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Wind turbine multidisciplinary design optimization is currently the focus of several investigations because it has showed potential in reducing the cost of energy. This design approach requires fast methods to evaluate wind turbine loads with a sufficiently high level of fidelity. This paper presents a method to estimate wind turbine fatigue damage suited for optimization design applications. The method utilizes a high-order linear wind turbine model. The model comprehends a detailed description of the wind turbine and the controller. The fatigue is computed with a spectral method applied to power spectral densities of wind turbine sensor responses to turbulent wind. In this paper, the model is validated both in time domain and frequency domain with a nonlinear aeroservoelastic model. The approach is compared quantitatively against fatigue damage obtained from the power spectra of time series evaluated with nonlinear aeroservoelastic simulations and qualitatively against rainflow counting. Results are presented for three cases: load evaluation at normal operation in the full wind speed range, load change evaluation due to two different controller tunings at normal operation at three different wind speeds above rated and load dependency on the number of turbulence seeds used for their evaluation. For the full-range normal operation, the maximum difference between the two frequency domain-based estimates of the tower base lateral fatigue moments is 36%, whereas the differences for the other sensors are less than 15%. For the load variation evaluation, the maximum difference of the tower base longitudinal bending moment variation is 22%. Such large difference occurs only when the change in controller tuning has a low effect on the loads. Furthermore, results show that loads evaluated with the presented method are less dependent on the turbulent wind realization; therefore, less turbulence seeds are required compared with time-domain simulations to remove the dependency on the wind realization used to estimate loads. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Wind turbine resonant vibrations are investigated based on aeroelastic simulations both in frequency and time domain. The investigation focuses on three different aspects: the need of a precise modeling when a wind turbine is operating close to resonant conditions; the importance of estimating wind turbine loads also at low turbulence intensity wind conditions to identify the presence of resonances; and the wind turbine response because of external excitations. In the first analysis, three different wind turbine models are analysed with respect to the frequency and damping of the aeroelastic modes. Fatigue loads on the same models are then investigated with two different turbulence intensities to analyse the wind turbine response. In the second analysis, a wind turbine model is excited with an external force. This analysis helps in identifying the modes that might be excited, and therefore, the frequencies at which minimal excitation should be present during operations. The study shows that significant edgewise blade vibrations can occur on modern wind turbines even if the aeroelastic damping of the edgewise modes is positive. When operating close to resonant conditions, small differences in the modeling can have a large influence on the vibration level. The edgewise vibrations are less visible in high turbulent conditions. Using simulations with low-level turbulence intensity will ease this identification and could avoid a redesign. Furthermore, depending on the external excitation, different aeroelastic modes can be excited. The investigation is performed using aeroelastic models corresponding to a 1.5 MW class wind turbine with slight variations in blade properties. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background:Agents targeting programmed death-1 receptor (PD-1) and its ligand (PD-L1) are showing promising results in non-small-cell lung cancer (NSCLC). It is unknown whether PD-1/PD-L1 are differently expressed in oncogene-addicted NSCLC.Methods:We analysed a cohort of 125 NSCLC patients, including 56 EGFR mutated, 29 KRAS mutated, 10 ALK translocated and 30 EGFR/KRAS/ALK wild type. PD-L1 and PD-1 expression were assessed by immunohistochemistry. All cases with moderate or strong staining (2+/3+) in >5% of tumour cells were considered as positive.Results:PD-1 positive (+) was significantly associated with current smoking status (P=0.02) and with the presence of KRAS mutations (P=0.006), whereas PD-L1+ was significantly associated to adenocarcinoma histology (P=0.005) and with presence of EGFR mutations (P=0.001). In patients treated with EGFR tyrosine kinase inhibitors (N=95), sensitivity to gefitinib or erlotinib was higher in PD-L1+ vs PD-L1 negative in terms of the response rate (RR: P=0.01) time to progression (TTP: P<0.0001) and survival (OS: P=0.09), with no difference in PD1+ vs PD-1 negative. In the subset of 54 EGFR mutated patients, TTP was significantly longer in PD-L1+ than in PD-L1 negative (P=0.01).Conclusions:PD-1 and PD-L1 are differentially expressed in oncogene-addicted NSCLC supporting further investigation of specific checkpoint inhibitors in combination with targeted therapies. [ABSTRACT FROM AUTHOR]

Natural wound healing products are in increased demand. The potential for unexplored Sedum species in wound healing was discovered based on benefits of the genus reported in traditional medicine. The objectives were to screen ten Sedum species for wound healing, to ascertain the optimal harvest period using the five best, and finally to investigate effects of extraction protocols on wound healing using the most promising species. Different protocols were used to extract leaf polyphenol and mucilage content. Wound healing was assessed from L929 fibroblast migration. April was the optimal harvest month for wound healing efficacy, whereas the highest polyphenol content and antioxidant activity were evident in September and November. S. album Murales (ALBU), the best candidate, was then compared with S. telephium (TELE), which is well recognized in skin care. The mucilage-containing aqueous extract of ALBU was shown for the first time to induce the highest fibroblast migration after 24 h, not evident in TELE. Moreover, functional constituents contained within the absolute acetone- and isopropanol-containing polyphenol pools from ALBU induced significantly higher migration compared to TELE. A prototype cream, containing the water- and solvent-extracted bioactive compounds was effective at inducing fibroblast migration at 24 h in ALBU. The potential of ALBU in wound healing was evidenced and warrants further investigation.

Background: There are currently few data about the safety and effectiveness of chemotherapy for patients with metastatic non-small-cell lung cancer (NSCLC) who have progressed from prior immunotherapy. Methods: Data from patients with consecutive stage IIIB-IV, ECOG performance status (PS) 0-2, non-small-cell lung cancer (NSCLC) treated with combination or single-agent chemotherapy following progression on an earlier immunotherapy regimen were retrospectively gathered. Recorded were baseline attributes, outcome metrics, and toxicities. The neutrophil/lymphocyte (N/L) ratio's predictive usefulness was examined through an exploratory analysis. Results: The analysis comprised one hundred subjects. The adeno/squamous carcinoma ratio was 77%/23%, the M/F ratio was 66%/34%, the ECOG PS was 0/1/≥2 47%/51%/2%, and the median PD-L1 expression was 50% (range 0-100). The median age was 67 (range 39-81) years. Prior immunotherapy included a single-agent treatment in 83% of cases, with pembrolizumab use being prevalent, and a median N/L ratio of four prior to chemotherapy. The overall median time-to-progression on previous immunotherapy was 6 months. After immunotherapy, just 33% of subjects underwent chemotherapy. A median of 4 (range 1-16) cycles of chemotherapy were administered; platinum doublets (primarily carboplatin) were delivered in only 31% of cases, vinorelbine accounted for 25%, taxanes for 25%, and gemcitabine for 8%. The median clinical benefit was 55%, while the overall response rate was 21%. The median overall survival was 5 months (range 1-22) and the median time to progression was 4 months (range 1-17). Subgroups with low and high N/L ratios were compared, but there was no discernible difference in survival. Conclusions: After immunotherapy, a small percentage of patients with advanced NSCLC had chemotherapy. Following immunotherapy advancement, chemotherapy demonstrated a moderate level of therapeutic effectiveness; no adverse concerns were noted. The effectiveness of chemotherapy following immunotherapy was not predicted by the baseline N/L ratio.

Background: The present study evaluates the utility of NGS analysis of circulating free DNA (cfDNA), which incorporates small amounts of tumor DNA (ctDNA), at diagnosis or at disease progression (PD) in NSCLC patients., Methods: Comprehensive genomic profiling on cfDNA by NGS were performed in NSCLC patients at diagnosis (if tissue was unavailable/insufficient) or at PD to investigate potential druggable molecular aberrations. Blood samples were collected as routinary diagnostic procedures, DNA was extracted, and the NextSeq 550 Illumina platform was used to run the Roche Avenio ctDNA Expanded Kit for molecular analyses. Gene variants were classified accordingly to the ESCAT score., Results: A total of 106 patients were included in this study; 44 % of cases were requested because of tissue unavailability at the diagnosis and 56 % were requested at the PD. At least one driver alteration was observed in 62 % of cases at diagnosis. Driver druggable variants classified as ESCAT level I were detected in 34 % of patients, including ALK-EML4, ROS1-CD74, EGFR, BRAF, KRAS p.G12C, PI3KCA. In the PD group, most patients were EGFR-positive, progressing to a first line-therapy. Sixty-three percent of patients had at least one driver alteration detected in blood and 17 % of patients had a known biological mechanism of resistance allowing further therapeutic decisions., Conclusions: The present study confirms the potential of liquid biopsy to detect tumour molecular heterogeneity in NSCLC patients at the diagnosis and at PD, demonstrating that a significant number of druggable mutations and mechanisms of resistance can be detected by NGS analysis on ctDNA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Impaired autophagy, responsible for increased inflammation, constitutes a risk factor for the more severe COVID-19 outcomes. Spermidine (SPD) is a known autophagy modulator and supplementation for COVID-19 risk groups (including the elderly) is recommended. However, information on the modulatory effects of eugenol (EUG) is scarce. Therefore, the effects of SPD and EUG, both singularly and in combination, on autophagy were investigated using different cell lines (HBEpiC, SHSY5Y, HUVEC, Caco-2, L929 and U937). SPD (0.3 mM), EUG (0.2 mM) and 0.3 mM SPD + 0.2 mM EUG, significantly increased autophagy using the hallmark measure of LC3-II protein accumulation in the cell lines without cytotoxic effects. Using Caco-2 cells as a model, several crucial autophagy proteins were upregulated at all stages of autophagic flux in response to the treatments. This effect was verified by the activation/differentiation and migration of U937 monocytes in a three-dimensional reconstituted intestinal model (Caco-2, L929 and U937 cells). Comparable benefits of SPD, EUG and SPD + EUG in inducing autophagy were shown by the protection of Caco-2 and L929 cells against lipopolysaccharide-induced inflammation. SPD + EUG is an innovative dual therapy capable of stimulating autophagy and reducing inflammation in vitro and could show promise for COVID-19 risk groups.

Background: In advanced non-small-cell lung cancer, without activating mutations and with PD-L1≥50%, Pembrolizumab monotherapy is the therapeutic standard in Europe., Objective: To evaluate retrospectively the safety and efficacy of this drug and to investigate potential prognostic factors in daily clinical practice., Methods: From September 2017 to September 2019, 205 consecutive patients from 14 Italian Medical Oncology Units were enrolled in the study. Gender, Age (> or <70 years), ECOG-PS (0-1 or 2), histology (squamous or nonsquamous), presence of brain, bone and liver metastases at baseline, PD-L1 score (>90% or <90%), smoking status (never or former or current) were applied to the stratified log-rank. Cox's proportional hazards model was used for multivariate analysis., Results: At a median follow-up of 15.2 months, median progression-free and overall survival (mPFS and mOS) were 9.2 months (95% C.I., 4.8-13.5) and 15.9 months (95% C.I., not yet evaluable), respectively. Patients with Eastern Cooperative Oncology Group performance status (ECOG-PS) 2 had mPFS of 2.8 months (95% C.I., 2.1-3.4) and mOS of 3.9 months (95% C.I., 2.5-5.3). Patients with liver metastases at diagnosis had an mPFS of 3.2 months (95% C.I., 0.6-5.8) and an mOS of 6.0 months (95% C.I., 3.7-8.4). At multivariate analysis for OS gender, ECOG-PS 2, and presence of liver metastases were independent prognostic factors., Conclusion: Patients with ECOG-PS 2 derived little benefit from the use of first-line pembrolizumab. In patients with liver metastases, the association of pembrolizumab with platinum-based chemotherapy could be a better option than pembrolizumab alone., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Polyphenols are natural organic compounds produced by plants, acting as antioxidants by reacting with ROS. These compounds are widely consumed in daily diet and many studies report several benefits to human health thanks to their bioavailability in humans. However, the digestion process of phenolic compounds is still not completely clear. Moreover, bioavailability is dependent on the metabolic phase of these compounds. The LogP value can be managed as a simplified measure of the lipophilicity of a substance ingested within the human body, which affects resultant absorption. The biopharmaceutical classification system (BCS), a method used to classify drugs intended for gastrointestinal absorption, correlates the solubility and permeability of the drug with both the rate and extent of oral absorption. BCS may be helpful to measure the bioactive constituents of foods, such as polyphenols, in order to understand their nutraceutical potential. There are many literature studies that focus on permeability, absorption, and bioavailability of polyphenols and their resultant metabolic byproducts, but there is still confusion about their respective LogP values and BCS classification. This review will provide an overview of the information regarding 10 dietarypolyphenols (ferulic acid, chlorogenic acid, rutin, quercetin, apigenin, cirsimaritin, daidzein, resveratrol, ellagic acid, and curcumin) and their association with the BCS classification.

There is a need to assess the relationship between improved rheological properties and the immunogenic potential of wheat proteins. The present study aimed to investigate the in vitro effects of total protein extracts from three modern and two landrace Triticum aestivum commercial flour mixes, with significant differences in gluten strength (GS), on cell lines. Cytotoxicity and innate immune responses induced by wheat proteins were investigated using Caco-2 monocultures, two dimensional (2D) Caco-2/U937 co-cultures, and three dimensional (3D) co-cultures simulating the intestinal mucosa with Caco-2 epithelial cells situated above an extra-cellular matrix containing U937 monocytes and L929 fibroblasts. Modern wheat proteins, with increased GS, significantly reduced Caco-2 cell proliferation and vitality in monoculture and 2D co-cultures than landrace proteins. Modern wheat proteins also augmented Caco-2 monolayer disruption and tight junction protein, occludin, redistribution in 3D co-cultures. Release of interleukin-8 into the cell medium and increased U937 monocyte migration in both 2D and 3D co-cultures were similarly apparent. Immuno-activation of migrating U937 cells was evidenced from cluster of differentiation 14 (CD14) staining and CD11b-related differentiation into macrophages. The modern wheat proteins, with gluten polymorphism relatedness and increased GS, were shown to be more cytotoxic and immunogenic than the landrace wheat proteins.

Background: tyrosine kinase inhibitors (TKIs) inhibit phosphorylation of signaling proteins. TKIs often show large variations in the clinic due to poor pharmacology, possibly leading to resistance. We compared gut absorption of inhibitors of epidermal growth factor receptor (erlotinib, gefitinib, and afatinib), ALK-cMET (crizotinib), PDGFR/BCR-Abl (dasatinib), and multikinase inhibitors (sunitinib and sorafenib). In clinical samples, we measured the disposition of each compound within various blood compartments. Methods: we used an optimized CaCo2 gut epithelial model to characterize 20 µM TKI absorption. The apical/basolateral transfer is considered to represent the gut/blood transfer. Drugs were measured using LC-MS/MS. Results: sorafenib and sunitinib showed the highest apical/basolateral transfer (P app 14.1 and 7.7 × 10 -6 cm/s, respectively), followed by dasatinib (3.4), afatinib (1.5), gefitinib (0.38), erlotinib (0.13), and crizotinib (n.d.). However, the net absorptions for dasatinib, afatinib, crizotinib, and erlotinib were highly negative (efflux ratios >5) or neutral/negative, sorafenib (0.86), gefitinib (1.0), and sunitinib (1.6). A high negative absorption may result in resistance because of a poor exposure of tissues to the drug. Accumulation of the TKIs at the end of the transfer period (A->B) was not detectable for erlotinib, very low for afatinib 0.45 pmol/μg protein), followed by gefitinib (0.79), dasatinib (1.1), sorafenib (1.65), and crizotinib (2.11), being highest for sunitinib (11.9). A similar pattern was found for accumulation of these drugs in other colon cell lines, WiDr and HT29. In clinical samples, drugs accumulated consistently in red blood cells; blood to plasma ratios were all > 3 (sorafenib) or over 30 for erlotinib. Conclusions: TKIs are consistently poorly absorbed, but accumulation in red blood cells seems to compensate for this.

Objectives: The purpose of this study is to assess the performance of radiologists using a new software called "COVID-19 score" when performing chest radiography on patients potentially infected by coronavirus disease 2019 (COVID-19) pneumonia. Chest radiography (or chest X-ray, CXR) and CT are important for the imaging diagnosis of the coronavirus pneumonia (COVID-19). CXR mobile devices are efficient during epidemies, because allow to reduce the risk of contagion and are easy to sanitize., Material and Methods: From February-April 2020, 14 radiologists retrospectively evaluated a pool of 312 chest X-ray exams to test a new software function for lung imaging analysis based on radiological features and graded on a three-point scale. This tool automatically generates a cumulative score (0-18). The intra- rater agreement (evaluated with Fleiss's method) and the average time for the compilation of the banner were calculated., Results: Fourteen radiologists evaluated 312 chest radiographs of COVID-19 pneumonia suspected patients (80 males and 38 females) with an average age of 64, 47 years. The inter-rater agreement showed a Fleiss' kappa value of 0.53 and the intra-group agreement varied from Fleiss' Kappa value between 0.49 and 0.59, indicating a moderate agreement (considering as "moderate" ranges 0.4-0.6). The years of work experience were irrelevant. The average time for obtaining the result with the automatic software was between 7 s (e.g., zero COVID-19 score) and 21 s (e.g., with COVID-19 score from 6 to 12)., Conclusion: The use of automatic software for the generation of a CXR "COVID-19 score" has proven to be simple, fast, and replicable. Implementing this tool with scores weighed on the number of lung pathological areas, a useful parameter for clinical monitoring could be available., Competing Interests: There are no conflicts of interest., (© 2020 Published by Scientific Scholar on behalf of Journal of Clinical Imaging Science.)

Polyphenols display health-promoting properties linked to their biological activities. They are initially absorbed in the small intestine, then they are largely metabolized in the colon, whereupon they are able to exert systemic effects. The health-promoting properties of polyphenols have led to the development of food supplements, which are also largely consumed by healthy people, even if data on their safety are still yet lacking. In the present paper, the content of gallic acid and ferulic acid was analyzed in two supplements, and shown to be higher than the relative contents found in fruit and flour. To evaluate the effects of these phenolic compounds on epithelial intestinal tissue, gallic and ferulic acids were added to a new in vitro model of the intestinal wall at different concentrations. The effects on viability, proliferation and migration of these compounds were respectively tested on three different cell lines (Caco2, L929 and U937), as well as on a tridimensional intestinal model, composed of a mucosal layer and a submucosa with fibroblasts and monocytes. Results indicated that gallic and ferulic acids can exert toxic effects on in vitro cell models at high concentrations, suggesting that an excessive and uncontrolled consumption of polyphenols may induce negative effects on the intestinal wall., Competing Interests: The authors declare no conflict of interest.

Objectives: The incidence of any and of severe-grade immune-related adverse events (irAEs) with second-line nivolumab monotherapy is 31-65 % and 2-5 % respectively. While potentially serious and even fatal, in the absence of an appropriate therapy, such events might be indicators of the activation of the immune system and, potentially, of efficacy., Materials and Methods: We collected the records of 1959 non-small-cell lung cancer (NSCLC) patients treated with nivolumab in the Italian expanded access program, and we registered the appearance of any and of severe grade irAEs. We retrospectively searched for correlations between toxicity and efficacy parameters by using Cox's regression analysis., Results: Overall, 342 (17.8%) patients developed an irAE of any grade. We observed that patients developing irAE of any grade achieved a significantly higher response rate (RR 27.2% vs 15.2%; p < 0.0001), disease control rate (DCR 60.5% vs 40.2%; p < 0.0001), median progression-free survival (mPFS 6.0 months [95% CI 4.9-7.1] vs 3.0 [95% CI: 2.8-3.2], p < 0.0001) and median overall survival (mOS 16.7 months [95% CI: 13.5-19.9] vs 9.4 [95% CI: 8.4-10.4], p < 0.00001) compared to patients who did not. At multivariate analysis the development of an irAE remained an independent indicator of nivolumab efficacy (HR 1.44 [95% CI: 1.22-1.71] p < 0.0001)., Conclusions: This report, performed in Caucasian NSCLC patients, showed that the appearance of irAEs correlated with outcome., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Cytidine deaminase (CDA) plays a crucial role in the degradation of gemcitabine. In our previous retrospective study, CDA enzymatic activity was the strongest prognostic biomarker of the activity and efficacy of platinum/gemcitabine combinations. The aim of this prospective study was to validate the prognostic role of CDA activity in the first-line treatment of advanced non-small-cell lung cancer., Methods: A total of 124 untreated patients received standard doses of platinum/gemcitabine. CDA activity was baseline measured in plasma samples by spectrophotometric assay., Results: Using the median CDA level as cut-off, in the patients with high versus low CDA activity the response rate was 25.0% (95% CI, 14.7-37.8) and 54.1% (95% CI, 40.8-66.9), P = 0.0013; the 6-month progression rate was 34.5% (95% CI, 22.6-46.6) and 54.1% (95% CI, 40.9-65.6), HR = 2.01 (95% CI, 1.32-3.06), P < 0.001; the 1-year survival rate was 23.3% (95% CI, 13.6-34.6) and 57.3% (95% CI, 43.9-68.6), HR = 2.20 (95% CI, 1.46-3.34), P = 0.0002, respectively. CDA activity resulted to be an independent prognostic factor for progression and survival at multivariate analysis., Conclusions: This study validated prospectively the prognostic role of the CDA activity and should prompt larger and adequately designed randomised prospective studies to establish the predictive impact of this test in improving the outcome of selected patients.

A number of pharmacogenetic studies have been carried out in non-small-cell lung cancer (NSCLC) to identify and characterize genes involved in chemotherapy activity. However, the results obtained so far are controversial and no reliable biomarker is currently used to predict clinical benefit from platinum-based chemotherapy, which represents the cornerstone of treatment of advanced NSCLC. This study investigated the expression levels of ERCC1 and of six genes (RRM1, RRM2, hENT1, dCK, cN-II and CDA) involved in gemcitabine metabolism in locally/advanced NSCLC patients treated with gemcitabine/platinum combination. Gene expression was assessed by quantitative-PCR in laser-microdissected specimens and correlated with tumor response. Frequency distribution of responses above and below the median expression level of biomarkers was compared using a two-sided Fisher's test. 5'-nucleotidase (cN-II) was the only gene differently expressed ( p = 0.016) in the responders (complete/partial-response) compared to non-responders (stable/progressive disease). In the multivariate analysis, overexpression of this catabolic enzyme of gemcitabine remained a significant negative predictive factor. Patients with low cN-II had a modest trend toward increased survival, while both survival and progression-free survival were significantly longer in a more homogenous validation cohort of 40 advanced NSCLC (8.0 vs. 5.1 months, p = 0.026). Moreover, in vitro studies showed that silencing or pharmacological inhibition of cN-II increased the cytotoxicity of gemcitabine. This is the first study demonstrating the role of cN-II as a predictor of response to gemcitabine/platinum combinations in NSCLC. Its validation in prospective studies may improve clinical outcome of selected patients., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

The recent discovery of immune checkpoints inhibitors, especially anti-programmed cell death protein 1 (PD-1) and anti-programmed cell death protein ligand 1 (PD-L1) monoclonal antibodies, has opened new scenarios in the management of non-small cell lung cancer (NSCLC) and this new class of drugs has achieved a rapid development in the treatment of this disease. However, considering the costs of these drugs and the fact that only a subset of patients experience long-term disease control, the identification of predictive biomarkers for the selection of candidates suitable for treatment has become a priority. The research focused mainly on the expression of the PD-L1 receptor on both tumor cells and/or immune infiltrates determined by immunohistochemistry (IHC). However, different checkpoint inhibitors were tested, different IHC assays were used, different targets were considered (tumor cells, immune infiltrates or both) and different expression thresholds were employed in clinical trials. In some trials the assay was used prospectively to select the patients, while in other trials it was evaluated retrospectively. Some confusion emerges, which makes it difficult to easily compare the literature data and to translate them in practice management. This mini-review shows the possibilities and pitfalls of the PD-L1 expression to predict the activity and efficacy of anti PD1/PD-L1 monoclonal antibodies in the treatment of NSCLC., Competing Interests: Conflict-of-interest statement: None of the authors have any potential conflicts of interest associated with this research.

Purpose Considering promising results in phase II studies, a randomized phase III trial was designed to assess the efficacy of adding bevacizumab to first-line cisplatin plus etoposide for treatment of extensive-disease (ED) small-cell lung cancer (SCLC). Patients and Methods Treatment-naive patients with ED-SCLC were randomly assigned to receive either cisplatin plus etoposide (arm A) or the same regimen with bevacizumab (arm B) for a maximum of six courses. In the absence of progression, patients in arm B continued bevacizumab alone until disease progression or for a maximum of 18 courses. The primary end point was overall survival (OS). Results Two hundred four patients were randomly assigned and considered in intent-to-treat analyses (103 patients in arm A and 101 patients in arm B). At a median follow-up of 34.9 months in arm A and arm B, median OS times were 8.9 and 9.8 months, and 1-year survival rates were 25% and 37% (hazard ratio, 0.78; 95% CI, 0.58 to 1.06; P = .113), respectively. A statistically significant effect of bevacizumab on OS in patients who received maintenance was seen (hazard ratio, 0.60; 95% CI, 0.40 to 0.91; P = .011). Median progression-free survival times were 5.7 and 6.7 months in arm A and arm B, respectively ( P = .030). Regarding hematologic toxicity, no statistically significant differences were observed; for nonhematologic toxicity, only hypertension was more frequent in arm B (grade 3 or 4, 1.0% v 6.3% in arms A v B, respectively; P = .057). Conclusion The addition of bevacizumab to cisplatin and etoposide in the first-line treatment of ED-SCLC had an acceptable toxicity profile and led to a statistically significant improvement in progression-free survival, which, however, did not translate into a statistically significant increase in OS. Further research with novel antiangiogenic agents, particularly in the maintenance setting, is warranted.

Objective: To determine the prevalence of abnormal vaginal flora during pregnancy and associated maternal risk factors., Methods: A retrospective study was undertaken of cervicovaginal smears performed on pregnant women at a center in Turin, Italy, between 2000 and 2010. Patients were divided into three groups: women with symptoms of genital infections (G1), asymptomatic women at risk of preterm birth (G2), and asymptomatic women with no risk (G3). Logistic regression models identified variables associated with microorganisms., Results: Among 11 219 samples, 4913 (43.8%) were positive, of which 3783 (77.0%) were positive for a single microorganism. Multivariate analysis for G1 showed positive associations between multiple sexual partners and bacterial vaginosis/Ureaplasma urealyticum, and multiparity with preterm birth and U. urealyticum (P<0.05 for all). In G2, there were significant associations between multiparity with preterm birth and bacterial vaginosis/aerobic vaginitis, and North African origin and bacterial vaginosis/U. urealyticum (P<0.05 for all). In G3, there were associations between little education (<8 years) and bacterial vaginosis/U. urealyticum, multiple sexual partners and bacterial vaginosis/U. urealyticum, and bacterial vaginosis and Eastern European origin and not being married (P<0.05 for all)., Conclusion: Positive cervicovaginal smears were associated with a particular profile. Testing could be advisable for symptomatic women at any stage of pregnancy, during the first trimester for asymptomatic women at risk of preterm birth, and for some asymptomatic women., (Copyright © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.)

microRNAs (miRNAs) can act as oncosuppressors or oncogenes, induce chemoresistance or chemosensitivity, and are major posttranscriptional gene regulators. Anaplastic lymphoma kinase (ALK), EGF receptor (EGFR), and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) are major drivers of non-small cell lung cancer (NSCLC). The aim of this study was to assess the miRNA profiles of NSCLCs driven by translocated ALK, mutant EGFR, or mutant KRAS to find driver-specific diagnostic and prognostic miRNA signatures. A total of 85 formalin-fixed, paraffin-embedded samples were considered: 67 primary NSCLCs and 18 matched normal lung tissues. Of the 67 primary NSCLCs, 17 were echinoderm microtubule-associated protein-like 4-ALK translocated (ALK(+)) lung cancers; the remaining 50 were not (ALK(-)). Of the 50 ALK(-) primary NSCLCs, 24 were EGFR and KRAS mutation-negative (i.e., WT; triple negative); 11 were mutant EGFR (EGFR(+)), and 15 were mutant KRAS (KRAS(+)). We developed a diagnostic classifier that shows how miR-1253, miR-504, and miR-26a-5p expression levels can classify NSCLCs as ALK-translocated, mutant EGFR, or mutant KRAS versus mutation-free. We also generated a prognostic classifier based on miR-769-5p and Let-7d-5p expression levels that can predict overall survival. This classifier showed better performance than the commonly used classifiers based on mutational status. Although it has several limitations, this study shows that miRNA signatures and classifiers have great potential as powerful, cost-effective next-generation tools to improve and complement current genetic tests. Further studies of these miRNAs can help define their roles in NSCLC biology and in identifying best-performing chemotherapy regimens.

Background: Cytomegalovirus (CMV) is the leading infectious agent causing congenital sensorineural hearing loss and psychomotor retardation. CMV vaccine is currently unavailable and treatment options in pregnancy are limited. Susceptible pregnant women caring for children are at high risk for primary infection. CMV educational and hygienic measures have the potential to prevent primary maternal infection., Methods: A mixed interventional and observational controlled study was conducted to investigate the effectiveness of hygiene information among pregnant women at risk for primary CMV infection for personal/occupational reasons. In the intervention arm, CMV-seronegative women, identified at the time of maternal serum screening for fetal aneuploidy at 11-12 weeks of gestation, were given hygiene information and prospectively tested for CMV until delivery. The comparison arm consisted of women enrolled at delivery who were neither tested for nor informed about CMV during pregnancy, and who had a serum sample stored at the screening for fetal aneuploidy. By design, groups were homogeneous for age, parity, education, and exposure to at least one risk factor. The primary outcome was CMV seroconversion. Acceptance of hygiene recommendations was a secondary objective and was measured by a self-report., Findings: Four out of 331 (1.2%) women seroconverted in the intervention group compared to 24/315 (7.6%) in the comparison group (delta = 6.4%; 95% CI 3.2-9.6; P < 0.001). There were 3 newborns with congenital infection in the intervention group and 8 in the comparison group (1 with cerebral ultrasound abnormalities at birth). Ninety-three percent of women felt hygiene recommendations were worth suggesting to all pregnant women at risk for infection., Interpretation: This controlled study provides evidence that an intervention based on the identification and hygiene counseling of CMV-seronegative pregnant women significantly prevents maternal infection. While waiting for CMV vaccine to become available, the intervention described may represent a responsible and acceptable primary prevention strategy to reduce congenital CMV.

Purpose: Cytochrome P450 1B1 (CYP1B1) is involved in the metabolism of anticancer agents; its overexpression was associated with resistance to docetaxel, a commonly used drug for second-line treatment of NSCLC. Several functional single nucleotide polymorphisms (SNPs) have been associated with CYP1B1 expression and activity. The objective of this study was to retrospectively evaluate the correlation of CYP1B1 SNPs with the outcome of NSCLC patients treated with docetaxel in second or third line., Methods: Associations between CYP1B1 4326C>G and 4390A>G polymorphisms with response, progression-free survival (PFS) and overall survival (OS) were estimated using Pearson χ(2) test, Kaplan-Meier curves and log-rank test; a multivariate analysis was performed using Cox proportional hazards modeling., Results: A total of 65 advanced NSCLC patients were enrolled into the analysis. Median age was 66 years (range 46-81). Forty-nine patients were male; only five were never smokers. Performance status (PS) was 0 in 25 patients, 1 in 28 and 2 in 12. Histology was adenocarcinoma in 28 patients, squamous carcinoma in 22, other NSCLC in the remaining 15. At univariate analysis, stage and CYP1B1 4326C>G SNPs are associated with PFS, while PS and CYP1B1 4326C>G SNPs correlated with OS. In particular, patients with CYP1B1 4326-GG genotype had shorter PFS and OS than patients with other genotypes (PFS 1.80 vs. 2.70 months, p = 0.12; OS 3.63 vs. 9.83 months, p = 0.039). CYP1B1 4326C>G SNPs were also associated with response rate. Multivariate analysis confirmed the independent prognostic/predictive role of CYP1B1 4326C>G SNPs on OS (p = 0.042) with only a trend for PFS (p = 0.083)., Conclusions: CYP1B1 4326C>G polymorphism emerged as possible prognostic/predictive marker of activity and efficacy of docetaxel in NSCLC patients.

Background: Neoangiogenesis is particularly abundant in small-cell lung cancer (SCLC) and is associated with poor prognosis. As a result of the promising nature of phase II studies, a randomized phase III trial was designed to assess the efficacy of adding bevacizumab to first-line chemotherapy with cisplatin-etoposide for treatment of extensive disease SCLC. We present the treatment rationale and study design of GOIRC trial (FARM6PMFJM study), a multicenter randomized phase III study, supported by AIFA (Agenzia Italiana del Farmaco)., Patients and Methods: Patients are randomized to receive either cisplatin 25 mg/m(2) and etoposide 100 mg/m(2) intravenously on days 1 to 3 (control arm) or the same chemotherapy combined with bevacizumab 7.5 mg/kg intravenously on day 1 (experimental arm). Treatment is repeated every 3 weeks and for a maximum of 6 courses. Patients randomized to the experimental arm in the absence of disease progression after 6 cycles continue bevacizumab alone until progression or for a maximum of 18 courses. Tumor assessment is done every 3 cycles. Major eligibility criteria are: age ≥ 18 years; histologically or cytologically documented extensive disease SCLC; Eastern Cooperative Oncology Group performance status ≤ 2; adequate hematological, hepatic and renal functions; no history of grade 2 or higher hemoptysis; and no evidence of tumor cavitation. The primary end point of this study is overall survival. Secondary end points include response rate, time to progression, and toxicity., Conclusion: An interim futility analysis was performed by an Independent Data Monitoring Committee in September 2013 and the trial obtained approval to continue. As of July 31, 2014, 171 patients of 206 planned have been randomized., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The discovery of driver oncogene alterations in non-small cell lung cancer (NSCLC), such as EGFR, EML4-ALK, MET and RAS, as well as the identification of their specific targeted inhibitors have led to new opportunities for treatment of this tumor. Drug resistance, intrinsic or acquired, represents the major cause of failure of novel biological agents. MicroRNAs (miRNAs) are a family of small non-coding RNAs that can silence their cognate target genes by specifically binding mRNAs or inhibiting their translation. The recent evidences that several micro-RNAs can modulate the oncogenic driver pathways in NSCLC and that they are involved in drug resistance of their targeted inhibitors, have paved the way for new therapeutic strategies. This minireview aims 1) to explore the potential mechanisms by which key miRNAs may up-regulate or down-regulate specific oncogenic driver pathways; 2) highlight the role of microRNAs in the mechanisms of resistance to targeted therapies; 3) discuss the therapeutic potential by using short-interfering RNAs or artificial miRNAs as anti-cancer therapies.

Background: The purpose of this study was to evaluate the efficacy of afatinib in EGFR-mutant metastatic NSCLC patients with acquired resistance to erlotinib or gefitinib., Materials and Methods: We retrospectively analyzed the outcome of patients with EGFR-mutant advanced NSCLC treated with afatinib after failure of chemotherapy and EGFR TKIs., Results: A total of 96 individuals were included in the study. According to EGFR status, most patients (n = 63; 65.6%) harbored a deletion in exon 19, and de novo T790M mutation was detected in 2 cases (T790M and exon 19). Twenty-four (25%) patients underwent repeated biopsy immediately before starting afatinib and secondary T790M was detected in 8 (33%) samples. Among the 86 patients evaluable for efficacy, response rate was 11.6%, with a median progression free-survival (PFS) and overall survival (OS) of 3.9 and 7.3 months, respectively. No significant difference in PFS and OS was observed according to type of last therapy received before afatinib, type of EGFR mutation or adherence to Jackman criteria, and patients benefiting from afatinib therapy had longer PFS and OS (P < .001). Outcome results for repeated biopsy patients were similar to the whole population, with no evidence of response in T790M-positive patients. All patients were evaluable for toxicity, and 81% experienced an AE of any grade, with grade 3 to 4 AEs, mainly diarrhea and skin toxicity, occurring in 19 (20%) patients., Conclusion: Our results showed that afatinib has only modest efficacy in a real life population of EGFR mutant NSCLC patients with acquired resistance to erlotinib or gefitinib., (Copyright © 2014 Elsevier Inc. All rights reserved.)