bluuebunny/crossref_metadata_2025_split huggingface dataset:
Crizotinib-Resistant ROS1 Mutations Reveal a Predictive Kinase Inhibitor Sensitivity Model for ROS1- and ALK-Rearranged Lung Cancers
Authors: Facchinetti Francesco , Loriot Yohann , Kuo Mei-Shiue , Mahjoubi Linda , Lacroix Ludovic , Planchard David , Besse Benjamin , Farace Françoise , Auger Nathalie , Remon Jordi , Scoazec Jean-Yves , André Fabrice , Soria Jean-Charles , Friboulet Luc 
Published: July 2016

Abstract
Background: The identification of molecular mechanisms conferring resistance to tyrosine kinase inhibitor (TKI) is a key step to improve therapeutic results for patients with oncogene addiction. Several alterations leading to EGFR and anaplastic lymphoma kinase (ALK) resistance to TKI therapy have been described in non–small cell lung cancer (NSCLC). Only two mutations in the ROS1 kinase domain responsible for crizotinib resistance have been described in patients thus far.
Methods: A patient suffering from a metastatic NSCLC harboring an ezrin (EZR)–ROS1 fusion gene developed acquired resistance to the ALK/ROS1 inhibitor crizotinib. Molecular analysis (whole-exome sequencing, CGH) and functional studies were undertaken to elucidate the mechanism of resistance. Based on this case, we took advantage of the structural homology of ROS1 and ALK to build a predictive model for drug sensitivity regarding future ROS1 mutations.
Results: Sequencing revealed a dual mutation, S1986Y and S1986F, in the ROS1 kinase domain. Functional in vitro studies demonstrated that ROS1 harboring either the S1986Y or the S1986F mutation, while conferring resistance to crizotinib and ceritinib, was inhibited by lorlatinib (PF-06463922). The patient's clinical response confirmed the potency of lorlatinib against S1986Y/F mutations. The ROS1 S1986Y/F and ALK C1156Y mutations are homologous and displayed similar sensitivity patterns to ALK/ROS1 TKIs. We extended this analogy to build a model predicting TKI efficacy against potential ROS1 mutations.
Conclusions: Clinical evidence, in vitro validation, and homology-based prediction provide guidance for treatment decision making for patients with ROS1-rearranged NSCLC who progressed on crizotinib. Clin Cancer Res; 22(24); 5983–91. ©2016 AACR.
Transforming Big Data into Cancer-Relevant Insight: An Initial, Multi-Tier Approach to Assess Reproducibility and Relevance
Authors:   The Cancer Target Discovery and Development Network
Published: July 2016

Abstract
The Cancer Target Discovery and Development (CTD2) Network was established to accelerate the transformation of “Big Data” into novel pharmacologic targets, lead compounds, and biomarkers for rapid translation into improved patient outcomes. It rapidly became clear in this collaborative network that a key central issue was to define what constitutes sufficient computational or experimental evidence to support a biologically or clinically relevant finding. This article represents a first attempt to delineate the challenges of supporting and confirming discoveries arising from the systematic analysis of large-scale data resources in a collaborative work environment and to provide a framework that would begin a community discussion to resolve these challenges. The Network implemented a multi-tier framework designed to substantiate the biological and biomedical relevance as well as the reproducibility of data and insights resulting from its collaborative activities. The same approach can be used by the broad scientific community to drive development of novel therapeutic and biomarker strategies for cancer. Mol Cancer Res; 14(8); 675–82. ©2016 AACR.
Left Atrial Appendage Electrical Isolation and Concomitant Device Occlusion to Treat Persistent Atrial Fibrillation
Authors: Panikker Sandeep , Jarman Julian W.E. , Virmani Renu , Kutys Robert , Haldar Shouvik , Lim Eric , Butcher Charles , Khan Habib , Mantziari Lilian , Nicol Edward , Foran John P. , Markides Vias , Wong Tom 
Published: July 2016

Background—
Left atrial appendage (LAA) electric isolation is reported to improve persistent atrial fibrillation (AF) ablation outcomes. However, loss of LAA mechanical function may increase thromboembolic risk. Concomitant LAA electric isolation and occlusion as part of conventional AF ablation has never been tested in humans. We therefore evaluated the feasibility, safety, and efficacy of LAA electric isolation and occlusion in patients undergoing long-standing persistent AF ablation.

Methods and Results—

Patients with long-standing persistent AF (age, 68±7 years; left atrium diameter, 46±3 mm; and AF duration, 25±15 months) underwent AF ablation, LAA electric isolation, and occlusion. Outcomes were compared with a balanced (1:2 ratio) control group who had AF ablation alone. Among 22 patients who underwent ablation, LAA electric isolation was possible in 20. Intraprocedural LAA reconnection occurred in 17 of 20 (85%) patients, predominantly at anterior and superior locations. All were reisolated. LAA occlusion was successful in all 20 patients. There were no major periprocedural complications. Imaging at 45 days and 9 months confirmed satisfactory device position and excluded pericardial effusion. One of twenty (5%) patients had a gap of ≥5 mm requiring anticoagulation. Nineteen of twenty (95%) patients stopped warfarin at 3 months. Without antiarrhythmic drugs, freedom from AF at 12 months after a single procedure was significantly higher in the study group (19/20, 95%) than in the control group (25/40, 63%),
P
=0.036. Freedom from atrial arrhythmias was demonstrated in 12 of 20 (60%) and 18 of 20 (90%) patients after 1 and ≤2 procedures (mean, 1.3), respectively.

Conclusions—
Persistent AF ablation, LAA electric isolation, and mechanical occlusion can be performed concomitantly. This technique may improve the success of persistent AF ablation while obviating the need for chronic anticoagulation.

Clinical Trial Registration—

URL:
https://clinicaltrials.gov
. Unique identifier: NCT02028130.
Identification of Concealed and Manifest Long QT Syndrome Using a Novel T Wave Analysis Program
Authors: Sugrue Alan , Noseworthy Peter A. , Kremen Vaclav , Bos J. Martijn , Qiang Bo , Rohatgi Ram K. , Sapir Yehu , Attia Zachi I. , Brady Peter , Asirvatham Samuel J. , Friedman Paul A. , Ackerman Michael J. 
Published: July 2016

Background—
Congenital long QT syndrome (LQTS) is characterized by QT prolongation. However, the QT interval itself is insufficient for diagnosis, unless the corrected QT interval is repeatedly ≥500 ms without an acquired explanation. Further, the majority of LQTS patients have a corrected QT interval below this threshold, and a significant minority has normal resting corrected QT interval values. Here, we aimed to develop and validate a novel, quantitative T wave morphological analysis program to differentiate LQTS patients from healthy controls.

Methods and Results—

We analyzed a genotyped cohort of 420 patients (22±16 years, 43% male) with either LQT1 (61%) or LQT2 (39%). ECG analysis was conducted using a novel, proprietary T wave analysis program that quantitates subtle changes in T wave morphology. The top 3 discriminating features in each ECG lead were determined and the lead with the best discrimination selected. Classification was performed using a linear discriminant classifier and validated on an untouched cohort. The top 3 features were Tpeak–Tend interval, T wave left slope, and T wave center of gravity
x
axis (last 25% of the T wave). Lead V6 had the best discrimination. It could distinguish 86.8% of LQTS patients from healthy controls. Moreover, it distinguished 83.33% of patients with concealed LQTS from controls, despite having essentially identical resting corrected QT interval values.

Conclusions—
T wave quantitative analysis on the 12-lead surface ECG provides an effective, novel tool to distinguish patients with either LQT1/LQT2 from healthy matched controls. It can provide guidance while mutation-specific genetic testing is in motion for family members.
Retrograde Coronary Venous Ethanol Infusion for Ablation of Refractory Ventricular Tachycardia
Authors: Kreidieh Bahij , Rodríguez-Mañero Moisés , A. Schurmann Paul , Ibarra-Cortez Sergio Hugo , Dave Amish S. , Valderrábano Miguel 
Published: July 2016

Background—
Radiofrequency ablation (RFA) of ventricular tachycardia (VT) can fail because of inaccessibility to the VT substrate. Transarterial coronary ethanol ablation can be effective but entails arterial instrumentation risk. We hypothesized that retrograde coronary venous ethanol ablation can be an alternative bail-out approach to failed VT RFA.

Methods and Results—
Out of 334 consecutive patients undergoing VT/premature ventricular contraction ablation, 7 patients underwent retrograde coronary venous ethanol ablation. Six out of 7 patients had failed RFA attempts (including epicardial in 3). Coronary venogram-guided venous mapping was performed using a 4F quadripolar catheter or an alligator-clip–connected angioplasty wire. Targeted veins included those with early presystolic potentials and pace-maps matching VT/premature ventricular contraction. An angioplasty balloon (1.5–2×6 mm) was used to deliver 1 to 4 cc of 98% ethanol into a septal branch of the anterior interventricular vein in 5 patients with left ventricular summit VT, a septal branch of the middle cardiac vein, and a posterolateral coronary vein (n=1 each). The clinical VT was successfully ablated acutely in all patients. There were no complications of retrograde coronary venous ethanol ablation, but 1 patient developed pericardial and pleural effusion attributed to pericardial instrumentation. On follow-up of 590±722 days, VT recurred in 4 out of 7 patients, 3 of whom were successfully reablated with RFA.

Conclusions—
Retrograde coronary venous ethanol ablation is safe and feasible as a bail-out approach to failed VT RFA, particularly those originating from the left ventricular summit.
Prevalence, Features, and Prognostic Importance of Edge Dissection After Drug-Eluting Stent Implantation
Authors: Kobayashi Nobuaki , Mintz Gary S. , Witzenbichler Bernhard , Metzger D. Christopher , Rinaldi Michael J. , Duffy Peter L. , Weisz Giora , Stuckey Thomas D. , Brodie Bruce R. , Parvataneni Rupa , Kirtane Ajay J. , Stone Gregg W. , Maehara Akiko 
Published: July 2016

Background—
Intravascular ultrasound detects stent edge dissections after percutaneous coronary intervention that are not seen angiographically. This study investigated the association between stent edge dissections and clinical outcomes.

Methods and Results—

ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) was a large-scale, prospective, multicenter study of patients undergoing drug-eluting stent implantation. In this prospective substudy, 2062 patients (2433 lesions) were evaluated with intravascular ultrasound to characterize the morphological features and clinical outcomes of stent edge dissection after percutaneous coronary intervention. The prevalence of post–percutaneous coronary intervention stent edge dissection was 6.6% per lesion (161 of 2433). Calcified plaque at the proximal stent edge (relative risk [RR]=1.72;
P
=0.04) and proximal stent edge expansion (RR=1.18;
P
=0.004) were predictors for proximal dissection; attenuated plaque at the distal stent edge (RR=3.52;
P
=0.004), distal reference plaque burden (RR=1.56;
P
<0.0001), and distal edge stent expansion (RR=1.11;
P
=0.02) were predictors for distal dissection. At 1-year follow-up, target lesion revascularization was more common in lesions with versus without dissection (5.2% versus 2.7%;
P
=0.04). Multivariable analysis indicated that residual dissection was associated with target lesion revascularization at 1-year follow-up (RR=2.67;
P
=0.02). Among lesions with dissection, smaller effective lumen area increased the risk of target lesion revascularization at 1-year follow-up (cutoff value of 5.1 mm
2
;
P
=0.05).

Conclusions—
Greater stent expansion and the presence of large, calcified, and/or attenuated plaques were independent predictors of stent edge dissection. Residual stent edge dissection, especially with a smaller effective lumen area, was associated with target lesion revascularization during 1-year follow-up after drug-eluting stent implantation.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00638794.
One-Year Clinical Outcomes With SAPIEN 3 Transcatheter Aortic Valve Replacement in High-Risk and Inoperable Patients With Severe Aortic Stenosis
Authors: Herrmann Howard C. , Thourani Vinod H. , Kodali Susheel K. , Makkar Raj R. , Szeto Wilson Y. , Anwaruddin Saif , Desai Nimesh , Lim Scott , Malaisrie S. Chris , Kereiakes Dean J. , Ramee Steven , Greason Kevin L. , Kapadia Samir , Babaliaros Vasilis , Hahn Rebecca T. , Pibarot Philippe , Weissman Neil J. , Leipsic Jonathon , Whisenant Brian K. , Webb John G. , Mack Michael J. , Leon Martin B. 
Published: July 2016

Background:
In the initial PARTNER trial (Placement of Aortic Transcatheter Valves) of transcatheter aortic valve replacement for high-risk (HR) and inoperable patients, mortality at 1 year was 24% in HR and 31% in inoperable patients. A recent report of the 30-day outcomes with the low-profile SAPIEN 3 transcatheter aortic valve replacement system demonstrated very low rates of adverse events, but little is known about the longer-term outcomes with this device.

Methods:
Between October 2013 and September 2014, 583 HR (65%) or inoperable (35%) patients were treated via the transfemoral (84%) or transapical/transaortic (16%) access route at 29 US sites. Major clinical events at 1 year were adjudicated by an independent clinical events committee, and echocardiographic results were analyzed by a core laboratory.

Results:

Baseline characteristics included age of 83 years, 42% female, and median Society of Thoracic Surgeons score of 8.4%. At the 1-year follow-up, survival (all-cause) was 85.6% for all patients, 87.3% in the HR subgroup, and 82.3% in the inoperable subgroup. Survival free of all-cause and cardiovascular mortality in the transfemoral patients from the HR cohort was 87.7% and 93.3%, respectively. There was no severe paravalvular leak. Moderate paravalvular leak (2.7%) was associated with an increase in mortality at 1 year, whereas mild paravalvular leak had no significant association with mortality. Symptomatic improvement as assessed by the percentage of patients in New York Heart Association class III and IV (90.1% to 7.7% at 1 year;
P
<0.0001) and by Kansas City Cardiomyopathy Questionnaire overall summary score (improved from 46.9 to 72.4;
P
<0.0001) was marked. Multivariable predictors of 1-year mortality included alternative access, Society of Thoracic Surgeons score, and disabling stroke.

Conclusions:
In this large, adjudicated registry of SAPIEN 3 HR and inoperable patients, the very low rates of important complications resulted in a strikingly low mortality rate at 1 year. Between 30 and 365 days, the incidence of moderate paravalvular aortic regurgitation did not increase, and no association between mild paravalvular leak and 1-year mortality was observed, although a small increase in disabling stroke occurred. These results, which likely reflect device iteration and procedural evolution, support the use of transcatheter aortic valve replacement as the preferred therapy in HR and inoperable patients with aortic stenosis.

Clinical Trial Registration

: URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01314313.
Congenital Heart Disease With and Without Cyanotic Potential and the Long‐term Risk of Diabetes Mellitus: A Population‐Based Follow‐up Study
Authors: Madsen Nicolas L. , Marino Bradley S. , Woo Jessica G. , Thomsen Reimar W. , Videbœk Jørgen , Laursen Henning Bœkgaard , Olsen Morten 
Published: July 2016

Background

Long‐term survival for persons born with congenital heart disease (
CHD
) is improved, but limited knowledge exists of this growing population's acquired cardiovascular risk profile. This study's purpose was to assess
CHD
survivors’ risk for type 2 diabetes mellitus (T2DM) with attention to the impact of cyanotic
CHD
.

Methods and Results

This population‐based cohort study included Danish subjects with CHD who were born between 1963 and 1980 and were alive at age 30 years. For each
CHD
case, we identified 10 individuals from the general population matched by sex and birth year, by using the Danish Civil Registration System. Complete follow‐up was obtained through Danish public registries for death, emigration, and T2
D
M (diagnosis and prescriptions record). We computed cumulative incidences and hazard ratios of developing T2
DM
after age 30 for 5149
CHD
subjects compared with the general population. After adjusting for
CHD
severity, as well as age, sex, preterm birth, and extracardiac defects, we analyzed the impact of cyanotic compared with acyanotic
CHD
. By age 45 years, the cumulative incidence of T2
DM
after age 30 was 4% among subjects with CHD. Subjects with
CHD
were more likely to develop T2
DM
than the general population (hazard raio 1.4, 95%
CI
1.1–1.6). Subjects
CHD
who had cyanotic defects were more likely to develop T2
DM
than were subjects with acyanotic
CHD
(hazard ratio 1.9, 95%
CI
1.1–3.3).

Conclusions

CHD
survivors had an increased risk of developing T2
DM
after age 30. Patients with cyanotic
CHD
are at particular risk. Given the cardiovascular health burden of T2DM, attention to its development in
CHD
survivors seems warranted.
Advanced Left Atrial Remodeling and Appendage Contractile Dysfunction in Women Than in Men Among the Patients With Atrial Fibrillation: Potential Mechanism for Stroke
Authors: Yu Hee Tae , Lee Jihei Sara , Kim Tae‐Hoon , Uhm Jae‐Sun , Joung Boyoung , Hong Geu‐Ru , Lee Moon‐Hyoung , Shim Chi Young , Pak Hui‐Nam 
Published: July 2016

Background

The risk of stroke imposed by atrial fibrillation (
AF
) is significantly greater in women than men; however, the mechanism remains elusive. We hypothesized that left atrial (
LA
) remodeling and poor contractile function of
LA
appendage (
LAA
) would be more predominant in women than men among
AF
patients.

Methods and Results

A total of 579
AF
patients (216 women vs age‐,
AF
type–, and incidences of heart failure, hypertension, diabetes mellitus, stroke or transient ischemic attack, and vascular disease–matched 363 men, 61.3±10.2 years old, 70.1% paroxysmal
AF
) who underwent
AF
catheter ablation were included. Sex differences in
LA
volume index (
LAVI
) and
LAA
emptying flow velocity (
FV
) were analyzed in risk factor 0, 1, and ≥2 groups, according to their
CHA
2
DS
2
‐
VAS
c scores beyond sex category.
LAA
‐
FV
was more significantly reduced in women with risk factor ≥2 than in men of the same risk group (
P
=0.022). Women showed greater
LAVI
than their male counterparts in the risk factor ≥2 group (
P
<0.001). The majority of female patients with a history of stroke had a large
LAVI
and low
LAA
‐
FV
(
P
<0.001); however, no such distribution was observed in men (
P
=0.596).
LA
volume index (odds ratio [
OR
], 1.038; 95%
CI
, 1.003–1.075,
P
=0.035) or
LAA
‐
FV
(
OR
, 0.976; 95%
CI
, 0.952–0.999;
P
=0.047) was significantly associated with a history of stroke in women.

Conclusions

More‐extensive
LA
remodeling and deterioration in
LAA
function were noted in women than in men with high calculated risk of stroke in
AF
.
Catheter Ablation as a Treatment for Vasovagal Syncope: Long‐Term Outcome of Endocardial Autonomic Modification of the Left Atrium
Authors: Sun Wei , Zheng Lihui , Qiao Yu , Shi Rui , Hou Bingbo , Wu Lingmin , Guo Jinrui , Zhang Shu , Yao Yan 
Published: July 2016

Background

Autonomic modification through catheter ablation of ganglionated plexi (
GPs
) in the left atrium has been reported previously as a treatment for vasovagal syncope. This study aimed to observe the long‐term outcome in a larger cohort.

Methods and Results

A total of 57 consecutive patients (aged 43.2±13.4 years; 35 women) with refractory
vasovagal syncope
were enrolled, and high‐frequency stimulation and anatomically guided
GP
ablation were performed in 10 and 47 cases, respectively. A total of 127
GP
sites with positive vagal response were successfully elicited and ablated, including 52 left superior, 19 left lateral, 18 left inferior, 27 right anterior, and 11 right inferior
GP
s. During follow‐up of 36.4±22.2 months (range 12–102 months), 52 patients (91.2%) remained free from syncope. Prodromes recurred in 16 patients. No statistical differences were found between the high‐frequency stimulation and anatomically guided ablation groups in either freedom from syncope (100% versus 89.4%,
P
=0.348) or recurrent prodromes (50% versus 76.6%,
P
=0.167). The deceleration capacity, heart rate, and heart rate variability measurements demonstrated a reduced vagal tone lasting for at least 12 months after the procedure, with improved tolerance of repeated head‐up tilt testing. No complications were observed except for transient sinus tachycardia that occurred in 1 patient.

Conclusions

Left atrial
GP
ablation showed excellent long‐term clinical outcomes and might be considered as a therapeutic option for patients with symptomatic
vasovagal syncope
.
Time Dependence of the Effect of Right Ventricular Dysfunction on Clinical Outcomes After Myocardial Infarction: Role of Pulmonary Hypertension
Authors: Shahar Keren , Darawsha Wisam , Yalonetsky Sergey , Lessick Jonathan , Kapeliovich Michael , Dragu Robert , Mutlak Diab , Reisner Shimon , Agmon Yoram , Aronson Doron 
Published: July 2016

Background

The clinical importance of right ventricular (
RV
) function in acute myocardial infarction is well recognized, but the impact of concomitant pulmonary hypertension (
PH
) has not been studied.

Methods and Results

We studied 1044 patients with acute myocardial infarction. Patients were classified into 4 groups according to the presence or absence of
RV
dysfunction and
PH
, defined as pulmonary artery systolic pressure >35 mm Hg: normal right ventricle without
PH
(n=509), normal right ventricle and
PH
(n=373),
RV
dysfunction without
PH
(n=64), and
RV
dysfunction and
PH
(n=98). A landmark analysis of early (admission to 30 days) and late (31 days to 8 years) mortality and readmission for heart failure was performed. In the first 30 days,
RV
dysfunction without
PH
was associated with a high mortality risk (adjusted hazard ratio 5.56, 95%
CI
2.05–15.09,
P
<0.0001 compared with normal RV and
no PH
). In contrast, after 30 days, mortality rates among patients with
RV
dysfunction were increased only when
PH
was also present. Compared with patients having neither
RV
dysfunction nor
PH
, the adjusted hazard ratio for mortality was 1.44 (95%
CI
0.68–3.04,
P
=0.34) in
RV
dysfunction without
PH
and 2.52 (95%
CI
1.64–3.87,
P
<0.0001) in
RV
dysfunction with
PH
.
PH
with or without
RV
dysfunction was associated with increased risk for heart failure.

Conclusion

In the absence of elevated pulmonary pressures, the risk associated with
RV
dysfunction after acute myocardial infarction is entirely confined to the first 30 days. Beyond 30 days,
PH
is the stronger risk factor for long‐term mortality and readmission for heart failure.