bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase I Study of Veliparib in Combination with Metronomic Cyclophosphamide in Adults with Refractory Solid Tumors and Lymphomas
Authors: Kummar Shivaani , Ji Jiuping , Morgan Robert , Lenz Heinz-Josef , Puhalla Shannon L. , Belani Chandra P. , Gandara David R. , Allen Deborah , Kiesel Brian , Beumer Jan H. , Newman Edward M. , Rubinstein Larry , Chen Alice , Zhang Yiping , Wang Lihua , Kinders Robert J. , Parchment Ralph E. , Tomaszewski Joseph E. , Doroshow James H. 
Published: February 2012

Abstract
Purpose: Oral administration of the alkylating agent cyclophosphamide at low doses, metronomic dosing, is well tolerated, with efficacy in multiple tumor types. PARP inhibition potentiates effects of cyclophosphamide in preclinical models. We conducted a phase I trial of the PARP inhibitor veliparib and metronomic cyclophosphamide in patients with refractory solid tumors and lymphoid malignancies.
Experimental Design: Objectives were to establish the safety and maximum tolerated dose (MTD) of the combination; characterize veliparib pharmacokinetics (PK); measure poly(ADP-ribose) (PAR), a product of PARP, in tumor biopsies and peripheral blood mononuclear cells (PBMC); and measure the DNA-damage marker γH2AX in PBMCs and circulating tumor cells (CTC). Cyclophosphamide was administered once daily in 21-day cycles in combination with veliparib administered once daily for 7, 14, or 21 days.
Results: Thirty-five patients were enrolled. The study treatment was well tolerated, and the MTD was established as veliparib 60 mg with cyclophosphamide 50 mg given once daily. Seven patients had partial responses; an additional six patients had disease stabilization for at least six cycles. PAR was significantly decreased in PBMCs (by at least 50%) and tumor biopsies (by at least 80%) across dose levels (DL); γH2AX levels were increased in CTCs from seven of nine patients evaluated after drug administration.
Conclusions: The combination of veliparib with metronomic cyclophosphamide is well tolerated and shows promising activity in a subset of patients with BRCA mutations. A phase II trial of the combination compared with single-agent cyclophosphamide is ongoing in BRCA-positive ovarian cancer, triple-negative breast cancer, and low-grade lymphoma. Clin Cancer Res; 18(6); 1726–34. ©2012 AACR.
L1 Cell Adhesion Molecule Promotes Tumorigenicity and Metastatic Potential in Non–Small Cell Lung Cancer
Authors: Hai Josephine , Zhu Chang-Qi , Bandarchi Bizhan , Wang Yu-Hui , Navab Roya , Shepherd Frances A. , Jurisica Igor , Tsao Ming-Sound 
Published: February 2012

Abstract
Purpose: Non–small cell lung cancer (NSCLC) is a highly metastatic cancer with limited treatment options, thus requiring development of novel targeted therapies. Our group previously identified L1 cell adhesion molecule (L1CAM) expression as a member of a prognostic multigene expression signature for NSCLC patients. However, there is little information on the biologic function of L1CAM in lung cancer cells. This study investigates the functional and prognostic role of L1CAM in NSCLC.
Experimental Design: Cox proportional hazards regression analysis was done on four independent published mRNA expression datasets of primary NSCLCs. L1CAM expression was suppressed by short-hairpin RNA (shRNA)–mediated silencing in human NSCLC cell lines. Effects were assessed by examining in vitro migration and invasion, in vivo tumorigenicity in mice, and metastatic potential using an orthotopic xenograft rat model of lung cancer.
Results: L1CAM is an independent prognostic marker in resected NSCLC patients, with overexpression strongly associated with worse prognosis. L1CAM downregulation significantly decreased cell motility and invasiveness in lung cancer cells and reduced tumor formation and growth in mice. Cells with L1CAM downregulation were deficient in constitutive extracellular signal–regulated kinase (Erk) activation. Orthotopic studies showed that L1CAM suppression in highly metastatic lung cancer cells significantly decreases spread to distant organs, including bone and kidney.
Conclusion: L1CAM is a novel prometastatic gene in NSCLC, and its downregulation may effectively suppress NSCLC tumor growth and metastasis. Targeted inhibition of L1CAM may be a novel therapy for NSCLC. Clin Cancer Res; 18(7); 1914–24. ©2012 AACR.
The Fundamental Role of the p53 Pathway in Tumor Metabolism and Its Implication in Tumor Therapy
Authors: Shen Lan , Sun Xiang , Fu Zhenhong , Yang Guodong , Li Jianying , Yao Libo 
Published: February 2012

AbstractIt is well established that the altered metabolism exhibited by cancer cells, including high rates of glycolysis, lactate production, and biosynthesis of lipids, nucleotides, and other macromolecules, and which may occur either as a consequence or as a cause of tumorigenesis, plays an essential role in cancer progression. Recently, the tumor suppressor p53 was found to play a central role in this process. Here, we review the role of p53 in modulating tumor metabolism. Specifically, we focus on the functions of p53 in regulating aerobic glycolysis, oxidative phosphorylation, the pentose phosphate pathway, fatty acid synthesis and oxidation, and glutamine metabolism, and we discuss the therapeutic strategy whereby p53 helps to prevent malignant progression. Clin Cancer Res; 18(6); 1561–7. ©2012 AACR.
Absence of Acute Inhibitory Effect of Insulin on Chylomicron Production in Type 2 Diabetes
Authors: Nogueira Juan-Patricio , Maraninchi Marie , Béliard Sophie , Padilla Nadège , Duvillard Laurence , Mancini Julien , Nicolay Alain , Xiao Changting , Vialettes Bernard , Lewis Gary F. , Valéro René 
Published: February 2012

Objective—
Overproduction of intestinally derived apoB-48-containing triglyceride-rich lipoproteins (TRLs) (chylomicrons) has recently been described in type 2 diabetes, as is known for hepatic TRL-apoB-100 (very-low-density lipoprotein) production. Furthermore, insulin acutely inhibits both intestinal and hepatic TRL production, whereas this acute inhibitory effect on very-low-density lipoprotein production is blunted in type 2 diabetes. It is not currently known whether this acute effect on chylomicron production is similarly blunted in humans with type 2 diabetes.

Methods and Results—
We investigated the effect of acute hyperinsulinemia on TRL metabolism in 18 type 2 diabetic men using stable isotope methodology. Each subject underwent 1 control (saline infusion [SAL]) lipoprotein turnover study followed by a second study, under 1 of the 3 following clamp conditions: (1) hyperinsulinemic-euglycemic, (2) hyperinsulinemic-hyperglycemic, or (3) hyperinsulinemic-euglycemic plus intralipid and heparin. TRL-apoB-48 and TRL-apoB-100 production and clearance rates were not different between SAL and clamp and between the different clamp conditions, except for significantly lower TRL-apoB-100 clearance and production rates in hyperinsulinemic-euglycemic plus intralipid and heparin clamp compared with SAL.

Conclusion—
This is the first demonstration in individuals with type 2 diabetes that chylomicron production is resistant to the normal acute suppressive effect of insulin. This phenomenon may contribute to the highly prevalent dyslipidemia of type 2 diabetes and potentially to atherosclerosis.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00950209.
Intravascular Optical Coherence Tomography Detection of Atherosclerosis and Inflammation in Murine Aorta
Authors: Tahara Satoko , Morooka Toshifumi , Wang Zhao , Bezerra Hiram G. , Rollins Andrew M. , Simon Daniel I. , Costa Marco A. 
Published: February 2012

Objective—

The goal of this study was to evaluate the feasibility of imaging the aorta of apolipoprotein E–deficient (ApoE
–/–
) mice for the detection of atherosclerosis and macrophages using optical coherence tomography (OCT) compared with histology.

Methods and Results—

Atherosclerosis was induced by high-fat diet in 7-week-old ApoE
–/–
mice for 10 (n=7) and 22 (n=7) weeks. Nine-week-old ApoE
–/–
mice (n=7) fed a standard chow diet were used as controls. OCT images of a 10-mm descending aorta in situ were performed in 4 mice for each, and plaque and macrophages were determined at 0.5-mm intervals. Automated detection and quantification of macrophages were performed independently using a customized algorithm. Coregistered histological cross-sections were stained with hematoxylin-eosin, Mac-3, and von Kossa. Three mice in each group had en face OCT imaging to detect macrophages, which were compared with lipid-positive area with Sudan IV. OCT images were successfully acquired in all mice. OCT and histology were able to discriminate macrophages and plaque among the 3 groups and showed excellent correlation for (1) visual detection of plaque (
r
=0.98) and macrophages (
r
=0.93), (2) automated detection and quantification of macrophages by OCT versus Mac-3-positive area (
r
=0.92), and (3) en face OCT detection of macrophages versus Sudan IV–positive area (
r
=0.92).

Conclusion—
Murine intra-aortic OCT is feasible and shows excellent correlation with histology for detection of atherosclerotic plaque and macrophages.
In Vivo Targeting of Inflammation-Associated Myeloid-Related Protein 8/14 Via Gadolinium Immunonanoparticles
Authors: Maiseyeu Andrei , Badgeley Marcus A. , Kampfrath Thomas , Mihai Georgeta , Deiuliis Jeffrey A. , Liu Cuiqing , Sun Qinghua , Parthasarathy Sampath , Simon Daniel I. , Croce Kevin , Rajagopalan Sanjay 
Published: February 2012

Objective—
Myeloid-related protein (Mrp) 8/14 complex (is a highly expressed extracellularly secreted protein, implicated in atherosclerosis. In this study, we evaluated the feasibility of targeting Mrp in vivo through synthetic immuno-nanoprobes.

Methods and Results—

Anti-Mrp–14 and nonspecific IgG-conjugated gadolinium nanoprobes (aMrp-) were synthesized and characterized. Pharmacokinetics and vascular targeting via MRI of the formulations were assessed in vivo in high fat-fed apolipoprotein E deficient (ApoE
−/−
), ApoE
−/−
/Mrp14
−/−
(double knockout) and chow-fed wild-type (C57BL/6) mice. Bone marrow-derived myeloid progenitor cells were isolated from both ApoE
−/−
and double knockout mice, differentiated to macrophages, and were treated with LPS, with or without Mrp8, Mrp14, or Mrp8/14; conditioned media was used for in vitro studies. Mrp-activated cells secreted significant amounts of proinflammatory cytokines, which was abolished by pretreatment with aMrp-NP. We show in vitro that aMrp-NP binds endothelial cells previously treated with conditioned media containing Mrp8/14. MRI following intravenous delivery of aMrp-NP revealed prolonged and substantial delineation of plaque in ApoE
−/−
but not double knockout or wild-type animals. Nonspecific IgG-conjugated gadolinium nanoprobe-injected animals in all groups did not show vessel wall enhancement. Flow-cytometric analysis of aortic digesta revealed that aMrp-NP present in Ly-6G
+
, CD11b
+
, CD11c
+
, and CD31
+
cells in ApoE
−/−
but not in double knockout animals.

Conclusion—
Targeted imaging with aMrp-NP demonstrates enhancement of plaque with binding to inflammatory cells and reduction in inflammation. This strategy has promise as a theranostic approach for atherosclerosis.
Risk Prediction for Early In-Hospital Mortality Following Heart Transplantation in the United States
Authors: Singh Tajinder P. , Almond Christopher S. , Semigran Marc J. , Piercey Gary , Gauvreau Kimberlee 
Published: February 2012

Background—
Risk factors for early mortality after heart transplant (HT) have not been used for quantitative risk prediction. We sought to develop and validate a risk prediction model for posttransplant in-hospital mortality in HT recipients.

Methods and Results—

We derived the model in subjects aged ≥18 years who underwent primary HT in the United States from January 2007 to June 2009 (n=4248) and validated it internally using a bootstrapping technique (200 random samples, n=4248). We then assessed the model's performance in patients receiving an HT from July 2009 to October 2010 (external validation cohort, n=2346). Posttransplant in-hospital mortality was 4.7% in the model derivation cohort. The best-fitting model based on recipient characteristics at transplant had 6 variables: age, diagnosis, type of mechanical support, ventilator support, estimated glomerular filtration rate, and total serum bilirubin. Model discrimination for survivors versus nonsurvivors was acceptable during derivation and internal validation (C statistic, 0.722 and 0.731, respectively) as was model calibration during derivation (Hosmer Lemeshow [HL]
P
=0.47). Model performance was reasonable in the external validation cohort (predicted mortality, 4.9%; actual mortality, 4.3%;
R
2
=0.95; C statistic, 0.68; HL
P
=0.48). Adding the donor-related variables of age and ischemic time to the model improved its performance in both the model derivation (C statistic, 0.742; HL
P
=0.70) and the external validation (C statistic, 0.695; HL
P
=0.42) cohorts.

Conclusions—
The proposed model allows risk stratification of HT candidates for early posttransplant mortality and may be useful in counseling patients with regard to their posttransplant prognosis. The model with additional donor-related variables may be useful during donor selection.
Cost-Effectiveness of Transcatheter Aortic Valve Replacement Compared With Standard Care Among Inoperable Patients With Severe Aortic Stenosis
Authors: Reynolds Matthew R. , Magnuson Elizabeth A. , Wang Kaijun , Lei Yang , Vilain Katherine , Walczak Joshua , Kodali Susheel K. , Lasala John M. , O'Neill William W. , Davidson Charles J. , Smith Craig R. , Leon Martin B. , Cohen David J. 
Published: February 2012

Background—
In patients with severe aortic stenosis who cannot have surgery, transcatheter aortic valve replacement (TAVR) has been shown to improve survival and quality of life compared with standard therapy, but the costs and cost-effectiveness of this strategy are not yet known.

Methods and Results—
The PARTNER trial randomized patients with symptomatic, severe aortic stenosis who were not candidates for surgery to TAVR (n=179) or standard therapy (n=179). Empirical data regarding survival, quality of life, medical resource use, and hospital costs were collected during the trial and used to project life expectancy, quality-adjusted life expectancy, and lifetime medical care costs to estimate the incremental cost-effectiveness of TAVR from a US perspective. For patients treated with TAVR, mean costs for the initial procedure and hospitalization were $42 806 and $78 542, respectively. Follow-up costs through 12 months were lower with TAVR ($29 289 versus $53 621) because of reduced hospitalization rates, but cumulative 1-year costs remained higher ($106 076 versus $53 621). We projected that over a patient's lifetime, TAVR would increase discounted life expectancy by 1.6 years (1.3 quality-adjusted life-years) at an incremental cost of $79 837. The incremental cost-effectiveness ratio for TAVR was thus estimated at $50 200 per year of life gained or $61 889 per quality-adjusted life-year gained. These results were stable across a broad range of uncertainty and sensitivity analyses.

Conclusions—
For patients with severe aortic stenosis who are not candidates for surgery, TAVR increases life expectancy at an incremental cost per life-year gained well within accepted values for commonly used cardiovascular technologies.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00530894.
Cost-Effectiveness of Dabigatran Compared With Warfarin for Stroke Prevention in Patients With Atrial Fibrillation and Prior Stroke or Transient Ischemic Attack
Authors: Kamel Hooman , Johnston S. Claiborne , Easton J. Donald , Kim Anthony S. 
Published: February 2012

Background and Purpose—
The cost-effectiveness of dabigatran for stroke prevention in patients with atrial fibrillation and prior stroke or transient ischemic attack has not been directly assessed.

Methods—
A Markov decision model was constructed using data from the Randomized Evaluation of Long-Term Therapy (RE-LY) trial, other trials of warfarin therapy for atrial fibrillation, and the published cost of dabigatran. We compared the cost and quality-adjusted life expectancy associated with 150 mg dabigatran twice daily versus warfarin therapy targeted to an international normalized ratio of 2 to 3. The target population was a cohort of patients aged ≥70 years with nonvalvular atrial fibrillation, prior stroke or transient ischemic attack, and no contraindication to anticoagulation.

Results—
In the base case, dabigatran was associated with 4.27 quality-adjusted life-years compared with 3.91 quality-adjusted life-years with warfarin. Dabigatran provided 0.36 additional quality-adjusted life-years at a cost of $9000, yielding an incremental cost-effectiveness ratio of $25 000. In sensitivity analyses, the cost-effectiveness of dabigatran was inversely related to the quality of international normalized ratio control achieved with warfarin therapy. In Monte Carlo analysis, dabigatran was cost-effective in 57% of simulations using a threshold of $50 000 per quality-adjusted life-year and 78% of simulations using a threshold of $100 000 per quality-adjusted life-year.

Conclusions—
Dabigatran appears to be cost-effective relative to warfarin for stroke prevention in patients with atrial fibrillation and prior stroke or transient ischemic attack. Our analysis is limited by its reliance on data from a substudy of a single randomized trial, and our results may not apply in settings with uncommonly good international normalized ratio control using warfarin.
The iScore Predicts Effectiveness of Thrombolytic Therapy for Acute Ischemic Stroke
Authors: Saposnik Gustavo , Fang Jiming , Kapral Moira K. , Tu Jack V. , Mamdani Muhammad , Austin Peter , Johnston S. Claiborne 
Published: February 2012

Background and Purpose—
Tools to predict the clinical response after intravenous thrombolytic therapy (tPA) are scarce. The iScore is an existing validated tool to estimate outcomes after an acute ischemic stroke. The purpose of this study was to determine the ability of the iScore to predict clinical response and risk of hemorrhagic transformation after tPA.

Methods—

We applied the iScore (
www.sorcan.ca/iscore
) to patients presenting with an acute ischemic stroke at 11 stroke centers in Ontario, Canada, between 2003 and 2009 identified from the Registry of the Canadian Stroke Network. A cohort of patients with stroke treated at 154 centers in Ontario was used for external validation. We compared outcomes between patients receiving and not receiving tPA after adjusting for differences in baseline characteristics using propensity-score matching. Patients were stratified into 3 a priori defined groups according to stroke severity using the iScore.

Results—

Among 12 686 patients with an acute ischemic stroke, 1696 (13.4%) received intravenous thrombolysis. Higher iScores were associated with poor outcomes in both the tPA and non-tPA groups (
P
<0.001). Among those at low and medium risk based on their iScores, tPA use was associated with a benefit in the primary outcome (relative risk, 0.74 for those with low-risk iScores; 95% CI, 0.67–0.84; relative risk, 0.88 for those with medium risk iScores; 95% CI, 0.84–0.93). There was no difference in clinical outcomes between matched patients receiving and not receiving tPA in the highest iScore group (relative risk, 0.97; 95% CI, 0.94–1.01). Similar results were observed for disability at discharge and length of stay. The incident risk of neurological deterioration and hemorrhagic transformation (any or symptomatic) with tPA increased with the iScore risk. Results were similar in the validation cohort for risk of poor outcome with tPA by iScore level.

Conclusion—
The iScore may be used to predict clinical response and risk of hemorrhagic complications after tPA for an acute ischemic stroke. Patients with high iScores may not have a clinically meaningful benefit from intravenous tPA at the time of carrying a higher risk of hemorrhagic complications.
Can the Pathology of a Thyroid Nodule Be Determined by Positron Emission Tomography Uptake?
Authors: Boeckmann Jacob , Bartel Twyla , Siegel Eric , Bodenner Donald , Stack Brendan C. 
Published: February 2012

ObjectivesTo determine if standardized uptake values (SUV) on positron emission tomography (PET) are predictive of thyroid pathology and the significance of serial SUV measurements of thyroid nodules over time.Study DesignCase series with chart review.SettingAcademic health center.SubjectsIn total, 23,384 PET and PET/computed tomography (CT) scans were performed between December 2001 and April 2011.MethodsPatients with incidental thyroid uptake were identified. SUVmax, age, sex, size of thyroid lesion, indication for PET scan, and cytology/pathology were collected.ResultsIncidental thyroid uptake was noted in 1309 PET scans (5.60%), focal uptake in 690 (2.95%), and diffuse uptake in 619 (2.65%). Complete data were available for 359 PET scans from 103 patients. Malignancy was identified in 28 patients (27%). Twenty‐five of the 28 lesions (89%) were primary thyroid malignancies. A significant difference between malignant SUVmax and benign SUVmax was found (mean ± SD, 7.04 ± 7.88 for malignancies vs 3.85 ± 3.06 for benign tumors, P =. 0292). Receiver operating characteristics curves were constructed on patients with PET data within 3 months of diagnosis and indicated that a SUVmax of 4.2 differentiated maximally between benign and malignant lesions. Serial SUV uptake had no significant change over time.ConclusionAll thyroid nodules with focal uptake on 18F‐fluorodeoxyglucose–PET/CT should be considered at higher risk of malignancy than those discovered incidentally by other imaging modalities. Higher SUVmax values are more indicative of malignant lesions. All lesions should be evaluated with ultrasonography ± fine‐needle aspiration if no clinical contraindications exist. Size of the primary nodule does not influence SUVmax uptake.
Factors Associated with Revision Adenoidectomy
Authors: Dearking Amy C. , Lahr Brian D. , Kuchena Admire , Orvidas Laura J. 
Published: February 2012

ObjectiveTo determine whether patient factors (eg, indication for initial surgery, medical comorbidity, or age) are associated with adenoid regrowth and subsequent need for revision adenoidectomy and whether surgical factors (eg, surgical technique or level of surgeon’s training) are associated with adenoid regrowth and subsequent need for revision adenoidectomy.Study DesignHistorical cohort study.SettingTertiary care academic medical center.Subjects and MethodsChildren (≤18 years) who underwent adenoidectomy or adenotonsillectomy between 1980 and May 2009 were identified. Medical and surgical records were reviewed for sex, age at surgery, indication for surgery, training level of surgeon, surgical technique, and history of allergies, asthma, or gastroesophageal reflux disease.ResultsOf 8245 surgical cases (53.8% male), 163 were revision adenoidectomies. Age at initial adenoidectomy was a significant factor for revision adenoidectomy, with younger ages associated with higher increased risk. Indication for adenoidectomy was also a significant risk factor; adjusted for age, patients with ear rather than infectious indications were about 10 times more likely to require revision. A diagnosis of gastroesophageal reflux disease was a significant risk factor (hazard ratio, 2.23; P =. 002).ConclusionSeveral risk factors are associated with revision adenoidectomy: young age at initial procedure, indication for adenoidectomy, and diagnosis of gastroesophageal reflux disease. Surgical technique, level of experience of the initial surgeon, and diagnosis of asthma or allergies were not significant risk factors for revision adenoidectomy.