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Background First-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater. Methods This randomised, open-label, phase 3 study was done in 213 medical centres in 32 countries. Eligible patients were adults (≥18 years) with previously untreated locally advanced or metastatic non-small-cell lung cancer without a sensitising EGFR mutation or ALK translocation and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, life expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater. Randomisation was computer generated, accessed via an interactive voice-response and integrated web-response system, and stratified by region of enrolment (east Asia vs rest of world), ECOG performance status score (0 vs 1), histology (squamous vs non-squamous), and PD-L1 TPS (≥50% vs 1-49%). Enrolled patients were randomly assigned 1:1 in blocks of four per stratum to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles or the investigator's choice of platinum-based chemotherapy for four to six cycles. Primary endpoints were overall survival in patients with a TPS of 50% or greater, 20% or greater, and 1% or greater (one-sided significance thresholds, p=0·0122, p=0·0120, and p=0·0124, respectively) in the intention-to-treat population, assessed sequentially if the previous findings were significant. This study is registered at ClinicalTrials.gov, number NCT02220894. Findings From Dec 19, 2014, to March 6, 2017, 1274 patients (902 men, 372 women, median age 63 years [IQR 57-69]) with a PD-L1 TPS of 1% or greater were allocated to pembrolizumab (n=637) or chemotherapy (n=637) and included in the intention-to-treat population. 599 (47%) had a TPS of 50% or greater and 818 patients (64%) had a TPS of 20% or greater. As of Feb 26, 2018, median follow-up was 12·8 months. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations (≥50% hazard ratio 0·69, 95% CI 0·56-0·85, p=0·0003; ≥20% 0·77, 0·64-0·92, p=0·0020, and ≥1% 0·81, 0·71-0·93, p=0·0018). The median surival values by TPS population were 20·0 months (95% CI 15·4-24·9) for pembrolizumab versus 12·2 months (10·4-14·2) for chemotherapy, 17·7 months (15·3-22·1) versus 13·0 months (11·6-15·3), and 16·7 months (13·9-19·7) versus 12·1 months (11·3-13·3), respectively. Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively. Interpretation The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS. Funding Merck Sharp & Dohme.

Background Cangrelor, an intravenous, reversible P2Y12 antagonist, is approved for use in patients undergoing percutaneous coronary intervention (PCI). Objectives This study sought to evaluate the efficacy and safety of cangrelor compared with clopidogrel in subgroups that did and did not receive glycoprotein IIb/IIIa inhibitors (GPIs). Methods This pooled, patient-level analysis of the 3 CHAMPION (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition) trials analyzed all randomized patients who underwent PCI and received the study drug (n = 24,902). Only bailout/rescue GPI use was permitted, except in CHAMPION PCI, in which routine or bailout/rescue GPI use was at the site investigator’s discretion. The primary efficacy endpoint was the composite of all-cause mortality, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 h after randomization. Results Overall, 3,173 patients (12.7%) received a GPI, most commonly eptifibatide (69.4%). Despite variation in indications for GPIs, baseline characteristics were well balanced between the cangrelor and clopidogrel arms in subsets receiving and not receiving GPIs. Rates of the primary composite endpoint were lower with cangrelor compared with clopidogrel in patients who did (4.9% vs. 6.5%; odds ratio [OR]: 0.74; 95% confidence interval [CI]: 0.55 to 1.01) or did not receive a GPI (3.6% vs. 4.4%; OR: 0.82; 95% CI: 0.72 to 0.94; Pint = 0.55). Cangrelor did not increase the primary safety endpoint, GUSTO-defined severe/life-threatening bleeding, in patients who did (0.4% vs. 0.5%; OR: 0.71; 95% CI: 0.25 to 1.99) or did not receive GPIs (0.2% vs. 0.1%; OR: 1.56; 95% CI: 0.80 to 3.04; Pint = 0.21). GPI use was associated with increased risk of bleeding in both treatment arms. Conclusions Cangrelor’s efficacy in reducing ischemic complications in patients undergoing PCI was maintained irrespective of GPI administration. GPI use was associated with substantially higher bleeding rates, regardless of the randomization to cangrelor or clopidogrel. (A Clinical Trial to Demonstrate the Efficacy of Cangrelor [PCI]: NCT00305162 ; Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition [PLATFORM]: NCT00385138 ; A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI] [CHAMPION PHOENIX] [CHAMPION]: NCT01156571 )

Background: The unsatisfactory side branch (SB) ostial strut coverage remains a problem in coronary bifurcation stenting. Both the surplus and lack of struts at SB ostium may be the causative mechanism. We propose that the inability of available stents to cover the “extension distance” of the bifurcation region is the cause of in-stent restenosis. Methods: The extension distance (ED) is defined as the maximal distance at the carina tip, which must be covered by the stent struts to ensure optimal coverage of the main branch (MB) and SB openings. A mathematical model was created, representing the key factors that govern geometrical reconfigurations after stent implantation in bifurcations. There are two options—with and without bifurcation region deformation. The theoretical assumptions were tested on a bifurcation model (soft polyvinylchloride polymer tubes) permitting free wall deformations and the following parameters: Parent Vessel, MB, SB diameters of 3.5, 3.0, and 2.5 mm, respectively, with an angle of 45° between the MB and SB. After stenting, final KBI with 3.5 mm and 3.0 mm balloons was performed up to 20 atm. Results: After the carina displacement, the ED, which has to be covered, is considerably smaller if the suboptimal result (DS >50%) at the SB ostium is acceptable. The maximal EDs from the bench test measurements are: Vision, Abbott Vascular – 5.62 mm ± 0.04; Liberte, Boston Scientific Corp. – 5.2 mm ± 0.03; Chopin2, Balton – 4.58 mm ± 0.05; Volo, Invatec – 4.41 mm ± 0.04; Driver, Medtronics – 4.39 mm ± 0.04; BxSonic, Cordis, J&J – 4.48 mm ± 0.05. The theoretical maximal ED of the model is 6.91 mm—28–62% larger than actually observed with different stents. Conclusions: The achievement of perfect ostial coverage of the SB is unsatisfactory with most of the currently available stents, especially when poststenting excessive dilation of the ostium of the SB is performed. (J Interven Cardiol 2010;23:305–318)

Guidelines and Expert Consensus Documents summarize and evaluate all available evidence with the aim of assisting physicians in selecting the best management strategy for an individual patient suffering from a given condition, taking into account the impact on outcome and the risk benefit ratio of diagnostic or therapeutic means. Guidelines are no substitutes for textbooks and their legal implications have been discussed previously. Guidelines and recommendations should help physicians to make decisions in their daily practice. However, the ultimate judgement regarding the care of an individual patient must be made by his/her responsible physician(s). The recommendations for formulating and issuing ESC Guidelines and Expert Consensus Documents can be found on the ESC website (http://www.escardio.org/knowledge/ guidelines/rules). Members of this Task Force were selected by the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) to represent all physicians involved with the medical and surgical care of patients with coronary artery disease (CAD). A critical evaluation of diagnostic and therapeutic procedures is performed including assessment of the risk benefit ratio. Estimates of expected health outcomes for society are included, where data exist. The level of evidence and the strength of recommendation of particular treatment options are weighed and graded according to predefined scales, as outlined in Tables 1 and 2. The members of the Task Force have provided disclosure statements of all relationships that might be perceived as real or potential sources of conflicts of interest. These disclosure forms are kept on file at European Heart House, headquarters of the ESC. Any changes in conflict of interest that arose during the writing period were notified to the ESC. The Task Force report received its entire financial support from the ESC and EACTS, without any involvement of the pharmaceutical, device, or surgical industry. ESC and EACTS Committees for Practice Guidelines are responsible for the endorsement process of these joint Guidelines. The finalized document has been approved by all the experts involved in the Task Force, and was submitted to outside specialists selected by both societies for review. The document is revised, and finally approved by ESC and EACTS and subsequently published simultaneously in the European Heart Journal and the European Journal of Cardio-Thoracic Surgery. After publication, dissemination of the Guidelines is of paramount importance. Pocket-sized versions and personal digital assistant-downloadable versions are useful at the point of care. Some surveys have shown that the intended users are sometimes unaware of the existence of guidelines, or simply do not translate them into practice. Thus, implementation programmes are needed because it has been shown that the outcome of disease may be favourably influenced by the thorough application of clinical recommendations.

Ultrathin black phosphorus is a two-dimensional semiconductor with a sizeable band gap. Its excellent electronic properties make it attractive for applications in transistor, logic and optoelectronic devices. However, it is also the first widely investigated two-dimensional material to undergo degradation upon exposure to ambient air. Therefore a passivation method is required to study the intrinsic material properties, understand how oxidation affects the physical properties and enable applications of phosphorene. Here we demonstrate that atomically thin graphene and hexagonal boron nitride can be used for passivation of ultrathin black phosphorus. We report that few-layer pristine black phosphorus channels passivated in an inert gas environment, without any prior exposure to air, exhibit greatly improved n-type charge transport resulting in symmetric electron and hole transconductance characteristics.

There is mounting evidence that the use of the radial access, without compromising procedural success, reduces bleeding complications compared to the femoral. Despite the proven efficacy, safety and benefits, the rate of penetration of radial access worldwide is still low – around 10% with a wide variation in adoption from over 50% in France, 40% in Japan to as little as 1% in the US (around 5% according to most recent data). The benefits that are inherent to the radial approach occur when radial approach is used in >70% of patients. Like any new technique, the radial approach has an inherent learning curve which may be shortened by a properly implemented radial programme and optimal access technique1. In the current issue of this journal there are three articles on the radial approach which are focused on: predictors of choice and success; the effect of different heparin regimens on patency; and new puncture techniques. In a subanalysis of the previously published PREVAIL study, Pristipino et al have tried to identify the predictors of the choice and success rates of radial artery catheterisation (RAC) in contemporary real world cardiology practice2. To date, this is the first study that has sought to identify these factors formally in a large cohort of unselected patients undergoing RAC by operators with different levels of expertise and across centres with varying volumes of activity. The first original finding is that in 90% of cases the choice of first arterial access site was determined by operator preference, while clinical or technical factors affected the choice in only a small minority. Patients undergoing RAC at hospitals with high overall procedural volumes exhibited a similar rate of RAC failure as those undergoing the procedure at low volume hospitals. However, assessing RAC volumes alone, patients undergoing the procedure at high volume hospitals experienced a statistically lower rate of RAC failure than their low-volume hospital counterparts. The failure rate for first radial access decreased almost tenfold, from 33% to 3.8%, when operators with 85% of their personal case load performed by RAC. Currently, radial access failure rate for high-volume operators performing over 90% of procedures radially is less than 1%3. The authors conclude that a routine RAC is superior to a selective strategy in terms of feasibility and success rate. For the first time, the study provides evidence that, contrary to general belief, the routine use of RAC in all-comers is feasible, safe and more successful than its selective use. In the second article, Ludvwig et al describe a new approach for RA puncture that represents a combination of the two most frequently techniques used nowadays, namely the bare needle technique and the venous cannula puncture technique4. The choice between the two cited techniques is mainly operator dependent, and none of the two has emerged as clearly better than the other5. The modified radial puncture technique combines the advantages of the bare needle and venous cannula techniques. The proposed approach is achieved in two steps: First, the radial puncture is accomplished with a bare needle without local anaesthesia, and according to the authors, patient discomfort is minimal and radial spasm virtually eliminated. In the second step, the combination of the retrieved needle introduced into a venous cannula is inserted over the introducer wire into the artery. The described modification of mainstream techniques does not make easier or shorter the access to the radial artery and it may be even slightly more timeconsuming. The main advantage, however, is not an easier puncture, but the ability to perform angiography and locally apply drugs, if needed, before a sheath is introduced. In the third article, the elegantly designed study by Schiano et al focuses – for the first time – on the potential influence of different heparin regimens on radial artery occlusion and bleeding

Guidelines and Expert Consensus Documents summarize and evaluate all available evidence with the aim of assisting physicians in selecting the best management strategy for an individual patient suffering from a given condition, taking into account the impact on outcome and the risk–benefit ratio of diagnostic or therapeutic means. Guidelines are no substitutes for textbooks and their legal implications have been discussed previously. Guidelines and recommendations should help physicians to make decisions in their daily practice. However, the ultimate judgement regarding the care of an individual patient must be made by his/her responsible physician(s). The recommendations for formulating and issuing ESC Guidelines and Expert Consensus Documents can be found on the ESC website (http://www.escardio.org/knowledge/guidelines/rules). Members of this Task Force were selected by the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) to represent all physicians involved with the medical and surgical care of patients with coronary artery disease (CAD). A critical evaluation of diagnostic and therapeutic procedures is performed including assessment of the risk–benefit ratio. Estimates of expected health outcomes for society are included, where data exist. The level of evidence and the strength of recommendation of particular treatment options are weighed and graded according to predefined scales, as outlined in Tables 1 and 2 . View this table: Table 1 Classes of recommendations View this table: Table 2 Levels of evidence The members of the Task Force have provided disclosure statements of all relationships that might be perceived as real or potential sources of conflicts of interest. These disclosure forms are kept on file at European Heart House, headquarters of the ESC. Any changes in conflict of interest that arose during the writing period were notified to the ESC. The Task Force report received its entire financial support from the ESC and EACTS, without any involvement of the pharmaceutical, device, or surgical industry. ESC …

The two main problems unresolved in coronary bifurcation stenting are periprocedural side branch compromise and higher restenosis at long term. The purpose of this study is to reveal the link between periprocedural side branch compromise and long-term results after main vessel stenting only in coronary bifurcations.Eighty-four patients formed the study population. The inclusion criteria were good-quality angiograms, with maximal between-branch angle opening, no overlap, permitting accurate angiographic analysis. Carina angle (alpha)-the distal angle between main vessel (MV) before bifurcation and side branch (SB)-was measured pre- and poststenting. Clinical follow-up 9-12 months was obtained with coronary angiography if needed.The patient population was high-risk with 33% diabetics and 84% two- and three-vessel disease. Ninety-five stents were implanted in 92 lesions, with three T-stenting cases. Drug-eluting stents were implanted in 54%. Kissing-balloon (KBI) or sequential inflation was performed in 35%. SB functional closure occurred in 17.4%, with independent predictors alpha40 degrees and diameter ratio MB/SB1.22. After 12+/-4 months there were five myocardial infarctions (6%) and 13 (15%) target lesion revascularization procedures. Independent predictors of major cardiovascular events were carina angle40 degrees , MB lesion length8 mm, negative change of between-branch angle, DES usage, and KBI.Smaller carina angle with straightening of MV-main branch from stent implantation in coronary bifurcations predicted higher SB compromise, restenosis, and MACE rates during follow-up of 1 year.

catheterisation laboratory: the no-reflow phenomenon and coronary perforations Olivier Muller1, MD PhD; Stephan Windecker2, MD; Thomas Cuisset3, MD; Jean Fajadet4, MD; Mark Mason5, MD; Andrea Zuffi6, MD; Alexander Doganov7, MD; Eric Eeckhout6, MD PhD 1. Cardiovascular Center Aalst, OLV Clinic, Aalst, Belgium; 2. Department of Cardiology, University Hospital Bern, Bern, Switzerland; 3. Department of Cardiology, University Hospital La Timone, Marseille, France; 4. Unite de Cardiologie Interventionnelle, Clinique Pasteur, Toulouse, France; 5. Harefield Hospital, Royal Brompton and Harefield NHS Trust, Middlesex, United Kingdom; 6. Service de Cardiologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; 7. National Heart Institute, Sofia, Bulgaria

The objective of this study was to assess the implication of copy number changes of epidermal growth factor receptor (EGFR) and erbB2 genes in the etiology and progression of ovarian tumors. In our study, we used the highly reliable method of fluorescent in situ hybridization, applied on tissue microarray, containing 1006 ovarian tumors from different malignancy, histologic type and grade, and tumor stage, in order to analyze the correlations between gene copy number changes and tumor phenotype. We established copy number changes of erbB2 in 15.30% of malignant ovarian tumors-8.16% amplifications and 7.14% gains. The frequency of EGFR copy number changes was 10.67%-3.65% amplifications and 7.02% gains. EGFR gains occurred with approximately the same frequency in malignant (7.02%), low malignant potential (8.33%), and benign (7.19%) ovarian tumors. ErbB2 amplification was associated with clear cell type of ovarian cancer (P0.04). No amplification of EGFR and erbB2 genes was established in tumors with low malignant potency and in benign tumors. Regarding cancer phenotype, there was no statistically significant association between erbB2 copy number changes and histologic grade as well as tumor stage of ovarian cancer. EGFR gains are early events in ovarian tumorigenesis. Our results showed similar frequencies of EGFR gains in different grade tumors, while EGFR amplification increased from grades 1 to 2 to 3.

To ensure high-quality medical and dental care for the population, the health insurance system in Bulgaria and all relevant social relations, the Bulgarian Parliament adopted the Health Insurance Act, which aims to change the whole health system from a socialist system to a modern Western European-style health care system. The reform is partly financed by the World Bank, Washington D.C. One important component during this huge change is the definition of new health care processes and the conception and implementation of a new information system and infrastructure.

A 78-year-old woman with a Canadian Cardiovascular Society class III angina, despite maximal medical therapy, was admitted to our center for elective coronary angiography. The clinical history was remarkable for smoking, hypertension, hypercholesterolemia, and severe peripheral atherosclerosis with