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Abstract Background Despite promising outcomes of treatment with anti-programmed cell death (PD)-1/PD-ligand (L)1 agents in combination with platinum-doublet chemotherapy (PDC) in the first-line setting, a significant unmet medical need remains in patients with PD-L1-unselected non-small cell lung cancer (NSCLC). Methods This multicenter, open-label, phase 1b study comprising dose-confirmation and dose-expansion parts investigated the combination of spartalizumab and various PDC regimens, with or without canakinumab, in treatment-naïve patients with PD-L1-unselected, metastatic NSCLC. The primary objectives were to determine maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of spartalizumab, with or without canakinumab, in combination with PDC in the dose-confirmation part and antitumor activity of spartalizumab in the dose-expansion part. Results The MTD/RDE of spartalizumab was 300 mg every 3 weeks (Q3W) when administered with either gemcitabine (1250 mg/m2)/cisplatin (75 mg/m2) (group A; no dose-limiting toxicities [DLTs]), pemetrexed (500 mg/m2)/cisplatin (group B; 2 DLTs: grade 2 posterior reversible encephalopathy syndrome and grade 4 hyponatremia), or paclitaxel (200 mg/m2)/carboplatin area under the curve 6 min*mg/mL (group C; 1 DLT: grade 4 neutropenic colitis). The RDE of canakinumab combined with spartalizumab and pemetrexed/cisplatin (group E; no DLTs) was 200 mg Q3W (no dose-expansion part was initiated). No new safety signals were identified. In groups A, B, C, and E, the overall response rates were 57.6%, 55.3%, 51.5%, and 57.1%, respectively. Group B compared with other groups had the longest median progression-free survival (10.4 months vs. 6.2–7.5 months), overall survival (29.7 months vs. 16.1–21.0 months), and duration of response (30.1 months vs. 6.0-8.2 months). Conclusions The combination of spartalizumab and PDC, with or without canakinumab, was well tolerated across treatment groups. The antitumor activity across treatment groups was comparable with that of pembrolizumab and pemetrexed combination. Canakinumab did not appear to improve the antitumor activity when combined with spartalizumab, pemetrexed and cisplatin. Trial registration The trial was registered in Clinicaltrials.gov with identifier no. NCT03064854. Date of Registration: 06 February 2017.

BackgroundEntrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive solid tumours, including CNS activity due to its ability to penetrate the blood-brain barrier. We present an integrated efficacy and safety analysis of patients with metastatic or locally advanced solid tumours harbouring oncogenic NTRK1, NTRK2, and NTRK3 gene fusions treated in three ongoing, early-phase trials.MethodsAn integrated database comprised the pivotal datasets of three, ongoing phase 1 or 2 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), which enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion-positive solid tumours who received entrectinib orally at a dose of at least 600 mg once per day in a capsule. All patients had an Eastern Cooperative Oncology Group performance status of 0-2 and could have received previous anti-cancer therapy (except previous TRK inhibitors). The primary endpoints, the proportion of patients with an objective response and median duration of response, were evaluated by blinded independent central review in the efficacy-evaluable population (ie, patients with NTRK fusion-positive solid tumours who were TRK inhibitor-naive and had received at least one dose of entrectinib). Overall safety evaluable population included patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG (NCT02650401; treating young adult and paediatric patients [aged ≤21 years]), who received at least one dose of entrectinib, regardless of tumour type or gene rearrangement. NTRK fusion-positive safety evaluable population comprised all patients who have received at least one dose of entrectinib regardless of dose or follow-up. These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012-000148-88 (ALKA-372-001).FindingsPatients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018) the efficacy-evaluable population comprised 54 adults with advanced or metastatic NTRK fusion-positive solid tumours comprising ten different tumour types and 19 different histologies. Median follow-up was 12.9 months (IQR 8·77-18·76). 31 (57%; 95% CI 43·2-70·8) of 54 patients had an objective response, of which four (7%) were complete responses and 27 (50%) partial reponses. Median duration of response was 10 months (95% CI 7·1 to not estimable). The most common grade 3 or 4 treatment-related adverse events in both safety populations were increased weight (seven [10%] of 68 patients in the NTRK fusion-positive safety population and in 18 [5%] of 355 patients in the overall safety-evaluable population) and anaemia (8 [12%] and 16 [5%]). The most common serious treatment-related adverse events were nervous system disorders (three [4%] of 68 patients and ten [3%] of 355 patients). No treatment-related deaths occurred.InterpretationEntrectinib induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumours, and was well tolerated with a manageable safety profile. These results show that entrectinib is a safe and active treatment option for patients with NTRK fusion-positive solid tumours. These data highlight the need to routinely test for NTRK fusions to broaden the therapeutic options available for patients with NTRK fusion-positive solid tumours.FundingIgnyta/F Hoffmann-La Roche.

Background: The misuse of psychotropic medication has increased during the past decade, especially among adolescents. The aim of our study was to describe the prevalence and patterns of the nonmedical use of benzodiazepines (BDZ) and Z‐hypnotics among school‐aged adolescents through the lens of sex. In addition, we sought to analyze the temporal evolution of the nonmedical use of these drugs during the period 2016–2021. Methods: The temporal evolution of the nonmedical use of these drugs was analyzed based on survey data collected in 2016, 2018 and 2021, which includes the first years of the COVID‐19 pandemic. To assess the possible effect of the COVID‐19 pandemic, the year at survey was conducted was introduced as a categorical variable. We used data from the Spanish State Survey on Drug Use in Secondary Education, which covers drug use among students aged 14–18 years. Using multivariate logistic regression models, we estimated the independent effect of different variables (sociodemographic data, use of other psychoactive substances, risk perception and availability) on the nonmedical use of BDZ and Z‐hypnotics. Results: In total, survey data from 95,700 adolescents were included in our analysis. The nonmedical use of BDZ and Z‐hypnotics increased among adolescents during the study period. The adjusted odds ratio (AOR) from 2016 to 2018 was 1.11 (95% CI 0.94–1.31) and from 2018 to 2021 the AOR was 1.26 (95% CI 1.08–1.46), using 2016 and 2018, respectively, as reference years. The nonmedical use of BDZ and Z‐hypnotics was more likely in adolescent girls than boys (AOR = 2.11). The nonmedical use of prescription opioids (AOR = 3.44), novel psychoactive substances and other illicit psychoactive drugs (AOR = 4.10) were risk factors for the nonmedical use of BDZ and Z‐hypnotics in both sexes. Use of cannabis (AOR = 1.38) was a predictor of nonmedical use in female adolescents only. Conclusions: This study shows that the trend of the nonmedical use of BDZ and Z‐hypnotics among school‐aged adolescents in Spain increased between 2016 and 2021. Among adolescents aged 14 to 18, the probability of nonmedical use of these psychoactive substances was twice as high for female adolescents as for male adolescents. [ABSTRACT FROM AUTHOR]

The machining of implants and parts for dental prostheses to eliminate biofilm in the implantoplasty process causes a loss of mechanical properties and also characteristics of the surfaces, making tissue regeneration difficult. In the present work, treatments consisting of elements that can reduce infection, such as citric acid and magnesium, together with elements that can improve cell adhesion and proliferation, such as collagen, are proposed for implant–crown assembly. Titanium, zirconia, composite (PMMA + feldspar) and cobalt–chromium discs were immersed in four different solutions: 25% citric acid, 25% citric acid with the addition of collagen 0.25 g/L, 25% citric acid with the addition of 0.50 g/L and the latter with the addition of 1% Mg (NO3)2. After immersion was applied for 2 and 10 min, the roughness was determined by interferometric microscopy and the contact angle (CA) was evaluated. Human fibroblastic and osteoblastic line cells (HFFs and SaOS-2) were used to determine cell viability and proliferation capacity. Cell binding and cytotoxicity were determined by resazurin sodium salt assay (Alamar Blue) and cell morphology by confocal assay (immunofluorescence F-actin (phalloidin)) after 3 days of incubation. For the evaluation of bacterial activity, the bacterial strains Sptreptococcus gordonii (Gram+) and Pseudomonas aeruginosa (Gram−) were used. The antibacterial properties of the proposed treatments were determined by means of the resazurin sodium salt (Alamar Blue) assay after 1 day of incubation. The treatments considerably decreased the contact angle of the treated samples with respect to the control samples. The treatments endowed the surfaces of the samples with a hydrophilic/super-hydrophilic character. The combination of elements proposed for this study provided cell viability greater than 70%; considering the absence of cytotoxicity, it therefore promotes the adhesion and proliferation of fibroblasts and osteoblasts. In addition, it also endows the surface with antibacterial characteristics against from Gram+ and Gram− bacteria without damaging the cells. These results show that this mouthwash can be useful in oral applications to produce a new passivation layer that favors the hydrophilicity of the surface and promotes cellular activity for the formation of fibroblasts and osteoblasts, as well as showing bactericidal activity. [ABSTRACT FROM AUTHOR]

Implantoplasty is one of the most common techniques to remove peri-implantitis from the surface of dental implants. It is a process of mechanization of the titanium surface, causing the loss of the roughness of the dental implant, which leads to difficulty in tissue regeneration. The aim of this research is to apply a decontaminant based on citric acid and add collagen and magnesium cations to promote tissue formation and have a bactericidal character. Eighty commercially pure grade 3 titanium discs were used to perform the implantoplasty protocol, like the one used in dental clinics. They were treated with four different solutions: 25% citric acid, 25% citric acid with the addition of collagen 0.25 g/L, 25% citric acid with the addition of 0.50 g/L and the latter with the addition of 1% Mg (NO3)2. The roughness was determined by confocal microscopy, the contact angle, adhesion and proliferation of HFFs fibroblasts, proliferation of SaOS-2 osteoblasts and bactericidal behavior by culturing very common bacteria in the oral cavity, Gram-positive Streptococcus sanguinis and gordonii and as Gram-negative Pseudomonas aeruginosa. The results showed that the treatment with citric acid slightly increases the roughness and decreases the contact angle from 78 to 13°, making the surface superhydrophilic. Fibroblast proliferation studies show a very significant increase at 24 h, the most favorable solution being the one containing 0.50 g/L of collagen with the presence of magnesium in a 25% citric acid solution. This same solution shows the highest cytocompatibility and osteoblastic proliferation with statistically significant differences with respect to the control and the rest of the solutions. Microbiological studies show a bactericidal effect due to the presence of citric acid, which is especially effective on Gram-positive bacteria. The results allow us to have mouthwashes that can be applied in the patient's mouth, which will help the regeneration of tissues and avoid new bacterial colonization. [ABSTRACT FROM AUTHOR]

Purpose: Abemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has demonstrated preclinical activity in non-small cell lung cancer (NSCLC). A multicenter, nonrandomized, open-label phase Ib study was conducted to test safety, MTD, pharmacokinetics, and preliminary antitumor activity of abemaciclib in combination with other therapies for treatment in patients with metastatic NSCLC.Patients and Methods: An initial dose escalation phase was used to determine the MTD of twice-daily oral abemaciclib (150, 200 mg) plus pemetrexed, gemcitabine, or ramucirumab, followed by an expansion phase for each drug combination. Pemetrexed and gemcitabine were administered according to label. The abemaciclib plus ramucirumab study examined two dosing schedules.Results: The three study parts enrolled 86 patients; all received ≥1 dose of combination therapy. Across arms, the most common treatment-emergent adverse events were fatigue, diarrhea, neutropenia, decreased appetite, and nausea. The trial did not identify an abemaciclib MTD for the combination with pemetrexed or gemcitabine but did so for the combination of abemaciclib with days 1 and 8 ramucirumab (8 mg/kg). Plasma sample analysis showed that abemaciclib did not influence the pharmacokinetics of the combination agents and the combination agents did not affect abemaciclib exposure. The disease control rate was 57% for patients treated with abemaciclib-pemetrexed, 25% for abemaciclib-gemcitabine, and 54% for abemaciclib-ramucirumab. Median progression-free survival was 5.55, 1.58, and 4.83 months, respectively.Conclusions: Abemaciclib demonstrated an acceptable safety profile when dosed on a continuous twice-daily schedule in combination with pemetrexed, gemcitabine, or ramucirumab. Abemaciclib exposures remained consistent with those observed in single-agent studies. Clin Cancer Res; 24(22); 5543-51. ©2018 AACR.

In this article, I maintain that Nazi concentrationary model was not the par excellence place of modern biopolitics but rather mainly expressed the tanatopolitical face of biopower. For this purpose, I take up Hannah Arendt's analysis, that articulate antisemitism and imperialism to explain the concentrationary phenomenon as the nucleus of Nazi totalitarianism. From her work, as well as from testimonial texts by survivors, I deduce that Nazi concentrationary mechanism attempted to reduce human life from bios to zoé, in a clear biopolitical exercise although, at the same time, by heading towards the direct and selective extermination of certain population groups, responded more to "making die and letting live", typical of sovereignty power, rather than to "making live and letting die", which characterizes biopolitics. Therefore, it had a primarily tanatopolitical dimension. Finally, I recover the possible replications and mutations of the total concentrationary phenomenon, in the presence of current biopolitical dangers. [ABSTRACT FROM AUTHOR]