First-line atezolizumab plus nab-paclitaxel for unresectable, locally advanced, or metastatic triple-negative breast cancer: IMpassion130 final overall survival analysis.

BACKGROUND: Guidelines recommend atezolizumab plus nab-paclitaxel (A + nP) for first-line treatment of unresectable, locally advanced, or metastatic triple-negative breast cancer expressing programmed death-ligand 1 (PD-L1) on tumor-infiltrating immune cells (IC), based on IMpassion130. We report the final overall survival (OS) and safety of that study as per the prespecified analysis plan. PATIENTS AND METHODS: Patients were randomized to nP 100 mg/m2 (days 1, 8, and 15 of a 28-day cycle) with atezolizumab 840 mg (A + nP) or placebo (P + nP; days 1 and 15), until progression or unacceptable toxicity. Coprimary endpoints were progression-free survival [intention-to-treat (ITT) and PD-L1 IC-positive populations] and OS (tested hierarchically in the ITT population and, if significant, in the PD-L1 IC-positive population). RESULTS: Each arm comprised 451 patients; 666 (73.8%) had died by the final OS analysis cut-off (median follow-up, 18.8 months; interquartile range, 8.9-34.7 months). Median OS in the ITT population was 21.0 months [95% confidence interval (CI), 19.0-23.4 months] with A + nP, and 18.7 months (95% CI, 16.9-20.8 months) with P + nP [stratified hazard ratio (HR), 0.87; 95% CI, 0.75-1.02; P = 0.077]. Exploratory analysis in the PD-L1 IC-positive population showed a median OS of 25.4 months (95% CI, 19.6-30.7 months) with A + nP (n = 185) and 17.9 months (95% CI, 13.6-20.3 months) with P + nP (n = 184; stratified HR, 0.67; 95% CI, 0.53-0.86). Safety outcomes were consistent with previous analyses and the known toxicity profiles of each agent. Immune-mediated adverse events of special interest were reported in 58.7% and 41.6% of patients treated with A + nP and P + nP, respectively. CONCLUSION: Although the OS benefit in the ITT population was not statistically significant, precluding formal testing, clinically meaningful OS benefit was observed with A + nP in PD-L1 IC-positive patients, consistent with prior interim analyses. This combination remained safe and tolerable with longer follow-up.

Patient-reported outcomes from the phase III IMpassion130 trial of atezolizumab plus nab-paclitaxel in metastatic triple-negative breast cancer.

BACKGROUND: Metastatic triple-negative breast cancer (mTNBC) is incurable. A key treatment goal is providing palliation while maintaining patients' health-related quality of life (HRQoL). IMpassion130 demonstrated progression-free survival benefit with atezolizumab + nab-paclitaxel (A + nP) versus placebo + nab-paclitaxel (Pl + nP) in first-line treatment of mTNBC patients with programmed death-ligand 1 positive (PD-L1+) tumors. We report data on patient-reported outcomes (PROs), which capture patient perspectives of treatment. PATIENTS AND METHODS: Patients with untreated advanced or mTNBC received atezolizumab (840 mg) or placebo every 2 weeks in combination with nab-paclitaxel (100 mg/m2) on days 1, 8, and 15 of each 28-day cycle until progression or intolerance. Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and its Breast Cancer Module (QLQ-BR23) on day 1 of each cycle, at end of treatment, and every 4 weeks during 1 year of follow-up. Time-to-deterioration (TTD) in HRQoL (first ≥10-point decrease from baseline lasting two cycles) was a secondary end point. Exploratory end points included TTD in functioning and mean and mean change from baseline scores in HRQoL, functioning, and disease- and treatment-related symptoms. RESULTS: Baseline completion of PROs was 92% (QLQ-C30) and 89% (QLQ-BR23) and remained >80% through cycle 20 in intent-to-treat (ITT) and PD-L1+ patients. No differences between arms in median TTD in PD-L1+ patients were observed for HRQoL {hazard ratio (HR) 0.94 [95% confidence interval (CI) 0.69-1.28]} or physical [HR 1.02 (95% CI 0.76-1.37)] or role [HR 0.77 (95% CI 0.57-1.04)] functioning. Mean baseline scores for A + nP versus Pl + nP for HRQoL (67.5 versus 65.0) and physical (82.8 versus 79.4) and role (73.7 versus 71.7) functioning were comparable between arms and throughout the course of treatment, with no clinically meaningful (≥10 point) changes from baseline until patients discontinued treatment. No differences in clinically meaningful worsening in treatment symptoms (fatigue, diarrhea, or nausea/vomiting) were observed between arms. Results in ITT patients were similar. CONCLUSIONS: A + nP as first-line treatment for mTNBC delayed progression without compromising patients' day-to-day functioning or HRQoL or worsening treatment symptoms. CLINICALTRIAL. GOV IDENTIFIER: NCT02425891.

Encapsulation of ethylhexyl methoxycinnamate, a light-sensitive UV filter, in lipid nanoparticles.

The aim of this study was to encapsulate ethylhexyl methoxycinnamate (EMC), a commonly used UVB filter, in a solid lipid matrix in order to obtain microparticles and then nanoparticles to reduce its photo-instability under UV light exposure. Glyceryl behenate, rice bran wax and ozokerite were investigated for encapsulating EMC. The suspensions of nanoparticles contained 70% encapsulated EMC (relative to the lipid mass). The absorbance level at 310 nm of suspensions containing nanoparticles was more than twice that of those containing microparticles. So, decreasing the size of particles improved the efficiency of light protection, regardless of the lipid material used. Moreover, free EMC presented a 30% loss of its efficiency after 2 h of irradiation, whereas the three NLC formulations showed a loss of absorbency between 10% and 21%. The in vitro cutaneous penetration test did not show a higher potential penetration for EMC contained in nanosuspensions compared to free EMC.

In vitro evaluation of the cutaneous penetration of sprayable sunscreen emulsions with high concentrations of UV filters.

The aim of this study was to evaluate the possible penetration through human skin of organic and inorganic filters contained in sunscreen emulsions packaged in aerosol cans, using an in vitro method. Experiments were carried out on two different types of emulsion: W/Si and W/O. This study was conducted using static diffusion cells (Franz cells). The determination of organic UV filters [Methylene Bis Benzotriazolyl Tetramethylbutylphenol (MBBT); Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine (BEMT); Diethylamino Hydroxybenzoyl Hexyl Benzoate (DHHB); Ethylhexyl Methoxycinnamate (EMC); and 2-Ethylhexyl Dimethyl PABA (ED-PABA)] was performed by High Performance Liquid Chromatography (HPLC). Therefore, it was important to develop a single analytical method for the quantification of the five organic filters with the aim of facilitating the experiment. The determination of inorganic filters [titanium dioxide (TiO(2)) and zinc oxide (ZnO)] was performed using an emission spectrometric analysis method (ICP-OES). The HPLC and ICP-OES methods were validated. After a penetration test of 24 h duration, the results showed very low penetration only for two of the organic filters (maximum penetration of 1.21 microg cm(-2) h(-1) for EMC and 0.14 microg cm(-2) h(-1) for MBBT) and no penetration for the inorganic filters. Moreover, more than 50% of each sunscreen agent stayed on the surface on the skin. These results are consistent with those in the literature that presents similar experiments. This study showed that the sprayable sunscreen products developed, which contained high concentrations of UV filters, presented a low level of skin penetration.

Influence of different parameters on droplet size and size distribution of sprayable sunscreen emulsions with high concentration of UV-filters.

The purpose of this study was to evaluate the possible influence of different formulation and technological parameters such as sunscreen type and concentration, viscosity, propellant gas, actuator and valve type on size and size distribution of droplets in emulsions of waterproof sunscreens conditioned in aerosol cans. Different kinds of emulsion, W/Si and W/O, were prepared with high concentrations of organic and inorganic UV-filters. These formulations were incorporated in aerosol cans with gas (a blend of butane, propane and isobutane). The size and size distribution of the droplets were analysed by laser diffraction using a Malvern Spraytec. The results showed that the sprayability of the formulation and the particle size characteristics of the emitted sprays are dependent on the physicochemical properties of the formulations. Sprayable waterproof sunscreen emulsions, with a high sun protection factor and negligible percentage of emitted droplets below 30 mum, were successfully developed by optimizing formulation parameters and using appropriate actuators and valves.

Early effects of metformin in women with polycystic ovary syndrome: a prospective randomized, double-blind, placebo-controlled trial.

CONTEXT: Metformin is successfully used in the treatment of cycle disorders and anovulation in women with polycystic ovary syndrome (PCOS). No data of the exact point and the impact of insulin resistance (IR) on metformin's efficacy exist. OBJECTIVE: The objective of the study was to evaluate the early potential effects of metformin treatment, their time of onset, and the role of IR on metformin's efficacy. DESIGN: This was a prospective randomized, double-blind, placebo-controlled trial. SETTING: The study was conducted at the University of Heidelberg, Heidelberg, Germany. PATIENTS: The patient population was 45 oligo-/anovulatory PCOS women with typical ovaries. INTERVENTIONS: Women were stratified for IR (32 of 13) and then randomly allocated to receive either metformin (n = 22) or placebo (n = 23) and were assessed before and every 4 wk within a treatment period of 12 wk. MAIN OUTCOME MEASURES: Menstrual disturbance and markers of insulin metabolism were measured. RESULTS: The main outcome criterion menstrual disturbance was successfully improved in the metformin-treated group, depending on IR (12 of 15 vs. three of 17), whereas women without IR (four of seven vs. four of six) had no significant amelioration of their menstrual irregularities (P < 0.05). Estradiol levels increased continuously only in the treatment group (P < 0.005), indicating an improvement of ovulatory function. Sixty-seven percent of metformin-treated women had at least one ovulation, compared with only 45% in the placebo group, shown by biphasic body temperature curves. Insulin sensitivity improved within 4 wk after beginning of metformin as shown by an increased area under the curve glucose to insulin ratio, compared with baseline (P < 0.005). CONCLUSIONS: IR is a baseline predictor of clinical efficacy in metformin treatment in PCOS women measured by improved menstrual cyclicity and ovulatory function.

Micellar solubilisation of corticoids by nonionic surfactants.

Summary The availaibility of a drug in the presence of surfactants depends on the amount of free drug in solution. In previous work (1), we tried to measure the amount of free corticoïds (Dexamethasone, Fluprednylidene 21 - acetate and Betamethasone 17 - valerate) in topical preparations containing various amounts of non-ionic surfactants (ethers of polyoxyethyleneglycol. With this aim, experiments have been carried out to characterise the nature of the interaction between these drugs and the surfactants. We have studied the micellar solubilisation of the three steroïds by means of solubility measurements. From the results obtained, we have calculated the solubilising capacities of surfactants expressed on molar basis and we can assume that solubilisation probably takes place in the inner part of micelles. Calculations of solubility ratios (R) as a function of the percentage of surfactant enable determination of a binding capacity of the surfactants for the drugs. This value is a constant independent of the concentration of the surfactants. If the distribution law is obeyed, the interaction can also be expressed by a partition coefficient calculated from the results of the solubility measurements. To verify whether the distribution law really applies and if the interaction is independent of the amount of free drug in solution, we have employed, for Dexamethasone, the methods of equilibrium and differential dialysis.