Nanoscale metallic multilayers have been shown to have a wide range of outstanding properties, which differ to a great extent from those observed in monolithic films. Their exceptional properties are ...mainly associated with the large number of interfaces and the nanoscale layer thicknesses. Many studies have investigated these materials focusing on magnetic, mechanical, optical, or radiation tolerance properties. Thus, this review provides a summary of the findings in each area, including a description of the general attributes, the adopted synthesis methods and most common characterization techniques used. This information is followed by a compendium of the material properties and a brief discussion of related experimental data, as well as existing and promising applications. Other phenomena of interest, including thermal stability studies, self-propagating reactions and the progression from nano multilayers to amorphous and/or crystalline alloys, are also covered. In general, this review highlights the use of nano multilayer architectures as viable routes to overcome the challenges of designing and implementing new engineering materials at the nanoscale.
Patients with pretreated estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer have poor prognosis. Elacestrant is a novel, oral selective ER ...degrader that demonstrated activity in early studies.
This randomized, open-label, phase III trial enrolled patients with ER-positive/HER2-negative advanced breast cancer who had one-two lines of endocrine therapy, required pretreatment with a cyclin-dependent kinase 4/6 inhibitor, and ≤ 1 chemotherapy. Patients were randomly assigned to elacestrant 400 mg orally once daily or standard-of-care (SOC) endocrine monotherapy. Primary end points were progression-free survival (PFS) by blinded independent central review in all patients and patients with detectable
mutations.
Patients were randomly assigned to elacestrant (n = 239) or SOC (n = 238).
mutation was detected in 47.8% of patients, and 43.4% received two prior endocrine therapies. PFS was prolonged in all patients (hazard ratio = 0.70; 95% CI, 0.55 to 0.88;
= .002) and patients with
mutation (hazard ratio = 0.55; 95% CI, 0.39 to 0.77;
= .0005). Treatment-related grade 3/4 adverse events occurred in 7.2% receiving elacestrant and 3.1% receiving SOC. Treatment-related adverse events leading to treatment discontinuations were 3.4% in the elacestrant arm versus 0.9% in SOC. Nausea of any grade occurred in 35.0% receiving elacestrant and 18.8% receiving SOC (grade 3/4, 2.5% and 0.9%, respectively).
Elacestrant is the first oral selective ER degrader demonstrating a significant PFS improvement versus SOC both in the overall population and in patients with
mutations with manageable safety in a phase III trial for patients with ER-positive/HER2-negative advanced breast cancer.
Background
Abemaciclib demonstrated efficacy in hormone receptor‐positive, human epidermal growth factor receptor 2‐negative advanced breast cancer. Here we provide a comprehensive summary of the ...most common adverse events (AEs), their management, and whether AEs or dose reductions influenced progression‐free survival (PFS), in the MONARCH 2 and 3 trials.
Materials and Methods
Incidence of the most clinically relevant AEs, management, and outcomes were summarized. Time‐dependent covariate analyses examined the impact of dose reductions on PFS. PFS was estimated for patients with and without early onset of diarrhea or neutropenia.
Results
The most frequently reported AE was diarrhea, with clinically significant diarrhea (grade ≥2) reported for 42.8% of patients taking abemaciclib. Median time to onset was 1 week, and duration ranged from 6 to 12 days, depending on grade and study. Diarrhea was adequately managed by antidiarrheal medication (72.8%), dose omissions (17.3%), and reductions (16.7%). The highest rates of grade ≥2 diarrhea were observed in the first cycles and decreased in subsequent cycles. Neutropenia (grade ≥3) occurred in 25.4% of abemaciclib‐treated patients. Neutropenia resolved with dose omissions (16.8%) and/or dose reductions (11.2%). Incidence of febrile neutropenia (0.7%) or other relevant grade ≥3 hematological events (<9%) was low. Venous thromboembolic events (5.3%) were primarily treated with anticoagulants. Interstitial lung disease/pneumonitis (3.4%) was treated with corticosteroids and/or antibiotics. PFS benefit of abemaciclib was not impacted by dose reductions or early onset of toxicities.
Conclusion
Abemaciclib was generally well tolerated. The most common AEs were effectively managed by supportive medications, and/or dose adjustments, with no detriment to PFS.
Implications for Practice
Treatment with abemaciclib plus fulvestrant or nonsteroidal aromatase inhibitors is generally well tolerated in patients with hormone receptor‐positive, human epidermal growth factor receptor 2‐negative advanced breast cancer. In MONARCH 2 and MONARCH 3, any‐grade diarrhea and grade ≥3 neutropenia were effectively managed with supportive medication and/or dose adjustment. Venous thromboembolic events were treated with anticoagulants and did not often require treatment discontinuation. Interstitial lung disease/pneumonitis was infrequent and treated with corticosteroids and/or antibiotics. Clinicians should be aware of and implement management strategies, including dose adjustments according to local labels, for commonly occurring and serious adverse events to ensure continued treatment and optimize clinical benefit/risk ratio.
This article presents the results of a comprehensive safety analysis of abemaciclib‐associated adverse events, focusing on management of serious adverse events and whether adverse events and dose adjustments affect progression‐free survival.
The efficacy and safety of a novel combination of weekly paclitaxel and the epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab for the first-line treatment of recurrent and/or ...metastatic squamous cell carcinoma of the head and neck were investigated.
Patients received paclitaxel (80 mg/m2) and cetuximab (400/250 mg/m2), weekly, until disease progression or unacceptable toxicity. The primary end point was response rate.
Among 46 patients enrolled, the overall response rate was 54% 95% confidence interval (CI) 39% to 69%, with 10 (22%) complete responses and a disease control rate of 80%. Median progression-free and overall survival times were 4.2 (95% CI 2.9–5.5 months) and 8.1 months (95% CI 6.6–9.6 months), respectively. Common grade 3/4 adverse events were acne-like rash (24%), asthenia (17%) and neutropenia (13%). Prior chemotherapy and the development of acne-like rash were associated with tumor response but not survival. No association between tumor EGFR expression or EGFR gene copy number and response or survival was found.
The combination of cetuximab and weekly paclitaxel was active and well tolerated by these poor prognosis patients and may be an option for the treatment of medically unfit patients, particularly those for whom platinum is contraindicated.
The objective of this study was to review the characteristics and outcome of prosthetic joint infections (PJI) due to Enterococcus sp. collected in 18 hospitals from six European countries. Patients ...with a PJI due to Enterococcus sp. diagnosed between January 1999 and July 2012 were retrospectively reviewed. Relevant information about demographics, comorbidity, clinical characteristics, microbiological data, surgical treatment and outcome was registered. Univariable and multivariable analyses were performed. A total of 203 patients met the inclusion criteria. The mean (SD) was 70.4 (13.6) years. In 59 patients the infection was diagnosed within the first 30 days (29.1%) from arthroplasty, in 44 (21.7%) between 31 and 90 days, in 54 (26.6%) between 91 days and 2 years and in 43 (21%) after 2 years. Enterococcus faecalis was isolated in 176 cases (89%). In 107 (54%) patients the infection was polymicrobial. Any comorbidity (OR 2.53, 95% CI 1.18–5.40, p 0.01), and fever (OR 2.65, 95% CI 1.23–5.69, p 0.01) were independently associated with failure. The only factor associated with remission was infections diagnosed later than 2 years (OR 0.25, 95% CI 0.09–0.71, p 0.009). In conclusion, prosthetic joint infections due to Enterococcus sp. were diagnosed within the first 2 years from arthroplasty in >70% of the patients, almost 50% had at least one comorbidity and infections were frequently polymicrobial (54%). The global failure rate was 44% and patients with comorbidities, fever, and diagnosed within the first 2 years from arthroplasty had a poor prognosis.
It is important to know the spectrum of the microbial aetiology of prosthetic joint infections (PJIs) to guide empiric treatment and establish antimicrobial prophylaxis in joint replacements. There ...are no available data based on large contemporary patient cohorts. We sought to characterize the causative pathogens of PJIs and to evaluate trends in the microbial aetiology. We hypothesized that the frequency of antimicrobial-resistant organisms in PJIs has increased in the recent years. We performed a cohort study in 19 hospitals in Spain, from 2003 to 2012. For each 2-year period (2003–2004 to 2011–2012), the incidence of microorganisms causing PJIs and multidrug-resistant bacteria was assessed. Temporal trends over the study period were evaluated. We included 2524 consecutive adult patients with a diagnosis of PJI. A microbiological diagnosis was obtained for 2288 cases (90.6%). Staphylococci were the most common cause of infection (1492, 65.2%). However, a statistically significant rising linear trend was observed for the proportion of infections caused by Gram-negative bacilli, mainly due to the increase in the last 2-year period (25% in 2003–2004, 33.3% in 2011–2012; p 0.024 for trend). No particular species contributed disproportionally to this overall increase. The percentage of multidrug-resistant bacteria PJIs increased from 9.3% in 2003–2004 to 15.8% in 2011–2012 (p 0.008), mainly because of the significant rise in multidrug-resistant Gram-negative bacilli (from 5.3% in 2003–2004 to 8.2% in 2011–2012; p 0.032). The observed trends have important implications for the management of PJIs and prophylaxis in joint replacements.
Lomentospora prolificans is an emerging cause of serious invasive fungal infections. Optimal treatment of these infections is unknown, although voriconazole-containing treatment regimens are ...considered the treatment of choice. The objective of this study was to evaluate the role of combination antifungal therapy for L. prolificans infections.
We performed a retrospective review of medical records of patients with invasive L. prolificans infection diagnosed between 1 January 2008 and 9 September 2019 that were documented in the FungiScope® registry of rare invasive fungal infections. We compared clinical outcomes between antifungal treatment strategies.
Over the study period, 41 individuals with invasive L. prolificans infection from eight different countries were documented in the FungiScope® registry. Overall, 17/40 (43%) had treatment response/stable disease and 21/40 (53%) had a fatal outcome attributed to invasive fungal infection. Combination antifungal therapy was associated with increased 28-day survival (15/24 survived versus 4/16 receiving monotherapy; p 0.027) and the combination voriconazole plus terbinafine trended to be associated with higher rates of treatment success (10/16, 63%, 95% CI 35%–85%) compared with other antifungal treatment regimens (7/24, 29%, 95% CI 13%–51%, p 0.053). In Kaplan–Meier survival analysis there was a higher survival probability in individuals receiving the voriconazole/terbinafine combination compared with other antifungal regimens (median survival 150 days versus 17 days).
While overall mortality was high, combination antifungal treatment, and in particular combination therapy with voriconazole plus terbinafine may be associated with improved treatment outcomes compared with other antifungal regimens for the treatment of invasive L. prolificans infections.
Aim: The antioxidant capacity of human milk reflects the presence and activity of multiple components, which prevent oxidative rancidity. The aim of this study was to use the Oxygen Radical ...Absorbance Capacity assay to assess human milk antioxidant capacity and find correlations with milk components.
Methods: Milk samples collected from 60 breastfeeding women at 1 month postpartum were assayed for antioxidant capacity, vitamins E and A, and fatty acids. Potential statistical relationships of concentrations of vitamins A and E and polyunsaturated fatty acids on the antioxidant capacity of human milk were determined.
Results: Human milk antioxidant capacity was positively attributed to α‐tocopherol concentration (ρ < 0.05). The vitamin A concentration did not significantly contribute to milk antioxidant capacity, but was correlated to milk α‐tocopherol concentration (r = 0.587; ρ < 0.001). There was no evidence of an inverse relationship between polyunsaturated fatty acids concentration and the antioxidant capacity value of milk.
Conclusion: This study shows that α‐tocopherol is an important contributor to the oxidative stability of human milk. Moreover, there was no evidence obtained to show that women who have high levels of milk polyunsaturated fatty acids are predisposed to lower milk antioxidant capacity.
The elastodynamic half-space Green’s function has been the subject of research for more than a century since the Lamb’s classical solution. Here, we revisit the problem and present a new closed ...analytical solution, in frequency domain, based upon the Principle of Equipartition (EQP) of Energy. This principle asserts that the imaginary parts of the Green’s tensor components equal the average cross-correlations of the fields generated by the uniform incidence of
P
and
S
body waves and by Rayleigh surface waves with amplitudes weighted by partition factors. The real part of the Green’s function is the Hilbert transform of the imaginary part. We validate our results by comparing synthetic seismograms of well-known solutions for surface and buried forces and discuss the implications of this new solution. Constructing synthetic diffuse fields is a first step for identifying them in nature.
Graphical Abstract
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