Therapeutic Implications of Tumor Microenvironment in Lung Cancer: Focus on Immune Checkpoint Blockade

In the last decade, the treatment of non-small cell lung cancer (NSCLC) has been revolutionized by the introduction of immune checkpoint inhibitors (ICI) directed against programmed death protein 1 (PD-1) and its ligand (PD-L1), or cytotoxic T lymphocyte antigen 4 (CTLA-4). In spite of these improvements, some patients do not achieve any benefit from ICI, and inevitably develop resistance to therapy over time. Tumor microenvironment (TME) might influence response to immunotherapy due to its prominent role in the multiple interactions between neoplastic cells and the immune system. Studies investigating lung cancer from the perspective of TME pointed out a complex scenario where tumor angiogenesis, soluble factors, immune suppressive/regulatory elements and cells composing TME itself participate to tumor growth. In this review, we point out the current state of knowledge involving the relationship between tumor cells and the components of TME in NSCLC as well as their interactions with immunotherapy providing an update on novel predictors of benefit from currently employed ICI or new therapeutic targets of investigational agents. In first place, increasing evidence suggests that TME might represent a promising biomarker of sensitivity to ICI, based on the presence of immune-modulating cells, such as Treg, myeloid derived suppressor cells, and tumor associated macrophages, which are known to induce an immunosuppressive environment, poorly responsive to ICI. Consequently, multiple clinical studies have been designed to influence TME towards a pro-immunogenic state and subsequently improve the activity of ICI. Currently, the mostly employed approach relies on the association of \u201cclassic\u201d ICI targeting PD-1/PD-L1 and novel agents directed on molecules, such as LAG-3 and TIM-3. To date, some trials have already shown promising results, while a multitude of prospective studies are ongoing, and their results might significantly influence the future approach to cancer immunotherapy

Brivaracetam use in clinical practice: a Delphi consensus on its role as first add-on therapy in focal epilepsy and beyond

Background Antiseizure medications remain the cornerstone of treatment for epilepsy, although a proportion of individuals with the condition will continue to experience seizures despite appropriate therapy. Treatment choices for epilepsy are based on variables related to both the individual patient and the available medications. Brivaracetam is a third-generation agent antiseizure medication.Methods We carried out a Delphi consensus exercise to define the role of brivaracetam in clinical practice and to provide guidance about its use as first add-on ASM and in selected clinical scenarios. A total of 15 consensus statements were drafted by an expert panel following review of the literature and all were approved in the first round of voting by panelists. The consensus indicated different clinical scenarios for which brivaracetam can be a good candidate for treatment, including first add-on use.Results Overall, brivaracetam was considered to have many advantageous characteristics that render it a suitable option for patients with focal epilepsy, including a fast onset of action, favorable pharmacokinetic profile with few drug-drug interactions, broad-spectrum activity, and being well tolerated across a range of doses. Brivaracetam is also associated with sustained clinical response and good tolerability in the long term.Conclusions These characteristics also make it suitable as an early add-on for the elderly and for patients with post-stroke epilepsy or status epilepticus as highlighted by the present Delphi consensus

Adattamenti ematologici, ematochimici e funzionali nel cavallo in corso di addestramento

Seven horses were submitted to conventional drilling sessions, during two consecutive weeks. Blood samples were drawn before and after drilling sessions. Compared to basal values, horses submitted to drilling sessions during 2 weeks showed lower glucose levels post exercise at the 3 rd day, and higher lactate levels post exercise both after the 1st and 2nd week of drilling. Compared to basal values, Hgb and Hct showed higher levels post exercise at the 1st day of 1st week; Plt and Pct showed higher levels post exercise at the 2nd and 3rd day of both 1st and 2nd week. HR, RR, RT showed a trend to increase in all postexercise sampling times. No significant differences were observed between the 2 drilling week sessions on hematological, hematochemical and functional values

Risposta corticosurrenalica nel cavallo quarter horse in corso di sedute di allenamento e di gara simulata di barrel racing

ABSTRACT - Cortisol changes of 12 Quarter horses utilized in both training and not competitive Barrel Racing sessions were examined before and after both activities. The subjects in the study were divided into 2 groups, group A (control) and group B (exercise). From the comparison between cortisol basal levels of both groups, the statistical analysis showed a significant training effect on cortisol (F=8.86; P=0.011) changes. In the comparison between the last training session (the 6th) and the race simulation, statistical analysis showed a significant effect of not competitive race on cortisol (F=10.91; P=0.02) levels. One-way RM-ANOVA showed a significant effect of exercise on cortisol changes during both all-training weeks and not competitive sessions, with significant (F=10.91; P=0.02) higher levels in the not competitive session compared to the last training session

Symptomatic carotid atherosclerotic plaques are associated with increased infiltration of natural killer (NK) cells and higher serum levels of NK activating receptor ligands

A wide array of immune cells, including lymphocytes, is known to be present and to play a pathogenetic role in atherosclerotic lesions. However, limited information is currently available regarding the presence of Natural Killer (NF cell subsets within vessel plaque, and more in general, regarding their role in human atherosclerosis. We evaluated the distribution of NK cells in human carotid atherosclerotic plaques, dissecting asymptomatic and symptomatic patients (identified as affected by stroke, transient ischemic attack, or amaurosis fugax within 6 months) with the aim of shedding light on the putative contribution of NK cells to the pathogenic process that leads to plaque instability and subsequent clinical complications. We observed that carotid plaques were consistently infiltrated by NK cells and, among them, CD56(bright)perforin(low) NK cells were abundantly present and displayed different markers of tissue residency (i.e., CD103 CD69 and CD49a). Interestingly, carotid atherosclerotic plaques of symptomatic patients showed a higher content of NK cells and an increased ratio between CD56(bright)perforin(low) NK cells and their CD56(dim)perforin(high)counterpart. NK cells isolated from plaques of symptomatic patients were also stronger producers of IFN-gamma. Analysis of the expression of NK activating receptor ligands (including MICA/B, ULBP-3, and B7-H6) in atherosclerotic carotid plaques revealed that they were abundantly expressed by a HLA-DR(+)CD11c(+) myeloid cell population resident in the plaques. Remarkably, sera of symptomatic patients contained significant higher levels of soluble ligands for NK activating receptors. Our observations indicate that CD56(bright)( )NK cells accumulate within human atherosclerotic lesions and suggest a possible contribution of NK cells to the process determining plaque instability

Modificazioni dell'assetto elettrolitico ed ematochimico nella cavalla nell’ultimo trimestre di gravidanza e nel primo mese di lattazione

ABSTRACT - The electrolyte and biochemical variables were evaluated in 8 healthy mares, aged 4-10 years. Blood samples were taken after the 8th month of gestation, and then, every 30 days, for 3 consecutive months. During the lactation, blood samples were taken in the day 7, 15, 30 post partum. Mares were bled from the jugular vein between 7:30-9:00 AM. The purpose of this study was to determine which physiological changes occur in serum clinical biochemical analytes in pregnant and lactating mares and to determine whether the changes between pregnancy and lactation conditions are significant. Two way RMANOVA showed significant effects of lactation on the changes of all electrolytes and hematochemical variables, with higher levels of Na+, Pi and urea, and lower levels of Na+, Ca++, K+, creatinine, bilirubin and triglycerides in lactation than in pregnancy

Adjunctive brivaracetam and sustained seizure frequency reduction in very active focal epilepsy

Objective: This study aimed to explore the effectiveness of brivaracetam (BRV) according to baseline seizure frequency and past treatment history in subjects with focal epilepsy who were included in the Brivaracetam Add-On First Italian Network Study (BRIVAFIRST). Methods: BRIVAFIRST was a 12-month retrospective, multicenter study including adults prescribed adjunctive BRV. Study outcomes included sustained seizure response (SSR), sustained seizure freedom (SSF), and the rates of treatment discontinuation and adverse events (AEs). Baseline seizure frequency was stratified as <5, 5–20, and >20 seizures per month, and the number of prior antiseizure medications (ASMs) as <5 and ≥6. Results: A total of 994 participants were included. During the 1-year study period, SSR was reached by 45.8%, 39.3%, and 22.6% of subjects with a baseline frequency of <5, 5–20, and >20 seizures per month (p <.001); the corresponding figures for the SSF were 23.4%, 9.8%, and 2.8% (p <.001). SSR was reached by 51.2% and 26.5% participants with a history of 1–5 and ≥6 ASMs (p <.001); the corresponding rates of SSF were 24.7% and 4.5% (p <.001). Treatment discontinuation due to lack of efficacy was more common in participants with >20 seizures compared to those with <5 seizures per month (25.8% vs. 9.3%, p <.001), and in participants with history of ≥6 prior ASMs compared to those with history of 1–5 ASMs (19.6% vs. 12.2%, p =.002). There were no differences in the rates of BRV withdrawal due to AEs and the rates of AEs across the groups of participants defined according to the number of seizures at baseline and the number of prior ASMs. Significance: The baseline seizure frequency and the number of previous ASMs were predictors of sustained seizure frequency reduction with adjunctive BRV in subjects with focal epilepsy

Adjunctive Brivaracetam in Focal Epilepsy: Real-World Evidence from the BRIVAracetam add-on First Italian netwoRk STudy (BRIVAFIRST)

Background: In randomized controlled trials, add-on brivaracetam (BRV) reduced seizure frequency in patients with drug-resistant focal epilepsy. Studies performed in a naturalistic setting are a useful complement to characterize the drug profile. Objective: This multicentre study assessed the effectiveness and tolerability of adjunctive BRV in a large population of patients with focal epilepsy in the context of real-world clinical practice. Methods: The BRIVAFIRST (BRIVAracetam add-on First Italian netwoRk STudy) was a retrospective, multicentre study including adult patients prescribed adjunctive BRV. Patients with focal epilepsy and 12-month follow-up were considered. Main outcomes included the rates of seizure\u2010freedom, seizure response ( 65 50% reduction in baseline seizure frequency), and treatment discontinuation. The incidence of adverse events (AEs) was also considered. Analyses by levetiracetam (LEV) status and concomitant use of strong enzyme-inducing antiseizure medications (EiASMs) and sodium channel blockers (SCBs) were performed. Results: A total of 1029 patients with a median age of 45 years (33\u201356) was included. At 12 months, 169 (16.4%) patients were seizure-free and 383 (37.2%) were seizure responders. The rate of seizure freedom was 22.3% in LEV-naive patients, 7.1% in patients with prior LEV use and discontinuation due to insufficient efficacy, and 31.2% in patients with prior LEV use and discontinuation due to AEs (p < 0.001); the corresponding values for 65 50% seizure frequency reduction were 47.9%, 29.7%, and 42.8% (p < 0.001). There were no statistically significant differences in seizure freedom and seizure response rates by use of strong EiASMs. The rates of seizure freedom (20.0% vs. 16.6%; p = 0.341) and seizure response (39.7% vs. 26.9%; p = 0.006) were higher in patients receiving SCBs than those not receiving SCBs; 265 (25.8%) patients discontinued BRV. AEs were reported by 30.1% of patients, and were less common in patients treated with BRV and concomitant SCBs than those not treated with SCBs (28.9% vs. 39.8%; p = 0.017). Conclusion: The BRIVAFIRST provided real-world evidence on the effectiveness of BRV in patients with focal epilepsy irrespective of LEV history and concomitant ASMs, and suggested favourable therapeutic combinations

Association of intronic variants of the KCNAB1 gene with lateral temporal epilepsy.

The KCNAB1 gene is a candidate susceptibility factor for lateral temporal epilepsy (LTE) because of its functional interaction with LGI1, the gene responsible for the autosomal dominant form of LTE. We investigated association between polymorphic variants across the KCNAB1 gene and LTE. The allele and genotype frequencies of 14 KCNAB1 intronic SNPs were determined in 142 Italian LTE patients and 104 healthy controls and statistically evaluated. Single SNP analysis revealed one SNP (rs992353) located near the 3'end of KCNAB1 slightly associated with LTE after multiple testing correction (odds ratio=2.25; 95% confidence interval 1.26-4.04; P=0.0058). Haplotype analysis revealed two haplotypes with frequencies higher in cases than in controls, and these differences were statistically significant after permutation tests (Psim=0.047 and 0.034). One of these haplotypes was shown to confer a high risk for the syndrome (odds ratio=12.24; 95% confidence interval 1.32-113.05) by logistic regression analysis. These results support KCNAB1 as a susceptibility gene for LTE, in agreement with previous studies showing that this gene may alter susceptibility to focal epilepsy

IL-27 Imparts Immunoregulatory Function to Human NK Cell Subsets

Interleukin-27 (IL-27) is a cytokine with multiple roles in regulating the immune response, but its effect on human CD56bright and CD56dim NK cell subsets is unknown. NK cell subsets interact with other components of the immune system, leading to cytotoxicity or immunoregulation depending on stimulating factors. We found that IL-27 treatment results in increased IL-10 and IFN-γ expression, increased viability and decreased proliferation in both CD56bright and CD56dim NK cell subsets. More importantly, IL-27 treatment imparts regulatory activity to CD56bright NK cells, which mediates its suppressive function on T cells in a contact-dependent manner. There is growing evidence that CD56bright NK cell-mediated immunoregulation plays an important role in the control of autoimmunity. Thus, understanding the role of IL-27 in NK cell function has important implications for treatment of autoimmune disorders