Limited prospective data are available on sequential immunotherapy and BRAF/MEK inhibition for
-mutant metastatic melanoma.
SECOMBIT is a randomized, three-arm, noncomparative phase II trial ...(ClinicalTrials.gov identifier: NCT02631447). Patients with untreated, metastatic
-mutant melanoma from 37 sites in nine countries were randomly assigned to arm A (encorafenib 450 mg orally once daily plus binimetinib 45 mg orally twice daily until progressive disease PD -> ipilimumab plus nivolumab ipilimumab 3 mg/kg once every 3 weeks and nivolumab 1 mg/kg once every 3 weeks × four cycles -> nivolumab 3 mg/kg every 2 weeks), arm B ipilimumab plus nivolumab until PD -> encorafenib plus binimetinib, or arm C (encorafenib plus binimetinib for 8 weeks -> ipilimumab plus nivolumab until PD -> encorafenib plus binimetinib). The primary end point was overall survival (OS) at 2 years. Secondary end points included total progression-free survival, 3-year OS, best overall response rate, duration of response, and biomarkers in the intent-to-treat population. Safety was analyzed throughout sequential treatment in all participants who received at least one dose of study medication.
A total of 209 patients were randomly assigned (69 in arm A, 71 in arm B, and 69 in arm C). At a median follow-up of 32.2 (interquartile range, 27.9-41.6) months, median OS was not reached in any arm and more than 30 patients were alive in all arms. Assuming a null hypothesis of median OS of ≤ 15 months, the OS end point was met for all arms. The 2-year and 3-year OS rates were 65% (95% CI, 54 to 76) and 54% (95% CI, 41 to 67) in arm A, 73% (95% CI, 62 to 84) and 62% (95% CI, 48 to 76) in arm B, and 69% (95% CI, 59 to 80) and 60% (95% CI, 58 to 72) in arm C. No new safety signals emerged.
Sequential immunotherapy and targeted therapy provide clinically meaningful survival benefits for patients with
-mutant melanoma.
Background and Objective
No previous study has directly compared the levels of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) between smokers and individuals with ...diabetes mellitus (DM) with periodontitis. Therefore, the aim of this study was to evaluate the gene expression of MMP‐1, MMP‐2, MMP‐8, MMP‐9, TIMP‐1 and TIMP‐2 in tissues with chronic periodontitis (ChP) of smokers and individuals with type 2 DM.
Material and Methods
Gingival biopsies were harvested from: non‐smokers and non‐diabetic individuals with ChP (n = 18) (ChP group); non‐diabetic smokers (≥ 10 cigarettes per day for at least the past 5 years) with ChP (n = 18) (SChP group); non‐smoking individuals with type 2 diabetes (glycated hemoglobin levels ≥ 7.5%) and ChP (n = 18) (DMChP group). The tissue levels of mRNA of MMP‐1, MMP‐2, MMP‐8, MMP‐9, TIMP‐1 and TIMP‐2 were evaluated by quantitative real‐time polymerase chain reaction.
Results
The MMP‐8 expression was the lowest in the ChP group (p < 0.05). The DMChP group presented increased mRNA levels of MMP‐2 and MMP‐9, when compared to the SChP group (p < 0.05). MMP‐1 expression and the MMP‐1/TIMP‐1, MMP‐2/TIMP‐1, MMP‐8/TIMP‐1, MMP‐9/TIMP‐1, MMP‐1/TIMP‐2 and MMP‐2/TIMP‐2 ratios were higher in the DMChP group than in the ChP and SChP groups (p < 0.05). The DMChP group presented lower mRNA levels of TIMP‐1 than the ChP group (p < 0.05). The MMP‐8/TIMP‐2 ratio was the highest in the SChP group (p < 0.05).
Conclusion
Uncontrolled type 2 DM upregulates the ratio of MMP/TIMPs in sites with ChP more than smoking, which may contribute to a greater extracellular matrix degradation and periodontal breakdown in DM‐related periodontitis.
After myocardial infarction, the hemodynamics under basal conditions might appear to be unaltered, which makes it difficult to identify cardiac dysfunction by the usual approaches. Thus, we tested ...the response to sudden afterload stress in infarcted rats with apparently normal ejection function. Control (CT) and infarcted (MI) Wistar rats with various MI sizes were submitted to echocardiography 30 days after coronary occlusion, followed by assessment of hemodynamics under basal conditions and during a pharmacologically induced sudden pressure overload (phenylephrine 15−25 µg/kg, i.v.). Coronary occlusion resulted in cardiac remodeling proportional to MI size, although several functional parameters such as systolic pressure (SP), stroke volume (SV), and stroke work (SW) of all MI rats were similar to those of CT rats. However, the afterload stress that was produced led to a relative preservation of SV and an increase of SW in CT rats;; MI rats exhibited a significant reduction in SV and SW generation, although global cardiac function was normal under basal conditions, as indicated by regular echocardiography and hemodynamics assessment. Thus, we propose the use of sudden pharmacologically induced afterload stress as a practical and efficient procedure for identifying impaired performance of the heart in anesthetized rats, providing an additional physiological variable to be evaluated in experimental therapeutic studies.
To evaluate the frequency of maxillary dentures-related lesions and the possible associated risk factors.
Ninety-seven participants were selected, and a complete anamnesis, physical examination and ...tests of occlusion vertical dimension (OVD), retention and stability of the denture, biofilm quantification, cytopathology, sialometry, pH analysis and buffer capacity of the saliva were performed. Statistical analyses were performed with the Pearson's chi-square, Mann-Whitney tests, and Pearson's coefficient (p<0.05).
In 78% of the participants at least one denture-related lesion was found. Denture-associated stomatitis (63%), inflammatory fibrous hyperplasia (19%) and traumatic ulceration (11%) were the 3 most frequent lesions. The habit of night use of the denture was considered an independent risk factor for the development of oral lesions OR=3.0 (95% CI 1.09-8.56); p<0.05. Furthermore, the longest period of use of the same denture and biofilm also had statistically significant relation to oral lesions. The biofilm seems to be more related to the prevalence of oral lesions according to the multiple logistic regression OR=1.3 (95% CI: 1.01-1.83) p<0.05. The lack of a dentures' cleaning solution and detrition of the prothesis were independent risk factors for denture-associated stomatitis. Male gender, loss of OVD and bad buffer capacity were risk factors for angular cheilitis. Fractures of the base and repair of broken dentures were risk factors for traumatic ulcers.
These results show a high frequency of denture-related lesions. Besides, participants hygiene habits and poor quality of the dentures were the main factors for the development of these lesions.
•EEG/ERP measures are consistently abnormal in major VCI patients.•Main EEG abnormalities affect delta, theta, and alpha rhythms.•Main event-related potential abnormalities include delayed “oddball” ...N200/P300 peaks.•Those EEG measures are not diagnostic but promising as predictors and endpoints.
Vascular contribution to cognitive impairment (VCI) and dementia is related to etiologies that may affect the neurophysiological mechanisms regulating brain arousal and generating electroencephalographic (EEG) activity. A multidisciplinary expert panel reviewed the clinical literature and reached consensus about the EEG measures consistently found as abnormal in VCI patients with dementia. As compared to cognitively unimpaired individuals, those VCI patients showed (1) smaller amplitude of resting state alpha (8–12 Hz) rhythms dominant in posterior regions; (2) widespread increases in amplitude of delta (< 4 Hz) and theta (4–8 Hz) rhythms; and (3) delayed N200/P300 peak latencies in averaged event-related potentials, especially during the detection of auditory rare target stimuli requiring participants’ responses in “oddball” paradigms. The expert panel formulated the following recommendations: (1) the above EEG measures are not specific for VCI and should not be used for its diagnosis; (2) they may be considered as “neural synchronization” biomarkers to enlighten the relationships between features of the VCI-related cerebrovascular lesions and abnormalities in neurophysiological brain mechanisms; and (3) they may be tested in future clinical trials as prognostic biomarkers and endpoints of interventions aimed at normalizing background brain excitability and vigilance in wakefulness.
No prospective data were available prior to 2021 to inform selection between combination BRAF and MEK inhibition versus dual blockade of programmed cell death protein-1 (PD-1) and cytotoxic T ...lymphocyte antigen-4 (CTLA-4) as first-line treatment options for BRAFV600-mutant melanoma. SECOMBIT (NCT02631447) was a randomized, three-arm, noncomparative phase II trial in which patients were randomized to one of two sequences with immunotherapy or targeted therapy first, with a third arm in which an 8-week induction course of targeted therapy followed by a planned switch to immunotherapy was the first treatment. BRAF/MEK inhibitors were encorafenib plus binimetinib and checkpoint inhibitors ipilimumab plus nivolumab. Primary outcome of overall survival was previously reported, demonstrating improved survival with immunotherapy administered until progression and followed by BRAF/MEK inhibition. Here we report 4-year survival outcomes, confirming long-term benefit with first-line immunotherapy. We also describe preliminary results of predefined biomarkers analyses that identify a trend toward improved 4-year overall survival and total progression-free survival in patients with loss-of-function mutations affecting JAK or low baseline levels of serum interferon gamma (IFNy). These long-term survival outcomes confirm immunotherapy as the preferred first-line treatment approach for most patients with BRAFV600-mutant metastatic melanoma, and the biomarker analyses are hypothesis-generating for future investigations of predictors of durable benefit with dual checkpoint blockade and targeted therapy.
Emerging and re-emerging infectious disease in otorhinolaryngology (ENT) are an area of growing epidemiological and clinical interest. The aim of this section is to comprehensively report on the ...epidemiology of key infectious disease in otorhinolaryngology, reporting on their burden at the national and international level, expanding of the need of promoting and implementing preventive interventions, and the rationale of applying evidence-based, effective and cost- effective diagnostic, curative and preventive approaches. In particular, we focus on i) ENT viral infections (HIV, Epstein-Barr virus, Human Papilloma virus), retrieving the available evidence on their oncogenic potential; ii) typical and atypical mycobacteria infections; iii) non-specific granulomatous lymphadenopathy; iv) emerging paediatric ENT infectious diseases and the prevention of their complications; v) the growing burden of antimicrobial resistance in ENT and the strategies for its control in different clinical settings. We conclude by outlining knowledge gaps and action needed in ENT infectious diseases research and clinical practice and we make references to economic analysis in the field of ENT infectious diseases prevention and care.
Context. We present an extensive study of the BL Lac object Mrk 501 based on a data set collected during the multi-instrument campaign spanning from 2009 March 15 to 2009 August 1, which includes, ...among other instruments, MAGIC, VERITAS, Whipple 10 m, and Fermi-LAT to cover the γ-ray range from 0.1 GeV to 20 TeV; RXTE and Swift to cover wavelengths from UV tohard X-rays; and GASP-WEBT, which provides coverage of radio and optical wavelengths. Optical polarization measurements were provided for a fraction of the campaign by the Steward and St. Petersburg observatories. We evaluate the variability of the source and interband correlations, the γ-ray flaring activity occurring in May 2009, and interpret the results within two synchrotron self-Compton (SSC) scenarios. Aims. The multiband variability observed during the full campaign is addressed in terms of the fractional variability, and the possible correlations are studied by calculating the discrete correlation function for each pair of energy bands where the significance was evaluated with dedicated Monte Carlo simulations. The space of SSC model parameters is probed following a dedicated grid-scan strategy, allowing for a wide range of models to be tested and offering a study of the degeneracy of model-to-data agreement in the individual model parameters, hence providing a less biased interpretation than the “single-curve SSC model adjustment” typically reported in the literature. Methods. We find an increase in the fractional variability with energy, while no significant interband correlations of flux changes are found on the basis of the acquired data set. The SSC model grid-scan shows that the flaring activity around May 22 cannot be modeled adequately with a one-zone SSC scenario (using an electron energy distribution with two breaks), while it can be suitably described within a two (independent) zone SSC scenario. Here, one zone is responsible for the quiescent emission from the averaged 4.5-month observing period, while the other one, which is spatially separated from the first, dominates the flaring emission occurring at X-rays and very-high-energy (>100 GeV, VHE) γ rays. The flaring activity from May 1, which coincides with a rotation of the electric vector polarization angle (EVPA), cannot be satisfactorily reproduced by either a one-zone or a two-independent-zone SSC model, yet this is partially affected by the lack of strictly simultaneous observations and the presence of large flux changes on sub-hour timescales (detected at VHE γ rays). Results. The higher variability in the VHE emission and lack of correlation with the X-ray emission indicate that, at least during the 4.5-month observing campaign in 2009, the highest energy (and most variable) electrons that are responsible for the VHE γ rays do not make a dominant contribution to the ~1 keV emission. Alternatively, there could be a very variable component contributing to the VHE γ-ray emission in addition to that coming from the SSC scenario. The studies with our dedicated SSC grid-scan show that there is some degeneracy in both the one-zone and the two-zone SSC scenarios probed, with several combinations of model parameters yielding a similar model-to-data agreement, and some parameters better constrained than others. The observed γ-ray flaring activity, with the EVPA rotation coincident with the first γ-ray flare, resembles those reported previously for low frequency peaked blazars, hence suggesting that there are many similarities in the flaring mechanisms of blazars with different jet properties.
Aim: The aim of this paper was to compare the quantity and frequency of alcohol use and its associated negative consequences between two groups of college students who were identified as being “risky ...drinkers.” Subjects were randomly allocated in a clinical trial to intervention or control groups. Methods: Risky drinking use was defined as Alcohol Use Disorders Identification Test (AUDIT) ≥8 and/or Rutgers Alcohol Problem Index (RAPI) ≥5 problems in the previous year. Students who had undergone the Brief Alcohol Screening and Intervention for College Students (BASICS) (N = 145 at baseline; 142 at 12 months, and 103 at 24 months, loss of 29.7%) were compared with a control group (N = 121 at baseline; 121 at 12 months and 113 at 24 months, loss of 9.3%), the nonintervention group. Variables included drinking frequency, quantity and peak consumption, dependence assessment, and family and friends’ abuse assessment. Results: Treated students at a 24-month follow-up decreased quantity of alcohol use per occasion and lowered AUDIT and RAPI scores. Conclusions: This is the first brief intervention work on risky drinking with college students in Brazil and the results are encouraging. However, it is difficult to conduct individual prevention strategies in a country where culture fosters heavy drinking through poor public policy on alcohol and lack of law enforcement.
The toughening effect in the alumina–zirconia system was simulated by a simple model based on two concentric spheres and a crack in the matrix, near the interface of the inclusion. The effects due to ...the zirconia
t
→
m phase transformation and the thermal stresses, which develop during the cooling stage of sintering, were also taken into account. The toughening effect was simulated imposing a temperature field both to the matrix and the inclusion and the analysis was carried out at different temperatures. The results of the simulation at room temperature were compared with the experimental data of fracture toughness obtained testing alumina–zirconia composites, containing different percentages of the oxides.
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