolism to increase total- and LDL-cholesterol. Future investigative studies are needed to substantiate these findings and their potential impact on cancer progression and cardiovascular risk.
Olaparib versus chemotherapy treatment of physician’s choice in patients with a germline <i>BRCA</i> mutation and HER2-negative metastatic breast cancer (OlympiAD): Efficacy in patients with visceral metastases.
Authors: Nadine M. Tung, Seock-Ah Im, Elzbieta Senkus-Konefka, Binghe Xu, Susan M. Domchek, Norikazu Masuda, Wei Li, Anne Caroline Armstrong, Pier Franco Conte, Wenting Wu, Carsten Dietrich Goessl, Sarah Runswick, Mark E. Robson
Journal: Journal of Clinical Oncology (2018)

1052 Background: The OlympiAD study showed a significant progression-free survival (PFS) benefit for olaparib over chemotherapy treatment of physician's choice (TPC) in patients with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm; HR 0.58, 95% CI 0.43–0.80). Objective response rate (ORR) was 59.9% in the olaparib arm and 28.8% in the TPC arm. Prognosis may vary by location of metastases, so we investigated the overall efficacy of olaparib vs TPC in mBC patients with specific sites of visceral metastasis. Methods: OlympiAD was a randomized Phase III study in patients with HER2-negative mBC and a gBRCAm who had ≤2 chemotherapy lines for mBC (NCT02000622). Patients were randomized 2:1 to olaparib tablet monotherapy (300 mg bd) or single-agent TPC (capecitabine, eribulin or vinorelbine). Cox proportional hazard models were used for these post-hoc analyses. Results: The study was not powered to detect differences in treatment effect between subgroups, and results should be interpreted with caution due to modest patient numbers and baseline imbalances. Key baseline characteristics and PFS by site of metastases are shown in the table. Within these subgroups, overall ORR in evaluable patients was: lung/pleura, 61.2% vs 22.2%; liver, 59.5% vs 25.8%; and brain/CNS metastases, 64.7% vs 20.0%, for olaparib vs TPC, respectively. Conclusions: Among patients with HER2-negative mBC and a gBRCAm who had metastases in the lung/pleura, liver or brain/CNS, the benefit for olaparib vs TPC appeared consistent with that seen overall, for both PFS and ORR. Clinical trial information: NCT02000622. Lung/pleura Liver Brain/CNS Olaparib TPC Olaparib TPC Olaparib TPC N 117 54 79 37 18 8 Median age, years 44 44 46 44 44 39 Triple negative BC, % 60 (51.3) 33 (61.1) 26 (32.9) 16 (43.2) 10 (55.6) 6 (75.0) Prior chemo for mBC 81 (69.2) 35 (64.8) 62 (78.5) 28 (75.7) 16 (88.9) 6 (75.0) Prior platinum 35 (29.9) 13 (24.1) 24 (30.4) 9 (24.3) 5 (27.8) 4 (50.0) Median PFS, months 5.7 3.0 5.6 2.9 8.3 2.8 HRPFS (95% CI) 0.59 (0.41, 0.88) 0.73 (0.48, 1.15) 0.51 (0.19, 1.58) HR, hazard ratio
Response by Hyman et al to Letter Regarding Article, “Conscious Sedation Versus General Anesthesia for Transcatheter Aortic Valve Replacement: Insights From the National Cardiovascular Data Registry Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry”
Authors: Matthew C. Hyman, Prakash A. Patel, Jay Giri
Journal: Circulation (2018)
ADWE-02 Diagnostic yield and early discharge in gastrointestinal bleeding: comparative trial between capsule endoscopy and gastroscopy
Authors: Hey-long Ching, Melissa F Hale, Reena Sidhu, Sabina Beg, Krish Ragunath, Mark E McAlindon
Journal: Endoscopy (2018)

<h3>Introduction</h3> Capsule endoscopy may have a role in triaging patients with suspected acute upper gastrointestinal (GI) bleeding who need further invasive investigation. <h3>Method</h3> The Mirocam Navi (Intromedic Ltd., Korea) is a single camera capsule endoscope steerable by a handheld magnet. Magnetically assisted capsule endoscopy (MACE) was performed in stable patients with suspected acute upper GI bleeding and a decision made as to whether same day discharge was appropriate, prior to gastroscopy (OGD) performed by a different, blinded endoscopist followed by standard care by the admitting team during which small bowel capsule endoscopy was completed. Diagnostic yield and comfort were compared. Potential impact on hospital stay was examined and MACE mucosal visualisation quality was assessed. <h3>Results</h3> A total of 90 upper GI lesions were detected in 30 patients (80% male, median age 57 years (IQR=26)): 21 (23%) concomitantly identified by MACE and OGD, 49 (54%) by MACE alone and 20 (22%) by OGD alone (CI 0.05–0.58; p=0.0007). MACE and OGD concomitantly detected 50% of major pathologies (gastric and duodenal ulcers and oesophageal and gastric varices (n=2 each)). MACE alone identified 31% (D1 ulcers (n=4) and varices (n=1)) whereas OGD alone identified three D1 ulcers (19%; p=0.7). Ulcers (all classified as Forest class III at OGD) missed by MACE were due to rapid D1 transit and insufficient imaging. Review of small bowel images identified additional causes for GI bleeding distal to D2 in five cases: small bowel lymphoma (n=1), angioectasia (n=2), fresh bleeding in the proximal and distal small bowel with no culprit lesion seen (n=1 for each). MACE correctly suggested safe discharge for 21/21 patients. The median hospital stay of uncomplicated admissions where MACE suggested discharge was 53 (range 14–103) hours. Pain, discomfort and distress scores were lower with MACE than OGD (p&lt;0.05). Median MACE visualisation scores (worst-best:1–5) were excellent in the cardia (5), gastric body (5), antrum (5) and pylorus (5), good in the oesophagus (4) and fundus (3) but poor in D1 (0) and D2 (0): Kruskal-Wallis H test, χ<sup>2</sup>=133 (p&lt;0.05), lowest rank visualisation score in D1. <h3>Conclusions</h3> MACE has better diagnostic yield than OGD in suspected upper GI bleeding (with both modalities missing lesions), is better tolerated and used 'at the front door' might allow immediate discharge for two thirds of patients saving a median hospital stay for each of over two days. In addition, it suggests that about 10% of suspected upper GI bleeding may have a small bowel source.
Abstract 422: Small Molecule and Activated Fibroblast Targeting of the Gβγ-GRK2 Interface After Myocardial Ischemia Attenuates Heart Failure Progression
Authors: Joshua G Travers, Fadia A Kamal, Inigo Valiente-Alandi, Michelle L Nieman, Michelle A Sargent, John N Lorenz, Jeffery D Molkentin, Burns C Blaxall
Journal: Circulation Research (2017)

Cardiac fibroblasts are a critical cell population responsible for myocardial extracellular matrix homeostasis. Upon injury or pathologic stimulation, these cells transform to an activated myofibroblast state and play a fundamental role in myocardial fibrosis and remodeling. Chronic sympathetic overstimulation, a hallmark of heart failure, induces pathologic signaling through G protein βγ subunits and their interaction with G protein-coupled receptor kinase 2 (GRK2). We hypothesized that Gβγ-GRK2 inhibition/ablation after myocardial injury would attenuate pathologic myofibroblast activation and cardiac remodeling. The therapeutic potential of small molecule Gβγ-GRK2 inhibition alone or in combination with activated fibroblast- or myocyte-specific GRK2 ablation, each initiated after myocardial ischemia/reperfusion (I/R) injury, was investigated to evaluate possible salutary effects on post-I/R fibroblast activation, pathologic remodeling and cardiac function. Small molecule Gβγ-GRK2 inhibition initiated one week post-injury was cardioprotective in the I/R model of chronic heart failure, including preservation of cardiac contractility and reduction in cardiac fibrotic remodeling. Systemic small molecule Gβγ-GRK2 inhibition initiated one week post-I/R in cardiomyocyte-restricted GRK2 ablated mice (also post-I/R) demonstrated additional cardioprotection, suggesting a potential protective role beyond the cardiomyocyte. Inducible ablation of GRK2 in activated fibroblasts (i.e. myofibroblasts) post-I/R injury demonstrated significant functional cardioprotection with reduced myofibroblast transformation and fibrosis. Systemic small molecule Gβγ-GRK2 inhibition initiated one week post-I/R provided little to no further protection in mice with ablation of GRK2 in activated fibroblasts alone. Finally, Gβγ-GRK2 inhibition significantly attenuated activation characteristics of failing human cardiac fibroblasts isolated from end stage heart failure patients. These findings suggest a potential therapeutic role for Gβγ-GRK2 inhibition in limiting pathologic myofibroblast activation, interstitial fibrosis and heart failure progression.
Noncontact Wearable Wireless ECG Systems for Long-Term Monitoring
Authors: Sumit Majumder, Leon Chen, Ognian Marinov, Chih-Hung Chen, Tapas Mondal, M. Jamal Deen
Journal: IEEE Reviews in Biomedical Engineering (2018)

Electrocardiography (ECG) is the most common and extensively used vital sign monitoring method in modern healthcare systems. Different designs of ambulatory ECG systems were developed as alternatives to the commonly used 12-lead clinical ECG systems. These designs primarily focus on portability and user convenience, while maintaining signal integrity and lowering power consumption. Here, a wireless ECG monitoring system is developed using flexible and dry capacitive electrodes for long-term monitoring of cardiovascular health. Our capacitive-coupled dry electrodes can measure ECG signals over a textile-based interface material between the skin and electrodes. The electrodes are connected to a data acquisition system that receives the raw ECG signals from the electrodes and transmits the data using Bluetooth to a computer. A software application was developed to process, store, and display the ECG signal in real time. ECG measurements were obtained over different types of textile materials and in the presence of body movements. Our experimental results show that the performance of our ECG system is comparable to other reported ECG monitoring systems. In addition, to put this research into perspective, recent ambulatory ECG monitoring systems, ECG systems-on-chip, commercial ECG monitoring systems, and different state-of-the-art ECG systems are reviewed, compared, and critically discussed.
Abstract 12943: Assessment of Both Coronary Microvascular Damage and Left Ventricular Chamber Stiffness After Successful Percutaneous Coronary Intervention Predicts Left Ventricular Aneurysm in ST-Segment Elevation Myocardial Infarction
Authors: Atsushi Yamamuro, Koichi Tamita, Junichi Yoshikawa, Shuichiro Kaji, Yukaka Furukawa
Journal: Circulation (2015)

Background: In ST-segment elevation myocardial infarction (STEMI), the short deceleration time of left ventricular (LV) early filling by Doppler is a powerful independent predictor of LV remodeling. On the other hand, recent studies have shown that even if successful reperfusion is achieved in epicardial coronary arteries, microvascular obstruction results in insufficient reperfusion of the infarcted myocardium, leading to LV dysfunction. The purpose of this study was to examine the effects of both microvascular damage and LV chamber stiffness on the risk of LV aneurysm after successful percutaneous coronary intervention (PCI) in STEMI patients. Methods: Two hundred and twenty-one consecutive patients with first anterior STEMI were studied following successful PCI. Microvascular damage was evaluated on the basis of coronary flow velocity patterns using Doppler guidewires. We defined the presence of microvascular obstruction as diastolic deceleration time of ≤600ms and the presence of systolic flow reversal. LV filling patterns were determined by LV inflow pulsed-wave Doppler examination on day 3 after STEMI. Deceleration time ≤130 ms was defined as restrictive. We classified patients into three categories: without restrictive and microvascular obstruction (group 1, n=125), with restrictive or microvascular obstruction (group 2, n= 43), and with restrictive and microvascular obstruction (group 3, n=53). Left ventriculogram obtained 6 months after the infarction was analyzed to measure the LV volume. True LV aneurysm was defined as a deformity of the infarct segment that was apparent during diastole as well as during systole, and demonstrated diastolic contour abnormality. Results: Group 3 was at the highest risk of true LV aneurysm, while group 1 was at the lowest (2/125 [2%], 15/43 [35%], and 30/53 [57%]; P&lt;0.01). The assessment of both examinations was related to the LV volume index at 6 months after the infarction: patients in a poor group had a larger end-diastolic volume index (65±22 vs 91±28 vs 128±31ml/m2; P&lt;0.01). Conclusions: Assessment of both microvascular damage and LV chamber stiffness can accurately predict the risk of LV aneurysm in STEMI patients who underwent successful reperfusion, identifying a subset of high risk patients.
Assessing the effectiveness of adjuvant radiation therapy in patients with rare breast cancers including metaplastic and phyllodes tumors.
Authors: Nghia Pham, Brendan Martin, Tarita Thomas
Journal: Journal of Clinical Oncology (2018)

e12564 Background: Metaplastic (MBC) and phyllodes (PBC) breast cancers are rare histologies of breast neoplasms, each representing less than 1% of total breast cancers. Literature over the past decade has reported different results on the effect of radiation therapy (RT) on survival outcomes for MBC and PBC. We evaluated the utilization of RT and disease outcomes for these two subtypes of breast carcinomas using the National Cancer Database (NCDB) in order to analyze patient characteristics, disease features and prognosis for these tumors. Methods: Initially, 2,246,280 patients with a diagnosis of breast cancer were identified within NCDB. We excluded any non-surgical patients with a breast cancer histology other than MBC and PBC, with < 6 months follow-up, RT before surgery, unknown RT sequence, or unknown pathologic T or N stage. We collected information on demographics, pathology characteristics, chemotherapy dosing, and RT plans and dosing. Frailty survival models were used to estimate the instantaneous hazard of death as a function of univariable and multivariable patient demographic, pathologic and clinical risk factors. Results: 2,984 patients were included in the analysis, with 749 being PBC and 2,235 being MBC. Two-year and five-year overall survival is 87.5% (95 CI: 56.3% - 88.7%) and 73.7% (95 CI: 71.8% - 75.4%), respectively for the cohort. Median follow-up was 47 months (IQR: 25 – 78). On univariable analysis, the hazard of death at any given time for patients who received adjuvant doses of RT following surgery was 23% (HR = 0.77, 95 CI: 0.67 – 0.89) lower than those who only underwent surgery (p < .001). While adjuvant RT alone was no longer significant on multivariable analysis (MVA), the hazard of death at any given time for patients who received adjuvant doses of RT with concurrent chemotherapy following surgery was 28% (HR = 0.72, 95 CI: 0.58 – 0.90) lower than those who only underwent surgery (p = .004). Conclusions: Adjuvant RT did have a meaningful effect on survival outcomes in this cohort of patients. Prospective studies could provide more information on the optimal treatment plans and sequencing in patients with PBC and MBC in order to further improve clinical outcomes.