tbuckley/cabot-search huggingface dataset:
Multitrial evaluation of progression-free survival (PFS) as a surrogate endpoint for overall survival (OS) in previously untreated extensive-stage small cell lung cancer (ES-SCLC): An Alliance-led analysis.
Authors: Nathan R. Foster, Lindsay A. Renfro, Steven E. Schild, Mary Weber Redman, Xiaofei F. Wang, Suzanne Eleanor Dahlberg, Keyue Ding, Penelope Ann Bradbury, Suresh S. Ramalingam, David R. Gandara, Everett E. Vokes, Alex A. Adjei, Sumithra J. Mandrekar
Journal: Journal of Clinical Oncology (2013)

7510 Background: We previously demonstrated that PFS may be a candidate surrogate endpoint for OS in ES-SCLC using data from 3 randomized trials (Foster, Cancer 2011). Here, we sought to formally assess the patient- and trial-level surrogacy of PFS using data from 9 additional randomized phase II and III trials conducted by the NCI-funded cancer cooperative groups since 1986. Methods: Individual patient data from all 12 trials (3178 patients: 9 phase III and 3 phase II) were pooled. OS was the primary endpoint in all phase III trials; 3 phase III and 1 phase II trial were positive per protocol. Patient-level surrogacy (Kendall’s tau) was assessed using the Clayton copula bivariate survival model. Trial-level surrogacy was assessed via association of the log hazard ratios on OS and PFS across trials, including: weighted (by trial size) least squares regression of Cox model effects (R² WLS) and weighted (by trial size) correlation of the copula effects (R² Copula). One trial had 4 treatment arms thus 14 total two-arm comparisons were made. Results: With a median follow-up of 41.8 months in the 106 patients still alive, the median OS and PFS across trials were 9.7 months (95% CI: 9.5, 9.9) and 5.7 months (95% CI: 5.5, 5.8), respectively. There were 3120 PFS events in total (2564 disease progressions and 556 deaths without progression). The median time from progression to death was 4.1 months (95% CI: 3.9, 4.3). PFS showed modest association with OS at the patient-level (tau= 0.56) and at the trial-level (R² WLS = 0.58; R² Copula (standard error) = 0.55 (0.29)). The 95% CIs for the predicted HR for OS given observed HR on PFS under a weighted leave-one-out prediction always included the observed HR for OS; however such intervals were wide, suggesting uncertainty on the practical use of PFS as a surrogate for OS in this setting. Conclusions: PFS failed to demonstrate surrogacy for OS in ES-SCLC based on this large pooled analysis. Given that the difference in the median PFS and OS is less than 6 months, we recommend using OS as the primary endpoint in phase III trials of previously untreated ES-SCLC.
Abstract 14559: Utility of New Left Bundle Branch Block as a Diagnostic Criterion for Acute Myocardial Infarction
Authors: Sonia Jain, Henry T Ting, Malcolm Bell, Christine M Bjerke, Ryan J Lennon, Bernard J Gersh, Charanjit S Rihal, Abhiram Prasad
Journal: Circulation (2010)

Background: The clinical utility of new or ‘presumably new’ left bundle branch block (LBBB) as a ST-elevation myocardial infarction (STEMI)-equivalent ECG diagnostic criterion in contemporary pract...
Abstract 3739: Aggravated Myocardial Damage in Lectin-like Domain Deficient Thrombomodulin Mice is Mediated by HMGB1
Authors: Anika Lorenz, Christine Herzog, Jan Larmann, Martina Schmitz, Ed Conway, Gregor Theilmeier
Journal: Circulation (2009)

Background: Cardiac failure due to adverse myocardial remodelling is a frequent cause of cardiovascular morbidity and mortality. We demonstrated that thrombomodulin (TM), through its anti-inflammat...
流产后再次妊娠间隔时间对妊娠结局的影响：苏格兰医院回顾性资料分析（摘要）
Authors: Eleanor, Love, Siladitya, Bhattacharya, Norman, Smith, Sohinee, 沈洁, 杨孜
Journal: BMJ (2010)

目的 探讨初次有记录的妊娠流产后再次妊娠的最佳时间间隔。 设计 基于人群的回顾性队列研究。 地点 苏格兰医院，1981年至2000年 研究对象 30937名首次妊娠记录为流产的再次妊娠妇女。
Abstract 3646: Oxidative Stress-Mediated Thombospondin-2 Upregulation Contributes to Diabetic Endothelial Progenitor Cell Dysfunction via Matrix Metalloproteinase-9 Activation
Authors: Ok-Nam Bae, Alex F Chen
Journal: Circulation (2008)

Endothelial progenitor cells (EPCs) play an essential role in angiogenesis but are dysfunctional in diabetes featuring excessive oxidative stress. Thrombospondin-2 (TSP-2) and matrix metalloproteinase-9 (MMP-9) possess potent anti-angiogenic properties, but their roles on EPC dysfunction in diabetes remain unknown. We tested the hypothesis that increased oxidative stress up-regulates TSP-2 and contributes to diabetic EPC dysfunction through MMP-9 activation in type 2 diabetes. Bone marrow-derived EPCs from adult male type 2 diabetic db/db mice (C57BLKS/J, 9 –13 weeks) and control db/+ mice on the same genetic background were used (blood glucose level, 451.0±8.2 mg/dL for db/db, n=38, vs. 141.3±3.7 mg/dL for db/+, n=28, p&lt;0.01). TSP-2 mRNA and protein were both up-regulated in diabetic EPCs (3.43±0.41 folds of mRNA by qRT-PCR, n=6, p&lt;0.01; 2.35±0.16 folds of protein by Western blot analysis, n= 5, p&lt;0.01, vs. db/+). Silencing TSP-2 by its siRNA in diabetic EPCs improved their angiogenesis in vitro (Matrigel tube formation assay, n=4, p&lt;0.05 vs. scrambled RNA). The increase of TSP-2 in diabetic EPCs was reversed by adenoviral vector-mediated overexpression of dominant-negative Rac1 (68±9%, n=5, p&lt;0.05 vs. β-galactosidase reporter gene), which retards endogenous NADPH oxidase subunit Rac1 activity. Furthermore, both MMP-9 mRNA and enzymatic activity were significantly increased in diabetic EPCs (6.42±2.46 folds of mRNA by qRT-PCR, n=6, p&lt;0.01; 1.37±0.08 folds activity by gelatin zymography, n=3, p&lt;0.01, vs. db/+). The increased MMP-9 activity was significantly inhibited by silencing TSP-2 by its siRNA in diabetic EPCs (47±15%, n=5, p&lt;0.05 vs. scrambled RNA). Our results suggest that up-regulation of TSP-2 mediated by increased oxidative stress contributes to dysfunction of EPC angiogenesis through MMP-9 activation in type 2 diabetes. These findings may provide a basis of targeting oxidative stress/TSP-2/MMP-9 pathway for restoring EPC angiogenic function and cell therapy of diabetic vascular complications.
文拉法辛、西酞普兰、氟西汀和度硫平治疗期间自杀的危险：回顾性队列研究
Authors: 薛海波（译）, 张明园（校）
Journal: BMJ (2007)

近期英国的一项回顾性队列研究比较了使用文拉法辛与使用西酞普兰、氟西汀和度硫平的成人患者自杀的风险．该研究从英国全科研究数据库中选取了18—89岁的219088例患者，在1995年至2005年间这些患者服用文拉法辛、西酞普兰、氟西汀或度硫平。主要结果测量指标为自杀人数和自杀未遂人数。结果：文拉法辛使用者自杀危险因素负担更高，包括以前有自杀未遂史，有严重抑郁症或难治性抑郁症史。
Abstract 3594: Nogo-B is Essential for Macrophage Dependent Inflammatory Arteriogenesis and Angiogenesis
Authors: Jun Yu, Carlos Fernandez-Hernando, Yajaira Suarez, Yajaira Suarez, Michael Schleicher, Zhengrong Hao, Paulette L Wright, Themis R Kyriakides, William C Sessa
Journal: Circulation (2008)

Nogo-B, a member of the reticulon 4 family of proteins, is the dominant isoform expressed in endothelial, vascular smooth muscle and inflammatory cells. We previously have shown Nogo-B plays a critical role in vascular remodeling after injury in vivo . In mice and rabbits, neointimal expansion of injured blood vessels is associated with a marked reduction in Nogo-B, and, in humans, the loss of Nogo-B correlates with stenotic lesions and plaque rupture. However, the role of Nogo-B in regulating arteriogenesis or angiogenesis is not known. In the present study, we investigated the role of Nogo-B in arteriogenesis/angiogenesis using a mouse hindlimb ischemia model in Nogo-A/B KO (NgKO) and wild-type (WT) littermate control mice. Nogo-B mRNA and protein levels increased in the ischemic leg relative to the contralateral leg in WT. Hindlimb ischemia reduces tissue perfusion by 80% followed by a complete recovery of flow to pre-surgical values in WT after 4 weeks. In NgKO, there was a marked decrease in blood flow recovery post-ischemia, which was accompanied by a reduction in capillary density (assessed by isolectin staining), a decrease in smooth muscle/pericyte recruitment and an impaired collateral artery remodeling (assessed by quantitative angiography) compared to WT. Blood vessel formation and remodeling during ischemia requires coordination of the inflammatory response with regulated gene expression that promotes blood vessel assembly. Thus, we assessed the presence of tissue macrophages (F4/80 immunochemistry) 3 days after ischemia and found a 76% reduction of F4/80 positive cells in ischemic tissue in NgKO compared to WT. Mechanistically, the impaired recruitment of tissue macrophages was associated with reduced spreading, impairment of chemotaxis in response to monocyte chemokines compared to WT cells (76±4 vs. 113±8 cells/field in NgKO vs. WT), but not adhesion, of isolated bone marrow derived monocytes from NgKO compared to controls. Moreover, NgKO macrophage demonstrated impaired Rac activation, translocation and cytoskeletal organization upon stimulation of with chemokines. In conclusion, our data suggests that endogenous Nogo coordinates macrophage mediated inflammation with angiogenesis, arteriogenesis and blood flow control.
Abstract 15517: Deficiency of AMPK Exacerbates Lipopolysaccharide-Induced Cardiac Contractile Dysfunction: The Role of Autophagy
Authors: Fuling Luo, Jun Ren
Journal: Circulation (2013)

Lipopolysaccharide (LPS),the main component of the gram-negative bacteria, is the culprit player responsible for sepsis-induced cardiac dysfunction. Accumulating evidence has indicated a pivotal role of AMP-activated protein kinase (AMPK) in inflammatory responses and pathology under sepsis. To this end, this study was designed to examine the role of AMPK deficiency in LPS-induced cardiac contractile dysfunction and the underlying mechanism(s) with a focus on autophagy. Wild-type (WT) and transgenic mice over-expressing a kinase-dead (KD) a2 isoform (K45R mutation) of AMPK were challenged with LPS (4mg/kg, i.p.). Cardiac function was evaluated using echocardiography and cardiomyocyte mechanics. MAPK and autophagic signaling proteins, including AMPK, mTOR, ULK1, Atgs, LC3B, LAMP1 and Rab7and P62, were examined. LPS challenge compromised cardiac contractile function accompanied by decreased phosphorylation of AMPK as well as increased p38MAPK and ERK, alongwith autophagosome maturation dysfunction (increased LC3BIIand p62, and decrease of LAMP1), the effect of which was exacerbated by AMPK deficiency.Moreover, the p38 and ERK inhibitors, SB203580 and U0126, respectively,partially reversed LPS-induced autophagy (LC3B expression and puncta), reduced the expression of P62 and restored cardiac contractile function. Inhibition of autophagosome fusion with lysosomal failed to influence the LPS-induced contraction anomalies. Nonetheless, the mTOR inhibitor rapamycin alleviated LPS-induced cardiac dysfunction and interruption of autophagic flux. These data have implicated that LPS triggered cardiomyocyte dysfunction associated with blockade of autophagyflux. AMPK deficiency exacerbated LPS-induced interruption of autophagy flux possibly through accentuating activation of p38MAPK and ERK.
Evaluation of the role of aromatase inhibitors (AIs) in the treatment of uterine leiomyosarcoma (uLMS)
Authors: R. O'Cearbhaill, Q. Zhou, A. Iasonos, R. A. Soslow, M. M. Leitao, C. A. Aghajanian, M. L. Hensley
Journal: Journal of Clinical Oncology (2009)

5590 Background: Although AIs are sometimes used in selected patients with uLMS, there are few data assessing the efficacy of AIs in this setting. Methods: A retrospective electronic medical record review of patients (pts) with uLMS treated with an AI at Memorial Sloan-Kettering Cancer Center between 1998–2008 was performed. The primary endpoint was progression free survival (PFS), defined as time from the start of AI until death, progression or last follow-up. PFS was estimated by Kaplan-Meier method. Best response using RECIST was also assessed. Results: 34 pts with advanced, measurable uLMS were treated with AIs. Median age was 53 yrs (range 35–74); median body mass index 28.1 kg/m 2 (range 16.1–52.1); LMS grade low: 5, high: 29; hormone receptor status: 19 ER+, 9 ER-, 6 ER unknown, 9 PR+, 9 PR-, 16 PR unknown; low volume of disease (no lesion &gt;2 cm): 19 pts(56%), high volume: 15 pts (44%). 23 pts (68%) had had prior chemotherapy (1 regimen: 29%, 2 regimens: 18%, 3 regimens: 15%, &gt;4 regimens: 6%); 12 pts (35%) had had prior pelvic radiotherapy. AIs used were: letrozole 74% (9% with leuprolide if premenopausal), anastrozole 21%, exemestane 6%. Median PFS was 2.9 months (95% CI: 1.8–5.1). 8 pts (23.5%) had a PFS &gt;6months. Among pts with ER or PR + uLMS, median PFS was 5months (95% CI: 1.8–9.4) versus 1.9months (95% CI: 0.9–3.2) with ER and PR negative uLMS. Best response was partial response in 3 pts (8.8%) (all of whom were ER+), stable disease in 12 (35%), and progressive disease in 19 (56%). Common toxicities were grade 1–2 asthenia (30%), hot flashes (30%), and arthralgias (27%). Conclusions: In this highly selected population of pts with uLMS AIs fail to achieve objective response. While relatively prolonged PFS was observed among ER and/or PR+ uLMS pts, in the absence of a no-treatment control group this outcome cannot be attributed solely to the activity of the AI treatment. No significant financial relationships to disclose.
Abstract 199: Targeted Deletion of Glycogen Synthase Kinase-3{alpha}(GSK-3{alpha}) vs. GSK-3{beta} identifies unique isoform-specific effects on development and hypertrophy
Authors: Jibin Zhou, Risto Kerkela, Katrina MaCauly, Lisa Kockeritz, Bradley W Doble, Kathleen Woulfe, Erhe Gao, Stephanie Pesant, Yonghong Lei, Chinmay M Trivedi, James R Woodgett, Jonathan A Epstein, Gordon S Huggins, Thomas L Force
Journal: Circulation (2007)
Paradoxical cutaneous squamous cell proliferations in patients treated with sorafenib
Authors: J. P. Arnault, C. Mateus, J. Wechsler, A. Spatz, G. Tomasic, V. Sibaud, S. Aractingi, J. D. Grange, B. Escudier, C. Robert
Journal: Journal of Clinical Oncology (2009)

9564 Background: The new multikinase inhibitor sorafenib is associated with multiple and usually manageable skin side effects. We report 12 patients presenting with solitary or multiple cutaneous squamous cell proliferations occurring in the months following initiation of sorafenib and we discuss the significance of this unexpected association. Results: Twelve patients treated by sorafenib for renal cell cancer or hepatocellular carcinoma presented one or several skin tumours with a typical keratoacanthoma (KA) appearance 3 to 9 months after the onset of sorafenib therapy. Some KAs had a spontaneous regression. No recurrence after surgical excision or metastatic dissemination was reported. Histologic examination of 22 lesions found classical non aggressive KAs in 16 cases and more aggressive squamous cell carcinoma-like lesions with deep dermis invasion and cellular atypias in 5 patients. Conclusions: Sorafenib treatment can be associated with cutaneous squamous cell proliferation resembling KAs. Although our observations suggest that these skin neoplasms have a low aggressive potential, these reports address the questions of the paradoxical proliferating effect of a drug that usually has an anti-proliferating effect. They also reactivate the unresolved controversy about the relationship between KA and authentic squamous cell carcinoma. More practically, although the exact frequency of this side effect is unknown, physicians should be aware of this side effect and regularly perform skin examination of their patients. Surgical excision is the treatment of choice in order to rule out authentic squamous cell carcinoma. Impact and management of these skin proliferations will have to be further evaluated, especially if sorafenib is to be tested in an adjuvant setting. No significant financial relationships to disclose.
Abstract 16364: The Lipid Paradox: Lowest Level of LDL-C Associated with Increased In-Hospital Mortality in Patients Following Acute Myocardial Infarction
Authors: Vanessa S Reddy, Quang T Bui, Joan R Jacobs, Susan M Begelman, Paul D Frederick, Dave P Miller, William J French
Journal: Circulation (2012)

Background: Lipoprotein levels are recognized as independent risk factors for long-term cardiovascular (CV) events in patients with acute myocardial infarction (AMI). During the acute phase reactio...
Mutational status of epidermal growth factor receptor is the only predictor of clinical response to gefitinib treatment in non-small cell lung cancer
Authors: Maria P. Wong, Daniel Tt Chua, James Cm Ho, Issan Ys Tam, Wah Kit Lam, Lap Ping Chung
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

4539 

The clinical profile of lung cancer in Hong Kong shows distinct characteristics. The incidences in both genders are comparable to those in Western populations with male (M):female (F) ratio of 2.4:1 in 2002. However, the majority of the women have never smoked and the smoker (SM):non-smoker (NS) ratio was 0.3:1, compared to 6.2:1 in male patients. Consistent with findings in various Asian populations, we have previously shown that mutations of the epidermal growth factor receptor (EGFR) in lung cancers are associated with adenocarcinomas, women and non-smokers. The purpose of this study was to examine the clinical correlates and EGFR mutational status (exons 18 to 21) of non-small cell lung cancer (NSCLC) in relation to clinical responses to the tyrosine kinase inhibitor gefitinib (Iressa). All patients who had resistant disease to conventional chemotherapy, had available clinical material (biopsy, fine needle aspiration, lavage or pleural effusion fluid) for mutation analysis, and who received gefitinib treatment in our institution were retrospectively evaluated. There were 27 F (26 NS, 1 SM) and 16 M (9 NS, 7 SM, p=0.002) aged 35-85 (median 64), and included 32 histologically confirmed adenocarcinomas (AD), 2 squamous and 9 NSCLC of advanced stage disease (IIIB and IV). Gefitinib (250mg/day) was given for 0.5 to 21.2 (median 3) months and patients were monitored for 0.5 to 26.4 (median 6.3) months. The median survival was 10.5 months (95% CI, 8.3-12.7) and one-year survival rate was 37.3%. There were 25 mutations (9 substitutions, 17 deletions) that resulted in amino acid changes from 20 F, 5 M (p=0.010), and 23 NS, 2 SM (p=0.052). One case showed both exon 19 deletion and exon 20 substitution. Common changes (exon 19 deletions, L858R) involved 88% of the mutants. 2 other cases showed silent mutations. Clinical response (CR) from gefitinib treatment was observed in 23 (53.5%) patients who showed either reduction of longest tumour diameter by ≥30%, improvement in performance status, and/or reduced serum carcinoembryonic antigen tumour marker. They included 17/27 (63%) female, 6/16 (37.5%) male, 19/35 (54.3%) NS, 4/8 (50%) SM, and 19/32 (59.4%) AD. Clinical response was correlated only with the EGFR mutation status (19/25 mutants, 4/18 wild types, p<0.001) but not patient gender, smoking history or tumor diagnosis. Survival analysis showed that patients with EGFR mutation had significantly better outcome than those without mutation (one-year survival rate 55.5% vs. 10.6%, p=0.013). Within the limits of the small patient number of this study, the data suggested that the EGFR mutational status is the only predictor of clinical response to gefitinib treatment for NSCLC in our population. (Supported by HKU CRCG 200507176201)
Psychological coping and cancer
Authors: M. Watson
Journal: BMJ (2003)

Editor—The review by Petticrew et al is flawed.1

Firstly, they do not compare like with like and ignore differing methods. Different instruments assess coping styles differently and may not be comparable. Thus conclusions cannot be drawn convincingly. Out of 28 studies, 13 had less than three years' follow up (shortest eight weeks). However, in relation to early breast cancer less than five years of follow up produces inconclusive results.

Secondly, our study was relegated to the realms of irrelevance by saying that the recent large UK study (n=578), while of higher quality, reported mixed findings: helplessness or hopelessness predicted recurrence when patients with high and low scores were compared but not when it was the predominant coping style.2 The main importance of our clearly stated findings concerning helplessness and hopelessness was missed. Mixed findings were not reported.

Although predominant coping style was arbitrarily defined, helplessness or hopelessness is robust across many studies. A high score on this subscale is a valid measure, reflecting a response amenable to psychological intervention. This finding was crucially important for encouraging adequate provision of psychological care in oncology, as was the small, cautiously interpreted tendency to poorer outcome found in severely depressed patients. Patient responsibility (or blame) is removed, and the onus shifts to the medical profession to identify and provide help for those at risk.

Dismissal of our study—which used rigorous methods, controlled for known prognostic variables, was sufficiently large, had a long follow up, and found a survival effect—does the research no service. Better to conclude that many poor studies fail to show any effect of coping response on survival, but high quality studies provide evidence suggesting that further good research is needed. Meanwhile the adverse effect on outcome of a helpless or hopeless coping response clearly argues for the provision of better psychological resources.
Design and application of a core genome multilocus sequence typing scheme for investigation of Legionnaires' disease incidents
Authors: J Moran-Gilad, K Prior, E Yakunin, T  G Harrison, A Underwood, T Lazarovitch, L Valinsky, C Lück, F Krux, V Agmon, I Grotto, D Harmsen
Journal: Eurosurveillance (2015)

Binary file ES_Abstracts_Final_ECDC.txt matches
Abstract 16508: Fusion of 3D Echocardiography and Computed Tomography for Optimization of Cardiac Resynchronization Therapy
Authors: Wendy Tsang, Agustina Sciancalepore, Amit R Patel, Lissa Sugeng, Lynn Weinert, Victor Mor-Avi, Roberto M Lang
Journal: Circulation (2010)

Introduction:  A high percentage of patients do not respond to cardiac resynchronization therapy (CRT), because the left ventricular (LV) lead is placed too far from the site of late myocardial activation. Optimal lead placement remains problematic, because different imaging modalities are used to depict coronary anatomy with high spatial resolution and LV wall dynamics with high temporal resolution. We hypothesized that fusion of computed tomography (CT) coronary veins with 3D transthoracic echocardiography (TTE) wall motion timing maps is feasible and may allow measurement of the distances between coronary veins and the site of late activation.   Methods:  In 9 patients with systolic heart failure (56+8 years, LVEF 34+9%), we obtained 3D full volume TTE of the LV and cardiac CT datasets. Prototype software (TomTec) was used to fuse coronary veins with 3D TTE parametric maps of the timing of LV wall motion superimposed on CT derived 3D endocardial surfaces. Distances were measured between the LV wall with latest activation to the closest and the second closest coronary veins, i.e. optimal and secondary implantation sites.   Results:  Fusion of CT coronary veins and parametric maps of the timing of LV wall motion obtained from 3D TTE was possible in all patients. No site of late activation was identified in one patient on 3D TEE. In the remaining 8 patients, measurements from the site of late activation to the optimal and secondary implantation sites were feasible. The measured distances ranged from 3 to 45 mm for the optimal and 21 to 106 mm for secondary implantation sites.   Conclusions:  This is the first study to demonstrate the feasibility of 3D fusion of CT anatomy with TTE functional information. This approach allows measurements that may be used to prospectively and noninvasively identify patients in whom the veins are too distant from the site of late activation to deliver effective pacing. This method may prove useful in planning LV lead placement and thus may improve outcomes of CRT.