Squamous-cell carcinoma (SCC) of the lung represents around 20% of non-small cell lung cancers. Although activating mutations of EGFR are rare in this subtype, its overexpression occurs in more than ...half the cases. Consequently, many epidermal growth factor receptor (EGFR)-targeted agents have been investigated in patients with SCC.
This review summarizes the potential roles of erlotinib and afatinib in SCC of the lung. The authors explore the rationale of targeting EGFR in SCC and the pharmacological properties of erlotinib and afatinib. Subsequently, they describe the most relevant clinical data involving each agent with regard to their safety profile and antineoplastic activity. Particular focus is given to the LUX-Lung 8 trial, which compared erlotinib and afatinib as a second-line treatment in a population of patients affected by advanced SCC of the lung.
Despite being overcome by new therapeutic strategies - in particular immune checkpoint inhibitors - afatinib and erlotinib still represent potential treatment options down the line in lung SCC because they have a more manageable toxicity profile compared to chemotherapy.
The role of CTLA-4 in negative regulation of T-cell mediated immune response is particularly well established. Much less is known about its expression and function in tumour cells, and to our ...knowledge, no data are available on its possible impact on prognosis of NSCLC patients. We investigated CTLA-4 expression and prognostic role in 81 patients with radically resected stage I–III NSCLC. The analysis was performed by tissue microarray immunohistochemistry, and the median
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of 20 was used as a threshold to define CTLA-4 overexpressing tumours. Correlation with standard prognostic factors was performed by using absolute and relative fold change indexes. Hazard ratios (HR) and corresponding 95% confidence limits (95% CL) were computed through the Cox model. A higher frequency of CTLA-4 overexpression (>20) was found in non-squamous than in squamous NSCLC (52.8 vs. 35.7%) and in Ki67 ≤ 15 expressing tumours, as compared to those with Ki67 > 15 (51.5 vs. 38.7%). A reduced death rate was found in CTLA-4 overexpressing tumours (HR = 0.60, 95% CL = 0.28/1.23), and a further decrease was observed when considering tumours with CTLA-4 > 20 and Ki67 ≤ 15, in comparison with tumours with CTLA-4 ≤ 20 and Ki67 > 15 (HR = 0.41; 95% CL = 0.15/1.13). Our observational and exploratory study provides a first and promising indication for an independent prognostic effect of CTLA-4 overexpression in radically resected NSCLC. We presume that this effect relies on modulation of the interaction of microscopic disease with CTLA-4-ligands expressing cells leading to NSCLC cell death.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
A versatile flexible biocomposite metal‐like conductor (≈10 Ω/υ) that can function under severe folding and abrasion events and can potentially replace metal conductors in a wide range of electronic ...applications ranging from detection of small stochastic biomedical signals (electromyography) to terahertz shielding for high speed electronics.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Introduction: Non-small cell lung cancer (NSCLC) remains one of the big cancer killers, despite the introduction of a number of approved therapeutics in recent times. Pemetrexed is a multi-target ...folate inhibitor, which is currently available to patients affected by advanced non-squamous NSCLC in combination with a platinum derivate in first-line therapy and as a single agent in second-line therapy.
Areas covered: This review covers presents the use pemetrexed in the management of NSCLC by exploring the data available from clinical trials and meta-analyses. Data from a phase III trial confirmed its role in the first-line setting in combination with immune checkpoint inhibitors (ICIs). Furthermore, data suggested a role for pemetrexed in local and advanced NSCLC.
Expert opinion: To date, in spite of the introduction of novel anti-neoplastic agents, pemetrexed still represents a cornerstone in the management of non-squamous NSCLC. Furthermore, recently published data support its role in innovative combinations including together with chemotherapy and immunotherapy.
Reliable predictors of benefit from immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC) are still limited. We aimed to evaluate the association between the expression of selected ...molecules involved in immune response and clinical outcomes in NSCLC patients receiving nivolumab. In our study, the outcomes of 46 NSCLC patients treated with nivolumab in second or subsequent lines (Nivolumab Cohort) were compared with the expression of PD-L1, PD-L2, PD-1, B7-H3, and B7-H4 assessed by immunohistochemistry (IHC). Samples from 17 patients (37.0%) in the Nivolumab Cohort were positive for B7-H4 expression. At univariate analyses, only B7-H4 expression was associated with significantly decreased progression-free survival (PFS; 1.7 vs. 2.0 months; p = 0.026) and with a disadvantage in terms of overall survival (OS) close to statistical significance (4.4 vs. 9.8 months; p = 0.064). At multivariate analyses, B7-H4 expression was significantly associated with decreased PFS (hazard ratio (HR) = 2.28; p = 0.021) and OS (HR = 2.38; p = 0.022). Subsequently, B7-H4 expression was compared with clinical outcomes of 27 NSCLC patients receiving platinum-based chemotherapy (Chemotherapy Cohort), but no significant association was observed. Our results suggest a negative predictive role of B7-H4 in a population of NSCLC treated with immune checkpoint inhibitors, which deserves further research.
Nivolumab is one of the most commonly used monoclonal antibodies for advanced non-small cell lung cancer treatment, to the extent that the presence of its anti-antibody is considered a negative ...prognostic factor. Vitamin D (VD) modulates expression of the genes involved in drug metabolism and elimination. Immune system regulation and immunodeficiency is frequent in non-small cell lung cancer patients. To date, no data have been reported about the relationship between nivolumab and VD. The aim of this study was to quantify plasma 25-hydroxyVD (25-VD) and 1,25-VD, nivolumab, and its anti-antibody before starting treatment (baseline) and at 15, 45 and 60 days of therapy. VD-pathway-associated gene single nucleotide polymorphisms (SNPs) were also evaluated. Molecules were quantified through enzyme-linked immunosorbent assay, and SNPs through real-time PCR. Forty-five patients were enrolled. Median nivolumab concentrations were 12.5 ug/mL, 22.3 ug/mL and 27.1 ug/mL at 15, 45 and 60 days respectively. No anti-nivolumab antibodies were found. Correlations were observed between nivolumab concentrations and 25-VD levels. Nivolumab concentrations were affected by VD-pathway-related gene SNPs.
AC/CC genotype and baseline 25-VD < 10 ng/mL predicted a nivolumab concentration cut-off value of <18.7ug/mL at 15 days, which was associated with tumor progression. This is the first study showing VD marker predictors of nivolumab concentrations in a real-life context of non-small cell lung cancer treatment.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Primary membranoproliferative glomerulonephritis (MPGN) is a rare glomerulopathy characterized by complement dysregulation. MPGN progresses rapidly to kidney failure when it is associated with ...nephrotic syndrome. We assessed the effects of C5 convertase blockade in patients with MPGN and terminal complement activation.
Prospective off-on-off-on open-label clinical trial.
Consenting patients with immune complex–mediated MPGN (n=6) or C3 glomerulonephritis (n=4) with sC5b-9 (serum complement membrane attack complex) plasma levels>1,000ng/mL and 24-hour proteinuria with protein excretion>3.5g identified from the Italian Registry of MPGN and followed up at the Istituto di Ricerche Farmacologiche Mario Negri IRCCS (Bergamo, Italy) between March 4, 2014, and January 7, 2015.
Anti-C5 monoclonal antibody eculizumab administered during 2 sequential 48-week treatment periods separated by one 12-week washout period.
Primary outcome was change in 24-hour proteinuria (median of 3 consecutive measurements) at 24 and 48 weeks.
Median proteinuria decreased from protein excretion of 6.03 (interquartile range IQR, 4.8-12.4) g/d at baseline to 3.74 (IQR, 3.2-4.4) g/d at 24 weeks (P=0.01) and to 5.06 (IQR, 3.1-5.8) g/d (P=0.006) at 48 weeks of treatment, recovered toward baseline during the washout period, and did not significantly decrease thereafter. Hypoalbuminemia, dyslipidemia, and glomerular sieving function improved during the first treatment period. 3 patients achieved partial remission of nephrotic syndrome and all had undetectable C3 nephritic factors before treatment. Mean measured glomerular filtration rate was 69.7±35.2 versus 87.4±55.1 and 75.8±42.7 versus 76.6±44.1mL/min/1.73m2 at the start versus the end of the first and second treatment periods, respectively, among all 10 study participants. Unlike C3, sC5b-9 plasma levels normalized during both treatment periods and recovered toward baseline during the washout in all patients.
Single-arm design, small sample size.
Eculizumab blunted terminal complement activation in all patients with immune complex–mediated MPGN or C3 glomerulonephritis and nephrotic syndrome, but persistently reduced proteinuria in just a subgroup.
Registered in the EU Clinical Trials Register with study no. 2013-003826-10.
•Dengue virus (DENV) is underreported in Democratic Republic of Congo (DRC).•We report an imported acute case of primary dengue from DRC to Italy.•Whole genome sequencing analysis confirmed the ...causative species to be DENV type 1.•The strain identified is closely related to 2013 strains derived from China and Angola.•Our finding raises awareness of DENV in DRC currently affected by the Ebola outbreak.
We report the full-genome sequence of a Dengue serotype-1 virus (DENV-1) isolated from a traveler returning in July 2019 to Italy from Democratic Republic of Congo (DRC), which is currently affected by Ebola and measles outbreaks. The sequence shows high similarity with two 2013 strains isolated in Angola and China.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Nowadays, the interest in hybrid vehicles is constantly increasing, not only in the automotive sector, but also in other transportation systems, to reduce pollution and emissions and to improve the ...overall efficiency of the vehicles. Although railway vehicles are typically the most eco-friendly transportation system, since commonly their primary energy source is electricity, they can still gain benefits from hybrid technologies, as many lines worldwide are not electrified. In fact, hybrid solutions allow ICE-powered (internal combustion engine) railway vehicles, such as diesel multiple units (DMUs), to operate in full-electric mode even when the track lacks electrification. The possibility to switch to full electric mode is of paramount importance when the vehicle runs on urban or underground track sections, where low or zero emission levels are required. We conduct the feasibility study of hybridization of an existing DMU vehicle, designed by Blue Engineering S.r.l., running on the Aosta–Torino Italian railway line, which includes a non-electrified urban track section and an electrified underground section. The hybridization is obtained by replacing one of the diesel generators installed on the original vehicle with a battery pack, which ensures the vehicle to operate in full-electric mode to complete its mission profile. The hybridization is also exploited to implement a regenerative braking strategy, which allows an increase in the energetical efficiency of the vehicle up to 18%. This work shows the sizing of the battery pack based on dynamic simulations performed on the Turin underground track section, and the results demonstrate the feasibility of the hybridization process.
Hyperphosphatemia is associated with increased risk for chronic kidney disease (CKD) progression and reduced antiproteinuric effects of renin-angiotensin system (RAS) blockers. We investigated ...whether the phosphate binder sevelamer carbonate may enhance the antiproteinuric effect of RAS inhibitors in patients with CKD.
Phase 2, randomized, controlled, open-label, crossover trial.
Between November 2013 and December 2014, we enrolled 53 patients with CKD with estimated glomerular filtration rates (eGFRs)>15mL/min/1.73m2 and residual proteinuria with protein excretion≥0.5g/24h despite maximal tolerated ramipril and/or irbesartan therapy from 2 nephrology units in Italy.
After stratification by serum phosphate level, ≤4 or>4mg/dL, patients were randomly assigned to 3 months of sevelamer (1,600mg thrice daily) treatment followed by 3 months without sevelamer separated by a 1-month washout period or 3 months without sevelamer followed by 3 months with sevelamer, also separated by a 1-month washout period.
The primary outcome was 24-hour proteinuria (n=49patients). Secondary outcomes included measured GFR (using iohexol plasma clearance), office blood pressure (BP), serum lipid levels, levels of inflammation and bone metabolism biomarkers, urinary electrolyte levels, and arterial stiffness.
Changes in proteinuria during the 3-month treatment with (from 1.36 IQR, 0.77-2.51 to 1.36 IQR, 0.77-2.60 g/24h) or without (from 1.36 IQR, 0.99-2.38 to 1.48 IQR, 0.81-2.77 g/24h) sevelamer were similar (P=0.1). Sevelamer reduced urinary phosphate excretion without affecting serum phosphate levels. Sevelamer reduced C-reactive protein (CRP), glycated hemoglobin, and total and low-density lipoprotein cholesterol levels and increased high-density lipoprotein cholesterol levels without affecting levels of office BP, measured GFR, fibroblast growth factor 23, klotho, intact parathyroid hormone, serum vitamin D, or other urinary electrolytes. Results were similar in the low- and high-phosphate groups. Sevelamer was well tolerated. Adverse events were comparable between treatment periods. One case of transient hypophosphatemia was observed during treatment with sevelamer.
Short treatment duration, lower pretreatment proteinuria than expected.
3-month sevelamer treatment did not reduce proteinuria in patients with CKD on maximal RAS blockade. Amelioration of inflammation and dyslipidemia with sevelamer treatment raises the possibility that it may confer benefit in patients with CKD beyond reduction of proteinuria.
Sanofi (Milan, Italy).
Registered at ClinicalTrials.gov with study number NCT01968759.
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