bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Impact of Non–Drug-Related Toxicities on the Estimation of the Maximum Tolerated Dose in Phase I Trials
Authors: Iasonos Alexia , Gounder Mrinal , Spriggs David R. , Gerecitano John F. , Hyman David M. , Zohar Sarah , O'Quigley John 
Published: July 2012

Abstract
The rate of observed dose-limiting toxicities (DLT) determines the maximum tolerated dose (MTD) in phase I trials. There are cases in which non–drug-related toxicities or other-cause toxicities (OCT) are flagged as DLTs, or vice versa, due to attribution errors. We aim to assess the impact of such errors on the final estimate of MTD. We compared the impact of attribution errors using 2 trial designs—the “3+3” dose-escalation scheme and the continual reassessment method (CRM). Two attribution errors are considered: when a DLT is classified as an OCT (type A error) and when an OCT is misclassified as a DLT (type B error). The impact of these errors on accuracy, patient safety, sample size, and study duration was evaluated by varying the probability of occurrence of each error through simulated trials. Under no errors, CRM is on average 35% more accurate than 3+3 in finding the true MTD. This improved accuracy is maintained in the presence of errors. At a 15% type B error rate, CRM recommends a dose within 2 levels of the true MTD 68% of the time, compared with 17% of the time using the 3+3 method. A DLT must be attributed as an OCT 30% of the time to increase the accuracy of 3+3; otherwise the method recommends a wrong dose approximately 75% of the time. CRM is more robust to toxicity attribution errors compared with the 3+3 as it uses information from all treated patients, leading to a more accurate MTD estimation at the frequency of attribution errors anticipated in phase I clinical trials. Clin Cancer Res; 18(19); 5179–87. ©2012 AACR.
Targeting the IKKβ/mTOR/VEGF Signaling Pathway as a Potential Therapeutic Strategy for Obesity-Related Breast Cancer
Authors: Chen Chun-Te , Du Yi , Yamaguchi Hirohito , Hsu Jung-Mao , Kuo Hsu-Ping , Hortobagyi Gabriel N. , Hung Mien-Chie 
Published: July 2012

Abstract
Clinical correlation studies have clearly shown that obesity is associated with breast cancer risk and patient survival. Although several potential mechanisms linking obesity and cancers have been proposed, the detailed molecular mechanism of obesity-mediated breast tumorigenesis has not yet been critically evaluated. In this study, we evaluated the effects of obesity on mammary tumor initiation and progression using mice with genetic and diet-induced obesity bearing mammary tumor xenografts and mouse mammary tumor virus-neu transgenic mice that were fed a high-fat diet. We show that obesity promoted mammary tumor growth and development in these animal models. Moreover, the expressions of TNFα, VEGF, IKKβ, and mTOR are upregulated in mammary tumors of obese mice, suggesting that the IKKβ/mTOR/VEGF signaling pathway is activated by TNFα in the tumors of obese mice. More importantly, inhibitors (rapamycin, bevacizumab, and aspirin) that target members of the pathway suppressed tumorigenesis and prolonged survival more effectively in obese mice than in nonobese mice. Here, we not only identified a specific signaling pathway that contributes to mammary tumorigenesis in obese mice but also a strategy for treating obesity-mediated breast cancer. Mol Cancer Ther; 11(10); 2212–21. ©2012 AACR.
Vasohibin-2 Expressed in Human Serous Ovarian Adenocarcinoma Accelerates Tumor Growth by Promoting Angiogenesis
Authors: Takahashi Yoshifumi , Koyanagi Takahiro , Suzuki Yasuhiro , Saga Yasushi , Kanomata Naoki , Moriya Takuya , Suzuki Mitsuaki , Sato Yasufumi 
Published: July 2012

Abstract
Vasohibin-1 (VASH1) is a VEGF-inducible endothelium-derived angiogenesis inhibitor and VASH2 is its homolog. Our previous analysis revealed that VASH1 is expressed in endothelial cells to terminate angiogenesis, whereas VASH2 is expressed in infiltrating mononuclear cells mobilized from bone marrow to promote angiogenesis in a mouse model of hypoxia-induced subcutaneous angiogenesis. To test the possible involvement of VASH2 in the tumor, we examined human ovarian cancer cells for the presence of VASH2. Immunohistochemical analysis revealed that VASH2 protein was preferentially detected in cancer cells of serous ovarian adenocarcinoma. We then used SKOV-3 and DISS, two representative human serous adenocarcinoma cell lines, and examined the role of VASH2 in the tumor. The knockdown of VASH2 showed little effect on the proliferation of cancer cells in vitro but notably inhibited tumor growth, peritoneal dissemination, and tumor angiogenesis in a murine xenograft model. Next, we stably transfected the human VASH2 gene into two types of murine tumor cells, EL-4 and MLTC-1, in which endogenous VASH2 was absent. When either EL-4 or MLTC-1 cells were inoculated into VASH2 (−/−) mice, the VASH2 transfectants formed bigger tumors when compared with the controls, and the tumor microvessel density was significantly increased. VASH2 stimulated the migration of endothelial cells, and its increased expression in cancer cells is related to the decrease of mir-200b. These results indicate that VASH2 expressed in serous ovarian carcinoma cells promoted tumor growth and peritoneal dissemination by promoting angiogenesis. Mol Cancer Res; 10(9); 1135–46. ©2012 AACR.
Demographics, Trends, and Outcomes in Pediatric Acute Myocarditis in the United States, 2006 to 2011
Authors: Ghelani Sunil J. , Spaeder Michael C. , Pastor William , Spurney Christopher F. , Klugman Darren 
Published: July 2012

Background—
There is a lack of clear diagnostic and management guidelines for acute myocarditis in the pediatric population. We used a multi-institutional database to characterize demographics, practice variability, and outcomes in this population.

Methods and Results—

Patients with acute myocarditis (n=514) were identified from April 2006 to March 2011 using the Pediatric Health Information System database, and regional variations in management and outcomes were analyzed. Ninety-seven patients (18.9%) received extracorporeal membrane oxygenation, 22 (4.3%) received ventricular assist device, 21 (4.1%) received heart transplantation, and 37 (7.2%) died. Of the 104 patients who received extracorporeal membrane oxygenation or ventricular assist device, 17 (16.3%) had heart transplantation, 25 (24%) died, and 62 (59.6%) showed recovery of myocardial function. There was a decrease in the use of endomyocardial biopsy (
P
=0.03) and an increase in the use of magnetic resonance imaging (
P
<0.01) over the study period. Although the use of medications and procedures varied between different regions, the occurrence of death or heart transplantation showed no significant regional associations. The use of extracorporeal membrane oxygenation (odds ratio, 5.8; 95% confidence interval, 2.9–11.4;
P
<0.01), ventricular assist device (odds ratio, 8.2; 95% confidence interval, 2.7–24.9;
P
<0.01), and vasoactive medications (odds ratio, 5.7; 95% confidence interval, 1.2–26.1;
P
=0.03) was independently associated with death/transplantation.

Conclusions—
There is significant temporal and regional variation in the diagnostic modalities and management used for pediatric myocarditis, which continues to have high morbidity and mortality. Extracorporeal membrane oxygenation, ventricular assist device, and vasoactive medications are independently associated with increased mortality/transplantation.
Variability in Surgeons’ Perioperative Practices May Influence the Incidence of Low-Output Failure After Coronary Artery Bypass Grafting Surgery
Authors: Likosky Donald S. , Goldberg Joshua B. , DiScipio Anthony W. , Kramer Robert S. , Groom Robert C. , Leavitt Bruce J. , Surgenor Stephen D. , Baribeau Yvon R. , Charlesworth David C. , Helm Robert E. , Frumiento Carmine , Sardella Gerald L. , Clough Robert A. , MacKenzie Todd A. , Malenka David J. , Olmstead Elaine M. , Ross Cathy S. ,   for the Northern New England Cardiovascular Disease Study Group
Published: July 2012

Background—
Postoperative low-output failure (LOF) is an important contributor to morbidity and mortality after coronary artery bypass grafting surgery. We sought to understand which pre- and intra-operative factors contribute to postoperative LOF and to what degree the surgeon may influence rates of LOF.

Methods and Results—

We identified 11 838 patients undergoing nonemergent, isolated coronary artery bypass grafting surgery using cardiopulmonary bypass by 32 surgeons at 8 centers in northern New England from 2001 to 2009. Our cohort included patients with preoperative ejection fractions >40%. Patients with preoperative intraaortic balloon pumps were excluded. LOF was defined as the need for ≥2 inotropes at 48 hours, an intra- or post-operative intraaortic balloon pumps, or return to cardiopulmonary bypass (for hemodynamic reasons). Case volume varied across the 32 surgeons (limits, 80–766; median, 344). The overall rate of LOF was 4.3% (return to cardiopulmonary bypass, 2.6%; intraaortic balloon pumps, 1.0%; inotrope usage, 0.8%; combination, 1.0%). The predicted risk of LOF did not differ across surgeons,
P
=0.79, and the observed rates varied from 1.1% to 10.2%,
P
<0.001. Patients operated by low-rate surgeons had shorter clamp and bypass times, antegrade cardioplegia, longer maximum intervals between cardioplegia doses, lower cardioplegia volume per anastomosis or minute of ischemic time, and less hot-shot use. Patients operated on by higher LOF surgeons had higher rates of postoperative acute kidney injury.

Conclusions—
Rates of LOF significantly varied across surgeons and could not be explained solely by patient case mix, suggesting that variability in perioperative practices influences risk of LOF.
A Comprehensive Evaluation of Rhythm Monitoring Strategies for the Detection of Atrial Fibrillation Recurrence
Authors: Charitos Efstratios I. , Stierle Ulrich , Ziegler Paul D. , Baldewig Malte , Robinson Derek R. , Sievers Hans-Hinrich , Hanke Thorsten 
Published: July 2012

Background—
Intermittent rhythm monitoring (IRM) to detect atrial fibrillation (AF) recurrence is employed to evaluate the success of therapeutic interventions. In a large population of patients with continuous monitoring (CM), we investigated the sensitivity of various frequencies and durations of IRM strategies on the detection of AF recurrence, the dynamics behind AF recurrence detection, and we describe measures to evaluate temporal AF recurrence.

Methods and Results—

Rhythm histories of 647 patients (mean AF burden, 0.12±0.22; median, 0.014; 687 patient-years) with implantable CM devices were reconstructed and analyzed. With the use of computationally intensive simulation, the sensitivity of IRM of various frequencies and durations on the identification of AF recurrence was evaluated. Prolonged-duration IRM was superior to shorter IRM (
P
<0.0001). However, even with aggressive IRM strategies, AF recurrence was not detected in a great proportion of patients. The temporal AF burden aggregation (AF density) was directly related to IRM sensitivity (
P
<0.0001). Even at similar AF burdens, patients with high-density AF required higher-frequency or prolonged-duration IRM to achieve the same sensitivity as in low-density AF (
P
<0.0001). Patients with high-density, low-burden AF benefit the most from CM for detection of AF recurrence.

Conclusions—
IRM follow-up is significantly inferior to CM. IRM strategies will not identify AF recurrence in a great proportion of patients at risk. Temporal AF characteristics play a significant role in AF recurrence detection with the use of IRM. For the scientific, evidence-based evaluation of AF treatments, CM should be strongly recommended. Prospective studies are required to evaluate whether CM to guide clinical management can also improve patient outcomes.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00806689.
Comparison of Everolimus-Eluting and Sirolimus-Eluting Coronary Stents
Authors: Kimura Takeshi , Morimoto Takeshi , Natsuaki Masahiro , Shiomi Hiroki , Igarashi Keiichi , Kadota Kazushige , Tanabe Kengo , Morino Yoshihiro , Akasaka Takashi , Takatsu Yoshiki , Nishikawa Hideo , Yamamoto Yoshito , Nakagawa Yoshihisa , Hayashi Yasuhiko , Iwabuchi Masashi , Umeda Hisashi , Kawai Kazuya , Okada Hisayuki , Kimura Kazuo , Simonton Charles A. , Kozuma Ken 
Published: July 2012

Background—
Several recent randomized trials comparing everolimus-eluting stent (EES) and sirolimus-eluting stent (SES) reported similar outcomes. However, only 1 trial was powered for a clinical end point, and no trial was powered for evaluating target-lesion revascularization.

Methods and Results—

Randomized Evaluation of Sirolimus-eluting versus Everolimus-eluting stent Trial is a prospective multicenter randomized open-label trial comparing EES with SES in Japan. The trial was powered for evaluating noninferiority of EES relative to SES in terms of target-lesion revascularization. From February and July 2010, 3197 patients were randomly assigned to receive either EES (1597 patients) or SES (1600 patients). At 1 year, the primary efficacy end point of target-lesion revascularization occurred in 65 patients (4.3%) in the EES group and in 76 patients (5.0%) in the SES group, demonstrating noninferiority of EES to SES (
P
noninferiority
<0.0001, and
P
superiority
=0.34). Cumulative incidence of definite stent thrombosis was low and similar between the 2 groups (0.32% versus 0.38%,
P
=0.77). An angiographic substudy enrolling 571 patients (EES, 285 patients and SES, 286 patients) demonstrated noninferiority of EES relative to SES regarding the primary angiographic end point of in-segment late loss (0.06±0.37 mm versus 0.02±0.46 mm,
P
noninferiority
<0.0001, and
P
superiority
=0.24) at 278±63 days after index stent implantation.

Conclusions—
One-year clinical and angiographic outcome after EES implantation was noninferior to and not different from that after SES implantation in a stable coronary artery disease population with relatively less complex coronary anatomy. One-year clinical outcome after both EES and SES use was excellent with a low rate of target-lesion revascularization and a very low rate of stent thrombosis.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01035450.
Distribution of Graupel and Hail With Size
Authors: AUER AUGUST H. 
Published: July 2012

Abstract
Observations have been made on the size and concentration of graupel and hail occurring in untreated convective cloud systems over the High Plains of the United States. From these data, an average graupel and hail distribution has been generated. The comparison of this .,ize spectrum with data from other studies, along with the implications to hail detection and hail suppression, is also discussed.
A multiscale modeling approach to analyze filament-wound composite pressure vessels
Authors: Nguyen Ba Nghiep , Simmons Kevin L 
Published: July 2012

A multiscale modeling approach to analyze filament-wound composite pressure vessels is developed in this article. The approach, which extends the Nguyen et al. [Prediction of the elastic-plastic stress/strain response for injection-molded long-fiber thermoplastics. J Compos Mater 2009; 43: 217–246.] model developed for discontinuous fiber composites to continuous fiber ones, spans three modeling scales. The microscale considers the unidirectional elastic fibers embedded in an elastic–plastic matrix obeying the Ramberg–Osgood relation and J2 deformation theory of plasticity. The mesoscale behavior representing the composite lamina is obtained through an incremental Mori–Tanaka [Average stress in matrix and average elastic energy of materials with misfitting inclusions. Acta Metall 1973; 21: 571–574.] type model and the Eshelby [The determination of the elastic field of an ellipsoidal inclusion and related problems. Proc R Soc Lond, Ser A 1957; 241: 376–396.] equivalent inclusion method. The implementation of the micro–meso constitutive relations in the ABAQUS® finite element package (via user subroutines) allows the analysis of a filament-wound composite pressure vessel (macroscale) to be performed. Failure of the composite lamina is predicted by a criterion that accounts for the strengths of the fibers and of the matrix as well as of their interface. The developed approach is validated in the analysis of an aluminum liner – T300 carbon/epoxy pressure vessel to predict the burst pressure. The predictions compare favorably with the numerical and experimental results by Lifshitz and Dayan [Filament-wound pressure vessel with thick metal liner. Compos Struct 1995; 32: 313–323]. The approach will be further demonstrated in the study of the effects of the lamina thickness, helical angle, and fiber–matrix material combination on the burst pressure.
Influence of sex, estrous cycle, and estrogen on intracranial dural mast cells
Authors: Boes Tanner , Levy Dan 
Published: July 2012

Background: The frequency of migraine headaches is higher in women than in men and in susceptible women attacks are related to changes in ovarian hormone levels. Intracranial mast cells (MCs) are likely to have a role in migraine headache genesis, and changes in the dural MC population might influence headache susceptibility. The present study thus tested the hypothesis that sex and ovarian hormones influence the density and phenotypic makeup of dural MCs. Methods: Histochemistry combined with quantitative analyses was used to investigate sex differences, estrous cycle and ovarian hormones on dural MC density, phenotype and degranulation level in male and female rats. Results: Our data show that in female rats, dural MC density fluctuates during the estrous cycle and is overall higher than in males. In ovariectomized rats, estradiol, but not progesterone, promoted an increase in dural MC density. This effect was abolished by a splenectomy, suggesting estrogen-related recruitment of MCs from the spleen. Finally, our data suggest that the phenotypic make up of dural MCs, which represents the level of cellular maturity, is also governed by changes in estrogen levels. Conclusions: Given the potential role of dural MCs in triggering headache, our data suggest that estrogen-related modulation of dural MC density and phenotypic makeup could have a role in mediating the higher frequency and severity of headaches such as migraine, in women.
The effect of shear on in vitro platelet and leukocyte material-induced activation
Authors: Chang Xiaojian , Gorbet Maud 
Published: July 2012

The failure to understand the mechanisms of biomaterial-associated thrombosis prevents us from improving the blood compatibility of stents and mechanical heart valves. Blood-material interactions trigger a complex series of events and anticoagulant and anti-platelet therapies are needed to reduce the risks of thrombotic complications with most cardiovascular materials. While material interaction with platelets has been widely studied, little is currently known on material-induced leukocyte activation in the presence of shear. In vitro experiments were performed to assess the effect of flow on blood cell activation induced by medical grade metals, ST316L and TiAl6V4. Blood was circulated in flow chambers preloaded with or without metal wires at shear rates of 100, 500, and 1500 s−1. Platelet and leukocyte activation, leukocyte-platelet aggregation, and tissue factor expression on monocytes were measured by flow cytometry. Metal surfaces were characterized by scanning electron microscopy. Under physiological shear rates, no significant platelet microparticle formation was observed. However, significant CD11b up-regulation, leukocyte-platelet aggregates, and tissue factor expression were observed at 100 s−1. As shear rate increased to 1500 s−1, leukocyte activation reduced to control values. TiAl6V4-induced leukocyte activation was generally lower than that of ST316L. Adhesion significantly decreased with increasing shear rate to 1500 s−1. In blood, increase within physiological shear rates led to a significant reduction in in vitro material-induced leukocyte activation, suggesting that difference between material biocompatibility may be better identified at low shear rates or under pathological shear conditions.
Can Gradual Dose Titration of Ketamine for Management of Neuropathic Pain Prevent Psychotomimetic Effects in Patients With Advanced Cancer?
Authors: Okamoto Yoshiaki , Tsuneto Satoru , Tanimukai Hitoshi , Matsuda Yoichi , Ohno Yumiko , Tsugane Mamiko , Uejima Etsuko 
Published: July 2012

Background: Ketamine is often used to manage neuropathic pain in patients with cancer. However, it occasionally causes psychotomimetic effects such as vivid dreams, nightmares, illusions, hallucinations, and altered body image. Objective: To examine whether gradual dose titration of ketamine for management of neuropathic pain prevents psychotomimetic effects in patients with advanced cancer. Methods: This was a retrospective chart review. We administered ketamine when neuropathic pain in patients with advanced cancer became refractory to opioids and oral adjuvant analgesics. The starting dose of ketamine was 10 mg/d by continuous intravenous infusion. The dose was gradually increased by 10 mg/d every 4 to 6 hours to 50 mg/d or until the pain was relieved. It was subsequently increased by 25 mg/d every 12 to 24 hours until the pain was relieved. Results: For this study, we enrolled 46 patients with advanced cancer. The mean age was 52.2 ± 16.9 years. The mean dose at onset of action and maximum dose of ketamine were 56 ± 58 and 272 ± 214 mg/d, respectively. The mean pain intensity (numerical rating scale) decreased significantly from 7.3 ± 2.0 to 3.5 ± 2.2 after the administration of ketamine ( P < .01). The effectiveness was 69.5%. No psychotomimetic effect of less than 300 mg/d was observed during the introduction phase even though psychotropic drugs were not prescribed. Mild sedation was observed in 3 patients (7%) as the only adverse effect during the introduction phase. Conclusion: Gradual dose titration of ketamine for management of neuropathic pain can prevent psychotomimetic effects in patients with advanced cancer.
Pediatric Hodgkin lymphoma: trade-offs between short- and long-term mortality risks
Authors: Yeh Jennifer M. , Diller Lisa 
Published: July 2012

AbstractAs pediatric Hodgkin lymphoma (HL) survival rates approach > 95%, treatment decisions are increasingly based on minimizing late effects. Using a model-based approach, we explored whether the addition of radiotherapy contributes to improved overall long-term survival. We developed a state-transition model to simulate the lifetime HL clinical course, and we compared 2 treatment strategies: chemotherapy alone (CT) and chemoradiotherapy (CRT). Data on HL relapse, late recurrence, and excess second cancer and cardiac late-effects mortality were estimated from the published literature and databases. Outcomes included conditional life expectancy, cause-specific mortality, and proportion alive at age 50. For a hypothetical cohort of HL patients (diagnosis age 15), conditional life expectancy was 57.2 years with CT compared with 56.4 years with CRT. Estimated lifetime HL mortality risk was 3.6% with CT versus 2.2% with CRT. In contrast, combined risk of excess late-effects mortality was lower for CT (1.8% vs 7.4% with CRT). Among those alive at age 50, only 9.2% of those initially treated with CT were at risk for radiation-related late effects (100% for CRT). Initial treatment with CT may be associated with longer average per-person life expectancy. These results support the need for careful consideration of the risk-benefit profile of radiation as frontline therapy in pediatric patients.