De-escalated therapy for HR+/HER2+ breast cancer patients with Ki67 response after 2 weeks letrozole: results of the PerELISA neoadjuvant study

BACKGROUND: In HER2+ breast cancers, neoadjuvant trials of chemotherapy plus anti-HER2 treatment consistently showed lower pathologic complete response (pCR) rates in hormone receptor (HR) positive vs negative tumors. The PerELISA study was aimed to evaluate the efficacy of a de-escalated, chemotherapy-free neoadjuvant regimen in HR+/HER2+ breast cancer patients selected on the basis of Ki67 inhibition after 2-weeks letrozole. PATIENTS AND METHODS: PerELISA is a phase II, multicentric study for postmenopausal patients with HR+/HER2+ operable breast cancer. Patients received 2-weeks letrozole, then underwent re-biopsy for Ki67 evaluation. Patients classified as molecular responders (Ki67 relative reduction >20% from baseline) continued letrozole and started trastuzumab-pertuzumab for 5 cycles. Patients classified as molecular non-responders started weekly paclitaxel for 13 weeks combined with trastuzumab-pertuzumab. Primary aim was breast and axillary pCR. According to a 2-stage Simon's design, to reject the null hypothesis, at least 8/43 pCR had to be documented. RESULTS: Sixty-four patients were enrolled, 44 were classified as molecular responders. All these patients completed the assigned treatment with letrozole-trastuzumab-pertuzumab and underwent surgery. A pCR was observed in 9/44 cases (20.5%, 95%CI 11.1%-34.5%). Among molecular non-responders, 16/17 completed treatment and underwent surgery, with pCR observed in 81.3% of the cases. PAM50 intrinsic subtype was significantly associated with Ki67 response and pCR. Among molecular responders, the pCR rate was significantly higher in HER2-enriched vs other subtypes (45.5% vs 13.8%, p=0.042). CONCLUSIONS: The primary endpoint of the study was met, by reaching the pre-specified pCRs. In patients selected using Ki67 reduction after short-term letrozole exposure, a meaningful pCR rate can be achieved without chemotherapy. PAM50 intrinsic subtyping further refines our ability to identify a subset of patients for whom chemotherapy might be spared

Forest biomass, carbon neutrality and climate change mitigation. From Science to Policy 3

The Paris Agreement and the EU Climate and Energy Framework set ambitious but necessary targets. Reducing greenhouse gas (GHG) emissions by phasing out the technologies and infrastructures that cause fossil carbon emissions is one of today’s most important challenges. In the EU, bioenergy is currently the largest renewable energy source used. Most Member States have in absolute terms increased the use of forest biomass for energy to reach their 2020 renewable energy targets.In recent years, the issue of ‘carbon neutrality’ has been debated with regard to the bioenergy products that are produced from forest biomass. There is no clear consensus among scientists on the issue and their messages may even appear contradictory to decision-makers and citizens. Divergence arises because scientists address the issue from different points of view, which can all be valid. It is important to find agreement on some basic principles, to inform policy makers. Guidance is also needed on how the results should be interpreted.This report provides insights into the current scientific debate on forest biomass, carbon neutrality and climate change mitigation. It draws on the science literature to give a balanced and policy-relevant synthesis, from both an EU and global perspective

Forest biomass, carbon neutrality and climate change mitigation. From Science to Policy 3

The Paris Agreement and the EU Climate and Energy Framework set ambitious but necessary targets. Reducing greenhouse gas (GHG) emissions by phasing out the technologies and infrastructures that cause fossil carbon emissions is one of today’s most important challenges. In the EU, bioenergy is currently the largest renewable energy source used. Most Member States have in absolute terms increased the use of forest biomass for energy to reach their 2020 renewable energy targets.In recent years, the issue of ‘carbon neutrality’ has been debated with regard to the bioenergy products that are produced from forest biomass. There is no clear consensus among scientists on the issue and their messages may even appear contradictory to decision-makers and citizens. Divergence arises because scientists address the issue from different points of view, which can all be valid. It is important to find agreement on some basic principles, to inform policy makers. Guidance is also needed on how the results should be interpreted.This report provides insights into the current scientific debate on forest biomass, carbon neutrality and climate change mitigation. It draws on the science literature to give a balanced and policy-relevant synthesis, from both an EU and global perspective

SPIRou @CFHT: design of the instrument control system

SPIRou is a near-IR (0.98-2.35\u3bcm), echelle spectropolarimeter / high precision velocimeter being designed as a next-generation instrument for the 3.6m Canada-France-Hawaii Telescope on Mauna Kea, Hawaii, with the main goals of detecting Earth-like planets around low-mass stars and magnetic fields of forming stars. The unique scientific and technical capabilities of SPIRou are described in a series of eight companion papers. In this paper, the means of controlling the instrument are discussed. Most of the instrument control is fairly normal, using off-the-shelf components where possible and reusing already available code for these components. Some aspects, however, are more challenging. In particular, the paper will focus on the challenges of doing fast (50 Hz) guiding with 30 mas repeatability using the object being observed as a reference and on thermally stabilizing a large optical bench to a very high precision ( 3c1 mK).Peer reviewed: YesNRC publication: Ye

HER2-enriched subtype and ERBB2 expression in HER2-positive breast cancer treated with dual HER2 blockade

BACKGROUND: Identification of HER2-positive breast cancers with high anti-HER2 sensitivity could help de-escalate chemotherapy. Here, we tested a clinically applicable RNA-based assay that combines ERBB2 and the HER2-enriched (HER2-E) intrinsic subtype in HER2-positive disease treated with dual HER2-blockade without chemotherapy. METHODS: A research-based PAM50 assay was applied in 422 HER2-positive tumors from five II-III clinical trials (SOLTI-PAMELA, TBCRC023, TBCRC006, PER-ELISA, EGF104090). In SOLTI-PAMELA, TBCRC023, TBCRC006, and PER-ELISA, all patients had early disease and were treated with neoadjuvant lapatinib or pertuzumab plus trastuzumab for 12-24\u2009weeks. Primary outcome was pathological complete response (pCR). In EGF104900, 296 women with advanced disease were randomized to receive either lapatinib alone or lapatinib plus trastuzumab. Progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) were evaluated. RESULTS: A total of 305 patients with early and 117 patients with advanced HER2-positive disease were analyzed. In early disease, HER2-E represented 83.8% and 44.7% of ERBB2-high and ERBB2-low tumors, respectively. Following lapatinib and trastuzumab, the HER2-E and ERBB2 (HER2-E/ERBB2)-high group showed a higher pCR rate compared to the rest (44.5%, 95% confidence interval [CI]\u2009=\u200935.4% to 53.9% vs 11.6%, 95% CI\u2009=\u20096.9% to 18.0%; adjusted odds ratio [OR] = 6.05, 95% CI\u2009=\u20093.10 to 11.80, P\u2009<\u2009.001). Similar findings were observed with neoadjuvant trastuzumab and pertuzumab (pCR rate of 66.7% in HER2-E/ERBB2-high, 95% CI\u2009=\u200922.3% to 95.7% vs 14.7% in others, 95% CI\u2009=\u20094.9% to 31.1%; adjusted OR\u2009=\u200911.60, 95% CI = 1.66 to 81.10, P\u2009=\u2009.01). In the advanced setting, the HER2-E/ERBB2-high group was independently associated with longer PFS (hazard ratio [HR]\u2009=\u20090.52, 95% CI = 0.35 to 0.79, P\u2009<\u2009.001); higher ORR (16.3%, 95% CI\u2009=\u20098.9% to 26.2% vs 3.7%, 95% CI\u2009=\u20090.8% to 10.3%, P\u2009=\u2009.02); and longer OS (HR\u2009=\u20090.66, 95% CI\u2009=\u20090.44 to 0.97, P\u2009=\u2009.01). CONCLUSIONS: Combining HER2-E subtype and ERBB2 mRNA into a single assay identifies tumors with high responsiveness to HER2-targeted therapy. This biomarker could help de-escalate chemotherapy in approximately 40% of patients with HER2-positive breast cancer

Influence of the timing of cardiac surgery on the outcome of patients with infective endocarditis and stroke.

BACKGROUND: The timing of cardiac surgery after stroke in infective endocarditis (IE) remains controversial. We examined the relationship between the timing of surgery after stroke and the incidence of in-hospital and 1-year mortalities. METHODS: Data were obtained from the International Collaboration on Endocarditis-Prospective Cohort Study of 4794 patients with definite IE who were admitted to 64 centers from June 2000 through December 2006. Multivariate logistic regression and Cox regression analyses were performed to estimate the impact of early surgery on hospital and 1-year mortality after adjustments for other significant covariates. RESULTS: Of the 857 patients with IE complicated by ischemic stroke syndromes, 198 who underwent valve replacement surgery poststroke were available for analysis. Overall, 58 (29.3%) patients underwent early surgical treatment vs 140 (70.7%) patients who underwent late surgical treatment. After adjustment for other risk factors, early surgery was not significantly associated with increased in-hospital mortality rates (odds ratio, 2.308; 95% confidence interval [CI], .942-5.652). Overall, probability of death after 1-year follow-up did not differ between 2 treatment groups (27.1% in early surgery and 19.2% in late surgery group, P = .328; adjusted hazard ratio, 1.138; 95% CI, .802-1.650). CONCLUSIONS: There is no apparent survival benefit in delaying surgery when indicated in IE patients after ischemic stroke. Further observational analyses that include detailed pre- and postoperative clinical neurologic findings and advanced imaging data (eg, ischemic stroke size), may allow for more refined recommendations on the optimal timing of valvular surgery in patients with IE and recent stroke syndromes

HACEK infective endocarditis: characteristics and outcomes from a large, multi-national cohort.

The HACEK organisms (Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens, and Kingella species) are rare causes of infective endocarditis (IE). The objective of this study is to describe the clinical characteristics and outcomes of patients with HACEK endocarditis (HE) in a large multi-national cohort. Patients hospitalized with definite or possible infective endocarditis by the International Collaboration on Endocarditis Prospective Cohort Study in 64 hospitals from 28 countries were included and characteristics of HE patients compared with IE due to other pathogens. Of 5591 patients enrolled, 77 (1.4%) had HE. HE was associated with a younger age (47 vs. 61 years; p&lt;0.001), a higher prevalence of immunologic/vascular manifestations (32% vs. 20%; p&lt;0.008) and stroke (25% vs. 17% p = 0.05) but a lower prevalence of congestive heart failure (15% vs. 30%; p = 0.004), death in-hospital (4% vs. 18%; p = 0.001) or after 1 year follow-up (6% vs. 20%; p = 0.01) than IE due to other pathogens (n = 5514). On multivariable analysis, stroke was associated with mitral valve vegetations (OR 3.60; CI 1.34-9.65; p&lt;0.01) and younger age (OR 0.62; CI 0.49-0.90; p&lt;0.01). The overall outcome of HE was excellent with the in-hospital mortality (4%) significantly better than for non-HE (18%; p&lt;0.001). Prosthetic valve endocarditis was more common in HE (35%) than non-HE (24%). The outcome of prosthetic valve and native valve HE was excellent whether treated medically or with surgery. Current treatment is very successful for the management of both native valve prosthetic valve HE but further studies are needed to determine why HE has a predilection for younger people and to cause stroke. The small number of patients and observational design limit inferences on treatment strategies. Self selection of study sites limits epidemiological inferences

Impact of early valve surgery on outcome of staphylococcus aureus prosthetic valve infective endocarditis: Analysis in the international collaboration of endocarditis-prospective cohort study

Background. The impact of early valve surgery (EVS) on the outcome of Staphylococcus aureus (SA) prosthetic valve infective endocarditis (PVIE) is unresolved. The objective of this study was to evaluate the association between EVS, performed within the first 60 days of hospitalization, and outcome of SA PVIE within the International Collaboration on Endocarditis-Prospective Cohort Study. Methods. Participants were enrolled between June 2000 and December 2006. Cox proportional hazards modeling that included surgery as a time-dependent covariate and propensity adjustment for likelihood to receive cardiac surgery was used to evaluate the impact of EVS and 1-year all-cause mortality on patients with definite left-sided S. aureus PVIE and no history of injection drug use. Results. EVS was performed in 74 of the 168 (44.3%) patients. One-year mortality was significantly higher among patients with S. aureus PVIE than in patients with non-S. aureus PVIE (48.2% vs 32.9%; P = .003). Staphylococcus aureus PVIE patients who underwent EVS had a significantly lower 1-year mortality rate (33.8% vs 59.1%; P = .001). In multivariate, propensity-adjusted models, EVS was not associated with 1-year mortality (risk ratio, 0.67 [95% confidence interval, .39-1.15]; P = .15). Conclusions. In this prospective, multinational cohort of patients with S. aureus PVIE, EVS was not associated with reduced 1-year mortality. The decision to pursue EVS should be individualized for each patient, based upon infection-specific characteristics rather than solely upon the microbiology of the infection causing PVIE