Summary Background For patients with breast cancer and metastases in the sentinel nodes, axillary dissection has been standard treatment. However, for patients with limited sentinel-node involvement, ...axillary dissection might be overtreatment. We designed IBCSG trial 23–01 to determine whether no axillary dissection was non-inferior to axillary dissection in patients with one or more micrometastatic (≤2 mm) sentinel nodes and tumour of maximum 5 cm. Methods In this multicentre, randomised, non-inferiority, phase 3 trial, patients were eligible if they had clinically non-palpable axillary lymph node(s) and a primary tumour of 5 cm or less and who, after sentinel-node biopsy, had one or more micrometastatic (≤2 mm) sentinel lymph nodes with no extracapsular extension. Patients were randomly assigned (in a 1:1 ratio) to either undergo axillary dissection or not to undergo axillary dissection. Randomisation was stratified by centre and menopausal status. Treatment assignment was not masked. The primary endpoint was disease-free survival. Non-inferiority was defined as a hazard ratio (HR) of less than 1·25 for no axillary dissection versus axillary dissection. The analysis was by intention to treat. Per protocol, disease and survival information continues to be collected yearly. This trial is registered with ClinicalTrials.gov , NCT00072293. Findings Between April 1, 2001, and Feb 28, 2010, 465 patients were randomly assigned to axillary dissection and 469 to no axillary dissection. After the exclusion of three patients, 464 patients were in the axillary dissection group and 467 patients were in the no axillary dissection group. After a median follow-up of 5·0 (IQR 3·6–7·3) years, we recorded 69 disease-free survival events in the axillary dissection group and 55 events in the no axillary dissection group. Breast-cancer-related events were recorded in 48 patients in the axillary dissection group and 47 in the no axillary dissection group (ten local recurrences in the axillary dissection group and eight in the no axillary dissection group; three and nine contralateral breast cancers; one and five regional recurrences; and 34 and 25 distant relapses). Other non-breast cancer events were recorded in 21 patients in the axillary dissection group and eight in the no axillary dissection group (20 and six second non-breast malignancies; and one and two deaths not due to a cancer event). 5-year disease-free survival was 87·8% (95% CI 84·4–91·2) in the group without axillary dissection and 84·4% (80·7–88·1) in the group with axillary dissection (log-rank p=0·16; HR for no axillary dissection vs axillary dissection was 0·78, 95% CI 0·55–1·11, non-inferiority p=0·0042). Patients with reported long-term surgical events (grade 3–4) included one sensory neuropathy (grade 3), three lymphoedema (two grade 3 and one grade 4), and three motor neuropathy (grade 3), all in the group that underwent axillary dissection, and one grade 3 motor neuropathy in the group without axillary dissection. One serious adverse event was reported, a postoperative infection in the axilla in the group with axillary dissection. Interpretation Axillary dissection could be avoided in patients with early breast cancer and limited sentinel-node involvement, thus eliminating complications of axillary surgery with no adverse effect on survival. Funding None.
Dual antiplatelet therapy with aspirin and a P2Y12 receptor blocker is a key strategy to reduce platelet reactivity and to prevent thrombotic events in patients treated with percutaneous coronary ...intervention. In an earlier consensus document, we proposed cutoff values for high on-treatment platelet reactivity to adenosine diphosphate (ADP) associated with post–percutaneous coronary intervention ischemic events for various platelet function tests (PFTs). Updated American and European practice guidelines have issued a Class IIb recommendation for PFT to facilitate the choice of P2Y12 receptor inhibitor in selected high-risk patients treated with percutaneous coronary intervention, although routine testing is not recommended (Class III). Accumulated data from large studies underscore the importance of high on-treatment platelet reactivity to ADP as a prognostic risk factor. Recent prospective randomized trials of PFT did not demonstrate clinical benefit, thus questioning whether treatment modification based on the results of current PFT platforms can actually influence outcomes. However, there are major limitations associated with these randomized trials. In addition, recent data suggest that low on-treatment platelet reactivity to ADP is associated with a higher risk of bleeding. Therefore, a therapeutic window concept has been proposed for P2Y12 inhibitor therapy. In this updated consensus document, we review the available evidence addressing the relation of platelet reactivity to thrombotic and bleeding events. In addition, we propose cutoff values for high and low on-treatment platelet reactivity to ADP that might be used in future investigations of personalized antiplatelet therapy.
The addition of clopidogrel to aspirin treatment reduces ischemic events in a wide range of patients with cardiovascular disease. However, recurrent ischemic event occurrence during dual antiplatelet ...therapy, including stent thrombosis, remains a major concern. Platelet function measurements during clopidogrel treatment demonstrated a variable and overall modest level of P2Y12 inhibition. High on-treatment platelet reactivity to adenosine diphosphate (ADP) was observed in selected patients. Multiple studies have now demonstrated a clear association between high on-treatment platelet reactivity to ADP measured by multiple methods and adverse clinical event occurrence. However, the routine measurement of platelet reactivity has not been widely implemented and recommended in the guidelines. Reasons for the latter include: 1) a lack of consensus on the optimal method to quantify high on-treatment platelet reactivity and the cutoff value associated with clinical risk; and 2) limited data to support that alteration of therapy based on platelet function measurements actually improves outcomes. This review provides a consensus opinion on the definition of high on-treatment platelet reactivity to ADP based on various methods reported in the literature and proposes how this measurement may be used in the future care of patients.
Abstract Objective We attempted to identify predictors of adverse outcomes after traditional open and hybrid zone 0 total aortic arch replacement. Methods We performed multivariable analysis using 16 ...variables to identify predictors of adverse outcomes (mortality, permanent neurologic events, and permanent renal failure necessitating hemodialysis) in 319 consecutive patients who underwent total aortic arch replacement in the past 8.5 years and a subgroup analysis in 25 propensity-matched pairs. A total of 274 patients (85.9%) had traditional open repair, and 45 patients (14.1%) had hybrid zone 0 total arch exclusion. Results Operative mortality was 10.3% (n = 33): 11.1% (n = 5) in the hybrid group and 10.2% (n = 28) in the traditional group ( P = .79). A total of 19 patients (5.9%) had permanent stroke (15 traditional 5.5% vs 4 hybrid 8.9%; P = .32), and 2 patients (both traditional) had permanent paraplegia ( P = 1.00). The hybrid group had more total neurologic events ( P = .051) but not more permanent strokes ( P = .32). Prior cardiac disease unrelated to the aorta ( P = .0033) and congestive heart failure ( P = .0053) independently predicted permanent adverse outcome (operative mortality, permanent neurologic event, or permanent renal failure). Concomitant coronary artery bypass grafting independently predicted permanent stroke ( P = .032), as did previous cerebrovascular disease ( P = .032). In multivariable analysis, procedure type (hybrid or traditional) was not an independent predictor of stroke ( P = .09). During a median follow-up of 4.5 years (95% confidence interval, 3.9-4.9), survival was 78.7%, with no intergroup difference ( P = .14). Conclusions Among contemporary cases, both traditional and hybrid total aortic arch replacement had acceptable results. Comparing these 2 different surgical treatment options is challenging, and an individualized approach offers the best results. Permanent adverse outcome was not significantly different between the 2 groups. Procedure type is not an independent predictor of permanent stroke. Prior cardiac disease, past or current smoking, and congestive heart failure predict adverse outcomes for total aortic arch replacement.
Summary Background The combined efficacy analysis of the TEXT and SOFT trials showed a significant disease-free survival benefit with exemestane plus ovarian function suppression (OFS) compared with ...tamoxifen plus OFS. We present patient-reported outcomes from these trials. Methods Between Nov 7, 2003, and April 7, 2011, 4717 premenopausal women with hormone-receptor positive breast cancer were enrolled in TEXT or SOFT to receive unmasked adjuvant treatment with 5 years of exemestane plus OFS or tamoxifen plus OFS. Gonadotropin-releasing hormone analogue triptorelin, bilateral oophorectomy, or bilateral ovarian irradiation were used to achieve OFS. Chemotherapy use was optional. Randomisation with permuted blocks was done with the International Breast Cancer Study Group's internet-based system and was stratified by chemotherapy use and status of lymph nodes. Patients completed a quality of life (QoL) form comprising several global and symptom indicators at baseline, every 6 months for 24 months, and then every year during years 3 to 6. Differences in the change of QoL from baseline between the two treatments were tested at 6 months, 24 months, and 60 months with mixed-models for repeated measures for each trial with and without chemotherapy and overall. The analysis was by intention to treat. At the time of analysis, the median follow-up was 5·7 years (IQR 3·7–6·9); treatment and follow-up of patients continue. The trials are registered with ClinicalTrials.gov , as NCT00066703 (TEXT) and NCT00066690 (SOFT). Findings Patients on tamoxifen plus OFS were more affected by hot flushes and sweats over 5 years than were those on exemestane plus OFS, although these symptoms improved. Patients on exemestane plus OFS reported more vaginal dryness, greater loss of sexual interest, and difficulties becoming aroused than did patients on tamoxifen plus OFS; these differences persisted over time. An increase in bone or joint pain was more pronounced, particularly in the short term, in patients on exemestane plus OFS than patients on tamoxifen plus OFS. Changes in global QoL indicators from baseline were small and similar between treatments over the 5 years. Interpretation Overall, from a QoL perspective, there is no strong indication to favour either exemestane plus OFS or tamoxifen plus OFS. The distinct effects of the two treatments on the burden of endocrine symptoms need to be addressed with patients individually. Funding Pfizer, International Breast Cancer Study Group, and US National Cancer Institute.
Focused cardiac ultrasound (FoCUS) is a simplified, clinician-performed application of echocardiography that is rapidly expanding in use, especially in emergency and critical care medicine. Performed ...by appropriately trained clinicians, typically not cardiologists, FoCUS ascertains the essential information needed in critical scenarios for time-sensitive clinical decision making. A need exists for quality evidence-based review and clinical recommendations on its use.
The World Interactive Network Focused on Critical UltraSound conducted an international, multispecialty, evidence-based, methodologically rigorous consensus process on FoCUS. Thirty-three experts from 16 countries were involved. A systematic multiple-database, double-track literature search (January 1980 to September 2013) was performed. The Grading of Recommendation, Assessment, Development and Evaluation method was used to determine the quality of available evidence and subsequent development of the recommendations. Evidence-based panel judgment and consensus was collected and analyzed by means of the RAND appropriateness method.
During four conferences (in New Delhi, Milan, Boston, and Barcelona), 108 statements were elaborated and discussed. Face-to-face debates were held in two rounds using the modified Delphi technique. Disagreement occurred for 10 statements. Weak or conditional recommendations were made for two statements and strong or very strong recommendations for 96. These recommendations delineate the nature, applications, technique, potential benefits, clinical integration, education, and certification principles for FoCUS, both for adults and pediatric patients.
This document presents the results of the first International Conference on FoCUS. For the first time, evidence-based clinical recommendations comprehensively address this branch of point-of-care ultrasound, providing a framework for FoCUS to standardize its application in different clinical settings around the world.
Speciation generally involves a three-step process--range expansion, range fragmentation and the development of reproductive isolation between spatially separated populations. Speciation relies on ...cycling through these three steps and each may limit the rate at which new species form. We estimate phylogenetic relationships among all Himalayan songbirds to ask whether the development of reproductive isolation and ecological competition, both factors that limit range expansions, set an ultimate limit on speciation. Based on a phylogeny for all 358 species distributed along the eastern elevational gradient, here we show that body size and shape differences evolved early in the radiation, with the elevational band occupied by a species evolving later. These results are consistent with competition for niche space limiting species accumulation. Even the elevation dimension seems to be approaching ecological saturation, because the closest relatives both inside the assemblage and elsewhere in the Himalayas are on average separated by more than five million years, which is longer than it generally takes for reproductive isolation to be completed; also, elevational distributions are well explained by resource availability, notably the abundance of arthropods, and not by differences in diversification rates in different elevational zones. Our results imply that speciation rate is ultimately set by niche filling (that is, ecological competition for resources), rather than by the rate of acquisition of reproductive isolation.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Despite a rich phenomenology, γ-ray bursts (GRBs) are divided into two classes based on their duration and spectral hardness-the long-soft and the short-hard bursts. The discovery of afterglow ...emission from long GRBs was a watershed event, pinpointing their origin to star-forming galaxies, and hence the death of massive stars, and indicating an energy release of about 1051 erg. While theoretical arguments suggest that short GRBs are produced in the coalescence of binary compact objects (neutron stars or black holes), the progenitors, energetics and environments of these events remain elusive despite recent localizations. Here we report the discovery of the first radio afterglow from the short burst GRB 050724, which unambiguously associates it with an elliptical galaxy at a redshift z = 0.257. We show that the burst is powered by the same relativistic fireball mechanism as long GRBs, with the ejecta possibly collimated in jets, but that the total energy release is 10-1,000 times smaller. More importantly, the nature of the host galaxy demonstrates that short GRBs arise from an old (> 1 Gyr) stellar population, strengthening earlier suggestions and providing support for coalescing compact object binaries as the progenitors.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Background Allergic rhinitis affects 10 to 40% of the population. It reduces quality of life, school and work performance, and is a frequent reason for office visits in general practice. ...Medical costs are large but avoidable costs associated with lost work productivity are even larger than those incurred by asthma. New evidence has accumulated since the last revision of the Allergic Rhinitis and its Impact on Asthma – ARIA guidelines in 2010 prompting its update. Objective To provide a targeted update of the ARIA guidelines. Methods The ARIA guideline panel identified new clinical questions and selected questions requiring an update. We performed systematic reviews of health effects and the evidence about patient values and preferences, and resource requirements (up to June 2016). We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) evidence-to-decision frameworks to develop recommendations. Results The 2016 revision of the ARIA guidelines provides updated and new recommendations about the pharmacological treatment of allergic rhinitis. It specifically addresses the relative merits of using oral H1-antihistamines, intranasal H1-antihistamines, intranasal corticosteroids, and leukotriene receptor antagonists either alone or their combination. The ARIA guideline panel provides specific recommendations for the choice of treatment, the rationale for the choice, and discusses specific considerations that clinicians and patients may want to review in order to choose the management most appropriate for an individual patient. Conclusions Appropriate treatment of allergic rhinitis may improve patients’ quality of life, school and work productivity. ARIA recommendations support patients, their caregivers, and health care providers in choosing the optimal treatment.
In this scientific statement from the American Heart Association, experts in the field of cardiomyopathy (heart muscle disease) in children address 2 issuesthe most current understanding of the ...causes of cardiomyopathy in children and the optimal approaches to diagnosis cardiomyopathy in children. Cardiomyopathies result in some of the worst pediatric cardiology outcomes; nearly 40% of children who present with symptomatic cardiomyopathy undergo a heart transplantation or die within the first 2 years after diagnosis. The percentage of children with cardiomyopathy who underwent a heart transplantation has not declined over the past 10 years, and cardiomyopathy remains the leading cause of transplantation for children >1 year of age. Studies from the National Heart, Lung, and Blood Institute–funded Pediatric Cardiomyopathy Registry have shown that causes are established in very few children with cardiomyopathy, yet genetic causes are likely to be present in most. The incidence of pediatric cardiomyopathy is ≈1 per 100 000 children. This is comparable to the incidence of such childhood cancers as lymphoma, Wilms tumor, and neuroblastoma. However, the published research and scientific conferences focused on pediatric cardiomyopathy are sparcer than for those cancers. The aim of the statement is to focus on the diagnosis and classification of cardiomyopathy. We anticipate that this report will help shape the future research priorities in this set of diseases to achieve earlier diagnosis, improved clinical outcomes, and better quality of life for these children and their families.
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