In human epidermal growth factor receptor 2 (HER2+) breast cancers, neoadjuvant trials of chemotherapy plus anti-HER2 treatment consistently showed lower pathologic complete response (pCR) rates in ...hormone receptor (HR) positive versus 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-week letrozole.
PerELISA is a phase II, multicentric study for postmenopausal patients with HR+/HER2+ operable breast cancer. Patients received 2-week letrozole, and 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 five cycles. Patients classified as molecular non-responders started weekly paclitaxel for 13weeks combined with trastuzumab-pertuzumab. Primary aim was breast and axillary pCR. According to a two-stage Simon’s design, to reject the null hypothesis, at least 8/43 pCR had to be documented.
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% confidence interval 11.1% to 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 than in other subtypes (45.5% versus 13.8%, P=0.042).
The primary end point 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.
2013-002662-40
NCT02411344
There is the need to identify new prognostic markers to refine risk stratification for HER2-positive early breast cancer patients. The aim of this study was to evaluate the association of ...tumor-infiltrating lymphocytes (TILs) with distant disease-free survival (DDFS) in patients with HER2-positive early breast cancer enrolled in the ShortHER adjuvant trial which compared 9 weeks versus 1-year trastuzumab in addition to chemotherapy, and to test the interaction between TILs and treatment arm.
Stromal TILs were assessed for 866 cases on centralized hematoxylin and eosin-stained tumor slides. The association of TILs as 10% increments with DDFS was assessed with Cox models. Kaplan–Meier curves were estimated for patients with TILs ≥20% and TILs <20%. Median follow-up was 6.1 years.
Median TILs was 5% (Q1–Q3 1%–15%). Increased TILs were independently associated with better DDFS in multivariable model hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.59–0.89, P = 0.006, for each 10% TILs increment. Five years DDFS rates were 91.1% for patients with TILs <20% and 95.7% for patients with TILs ≥20% (P = 0.025). The association between 10% TILs increments and DDFS was significant for patients randomized to 9 weeks of trastuzumab (HR 0.60, 95% CI 0.41–0.88) but not for patients treated with 1 year of trastuzumab (HR 0.89, 95% CI 0.71–1.12; test for interaction P = 0.088). For patients with TILs <20%, the HR for the comparison between the short versus the long arm was 1.75 (95% CI 1.09–2.80, P=0.021); whereas, for patients with TILs ≥20% the HR for the comparison of short versus long arm was 0.23 (95% CI 0.05–1.09, P = 0.064), resulting in a significant interaction (P = 0.015).
TILs are an independent prognostic factor for HER2-positive early breast cancer patients treated with adjuvant chemotherapy and trastuzumab and may refine the ability to identify patients at low risk of relapse eligible for de-escalated adjuvant therapy.
Fully-resolved simulations of the heating, ignition, volatile flame combustion and char conversion of single coal particles in convective gas environments are conducted and compared to experimental ...data (Molina and Shaddix, 2007). This work extends a previous computational study (Tufano et al., 2016) by adding a significant level of model fidelity and generality, in particular with regard to the particle interior description and heterogeneous kinetics. The model considers the elemental analysis of the given coal and interpolates its properties by linear superposition of a set of reference coals. The improved model description alleviates previously made assumptions of single-step pyrolysis, fixed volatile composition and simplified particle interior properties, and it allows for the consideration of char conversion. The results show that the burning behavior is affected by the oxygen concentration, i.e. for enhanced oxygen levels ignition occurs in a single step, whereas decreasing the oxygen content leads to a two-stage ignition process. Char conversion becomes dominant once the volatiles have been depleted, but also causes noticeable deviations of temperature, released mass, and overall particle conversion during devolatilization already, indicating an overlap of the two stages of coal conversion which are usually considered to be consecutive. The complex pyrolysis model leads to non-monotonous profiles of the combustion quantities which introduce a minor dependency of the ignition delay time τign on its definition. Regardless of the chosen extraction method, the simulations capture the measured values of τign very well.
In recent years, the number of trials incorporating health-related quality of life (HRQoL) data has increased. The impact of HRQoL on regulatory decision making in the European context and on ...clinical practice is not well established. We conducted an analysis of the role of QoL data extracted from the clinical trials of the drugs approved for hormone receptor positive/HER2-negative advanced/metastatic breast cancer (mBC). The results from the HRQoL were collected and a meta-analysis was performed to evaluate the impact of experimental drugs compared to standard treatments. The results showed a non-detrimental effect in HRQoL from the new treatments. As regards the approval process, from an examination of the European Medicine Agency (EMA) documents, HRQoL was reported nonextensively and contained and discussed in the European assessment reports (EPARs) for eleven trials in the approval process and cited in three cases in the EPARs and summary of medicinal product characteristics (SmPC). An effort should be made by all the stakeholders to increase the visibility of the HRQoL results in order to allow increased consideration in the approval process to make QoL data more easily and visibly available for the clinician and the patients. The evaluation should be reflected in the SmPC in order to increase the amount of information provided to the physician.
•The impact of HRQoL on regulatory decision making in Europe is not well established.•PROs allow the patient's perspective to be incorporated in assessing benefits/harms of treatments.•HRQoL data are contained/discussed not extensively in EPARs and SmPCs.•The meta-analysis on ten trials showed an overall improvement in global QoL.•An effort should be made to make QoL data more easily and visibly available.
•Glycerol pyrolysis can produce about 44–48%v hydrogen at 750–800°C.•A simplified 452 reactions kinetic model of glycerol pyrolysis has been developed.•The model has good agreement with experimental ...data.•Non condensable gas yields can reach 70%.
Pyrolysis of glycerol, a by-product of the biodiesel industry, is an important potential source of hydrogen. The obtained high calorific value gas can be used either as a fuel for combined heat and power (CHP) generation or as a transportation fuel (for example hydrogen to be used in fuel cells). Optimal process conditions can improve glycerol pyrolysis by increasing gas yield and hydrogen concentration. A detailed kinetic mechanism of glycerol pyrolysis, which involves 137 species and more than 4500 reactions, was drastically simplified and reduced to a new skeletal kinetic scheme of 44 species, involved in 452 reactions. An experimental campaign with a batch pyrolysis reactor was properly designed to further validate the original and the skeletal mechanisms. The comparisons between model predictions and experimental data strongly suggest the presence of a catalytic process promoting steam reforming of methane. High pyrolysis temperatures (750–800°C) improve process performances and non-condensable gas yields of 70%w can be achieved. Hydrogen mole fraction in pyrolysis gas is about 44–48%v. The skeletal mechanism developed can be easily used in Computational Fluid Dynamic software, reducing the simulation time.
•Resolved flow simulations of devolatilization and ignition of single coal particles.•Analysis of the impact of O2, N2 and CO2 concentration on ignition delay.•Comparison between predicted and ...measured ignition delay times.
A resolved laminar flow simulation approach is used to investigate the effect of enhanced oxygen levels on single coal particle ignition, comparing the numerical results against experimental data for well-defined conditions (Molina and Shaddix, 2007). Devolatilization is described by a generic boundary condition at the particle surface that accounts for both convective and diffusive phenomena during pyrolysis. The heating rate history of the particle is obtained by solving for intra-particle heat transfer and heat exchange between the particle and its surroundings. The time evolution of volatile release is captured by using the particle mean temperature to calculate the devolatilization rate from a single kinetic rate law with CPD-fitted parameters. The assumed volatile composition includes both light gases and larger hydrocarbons to represent tars. A skeletal kinetic mechanism for pyrolysis and oxidation of hydrocarbon and oxygenated fuels containing 52 species and 452 reactions is used to accurately describe homogeneous chemistry. Particle heat-up, pyrolysis, ignition and envelope flame stabilization are characterized in four gas atmospheres differing in oxygen content and the use of either N2 or CO2 as balance gas. In agreement with the experimental evidence, enhanced oxygen levels shorten ignition delay time τign and result in a higher intensity of the combustion process according to temperature and radical production peaks for all studied mixtures. For the studied oxy-mixtures the presence of CO2 in substitution of N2 delays ignition. The observed behavior is coherent with the different thermo-physical properties of the gas mixtures. The sensitivity of predicted ignition delay to a set of uncertainties is also discussed. It is found that while the absolute values of predicted ignition delay time are functions of potential particle preheating, particle Reynolds number and the chosen criterion to extract ignition delay, the relative trends among the gas mixtures remain in line with the experimental evidence.
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•An analysis on the evaporation of acetic acid and ethylene glycol is presented.•A multiregion approach for the fluid-solid heat transfer is adopted.•The fiber transports heat towards ...the liquid, which distribute it by convection.•The agreement with the experiments is excellent for all the cases.•Internal convection influences the preferential vaporization in the mixture.
A detailed analysis on the evaporation of acetic acid and ethylene glycol droplets is performed experimentally and numerically. The isolated droplet is positioned in a combustion chamber, suspended on a thermocouple and evaporated in buoyancy driven convection, following the thermal history throughout the droplet lifetime. The experiments provide quantitative and qualitative data on the evaporation physics of acetic acid, ethylene glycol and their mixture. The data are then modeled adopting the multiphase CFD code DropletSMOKE++, describing the flow field around the droplet, the heating rate and the evaporation process. The main novelty introduced in this work is a multiregion approach to describe the solid fiber, which allows to model the conjugate heat transfer with the liquid and the gas phase, as well as its impact on the droplet evaporation. DropletSMOKE++ results show a good agreement with the experimental data, regarding both the diameter decay and the liquid temperature, whose internal distribution in the liquid is shown to be highly affected by the heat flux from the fiber (which can contribute up to 30–40% in the total heat flux on the droplet). The effect of the thermocouple on the evaporation rate has been highlighted simulating the same experiments considering the solid as adiabatic, showing in this case a large underprediction of the vaporization rate and confirming the need of a detailed model for the fiber to correctly predict the vaporization phenomenon. The mixture evaporation has been investigated, emphasizing the importance of adopting a detailed thermodynamic model (which includes activity coefficients) and the impact of the mixture non-ideality on the evaporation process. The mixture also exhibits preferential vaporization, facilitated by the internal convection in the liquid phase.
The formation of pollutant species in turbulent diffusion flames is strongly affected by turbulence/chemistry interactions. Unsteady counterflow diffusion flames can be conveniently used to address ...the unsteady effects of hydrodynamics on the pollutant chemistry, because they exhibit a larger range of combustion conditions than those observed in steady flames.
In this paper, unsteady effects on the formation of soot (and its main precursors) and nitrogen oxides (NO
x
) are investigated by imposing harmonic oscillations on the strain rate of several counterflow diffusion flames fed with propane. Numerical results confirm that the dynamic response of each species is strongly affected by the strain rate oscillations and the characteristic time governing its chemistry. At low frequencies of imposed oscillations the soot and NO
x
profiles show strong deviations from the steady-state profile. At large frequencies a decoupling between the concentration and the velocity field is evident. In particular, the formation of soot and NO
x
is found less sensitive to velocity fluctuations for flames with large initial strain rate. The significant increase of soot and NO
x
concentrations in unsteady conditions appears to be a function of both forcing frequency and flame global strain rate. Moreover, the cut-off frequency, defined as the minimum frequency above which the strain rate oscillations have negligible effects on the formation of each species, was found to be strongly dependent on the chemical characteristic time and the flame global strain rate, but only marginally affected by the amplitude of imposed oscillations.
This work’s aim is the development of a simplified kinetic model for coal devolatilization, suitable for CFD applications. The detailed model of coal devolatilization, already developed and tested ...against a very large set of experiments and conditions, is too large to be implemented and used inside a CFD code.
An automatic procedure is developed to estimate the kinetic parameters and stoichiometric coefficients of a one step model. An optimization technique manages to minimize an objective function which measures the distance between the simple one step kinetic mechanism and the results of the detailed model of coal volatilization. The results show that rate parameters can be expressed as function of the coal rank, or better of its carbon content. Despite its simplicity, the one step model is able to characterize not only the weight loss, but also the relative yields of gaseous species (CO, H2O, CO2, H2, C2H4, HCN, H2S), tar species and char. The coal database discussed in this work includes 13 coals of different elemental composition, from lignite to anthracite. The agreement of the one step model with the detailed model of coal volatilization is satisfactory for both evolution rates and cumulative values. Finally, it is important to newly underline that the proposed model, based on the detailed model, is predictive and only needs the coal elemental composition (coal rank) as an input. Two sets of correlation for the distribution of the nitrogen and sulfur compounds into solid, tar and gas phases are also proposed.
18F-fluoroestradiol (FES) positron emission tomography (PET)/computed tomography (CT) is considered an accurate diagnostic tool to determine whole-body endocrine responsiveness. In the endocrine ...therapy (ET)-FES trial, we evaluated 18F-FES PET/CT as a predictive tool in estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC).
Eligible patients underwent an 18F-FES PET/CT at baseline. Patients with standardized uptake value (SUV) ≥ 2 received single-agent ET until progressive disease; patients with SUV < 2 were randomized to single-agent ET (arm A) or chemotherapy (ChT) (arm B). The primary objective was to compare the activity of first-line ET versus ChT in patients with 18F-FES SUV < 2.
Overall, 147 patients were enrolled; 117 presented with 18F-FES SUV ≥ 2 and received ET; 30 patients with SUV < 2 were randomized to ET or ChT. After a median follow-up of 62.4 months, 104 patients (73.2%) had disease progression and 53 died (37.3%). Median progression-free survival (PFS) was 12.4 months 95% confidence interval (CI) 3.1-59.6 months in patients with SUV < 2 randomized to arm A versus 23.0 months (95% CI 7.7-30.0 months) in arm B, hazard (HR) = 0.71, 95% CI 0.3-1.7 months; median PFS was 18.0 months (95% CI 11.2-23.1 months) in patients with SUV ≥ 2 treated with ET. Median overall survival (OS) was 28.2 months (95% CI 14.2 months-not estimable) in patients with SUV < 2 randomized to ET (arm A) versus 52.8 months (95% CI 16.2 months-not estimable) in arm B (ChT). Median OS was not reached in patients with SUV ≥ 2. 60-month OS rate was 41.6% (95% CI 10.4% to 71.1%) in arm A, 42.0% (95% CI 14.0% to 68.2%) in arm B, and 59.6% (95% CI 48.6% to 69.0%) in patients with SUV ≥ 2. In patients with SUV ≥ 2, 60-month OS rate was 72.6% if treated with aromatase inhibitors (AIs) versus 40.6% in case of fulvestrant or tamoxifen (P < 0.005).
The ET-FES trial demonstrated that ER+/HER2− MBC patients are a heterogeneous population, with different levels of endocrine responsiveness based on 18F-FES CT/PET SUV.
•18F-FES PET/CT may be used as a predictive tool of efficacy of ET to assess overall endocrine sensitivity.•Endocrine-sensitive patients (SUVmax ≥ 2) treated with single-agent ET have a prolonged OS.•In endocrine-sensitive patients, PFS and OS related to the use of AI were significantly higher than ER-directed agents.•18F-FES PET/CT can be used as a valid alternative to biopsy.
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