bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic Alterations in the RB Pathway Indicate Prognostic Outcomes of Early-Stage Lung Adenocarcinoma
Authors: Choi Seongmin , Kim Hyeong Ryul , Sung Chang Ohk , Kim Jongkyu , Kim Sukjun , Ahn Sung-Min , Choi Chang-min , Chun Sung-Min , Choi Eun Kyung , Kim Sang-We , Kim Yong-Hee , Lee Ji-Young , Song Joon Seon , Kim Deokhoon , Haq Farhan , Lee Sun Young , Lee Jong-eun , Jung Wang-rim , Jang Hye Yoon , Yang Eunho , Lee Charles , Yu Eunsil , Kong Gu , Baek Daehyun , Jang Se Jin 
Published: October 2014

Abstract
Purpose: To better understand the complete genomic architecture of lung adenocarcinoma.
Experimental Design: We used array experiments to determine copy number variations and sequenced the complete exomes of the 247 lung adenocarcinoma tumor samples along with matched normal cells obtained from the same patients. Fully annotated clinical data were also available, providing an unprecedented opportunity to assess the impact of genomic alterations on clinical outcomes.
Results: We discovered that genomic alternations in the RB pathway are associated with significantly shorter disease-free survival in early-stage lung adenocarcinoma patients. This association was also observed in our independent validation cohort. The current treatment guidelines for early-stage lung adenocarcinoma patients recommend follow-up without adjuvant therapy after complete resection, except for high-risk patients. However, our findings raise the interesting possibility that additional clinical interventions might provide medical benefits to early-stage lung adenocarcinoma patients with genomic alterations in the RB pathway. When examining the association between genomic mutation and histologic subtype, we uncovered the characteristic genomic signatures of various histologic subtypes. Notably, the solid and the micropapillary subtypes demonstrated great diversity in the mutated genes, while the mucinous subtype exhibited the most unique landscape. This suggests that a more tailored therapeutic approach should be used to treat patients with lung adenocarcinoma.
Conclusions: Our analysis of the genomic and clinical data for 247 lung adenocarcinomas should help provide a more comprehensive genomic portrait of lung adenocarcinoma, define molecular signatures of lung adenocarcinoma subtypes, and lead to the discovery of useful prognostic markers that could be used in personalized treatments for early-stage lung adenocarcinoma patients. Clin Cancer Res; 21(11); 2613–23. ©2014 AACR.
See related commentary by Collisson, p. 2418
Genetic Evolution of T-cell Resistance in the Course of Melanoma Progression
Authors: Sucker Antje , Zhao Fang , Real Birgit , Heeke Christina , Bielefeld Nicola , Maβen Stefan , Horn Susanne , Moll Iris , Maltaner Raffaela , Horn Peter A. , Schilling Bastian , Sabbatino Francesco , Lennerz Volker , Kloor Matthias , Ferrone Soldano , Schadendorf Dirk , Falk Christine S. , Griewank Klaus , Paschen Annette 
Published: October 2014

Abstract
Purpose: CD8+ T lymphocytes can kill autologous melanoma cells, but their activity is impaired when poorly immunogenic tumor phenotypes evolve in the course of disease progression. Here, we analyzed three consecutive melanoma lesions obtained within one year of developing stage IV disease for their recognition by autologous T cells.
Experimental Design: One skin (Ma-Mel-48a) and two lymph node (Ma-Mel-48b, Ma-Mel-48c) metastases were analyzed for T-cell infiltration. Melanoma cell lines established from the respective lesions were characterized, determining the T-cell–stimulatory capacity, expression of surface molecules involved in T-cell activation, and specific genetic alterations affecting the tumor–T-cell interaction.
Results: Metastases Ma-Mel-48a and Ma-Mel-48b, in contrast with Ma-Mel-48c, were infiltrated by T cells. The T-cell–stimulatory capacity was found to be strong for Ma-Mel-48a, lower for Ma-Mel-48b, and completely abrogated for Ma-Mel-48c cells. The latter proved to be HLA class I–negative due to an inactivating mutation in one allele of the beta-2-microglobulin (B2M) gene and concomitant loss of the other allele by a deletion on chromosome 15q. The same deletion was already present in Ma-Mel-48a and Ma-Mel-48b cells, pointing to an early acquired genetic event predisposing to development of β2m deficiency. Notably, the same chronology of genetic alterations was also observed in a second β2m-deficient melanoma model.
Conclusion: Our study reveals a progressive loss in melanoma immunogenicity during the course of metastatic disease. The genetic evolvement of T-cell resistance suggests screening tumors for genetic alterations affecting immunogenicity could be clinically relevant in terms of predicting patient responses to T-cell–based immunotherapy. Clin Cancer Res; 20(24); 6593–604. ©2014 AACR.
MHC Class I Loss Is a Frequent Mechanism of Immune Escape in Papillary Thyroid Cancer That Is Reversed by Interferon and Selumetinib TreatmentIn Vitro
Authors: Angell Trevor E. , Lechner Melissa G. , Jang Julie K. , LoPresti Jonathan S. , Epstein Alan L. 
Published: October 2014

AbstractPurpose: To evaluate MHC class I expression on papillary thyroid cancer (PTC) and analyze changes in MHC expression and associated immune activation with current and experimental treatments for thyroid cancer using in vitro PTC cell lines.Experimental Design: MHC class I expression and assessment of tumor-infiltrating leukocyte populations were evaluated by immunohistochemistry. PTC cell lines were analyzed for HLA-ABC expression by flow cytometry following tyrosine kinase inhibitor, IFNα or IFNγ, or radiation treatment. Functional changes in antigenicity were assessed by coculture of allogeneic donor peripheral blood leukocytes (PBL) with pretreated or untreated PTC cell lines and measurement of T-cell activation and cytokine production.Results: Both MHC class I and β2-microglobulin expression was reduced or absent in 76% of PTC specimens and was associated with reduced tumor-infiltrating immune cells, including effector (CD3+, CD8+, CD16+) and suppressor (FoxP3+) populations. Treatment of PTC cell lines with the MEK1/2 inhibitor selumetinib or IFN increased HLA-ABC expression. This phenotypic change was associated with increased T-cell activation (%CD25+ of CD3+) and IL2 production by PBL cocultured with treated PTC cell lines. Additive effects were seen with combination selumetinib and IFN treatment.Conclusions: MHC class I expression loss is frequent in human PTC specimens and represents a significant mechanism of immune escape. Increased antigenicity following selumetinib and IFN treatment warrants further study for immunotherapy of progressive PTC. Clin Cancer Res; 20(23); 6034–44. ©2014 AACR.
T-Cell Levels Are Prognostic in Mantle Cell Lymphoma
Authors: Nygren Lina , Wasik Agata M. , Baumgartner-Wennerholm Stefanie , Jeppsson-Ahlberg Åsa , Klimkowska Monika , Andersson Patrik , Buhrkuhl Daren , Christensson Birger , Kimby Eva , Wahlin Björn E. , Sander Birgitta 
Published: October 2014

Abstract
Purpose: The purpose of this study was to investigate the impact of T-cell subsets on pathologic and clinical features including disease outcome in mantle cell lymphoma (MCL).
Experimental Design: Cell populations were investigated using flow cytometry in diagnostic MCL (n = 153) and reactive (n = 26) lymph node biopsies. Levels of tumor cells, T cells, T-cell subsets, and the CD4:CD8 ratio were assessed and related to pathologic and clinical parameters.
Results: MCL cases with diffuse and nodular histologic subtypes showed lower levels of T cells, especially CD4+ T cells, than those with mantle zone growth pattern. Both CD3 and CD4 levels were lower in the nodular subtype than in mantle zone (P = 0.007; P = 0.003) and in the diffuse compared with the nodular subtype (P = 0.022; P = 0.015). The CD4:CD8 ratios were inversely correlated to tumor cell proliferation (P = 0.003). Higher levels of CD3+ and CD4+ T cells and higher CD4:CD8 ratios were associated with indolent disease (P = 0.043, 0.021, and 0.003 respectively). In univariate analysis, a high CD4:CD8 ratio, but not the histologic subtype, was correlated to longer overall survival (OS). In multivariate analysis, the CD4:CD8 ratio correlated with OS independently of Mantle Cell Lymphoma International Prognostic Index (MIPI) and high p53 expression (P = 0.023).
Conclusion: CD3+, CD8+, and particularly CD4+ T-cell levels are higher in indolent MCL and decrease with more aggressive histology as reflected by a diffuse growth pattern. High CD4:CD8 ratio correlated independently of other high-risk prognostic factors with longer OS, suggesting a prognostic role for T cells in MCL. Clin Cancer Res; 20(23); 6096–104. ©2014 AACR.
Identification of Recurrent FGFR3–TACC3 Fusion Oncogenes from Lung Adenocarcinoma
Authors: Capelletti Marzia , Dodge Michael E. , Ercan Dalia , Hammerman Peter S. , Park Seung-Il , Kim Jhingook , Sasaki Hidefumi , Jablons David M. , Lipson Doron , Young Lauren , Stephens Phil J. , Miller Vincent A. , Lindeman Neal I. , Munir Kiara J. , Richards William G. , Jänne Pasi A. 
Published: October 2014

Abstract
Purpose: Targetable oncogenic alterations are detected more commonly in patients with non–small cell lung cancer (NSCLC) who never smoked cigarettes. For such patients, specific kinase inhibitors have emerged as effective clinical treatments. However, the currently known oncogenic alterations do not account for all never smokers who develop NSCLC. We sought to identify additional oncogenic alterations from patients with NSCLC to define additional treatment options.
Experimental Design: We analyzed 576 lung adenocarcinomas from patients of Asian and Caucasian ethnicity. We identified a subset of cancers that did not harbor any known oncogenic alteration. We performed targeted next-generation sequencing (NGS) assay on 24 patients from this set with &gt;75% tumor cell content.
Results: EGFR mutations were the most common oncogenic alteration from both Asian (53%) and Caucasian (41.6%) patients. No known oncogenic alterations were present in 25.7% of Asian and 31% of Caucasian tumor specimens. We identified a FGFR3–TACC3 fusion event in one of 24 patients from this subset using targeted NGS. Two additional patients harboring FGFR3–TACC3 were identified by screening our entire cohort (overall prevalence, 0.5%). Expression of FGFR3–TACC3 led to IL3 independent growth in Ba/F3 cells. These cells were sensitive to pan-fibroblast growth factor receptor (pan-FGFR) inhibitors but not the epidermal growth factor (EGFR) inhibitor gefitinib.
Conclusions: FGFR3–TACC3 rearrangements occur in a subset of patients with lung adenocarcinoma. Such patients should be considered for clinical trials featuring FGFR inhibitors. Clin Cancer Res; 20(24); 6551–8. ©2014 AACR.
Predicting Breast Tumor Response to Neoadjuvant Chemotherapy with Diffuse Optical Spectroscopic Tomography prior to Treatment
Authors: Jiang Shudong , Pogue Brian W. , Kaufman Peter A. , Gui Jiang , Jermyn Michael , Frazee Tracy E. , Poplack Steven P. , DiFlorio-Alexander Roberta , Wells Wendy A. , Paulsen Keith D. 
Published: October 2014

Abstract
Purpose: To determine whether pretreatment biomarkers obtained from diffuse optical spectroscopic tomographic (DOST) imaging predicts breast tumor response to neoadjuvant chemotherapy (NAC), which would have value to potentially eliminate delays in prescribing definitive local regional therapy that may occur from a standard complete 6- to 8-month course of NAC.
Experimental Design: Nineteen patients undergoing NAC were imaged with DOST before, during, and after treatment. The DOST images of total hemoglobin concentration (HbT), tissue oxygen saturation (StO2), and water (H2O) fraction at different time points have been used for testing the abilities of differentiating patients having pathologic complete response (pCR) versus pathologic incomplete response (pIR).
Results: Significant differences (P &lt; 0.001, AUC = 1.0) were found between pCR patients versus pIR in outcome, based on the percentage change in tumor HbT within the first cycle of treatment. In addition, pretreatment tumor HbT (pretreatment HbT) relative to the contralateral breast was statistically significant (P = 0.01, AUC = 0.92) in differentiating pCR from pIR.
Conclusions: This is the first clinical evidence that DOST HbT may differentiate the two groups with predictive significance based on data acquired before NAC even begins. The study also demonstrates the potential of accelerating the validation of optimal NAC regimens through future randomized clinical trials by reducing the number of patients required and the length of time they need to be followed by using a validated imaging surrogate as an outcome measure. Clin Cancer Res; 20(23); 6006–15. ©2014 AACR.
Resistance to Anti-EGFR Therapy in Colorectal Cancer: From Heterogeneity to Convergent Evolution
Authors: Misale Sandra , Di Nicolantonio Federica , Sartore-Bianchi Andrea , Siena Salvatore , Bardelli Alberto 
Published: October 2014

Abstract
The EGFR-targeted antibodies cetuximab and panitumumab are used to treat metastatic colorectal cancers. Mutations in KRAS, NRAS, and BRAF and amplification of ERBB2 and MET drive primary (de novo) resistance to anti-EGFR treatment. Recently, the emergence of alterations in the same genes was detected in patients who responded to EGFR blockade and then relapsed. These results illuminate a striking overlap between genes that, when mutated, drive primary and secondary resistance to anti-EGFR antibodies. Remarkably, although the mechanisms of resistance are genetically heterogeneous, they biochemically converge on key signaling pathways. This knowledge is being translated in the rational design of additional lines of therapy.
Significance: Anti–EGFR-targeted therapies are used for the treatment of metastatic colorectal cancer. Molecular heterogeneity impairs their efficacy by fuelling de novo and acquired resistance. In this review, we highlight how genetically distinct resistance mechanisms biochemically converge on a limited number of signaling pathways that can be therapeutically intercepted. Cancer Discov; 4(11); 1269–80. ©2014 AACR.
Intracoronary Infusion of Encapsulated Glucagon-Like Peptide-1–Eluting Mesenchymal Stem Cells Preserves Left Ventricular Function in a Porcine Model of Acute Myocardial Infarction
Authors: de Jong Renate , van Hout Gerardus P.J. , Houtgraaf Jaco H. , Kazemi Kushan , Wallrapp Christine , Lewis Andrew , Pasterkamp Gerard , Hoefer Imo E. , Duckers Henricus J. 
Published: October 2014

Background—
Engraftment and survival of stem cells in the infarcted myocardium remain problematic in cell-based therapy for cardiovascular disease. To overcome these issues, encapsulated mesenchymal stem cells (eMSCs) were developed that were transfected to produce glucagon-like peptide-1, an incretin hormone with known cardioprotective effects, alongside MSC endogenous paracrine factors. This study was designed to investigate the efficacy of different doses of intracoronary infusion of eMSC in a porcine model of acute myocardial infarction (AMI).

Methods and Results—

One hundred pigs were subjected to a moderate AMI (posterolateral AMI; n=50) or a severe AMI (anterior AMI; n=50), whereupon surviving animals (n=36 moderate, n=33 severe) were randomized to receive either intracoronary infusion of 3 incremental doses of eMSC or Ringers’ lactate control. Cardiac function was assessed using invasive hemodynamics, echocardiography, and histological analysis. A trend was observed in the moderate AMI model, whereas in the severe AMI model, left ventricular ejection fraction improved by +9.3% (
P
=0.004) in the best responding eMSC group, because of a preservation of left ventricular end-systolic volume. Arteriolar density increased 3-fold in the infarct area (8.4±0.9/mm
2
in controls versus 22.2±2.6/mm
2
in eMSC group;
P
<0.001). Although not statistically significant, capillary density was 30% higher in the border zone (908.1±99.7/mm
2
in control versus 1209.0±64.6/mm
2
in eMSC group;
P
=ns).

Conclusions—
eMSCs enable sustained local delivery of cardioprotective proteins to the heart, thereby enhancing angiogenesis and preserving contractile function in an animal AMI model.
Prolonged PR Interval Predicts Clinical Recurrence of Atrial Fibrillation After Catheter Ablation
Authors: Park Junbeom , Kim Tae‐Hoon , Lee Jihei Sara , Park Jin Kyu , Uhm Jae Sun , Joung Boyoung , Lee Moon Hyoung , Pak Hui‐Nam 
Published: October 2014

Background

A prolonged
PR
interval is known to be a poor prognostic factor in cardiovascular disease. The aim of this study was to investigate the association between
PR
interval and clinical outcome in patients undergoing radiofrequency catheter ablation (
RFCA
) of atrial fibrillation (
AF
).

Methods and Results

We prospectively included 576 patients with
AF
(75.5% male, 57.8±11.6 years old, 68.8% paroxysmal
AF
) who underwent
RFCA
. We analyzed preprocedural sinus rhythm
ECG
s obtained in the absence of antiarrhythmic drug, and all enrolled patients were categorized into 4 groups based on the quartile values of the
PR
interval (166, 182, and 202 ms), and were analyzed according to the left atrium (LA) volume (CT; Computed tomography),
LA
voltage (NavX), and clinical outcome of
AF
ablation. Based on quartile value of
PR
interval, the highest quartile of
PR
interval (Q4;
PR
≥202 ms) was oldest (
P
<0.001), and most likely to have persistent
AF
(
P
<0.001) and hypertension (
P
=0.013) compared with the other groups. However, there was no significant difference in
LA
conduction velocity and atrial effective refractory period. Q4 had the greatest
LA
dimension (
P
<0.001) and volume index (
P
<0.001), and lowest
LA
appendage‐emptying velocity (
P
<0.032) and
LA
voltage (
P
<0.001) compared with the others. For 13.1±7.5 months, the classification based on the
PR
interval was a significant predictor of
AF
recurrence after
RFCA
of
AF
(
HR
=1.969, 95%
CI
1.343 to 2.886,
P
=0.001).

Conclusions

The
PR
interval was closely associated with advanced
LA
remodeling due to
AF
, and had a noninvasive significant predictive value of clinical recurrence of
AF
after
RFCA
.
Recurrent Stroke and Patent Foramen Ovale
Authors: Katsanos Aristeidis H. , Spence J. David , Bogiatzi Chrysi , Parissis John , Giannopoulos Sotirios , Frogoudaki Alexandra , Safouris Apostolos , Voumvourakis Konstantinos , Tsivgoulis Georgios 
Published: October 2014

Background and Purpose—
Recurrent cerebrovascular events are frequent in medically treated patients with patent foramen ovale (PFO), but it still remains unclear whether PFO is a causal or an incidental finding. Further uncertainty exists on whether the size of functional shunting could represent a potential risk factor. The aim of the present study was to evaluate if the presence of PFO is associated with an increased risk of recurrent stroke or transient ischemic attack and to investigate further if this relationship is related to the shunt size.

Methods—
We conducted a systematic review and meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines of all available prospective studies reporting recurrent cerebrovascular events defined as cryptogenic stroke and transient ischemic attacks in medically treated patients with PFO diagnosed by echocardiography or transcranial sonography.

Results—

We identified 14 eligible studies including a total of 4251 patients. Patients with stroke with PFO did not have a higher risk of the combined outcome of recurrent stroke/transient ischemic attack (risk ratio=1.18; 95% confidence interval=0.78–1.79;
P
=0.43) or in the incidence of recurrent strokes (risk ratio =0.85; 95% confidence interval=0.59–1.22;
P
=0.37) in comparison with stroke patients without PFO. In addition, PFO size was not associated with the risk of recurrent stroke or transient ischemic attack. We also documented no evidence of heterogeneity across the included studies.

Conclusions—
Our findings indicate that medically treated patients with PFO do not have a higher risk for recurrent cryptogenic cerebrovascular events, compared with those without PFO. No relation between the degree of PFO and the risk of future cerebrovascular events was identified.
Deep Convective Transition Characteristics in the Community Climate System Model and Changes under Global Warming
Authors: Sahany Sandeep , Neelin J. David , Hales Katrina , Neale Richard B. 
Published: October 2014

Abstract
Tropical deep convective transition characteristics, including precipitation pickup, occurrence probability, and distribution tails related to extreme events, are analyzed using uncoupled and coupled versions of the Community Climate System Model (CCSM) under present-day and global warming conditions. Atmospheric Model Intercomparison Project–type simulations using a 0.5° version of the uncoupled model yield good matches to satellite retrievals for convective transition properties analyzed as a function of bulk measures of water vapor and tropospheric temperature. Present-day simulations with the 1.0° coupled model show transition behavior not very different from that seen in the higher-resolution uncoupled version. Frequency of occurrence of column water vapor (CWV) for precipitating points shows reasonable agreement with the retrievals, including the longer-than-Gaussian tails of the distributions. The probability density functions of precipitating grid points collapse toward similar form when normalized by the critical CWV for convective onset in both historical and global warming cases. Under global warming conditions, the following statements can be made regarding the precipitation statistics in the simulation: (i) as the rainfall pickup shifts to higher CWV with warmer temperatures, the critical CWV for the current climate is a good predictor for the same quantity under global warming with the shift given by straightforward conditional instability considerations; (ii) to a first approximation, the probability distributions shift accordingly, except that (iii) frequency of occurrence in the longer-than-Gaussian tail increases considerably, with implications for occurrences of extreme events; and, thus, (iv) precipitation conditional averages on CWV and tropospheric temperature tend to extend to higher values.
Determinants of Quality of Life in Stroke Survivors After 6 Months, from a Comprehensive Stroke Unit
Authors: Lopez-Espuela Fidel , Zamorano Juan Diego Pedrera , Ramírez-Moreno José María , Jiménez-Caballero Pedro Enrique , Portilla-Cuenca Juan Carlos , Lavado-García Jesús María , Casado-Naranjo Ignacio 
Published: October 2014

Background: In the social model of stroke, health-related quality of life (HRQoL) is the result of interplay among stroke severity, social support, and health-promoting behaviors. Our objective was to identify determinants of HRQoL in stroke survivors. Methods: Ischemic stroke patients were evaluated at 6 months with the Short Form 12 Health Survey, including physical component survey (PCS) and mental health component survey (MCS) summary scores. Multivariate stepwise regression analyses determined independent predictors of scores. Models included age, gender, socioeconomic class, education, residential environment, social support, previous comorbidity (Charlson Index), previous stroke, side of stroke, National Institutes of Health Stroke Scale (NIHSS) score at admission, Barthel Index (BI) and modified Rankin Scale (mRS) scores at discharge, and length of stay. Results: A total of 131 patients participated (mean age 70.1, SD = 12.5; 62.6% males). In all, 33.6% had a BI score <90 and an mRS score >2 (poor outcome). The mean ( SD) PCS score was 39.46 (9.3) and mean ( SD) MCS score was 34.86 (10.1). Lower PCS score was associated with female sex (β = 0.204, p = .009), poor social support (β = −0.225, p = .003), and poor Charlson Index (β = −0.162, p = .032) and BI scores (β = 0.384, p < .0001). Lower MCS score was associated with female sex (β = 0.162, p = .062) and poor NIHSS (β = −0.265, p = .019) and BI scores (β = 0.203, p < .071). Conclusion: Stroke severity, disability, gender, social support, and previous stroke have significant impacts on the physical and mental domains of generic HRQoL.