A retrograde approach improves the success rate of percutaneous coronary interventions (PCIs) for chronic total occlusions (CTOs).
The authors describe the European experience with and outcomes of ...retrograde PCI revascularization for coronary CTOs.
Follow-up data were collected from 1,395 patients with 1,582 CTO lesions enrolled between January 2008 and December 2012 for retrograde CTO PCI at 44 European centers. Major adverse cardiac and cerebrovascular events were defined as the composite of cardiac death, myocardial infarction, stroke, and further revascularization.
The mean patient age was 62.0 ± 10.4 years; 88.5% were men. Procedural and clinical success rates were 75.3% and 71.2%, respectively. The mean clinical follow-up duration was 24.7 ± 15.0 months. Compared with patients with failed retrograde PCI, successfully revascularized patients showed lower rates of cardiac death (0.6% vs. 4.3%, respectively; p < 0.001), myocardial infarction (2.3% vs. 5.4%, respectively; p = 0.001), further revascularization (8.6% vs. 23.6%, respectively; p < 0.001), and major adverse cardiac and cerebrovascular events (8.7% vs. 23.9%, respectively; p < 0.001). Female sex (hazard ratio HR: 2.06; 95% confidence interval CI: 1.33 to 3.18; p = 0.001), prior PCI (HR: 1.73; 95% CI: 1.16 to 2.60; p = 0.011), low left ventricular ejection fraction (HR: 2.43; 95% CI: 1.22 to 4.83; p = 0.011), J-CTO (Multicenter CTO Registry in Japan) score ≥3 (HR: 2.08; 95% CI: 1.32 to 3.27; p = 0.002), and procedural failure (HR: 2.48; 95% CI: 1.72 to 3.57; p < 0.001) were independent predictors of major adverse cardiac and cerebrovascular events at long-term follow-up.
The number of retrograde procedures in Europe has increased, with high percents of success, low rates of major complications, and good long-term outcomes.
Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here we perform a comprehensive genomic (n = ...60) and transcriptomic (n = 69) analysis of 75 LCNECs and identify two molecular subgroups: "type I LCNECs" with bi-allelic TP53 and STK11/KEAP1 alterations (37%), and "type II LCNECs" enriched for bi-allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas and squamous cell carcinomas, no transcriptional relationship was found; instead LCNECs form distinct transcriptional subgroups with closest similarity to SCLC. While type I LCNECs and SCLCs exhibit a neuroendocrine profile with ASCL1
/DLL3
/NOTCH
, type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1
/DLL3
/NOTCH
, and an upregulation of immune-related pathways. In conclusion, LCNECs comprise two molecularly defined subgroups, and distinguishing them from SCLC may allow stratified targeted treatment of high-grade neuroendocrine lung tumors.
Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor prognosis. We sequenced 29 SCLC exomes, 2 genomes and 15 transcriptomes and found an extremely high mutation rate of 7.4±1 ...protein-changing mutations per million base pairs. Therefore, we conducted integrated analyses of the various data sets to identify pathogenetically relevant mutated genes. In all cases, we found evidence for inactivation of TP53 and RB1 and identified recurrent mutations in the CREBBP, EP300 and MLL genes that encode histone modifiers. Furthermore, we observed mutations in PTEN, SLIT2 and EPHA7, as well as focal amplifications of the FGFR1 tyrosine kinase gene. Finally, we detected many of the alterations found in humans in SCLC tumors from Tp53 and Rb1 double knockout mice. Our study implicates histone modification as a major feature of SCLC, reveals potentially therapeutically tractable genomic alterations and provides a generalizable framework for the identification of biologically relevant genes in the context of high mutational background.
Abstract Background A retrograde approach improves the success rate of percutaneous coronary interventions (PCIs) for chronic total occlusions (CTOs). Objectives The authors describe the European ...experience with and outcomes of retrograde PCI revascularization for coronary CTOs. Methods Follow-up data were collected from 1,395 patients with 1,582 CTO lesions enrolled between January 2008 and December 2012 for retrograde CTO PCI at 44 European centers. Major adverse cardiac and cerebrovascular events were defined as the composite of cardiac death, myocardial infarction, stroke, and further revascularization. Results The mean patient age was 62.0 ± 10.4 years; 88.5% were men. Procedural and clinical success rates were 75.3% and 71.2%, respectively. The mean clinical follow-up duration was 24.7 ± 15.0 months. Compared with patients with failed retrograde PCI, successfully revascularized patients showed lower rates of cardiac death (0.6% vs. 4.3%, respectively; p < 0.001), myocardial infarction (2.3% vs. 5.4%, respectively; p = 0.001), further revascularization (8.6% vs. 23.6%, respectively; p < 0.001), and major adverse cardiac and cerebrovascular events (8.7% vs. 23.9%, respectively; p < 0.001). Female sex (hazard ratio HR: 2.06; 95% confidence interval CI: 1.33 to 3.18; p = 0.001), prior PCI (HR: 1.73; 95% CI: 1.16 to 2.60; p = 0.011), low left ventricular ejection fraction (HR: 2.43; 95% CI: 1.22 to 4.83; p = 0.011), J-CTO (Multicenter CTO Registry in Japan) score ≥3 (HR: 2.08; 95% CI: 1.32 to 3.27; p = 0.002), and procedural failure (HR: 2.48; 95% CI: 1.72 to 3.57; p < 0.001) were independent predictors of major adverse cardiac and cerebrovascular events at long-term follow-up. Conclusions The number of retrograde procedures in Europe has increased, with high percents of success, low rates of major complications, and good long-term outcomes.
The use of transcatheter mitral valve repair (TMVR) has gained widespread acceptance in Europe, but data on immediate success, safety, and long-term echocardiographic follow-up in real-world patients ...are still limited.
The aim of this multinational registry is to present a real-world overview of TMVR use in Europe.
The Transcatheter Valve Treatment Sentinel Pilot Registry is a prospective, independent, consecutive collection of individual patient data.
A total of 628 patients (mean age 74.2 ± 9.7 years, 63.1% men) underwent TMVR between January 2011 and December 2012 in 25 centers in 8 European countries. The prevalent pathogenesis was functional mitral regurgitation (FMR) (n = 452 72.0%). The majority of patients (85.5%) were highly symptomatic (New York Heart Association functional class III or higher), with a high logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation) (20.4 ± 16.7%). Acute procedural success was high (95.4%) and similar in FMR and degenerative mitral regurgitation (p = 0.662). One clip was implanted in 61.4% of patients. In-hospital mortality was low (2.9%), without significant differences between groups. The estimated 1-year mortality was 15.3%, which was similar for FMR and degenerative mitral regurgitation. The estimated 1-year rate of rehospitalization because of heart failure was 22.8%, significantly higher in the FMR group (25.8% vs. 12.0%, plog-rank = 0.009). Paired echocardiographic data from the 1-year follow-up, available for 368 consecutive patients in 15 centers, showed a persistent reduction in the degree of mitral regurgitation at 1 year (6.0% of patients with severe mitral regurgitation).
This independent, contemporary registry shows that TMVR is associated with high immediate success, low complication rates, and sustained 1-year reduction of the severity of mitral regurgitation and improvement of clinical symptoms.
Pretreatment with clopidogrel can reduce the risks associated with percutaneous coronary intervention (PCI). To shorten the time for clopidogrel to become effective, a 600-mg loading dose has been ...used. We sought to validate this regimen in a large cohort and investigated the time dependence of the antiplatelet effect of 600 mg of clopidogrel.
Our study included 1001 patients who were scheduled for cardiac catheterization as potential candidates for PCI. We obtained blood samples before administration of 600 mg of clopidogrel and at the time of catheterization, which varied according to logistic needs. We assessed platelet aggregation by optical aggregometry and surface expression of P-selectin and activated glycoprotein IIb/IIIa by flow cytometry. Platelet aggregation induced by 5 micromol/L ADP was 51+/-14% when catheterization was performed at <1 hour, 41+/-14% at 1 to <2 hours, 37+/-15% at 2 to <4 hours, 36+/-13% at 4 to <6 hours, and 35+/-14% at > or =6 hours after clopidogrel administration. After 2 hours (n=718), the level of platelet aggregation and the surface expression of P-selectin and activated glycoprotein IIb/IIIa did not change significantly with time after clopidogrel (P>0.24 by univariate or multivariate regression). Comedication with CYP3A4 metabolized statins did not significantly affect platelet aggregation after clopidogrel (P=0.62). Among the 428 patients undergoing PCI, the 30-day composite rate of major adverse cardiac events was 1.9%, with no significant difference between patients undergoing PCI within 2 hours after clopidogrel loading and those undergoing PCI at a later time point.
After loading with 600 mg of clopidogrel, the full antiplatelet effect of the drug is achieved after 2 hours. Statins do not interfere with the level of platelet inhibition after this dose.
Cytochrome P450 2C19 681G>A Polymorphism and High On-Clopidogrel Platelet Reactivity Associated With Adverse 1-Year Clinical Outcome of Elective Percutaneous Coronary Intervention With Drug-Eluting ...or Bare-Metal Stents Dietmar Trenk, Willibald Hochholzer, Martin F. Fromm, Ligia-Emilia Chialda, Andreas Pahl, Christian M. Valina, Christian Stratz, Peter Schmiebusch, Hans-Peter Bestehorn, Heinz Joachim Büttner, Franz-Josef Neumann In 797 consecutive patients undergoing elective coronary stent placement (percutaneous coronary intervention), we investigated the impact of the loss of function CYP2C19 681G>A 2 polymorphism on the antiplatelet effect of clopidogrel. Between 2 carriers (n = 245) and wild-type homozygotes (n = 552) we found significant (p < 0.001) differences in the proportion of patients with residual platelet aggregation induced by adenosine diphosphate 5 μmol/l (residual platelet aggregation) >14%, both after loading with 600 mg (62.4% vs. 43.3%) and after maintenance dosing at pre-discharge (41.3% vs. 22.5%). Residual platelet aggregation >14% at pre-discharge incurred a 3.0-fold increase (95% confidence interval 1.4 to 6.8; p = 0.004) in the 1-year incidence of death and myocardial infarction.
Although KRAS mutations in NSCLC have been considered mutually exclusive driver mutations for a long time, there is now growing evidence that KRAS-mutated NSCLC represents a genetically heterogeneous ...subgroup. We sought to determine genetic heterogeneity with respect to cancer-related co-mutations and their correlation with different KRAS mutation subtypes.
Diagnostic samples from 4507 patients with NSCLC were analyzed by next-generation sequencing by using a panel of 14 genes and, in a subset of patients, fluorescence in situ hybridization. Next-generation sequencing with an extended panel of 14 additional genes was performed in 101 patients. Molecular data were correlated with clinical data. Whole-exome sequencing was performed in two patients.
We identified 1078 patients with KRAS mutations, of whom 53.5% had at least one additional mutation. Different KRAS mutation subtypes showed different patterns of co-occurring mutations. Besides mutations in tumor protein p53 gene (TP53) (39.4%), serine/threonine kinase 11 gene (STK11) (19.8%), kelch like ECH associated protein 1 gene (KEAP1) (12.9%), and ATM serine/threonine kinase gene (ATM) (11.9%), as well as MNNG HOS Transforming gene (MET) amplifications (15.4%) and erb-b2 receptor tyrosine kinase 2 gene (ERBB2) amplifications (13.8%, exclusively in G12C), we found rare co-occurrence of targetable mutations in EGFR (1.2%) and BRAF (1.2%). Whole-exome sequencing of two patients with co-occurring phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutation revealed clonality of mutated KRAS in one patient and subclonality in the second, suggesting different evolutionary backgrounds.
KRAS-mutated NSCLC represents a genetically heterogeneous subgroup with a high frequency of co-occurring mutations in cancer-associated pathways, partly associated with distinct KRAS mutation subtypes. This diversity might have implications for understanding the variability of treatment outcome in KRAS-mutated NSCLC and for future trial design.
Aims Although a 140 U/kg dose of unfractionated heparin (UFH) was comparable with bivalirudin in terms of net clinical outcome in the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early ...Action for Coronary Treatment (ISAR-REACT) 3 trial, it was associated with a higher risk of bleeding. We designed this study to assess whether a reduction in the UFH dose from 140 to 100 U/kg is associated with improved net clinical outcome. Methods and results A total of 2505 biomarker negative patients undergoing percutaneous coronary intervention (PCI) after clopidogrel pre-treatment received a single bolus of 100 U/kg UFH. The primary endpoint was net clinical outcome—a quadruple endpoint of death, myocardial infarction, urgent target-vessel revascularization within 30 days, or in-hospital REPLACE 2 defined major bleeding. The primary comparison was with the historical UFH group of ISAR-REACT 3 (2281 patients). In a second analysis, we checked for non-inferiority against the historical bivalirudin arm of ISAR-REACT 3 (2289 patients). The incidence of the primary endpoint was 7.3% in the lower UFH dose group compared with 8.7% in the higher UFH dose group hazard ratio (HR) 0.81; 95% confidence interval (CI) 0.67–1.00; P = 0.045. The incidence of major bleeding was 3.6% in the lower UFH dose group and 4.6% in the higher UFH dose group (HR 0.79; 95% CI 0.59–1.05; P = 0.11). The lower UFH dose met the criterion of non-inferiority compared with bivalirudin (P < 0.001). Conclusion In biomarker negative patients undergoing PCI after clopidogrel loading, a reduced dose of 100 U/kg UFH provided net clinical benefit compared with the historical control of 140 U/kg UFH in the ISAR-REACT 3 trial. The benefit was mostly driven by reduction in bleeding. Clinical trial registration information URL www.clinicaltrials.gov; Unique identifier NCT00735280.
Aims We investigated whether routine T-stenting reduces restenosis of the side branch as compared with provisional T-stenting in patients with de novo coronary bifurcation lesions. Methods and ...results Our randomized study assigned 101 patients with a coronary bifurcation lesion to routine T-stenting with sirolimus-eluting stents (SES) in both branches and 101 patients to provisional T-stenting with SES placement in the main branch followed by kissing-balloon angioplasty and provisional SES placement in the side branch only for inadequate results. Primary endpoint was per cent diameter stenosis of the side branch at 9 month angiographic follow-up. Angiographic follow-up in 192 (95%) patients revealed a per cent stenosis of the side branch of 23.0 ± 20.2% after provisional T-stenting (19% with side-branch stent) and of 27.7 ± 24.8% (P = 0.15) after routine T-stenting (98.2% with side-branch stent). The corresponding binary restenosis rates were 9.4 and 12.5% (P = 0.32), prompting re-intervention in 5.0 and 7.9% (P = 0.39), respectively. In the main branch, binary restenosis rates were 7.3% after provisional and 3.1% after routine T-stenting (P = 0.17). The overall 1 year incidence of target lesion re-intervention was 10.9% after provisional and 8.9% after routine T-stenting (P = 0.64). Conclusions Routine T-stenting with SES did not improve the angiographic outcome of percutaneous coronary intervention of coronary bifurcation lesions as compared with stenting of the main branch followed by kissing-balloon angioplasty and provisional side-branch stenting.
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