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Reliable and effective models for recapitulation of host-pathogen interactions are imperative for the discovery of potential therapeutics. Ex vivo models can fulfill these requirements as the multicellular native environment in the tissue is preserved and be utilized for toxicology, vaccine, infection and drug efficacy studies due to the presence of immune cells. Drug repurposing involves the identification of new applications for already approved drugs that are not related to the prime medical indication and emerged as a strategy to cope with slow pace of drug discovery due to high costs and necessary phases to reach the patients. Within the scope of the study, broad-spectrum serine protease inhibitor nafamostat mesylate was repurposed to inhibit influenza A infection and evaluated by a translational ex vivo organotypic model, in which human organ-level responses can be achieved in preclinical safety studies of potential antiviral agents, along with in in vitro lung airway culture. The safe doses were determined as 10 µM for in vitro, whereas 22 µM for ex vivo to be applied for evaluation of host-pathogen interactions, which reduced virus infectivity, increased cell/tissue viability, and protected total protein content by reducing cell death with the inflammatory response. When the gene expression levels of specific pro-inflammatory, anti-inflammatory and cell surface markers involved in antiviral responses were examined, the significant inflammatory response represented by highly elevated mRNA gene expression levels of cytokines and chemokines combined with CDH5 downregulated by 5.1-fold supported the antiviral efficacy of NM and usability of ex vivo model as a preclinical infection model., Competing Interests: Declaration of Competing Interest All authors declare no financial or commercial conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Lung cancer (LC) is a leading cause of cancer-related mortality worldwide. Approximately 80% of LC cases are of the non-small cell lung cancer (NSCLC) type, and approximately two-thirds of these cases are diagnosed in advanced stages. Only systemic treatment methods can be applied to patients in the advanced stages when there is no chance of surgical treatment. Identification of mutations that cause LC is of vital importance in determining appropriate treatment methods. New noninvasive methods are needed to repeat and monitor these molecular analyses. In this regard, liquid biopsy (LB) is the most promising method. This study aimed to determine the effectiveness of LB in detecting EGFR executive gene mutations that cause LC., Methods: One hundred forty-six patients in stages IIIB and IV diagnosed with non-squamous cell non-small cell LC were included. Liquid biopsy was performed as a routine procedure in cases where no mutation was detected in solid tissue or in cases with progression after targeted therapy. Liquid biopsy samples were also obtained for the second time from 10 patients who showed progression under the applied treatment. Mutation analyses were performed using the Cobas ® EGFR Test, a real-time PCR test designed to detect mutations in exons 18, 20, and 21 and changes in exon 19 of the EGFR gene., Results: Mutation positivity in paraffin blocks was 21.9%, whereas it was 32.2% in LB. Solids and LB were compatible in 16 patients. Additionally, while no mutation was found in solid tissue in the evaluation of 27 cases, it was detected in LB. It has been observed that new mutations can be detected not only at the time of diagnosis, but also in LB samples taken during the follow-up period, leading to the determination of targeted therapy., Discussion: The results showed that "liquid biopsy" is a successful and alternative non-invasive method for detecting cancer-causing executive mutations, given the limitations of conventional biopsies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Goksel, Özgür, Vardarlı, Koç, Karakuş, Özdemir, Erdoğan, Aldağ, Veral, Komurcuoglu, Gursoy, Arayici, Leblebici, Yiğitbaşı, Ellidokuz and Basbinar.)

A comprehensive lipid profile was analyzed in patients with non-small cell lung cancer (NSCLC) using nanoflow ultrahigh-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. This study investigated 297 and 202 lipids in saliva and plasma samples, respectively, comparing NSCLC patients to healthy controls. Lipids with significant changes (>2-fold, p < 0.05) were further analyzed in each sample type. Both saliva and plasma exhibited similar lipid alteration patterns in NSCLC, but saliva showed more pronounced changes. Total triglycerides (TGs) increased (>2-3-fold) in plasma and saliva samples. Three specific TGs (50:2, 52:5, and 54:6) were significantly increased in NSCLC for both sample types. A common ceramide species (d18:1/24:0) and phosphatidylinositol 38:4 decreased in both plasma and saliva by approximately two-fold. Phosphatidylserine 36:1 was selectively detected in saliva and showed a subsequent decrease, making it a potential biomarker for predicting lung cancer. We identified 27 salivary and 10 plasma lipids as candidate markers for NSCLC through statistical evaluations. Moreover, this study highlights the potential of saliva in understanding changes in lipid metabolism associated with NSCLC.

Objectives: Lung cancer (LC) is one of the most prevalent cancers with the highest fatality rate worldwide. Long noncoding RNAs (lncRNAs) are being considered potential new molecular targets for early diagnosis, follow-up, and individual treatment decisions in LC. Therefore, this study evaluated whether lncRNA expression levels obtained from exhaled breath condensate (EBC) samples play a role in the occurrence of metastasis in the diagnosis and follow-up of patients with advanced lung adenocarcinoma (LA). Methods: A total of 40 patients with advanced primary LA and 20 healthy controls participated in the study. EBC samples were collected from patients (during diagnosis and follow-up) and healthy individuals for molecular analysis. Liquid biopsy samples were also randomly obtained from 10 patients with LA and 10 healthy people. The expression of lncRNA genes, such as MALAT1, HOTAIR, PVT1, NEAT1, ANRIL, and SPRY4-IT1 was analyzed using cfRNA extracted from all clinical samples. Results: In the diagnosis and follow-up of patients with LA, lncRNA HOTAIR (5-fold), PVT1 (7.9-fold), and NEAT1 (12.8-fold), PVT1 (6.8-fold), MALAT1 (8.4-fold) expression levels were significantly higher than those in healthy controls, respectively. Additionally, the distinct lncRNA expression profiles identified in EBC samples imply that decreased ANRIL-NEAT1 and increased ANRIL gene expression levels can be used as biomarkers to predict the development of bone and lung metastases, respectively. Conclusion: EBC is an innovative, easily reproducible approach for predicting the development of metastases, molecular diagnosis, and follow-up of LC. EBC has shown potential in elucidating the molecular structure of LC, monitoring changes, and discovering novel biomarkers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tetik Vardarlı, Ozgur, Goksel, Korba, Karakus, Asık, Pelit and Gunduz.)

Purpose: Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non-small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting., Patients and Methods: This noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m 2 on day 1 and gemcitabine 1,250 mg/m 2 on days 1 and 8 (n = 863) or cisplatin 75 mg/m 2 and pemetrexed 500 mg/m 2 on day 1 (n = 862) every 3 weeks for up to six cycles., Results: Overall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia ( P ≤ .001); febrile neutropenia ( P = .002); and alopecia ( P < .001) were significantly lower, whereas grade 3 or 4 nausea ( P = .004) was more common., Conclusion: In advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type.

Minimally invasive approaches for cancer diagnosis are an integral step in the quest to improve cancer survival. Liquid biopsies such as blood samples are matrices explored to extract valuable information about the tumor and its state through various indicators, such as proteins, peptides, tumor DNA, or circulating tumor cells. Although these markers are scarce, making their isolation and detection in complex matrices challenging, the development in polymer chemistry producing interesting structures, including molecularly imprinted polymers, branched polymers, nanopolymer composites, and hybrids, allowed the development of enhanced platforms with impressive performance for liquid biopsies analysis. This review describes the latest advances and developments in polymer synthesis and their application for minimally invasive cancer diagnosis. The polymer structures improve the operational performances of biosensors through various processes, such as increased affinity for enhanced sensitivity, improved binding, and avoidance of non-specific interactions for enhanced specificity. Furthermore, polymer-based materials can be a tremendous help in signal amplification of usually low-concentrated targets in the sample. The pros and cons of these materials, how the synthesis process affects their performance, and the device applications for liquid biopsies diagnosis will be critically reviewed to show the essentiality of this technology in oncology and clinical biomedicine.

Associated with a high mortality rate, pulmonary fibrosis (PF) is the end stage of several interstitial lung diseases. Although many factors are linked to PF progression, initiation of the fibrotic process remains to be studied. Current research focused on generating new strategies to gain a better understanding of the underlying disease mechanism as the animal models remain insufficient to reflect human physiology. Herein, to account complex cellular interactions within the fibrotic tissue, a multicellular spheroid model where human bronchial epithelial cells incorporated with human lung fibroblasts was generated and treated with bleomycin (BLM) to emulate drug-induced PF. Recapitulating the epithelial-interstitial microenvironment, the findings successfully reflected the PF disease, where excessive alpha smooth muscle actin and collagen type I secretion were noted along with the morphological changes in response to BLM. Moreover, increased levels of fibrotic linked COL13A1, MMP2, WNT3 and decreased expression level of CDH1 provide evidence for the model reliability on fibrosis modelling. Subsequent administration of the Food and Drug Administration approved nintedanib and pirfenidone anti-fibrotic drugs proved the drug-responsiveness of the model., (© 2022 IOP Publishing Ltd.)

The increasing mutation frequency of the SARS-CoV-2 virus and the emergence of successive variants have made correct diagnosis hard to perform. Developing efficient and accurate methods to diagnose infected patients is crucial to effectively mitigate the pandemic. Here, we developed an electrochemical immunosensor based on SARS-CoV-2 antibody cocktail-conjugated magnetic nanoparticles for the sensitive and accurate detection of the SARS-CoV-2 virus and its variants in nasopharyngeal swabs. The application of the antibody cocktail was compared with commercially available anti-SARS-CoV-2 S1 (anti-S1) and anti-S2 monoclonal antibodies. After optimization and calibration, the limit of detection (LOD) determination demonstrated a LOD = 0.53-0.75 ng/mL for the antibody cocktail-based sensor compared with 0.93 ng/mL and 0.99 ng/mL for the platforms using anti-S1 and anti-S2, respectively. The platforms were tested with human nasopharyngeal swab samples pre-diagnosed with RT-PCR (10 negatives and 40 positive samples). The positive samples include the original, alpha, beta, and delta variants (n = 10, for each). The polyclonal antibody cocktail performed better than commercial anti-S1 and anti-S2 antibodies for all samples reaching 100% overall sensitivity, specificity, and accuracy. It also showed a wide range of variants detection compared to monoclonal antibody-based platforms. The present work proposes a versatile electrochemical biosensor for the indiscriminate detection of the different variants of SARS-CoV-2 using a polyclonal antibody cocktail. Such diagnostic tools allowing the detection of variants can be of great efficiency and economic value in the fight against the ever-changing SARS-CoV-2 virus., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Point of care (PoC) devices are highly demanding to control current pandemic, originated from severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2). Though nucleic acid-based methods such as RT-PCR are widely available, they require sample preparation and long processing time. PoC diagnostic devices provide relatively faster and stable results. However they require further investigation to provide high accuracy and be adaptable for the new variants. In this study, laser-scribed graphene (LSG) sensors are coupled with gold nanoparticles (AuNPs) as stable promising biosensing platforms. Angiotensin Converting Enzyme 2 (ACE2), an enzymatic receptor, is chosen to be the biorecognition unit due to its high binding affinity towards spike proteins as a key-lock model. The sensor was integrated to a homemade and portable potentistat device, wirelessly connected to a smartphone having a customized application for easy operation. LODs of 5.14 and 2.09 ng/mL was achieved for S1 and S2 protein in the linear range of 1.0-200 ng/mL, respectively. Clinical study has been conducted with nasopharyngeal swabs from 63 patients having alpha (B.1.1.7), beta (B.1.351), delta (B.1.617.2) variants, patients without mutation and negative patients. A machine learning model was developed with accuracy of 99.37% for the identification of the SARS-Cov-2 variants under 1 min. With the increasing need for rapid and improved disease diagnosis and monitoring, the PoC platform proved its potential for real time monitoring by providing accurate and fast variant identification without any expertise and pre sample preparation, which is exactly what societies need in this time of pandemic., Competing Interests: 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., (© 2022 Published by Elsevier B.V.)

The construction of a rapid and easy immunofluorescence bioassay for SARS-CoV-2 detection is described. We report for the first time a novel one-pot synthetic approach for simultaneous photoinduced step-growth polymerization of pyrene (Py) and ring-opening polymerization of ε-caprolactone (PCL) to produce a graft fluorescent copolymer PPy-g-PCL that was conjugated to SARS-CoV-2-specific antibodies using EDC/NHS chemistry. The synthesis steps and conjugation products were fully characterized using standard spectral analysis. Next, the PPy-g-PCL was used for the construction of a dot-blot assay which was calibrated for applications to human nasopharyngeal samples. The analytical features of the proposed sensor showed a detection range of 6.03-8.7 LOG viral copy mL -1 (Ct Scores: 8-25), the limit of detection (LOD), and quantification (LOQ) of 1.84 and 6.16 LOG viral copy mL -1 , respectively. The repeatability and reproducibility of the platform had a coefficient of variation (CV) ranging between 1.2 and 5.9%. The fluorescence-based dot-blot assay was tested with human samples. Significant differences were observed between the fluorescence intensity of the negative and positive samples, with an overall correct response of 93.33%. The assay demonstrated a high correlation with RT-PCR data. This strategy opens new insights into simplified synthesis procedures of the reporter molecules and their high potential sensing and diagnosis applications., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Supply shortage for the development and production of preventive, therapeutic, and diagnosis tools during the COVID-19 pandemic is an important issue affecting the wealthy and poor nations alike. Antibodies and antigens are especially needed for the production of immunological-based testing tools such as point-of-care tests. Here, we propose a simple and quick magnetic nanoparticle (MNP)-based separation/isolation approach for the repurposing of infected human samples to produce specific antibodies and antigen cocktails. Initially, an antibody cocktail was purified from serums via precipitation and immunoaffinity chromatography. Purified antibodies were conjugated onto MNPs and used as an affinity matrix to separate antigens. The characterization process was performed by ELISA, SDS-PAGE, electrochemistry, isothermal titration calorimetry, and LC-Q-TOF-MS/MS analyses. The MNP-separated peptides can be used for mass spectrometry-based as well as paper-based lateral flow assay diagnostic. The exploitation of the current workflow for the development of efficient diagnostic tools, specific treatments, and fundamental research can significantly impact the present or eventual pandemic. This workflow can be considered as a two birds, one stone-like strategy., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Real-time reverse transcriptase-polymerase chain reaction (RT-PCR)-based assays are the gold standard for virus diagnosis. Point-of-care (POC) technologies have shown great progress during this period. Herein, we propose a novel fuchsine dye-loaded polymersome for a colorimetric paper-based dot blot spike protein diagnostic assay for COVID-19 via smartphone-assisted sensing. The prepared platform aimed to create an adaptable tool that competes with traditional nanoparticle-based assays employing gold and silver. Analytical characterization and application of the testing platform showed high sensitivity (10 times better than gold nanoparticles), stability, fast turnaround, and reproducibility. The potential and possibilities demonstrated by the current platform could be observed in its adaptability for different markers and pathologies. In addition, smartphone-assisted sensing emphasizes the ability to use the tool at home by common peoples which can lower the burden on the healthcare facilities and reach more underdeveloped regions., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The global pandemic of COVID-19 continues to be an important threat, especially with the fast transmission rate observed after the discovery of novel mutations. In this perspective, prompt diagnosis requires massive economical and human resources to mitigate the disease. The current study proposes a rational design of a colorimetric lateral flow immunoassay (LFA) based on the repurposing of human samples to produce COVID-19-specific antigens and antibodies in combination with a novel dye-loaded polymersome for naked-eye detection. A group of 121 human samples (61 serums and 60 nasal swabs) were obtained and analyzed by RT-PCR and ELISA. Pooled samples were used to purify antibodies using affinity chromatography, while antigens were purified via magnetic nanoparticles-based affinity. The purified proteins were confirmed for their specificity to COVID-19 via commercial LFA, ELISA, and electrochemical tests in addition to sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis. Polymersomes were prepared using methoxy polyethylene glycol- b -polycaprolactone (mPEG- b -PCL) diblock copolymers and loaded with a Coomassie Blue dye. The polymersomes were then functionalized with the purified antibodies and applied for the preparation of two types of LFA (antigen test and antibody test). Overall, the proposed diagnostic tests demonstrated 93 and 92.2% sensitivity for antigen and antibody tests, respectively. The repeatability (92-94%) and reproducibility (96-98%) of the tests highlight the potential of the proposed LFA. The LFA test was also analyzed for stability, and after 4 weeks, 91-97% correct diagnosis was observed. The current LFA platform is a valuable assay that has great economical and analytical potential for widespread applications.

The global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has revealed the urgent need for accurate, rapid, and affordable diagnostic tests for epidemic understanding and management by monitoring the population worldwide. Though current diagnostic methods including real-time polymerase chain reaction (RT-PCR) provide sensitive detection of SARS-CoV-2, they require relatively long processing time, equipped laboratory facilities, and highly skilled personnel. Laser-scribed graphene (LSG)-based biosensing platforms have gained enormous attention as miniaturized electrochemical systems, holding an enormous potential as point-of-care (POC) diagnostic tools. We describe here a miniaturized LSG-based electrochemical sensing scheme for coronavirus disease 2019 (COVID-19) diagnosis combined with three-dimensional (3D) gold nanostructures. This electrode was modified with the SARS-CoV-2 spike protein antibody following the proper surface modifications proved by X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM) characterizations as well as electrochemical techniques. The system was integrated into a handheld POC detection system operated using a custom smartphone application, providing a user-friendly diagnostic platform due to its ease of operation, accessibility, and systematic data management. The analytical features of the electrochemical immunoassay were evaluated using the standard solution of S-protein in the range of 5.0-500 ng/mL with a detection limit of 2.9 ng/mL. A clinical study was carried out on 23 patient blood serum samples with successful COVID-19 diagnosis, compared to the commercial RT-PCR, antibody blood test, and enzyme-linked immunosorbent assay (ELISA) IgG and IgA test results. Our test provides faster results compared to commercial diagnostic tools and offers a promising alternative solution for next-generation POC applications.

Aim: Lung adenocarcinoma is characterized by poor prognosis and short survival rates. Therefore, tools to identify the tumoural molecular structure and guide effective diagnosis and therapy decisions are essential. Surgical biopsies are highly invasive and not conducive for patient follow-up. To better understand disease prognosis, novel non-invasive analytic methods are needed. The aim of the present study is to identify the genetic mutations in formalin-fixed paraffin-embedded (FFPE) tissue, plasma, and exhaled breath condensate (EBC) samples by next-generation sequencing and evaluate their utility in the diagnosis and follow-up of patients with lung adenocarcinoma., Method: FFPE, plasma, and EBC samples were collected from 12 lung adenocarcinoma patients before treatment. DNA was extracted from the specimens using an Invitrogen PureLink Genomic DNA Kit according to the manufacturer's instructions. Amplicon-based sequencing was performed using Ion AmpliSeq Colon and Lung Cancer Research Panel v2., Results: Genetic alterations were detected in all FFPE, plasma, and EBC specimens. The mutations in PIK3CA, MET, PTEN, SMAD4, and FGFR2 genes were highly correlated in six patients. Somatic and novel mutations detected in tissue and EBC samples were highly correlated in one additional patient. The EGFR p.L858R and KRAS p.G12C driver mutations were found in both the FFPE tissue specimens and the corresponding EBC samples of the lung adenocarcinoma patients., Conclusion: The driver mutations were detected in EBC samples from lung adenocarcinoma patients. The analysis of EBC samples represents a promising non-invasive method to detect mutations in lung cancer and guide diagnosis and follow-up.

Exhaled breath is a source of volatile and nonvolatile biomarkers in the body that can be accessed non-invasively and used for monitoring. The collection of lung secretions by conventional methods such as bronchoalveolar lavage, induced sputum collection, and core biopsies is limited by the invasive nature of these methods. Non-invasive collection of exhaled breath condensate (EBC) provides fluid samples that are representative of airway lining fluids. Various volatile and nonvolatile biomarkers can be detected in volatile condensates, such as H 2 O 2 , nitric oxide, lipid mediators, cytokines, chemokines, DNA, and microRNAs. Studies have examined cell-free DNA (cfDNA) in plasma samples from non-small-cell lung cancer patients, offering to new insights and fostering development of the liquid biopsy. However, few studies have examined cfDNA in EBC samples. This study examined whether EBC is an appropriate source of cfDNA using housekeeping-gene-specific primer probes and quantitative real-time polymerase chain reaction in healthy subjects. Ambient (room) air is contaminated with DNA, so caution is needed. Preliminary studies indicated that volatile biopsies are becoming an important diagnostic tool in lung cancer.

Background: A minority of European countries have participated in international comparisons with high level data on lung cancer. However, the nature and extent of data collection across the continent is simply unknown, and without accurate data collection it is not possible to compare practice and set benchmarks to which lung cancer services can aspire., Methods: Using an established network of lung cancer specialists in 37 European countries, a survey was distributed in December 2014. The results relate to current practice in each country at the time, early 2015. The results were compiled and then verified with co-authors over the following months., Results: Thirty-five completed surveys were received which describe a range of current practice for lung cancer data collection. Thirty countries have data collection at the national level, but this is not so in Albania, Bosnia-Herzegovina, Italy, Spain and Switzerland. Data collection varied from paper records with no survival analysis, to well-established electronic databases with links to census data and survival analyses., Conclusion: Using a network of committed clinicians, we have gathered validated comparative data reporting an observed difference in data collection mechanisms across Europe. We have identified the need to develop a well-designed dataset, whilst acknowledging what is feasible within each country, and aspiring to collect high quality data for clinical research.

Background: Sarcoidosis is known as a Th1-mediated disease, which can mimic many primary rheumatologic diseases or sometimes co-exist with them. Clinical characteristics of sarcoid arthropathy are not well described and the studies reported in the literature so far are mostly based on data from referrals. The aim of this study was to evaluate the incidence and clinical characteristics of sarcoid arthropathy., Methods: All our patients were prospectively evaluated in our rheumatology outpatient center from 2011 to 2015. A total of 114 (32 male) patients with sarcoidosis who were admitted to our clinic were included in the study. Clinical, demographical, laboratory, radiological and histological data of these patients obtained during 4-year follow-up and treatment period were compiled and analyzed., Results: The mean patient age was 48.1 years (range, 20-82 years), and the mean disease duration was 40.5 months (range, 1-300 months). Sarcoid arthritis was observed in 71 (62.3%), and arthralgia in 106 (92.9%) patients. Out of the 71 patients with arthritis, 61 (85.9%) had involvement of ankle, 7 (9.8%) knee, 2 (2.8%) wrist, MCP and PIP joints, and 1 (1.4%) had shoulder periarthritis. Oligoarthritis (two to four joints) was the most common pattern followed by monoarthritis and polyarthritis. Arthritis and erytjhema nodosum and arthritis and female sex was found to be correlated ( p = 0.03 and p = 0.001). Again, in patients with arthritis, even higher levels of CRP/ESR as well as ANA and RF positivity were observed ( p = 0.03, p = 0.01, p = 0.01, and p = 0.02, respectively). A total of 11 patients had another rheumatic pathology concurrent with sarcoidosis., Conclusions: Inflammatory arthritis occurs in a majority of patients with sarcoidosis. Acute arthritis with bilateral ankle involvement is the most common pattern of sarcoid arthropathy. Sarcoidosis can mimic many primary rheumatic diseases or may coexist with them. Sarcoidosis should be considered not only as a mimicker but also as a Th1-mediated primary rheumatologic pathology., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

Objectives: REVEL demonstrated that ramucirumab+docetaxel (RAM+DTX) improved overall survival, progression-free survival, and objective response rate in patients with advanced/metastatic non-small cell lung cancer with progression after platinum-based chemotherapy. This analysis examined quality of life (QoL) as assessed by the Lung Cancer Symptom Scale (LCSS) and clinician-reported functional status., Materials and Methods: The LCSS includes 6 symptom and 3 global items measured on a 0-100-mm scale; higher scores represent greater symptom burden. LCSS and ECOG PS data were collected at baseline, every 3-week cycle, the summary visit, and at the 30-day follow-up. LCSS total score and Average Symptom Burden Index (ASBI) were calculated. The primary analysis compared time to deterioration (TtD) between treatment arms for all individual items and summary scores, defined as increase from baseline by ≥ 15 mm using the Kaplan-Meier method and Cox regression. TtD to ECOG PS ≥ 2 was analyzed., Results: There were 1253 patients randomized to receive RAM+DTX or placebo+docetaxel (PL+DTX). Across all assessments, LCSS compliance was approximately 75% and balanced across arms. The mean (SD) baseline LCSS total score was 27.3mm (17.08 mm) on RAM+DTX and 29.6mm (17.59 mm) on PL+DTX. At 30-day follow-up, mean (SD) LCSS total score was 32.0 (19.03) on RAM+DTX and 32.5 (19.87) on PL+DTX. The TtD for all LCSS scores was similar between treatment arms. Stratified HRs (95% CI) for LCSS total score and ASBI were HR=0.99 (0.81, 1.22), p=0.932 and HR=0.93 (0.75, 1.15), p=0.514 with approximately 70% of patients censored. TtD to PS ≥ 2 was similar between treatment arms (HR=1.03 [95% CI: 0.85, 1.26], p=0.743) with approximately two-thirds of the patients censored., Conclusion: In addition to improvement of clinical efficacy outcomes demonstrated in REVEL, these results suggest that adding ramucirumab to docetaxel did not impair patient QoL, symptoms, or functioning., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Sarcoidosis is a chronic granulomatous disease. Pyrin has anti-inflammatory activity in the regulation of inflammasomes and is encoded by the Mediterranean fever (MEFV) gene. MEFV gene mutations trigger the inflammatory cascade and cause familial Mediterranean fever (FMF). A relationship between various rheumatic diseases and MEFV gene mutations has been demonstrated. The aim of this study was to determine the prevalence of the MEFV gene mutation in Turkish patients with sarcoidosis and to detect any possible correlation with disease phenotype., Method: The study included 78 sarcoidosis patients and 85 healthy subjects matched for age, gender, and ethnicity. MEFV gene mutations were investigated with the FMF strip assay, which is based on reverse hybridization of biotinylated polymerase chain reaction (PCR) products., Results: Of the 78 patients with sarcoidosis, nine (11.5%) were found to be carriers of MEFV gene mutations. The distribution of these nine mutations were: three (3.8%) V726A, two (2.5%) E148Q, two (2.5%) M680I, one (1.3%) A744S, and one (1.3%) K695R. Carriers of M694V, M694I, R761H, and P369S were not detected in any of the sarcoidosis patients. None of the sarcoidosis patients were found to be compound heterozygous carriers. The prevalence of the MEFV gene mutation carrier detected in the healthy control group was 22.4%. The distribution of the 19 MEFV gene mutations found in the healthy controls was: nine (10.6%) E148Q, two (2.3%) M694V, one (1.2%) M694I, one (1.2%) M680I, two (2.3%) V726A, one (1.2%) A744S, two (2.3%) K695R, and one (1.2%) P369S. When compared with the control group, a lower prevalence of the MEFV gene mutation carrier was found in sarcoidosis patients but this was not statistically significant (p = 0.067). In nine patients found to be MEFV gene mutation carriers, higher serum erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels and higher numbers patients with arthritis, enthesitis, and ankle arthritis were found (p = 0.01, p = 0.04, p = 0.028, p = 0.05, p = 0.05, respectively)., Conclusions: When we compared Turkish sarcoidosis patients with the healthy control group, we found a lower prevalence of MEFV gene mutations. In sarcoidosis patients, the MEFV gene mutation carrier was found to be related to high acute-phase responses, arthritis, and enthesitis. The existence of MEFV gene mutations may have a preventive role with regard to the development of sarcoidosis. Prospective studies that include larger patient populations are needed.

Follicular bronchiolitis (FB) is a rare small-airway pathology that is associated mainly with connective tissue diseases. This case report presents a new, diagnosed, different airway disease in a non-smoker with rheumatoid arthritis in remission who was treated for presumed asthma, but was not controlled. She was ultimately diagnosed with FB after video-assisted thoracoscopic surgery. The clinical findings of FB were controlled successfully by colchicine after she did not respond to systemic steroid therapy. This is the first case report of FB associated with rheumatoid arthritis that responded to colchicine., (Copyright © 2015 by Daedalus Enterprises.)

Background: Chemotherapy is one of the main treatments for lung cancer, and in these patients, discontinuation of treatment due to uncontrollable hypersensitivity reactions (HSRs) is an important problem., Aim: To determine the frequency of HSRs during chemotherapy and to review current approaches., Methods: We did a cross sectional study in patients undergoing chemotherapy for lung cancer in a reference chemotherapy unit from January 2012 to January 2013. Patients who developed immediate-HSRs or delayed-HSRs to chemotherapeutics and gave consent were included into study. The effectiveness of a standardised 12-step "rapid drug desensitisation" (RDD) procedure was investigated in patients with immediate-HSRs., Results: In total, 1,099 cycles of chemotherapy were administered to 292 patients in 1 year. We observed ten HSRs, during ten cycles in ten patients (~3 % of the patients). Two HSRs were delayed-type, eight were immediate-type at grade 1-3. Of those with immediate-type HSR, five patients with grade 2-3, and additional two referred patients with grade 4 HSRs were successfully given their culprit drug in 35 cycles of chemotherapy with 12-step or modified 20-step RDD protocol., Conclusions: HSRs to chemotherapeutics are not so rare. Premedication alone does not prevent such reactions. The results of RDD treatment look promising for continuing treatment with the culprit chemotherapeutic agent.

Background: Ramucirumab is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. We aimed to assess efficacy and safety of treatment with docetaxel plus ramucirumab or placebo as second-line treatment for patients with stage IV non-small-cell-lung cancer (NSCLC) after platinum-based therapy., Methods: In this multicentre, double-blind, randomised phase 3 trial (REVEL), we enrolled patients with squamous or non-squamous NSCLC who had progressed during or after a first-line platinum-based chemotherapy regimen. Patients were randomly allocated (1:1) with a centralised, interactive voice-response system (stratified by sex, region, performance status, and previous maintenance therapy [yes vs no]) to receive docetaxel 75 mg/m(2) and either ramucirumab (10 mg/kg) or placebo on day 1 of a 21 day cycle until disease progression, unacceptable toxicity, withdrawal, or death. The primary endpoint was overall survival in all patients allocated to treatment. We assessed adverse events according to treatment received. This study is registered with ClinicalTrials.gov, number NCT01168973., Findings: Between Dec 3, 2010, and Jan 24, 2013, we screened 1825 patients, of whom 1253 patients were randomly allocated to treatment. Median overall survival was 10·5 months (IQR 5·1-21·2) for 628 patients allocated ramucirumab plus docetaxel and 9·1 months (4·2-18·0) for 625 patients who received placebo plus docetaxel (hazard ratio 0·86, 95% CI 0·75-0·98; p=0·023). Median progression-free survival was 4·5 months (IQR 2·3-8·3) for the ramucirumab group compared with 3·0 months (1·4-6·9) for the control group (0·76, 0·68-0·86; p<0·0001). We noted treatment-emergent adverse events in 613 (98%) of 627 patients in the ramucirumab safety population and 594 (95%) of 618 patients in the control safety population. The most common grade 3 or worse adverse events were neutropenia (306 patients [49%] in the ramucirumab group vs 246 [40%] in the control group), febrile neutropenia (100 [16%] vs 62 [10%]), fatigue (88 [14%] vs 65 [10%]), leucopenia (86 [14%] vs 77 [12%]), and hypertension (35 [6%] vs 13 [2%]). The numbers of deaths from adverse events (31 [5%] vs 35 [6%]) and grade 3 or worse pulmonary haemorrhage (eight [1%] vs eight [1%]) did not differ between groups. Toxicities were manageable with appropriate dose reductions and supportive care., Interpretation: Ramucirumab plus docetaxel improves survival as second-line treatment of patients with stage IV NSCLC., Funding: Eli Lilly., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Hamartomas are the most common benign tumors of the lung. Endobnronchial hamartomas are even rarer and infrequently causes hemoptysis. We report a case of endobronchial hamartoma that was originating from a segment bronchus and invisible in chest X-ray. A 63-year-old man was admitted to hospital with hemoptysis. A CT scan revealed endobronchial mass obstructing anterior bronchus of the right lower lob of the right lung. It wasn't radiographically presented. Flexible bronchoscopy detected a polypoid mass (1.5 x 1.0 cm) that arising from the posterior wall of the anterior segment of right lower lob. Histopathologic examination revealed lipoumatous hamartoma. It was resected with an electro-surgical snare. Cryotherapy was applied to residual lesion on surface of the bronchus. The patient was successfully recovered. In conclusion, lipoumatous hamartoma may presented as rare cause of hemoptysis. Endoscopic treatment is safe and currently modality used for select cases.

: The effect of repeated doses of aflibercept on ventricular repolarization in cancer patients was evaluated in an intensive electrocardiogram trial. This randomized, placebo-controlled, double-blind trial was conducted in 87 treated solid tumor patients. Treatment was with 6 mg/kg aflibercept, 1-hour intravenous (n = 43), or placebo (n = 44), combined with ≤75 mg/m docetaxel, every 3 weeks. Electrocardiograms were collected for 6 hours posttreatment using digital 12-lead Holter recorders, at day 1, in cycles 1 and 3. Free and vascular endothelial growth factor-bound aflibercept concentrations were assessed at similar time points. Eighty-four patients (43 placebo and 41 aflibercept) were evaluable for QT interval, Fridericia correction (QTcF) at cycle 1 and 59 (31 placebo and 28 aflibercept) at cycle 3. During cycle 3, from 30 minutes to 6 hours after the start of aflibercept, the maximum observed upper limit of the QTcF 90% confidence interval was 16 ms, for a mean of 8.4 ms. QTcF prolongation above 480 ms and 60 ms above baseline was observed in 1 aflibercept patient (2%). The slope of the relationship between free aflibercept concentration and QTcF was 0.048 (95% confidence interval, 0.013-0.082), corresponding to a 5-ms increase per 100 µg/mL increase in concentration. These results exclude a clinically important effect of aflibercept on ventricular repolarization.

A 39-year-old African American woman presented for treatment of a symptomatic mandibular right first molar with a large, periapical radiolucency. After initial attempts at endodontic therapy, this tooth was ultimately extracted owing to unabated symptoms. The extraction site underwent ridge preservation grafting, implant placement, and restoration. After 26 months of implant function, the patient returned with clinical symptoms of pain, buccal swelling, and the sensation of a "loose" implant. This case report details a diagnosis of 2 distinct disease entities associated with the implant site, a cemento-ossifying fibroma and florid cemento-osseous dysplasia of the mandible. This diagnosis was determined from clinical, surgical, radiographic, and histopathologic evidence after biopsy and removal of the previously osseointegrated implant following postinsertion failure by fibrous encapsulation. Before implant therapy, it is essential to conduct a thorough radiographic evaluation of any dental arch with suspected bony lesions to prevent implant failure., (Published by Mosby, Inc.)

Background: Bronchioloalveolar carcinoma (BAC) is considered a subtype of adenocarcinoma of the lung. Recently BAC has been variously termed adenocarcinoma in situ, minimally invasive adenocarcinoma, lepidic predominant invasive adenocarcinoma, and invasive mucinous adenocarcinoma. The aim of the study was to analyze and detect prognostic factors of patients with BAC over a 7-year period., Materials and Methods: This retrospective single-center study included 44 patients with BAC. The impact on survival of fifteen variables (gender, age, smoking status, cough, dyspnea, hemoptysis, fever, chest pain, sputum, metastasis number, Karnofsky performance status, pT, pN, TNM stage, cytotoxic chemoterapy) were assessed., Results: Median age was 55 years (38-83). Most patients were male (63.6%) and stage IV (59.1%). Twenty-one patients (47.7%) received cytotoxic chemotherapy (platinum-based regimens) for metastatic disease. Objective response rate was 33.3% (4 partial, 3 complete responses). Stable disease was observed in nine in patients (42.8%). Disease progression was noted in 5 (23.8%). The median OS for all patients was 12 months (95%CI, 2.08-22.9 months). Independent predictors for overall survival were: Karnofsky performance status (HR:3.30, p 0.009), pN (HR:3.81, p 0.018), TNM stage (HR:6.49, p 0.012) and hemoptysis (HR:2.31, p 0.046)., Conclusions: Karnofsky performance status, pN, TNM stage and hemoptysis appear to have significant impact on predicting patient survival in cases of BAC.

Purpose: To compare the efficacy of aflibercept (ziv-aflibercept), a recombinant human fusion protein targeting the vascular endothelial growth factor (VEGF) pathway, with or without docetaxel in platinum-pretreated patients with advanced or metastatic nonsquamous non-small-cell lung cancer., Patients and Methods: In this international, double-blind, placebo-controlled phase III trial, 913 patients were randomly assigned to (ziv-)aflibercept 6 mg/kg intravenous (IV; n = 456) or IV placebo (n = 457), both administered every 3 weeks and in combination with docetaxel 75 mg/m(2). The primary end point was overall survival (OS). Other efficacy outcomes, safety, and immunogenicity were also assessed., Results: Patient characteristics were balanced between arms; 12.3% of patients had received prior bevacizumab. (Ziv-)Aflibercept did not improve OS (hazard ratio [HR], 1.01; 95% CI, 0.87 to 1.17; stratified log-rank P = .90). The median OS was 10.1 months (95% CI, 9.2 to 11.6 months) for (ziv-)aflibercept and 10.4 months (95% CI, 9.2 to 11.9 months) for placebo. In exploratory analyses, median progression-free survival was 5.2 months (95% CI, 4.4 to 5.6 months) for (ziv-)aflibercept versus 4.1 months (95% CI, 3.5 to 4.3 months) for placebo (HR, 0.82; 95% CI, 0.72 to 0.94; P = .0035); overall response rate was 23.3% of evaluable patients (95% CI, 19.1% to 27.4%) in the (ziv-)aflibercept arm versus 8.9% (95% CI, 6.1% to 11.6%; P < .001) in the placebo arm. Grade ≥ 3 adverse events occurring more frequently in the (ziv-)aflibercept arm versus the placebo arm were neutropenia (28.0% v 21.1%, respectively), fatigue (11.1% v 4.2%, respectively), stomatitis (8.8% v 0.7%, respectively), and hypertension (7.3% v 0.9%, respectively)., Conclusion: The addition of (ziv-)aflibercept to standard docetaxel therapy did not improve OS. In exploratory analyses, secondary efficacy end points did seem to be improved in the (ziv-)aflibercept arm. The study regimen was associated with increased toxicities, consistent with known anti-VEGF and chemotherapy-induced events.

Objective: A retrospective study was conducted to identify the effect of blood vessel invasion on prognosis in surgically treated stage I non-small cell lung cancer patients., Methods: A total of 71 consecutive patients who had undergone complete resection for stage I primary non-small cell lung cancer (NSCLC) between 1998 and 2007 were evaluated. All pathological specimens were examined for evidence of blood vessel invasion. The follow-up period was 5-118 months. Survival data were analyzed for all patients using the Kaplan-Meier test., Results: There were 63 men and 8 women (mean age 59.2, age range 35-86). The most common tumor types were adenocarcinoma (35 patients, 49 %) and squamous cell carcinoma (26 patients, 37 %). Twenty-five patients (35 %) had stage IA disease, and 46 had (65 %) stage IB disease. In 13 cases (18 %) blood vessel invasion was demonstrated, whereas in the remaining 58 cases there was no evidence of vascular invasion. Minimum and maximum follow-up periods were 5 and 118 months respectively, with a mean of 41.76 +/- 27 months (median 33.5 months). Overall disease-free survival was 79.6 +/- 6.4 months: 38.3 +/- 12.0 months for the group with blood vessel invasion and 87.5 +/- 6.7 months for the remaining group. The difference between the two groups was statistically significant ( P < 0.003). Overall survival rate was 86.7 +/- 6.7 months: 44.5 +/- 11.3 months for blood vessel invasion group and 98.2 +/- 6.2 months for the remaining group. The difference between the two groups was statistically significant ( P < 0.001)., Conclusion: Vascular invasion can be an important factor for predicting unfavorable prognosis in stage I NSCLC patients.

Background: In a large phase III study, cisplatin and pemetrexed had non-inferior efficacy and better tolerability compared with cisplatin and gemcitabine in chemonaïve patients with non-small cell lung cancer (NSCLC). The current analysis characterised the clinical benefit (i.e. survival) relative to clinical risk (i.e. drug-related toxicity) of the doublets., Patients and Methods: A total of 1669 patients (of 1725 randomised) received 500 mg/m(2) pemetrexed IV followed by 75 mg/m(2) cisplatin IV on day 1 or gemcitabine 1250 mg/m(2) on days 1 and 8 and 75 mg/m(2) cisplatin on day 1, administered every 3 weeks for up to 6 cycles. Survival without toxicity (i.e. clinical benefit to risk) was defined as the time from randomisation to the first occurrence of any grade 3 or 4 drug-related toxicity or death, and was analysed using Kaplan-Meier and Cox methods., Results: In the overall patient population, survival without grade 3 or 4 drug-related toxicity was significantly longer for patients treated with cisplatin and pemetrexed versus cisplatin and gemcitabine (HR=0.70; P<0.001), as was survival without grade 4 drug-related toxicity (HR=0.83; P<0.001). For patients with non-squamous NSCLC, survival without toxicity with cisplatin and pemetrexed was superior to cisplatin and gemcitabine for grade 3 or 4 drug-related toxicity (HR=0.64; P<0.001) and for grade 4 drug-related toxicity (HR=0.77; P<0.001), whereas no treatment-arm difference was observed in the squamous subgroup., Conclusions: Patients with non-squamous NSCLC treated with front-line cisplatin and pemetrexed have superior survival without toxicity (i.e. clinical benefit-to-risk profile) compared with patients treated with cisplatin and gemcitabine.

The aim of this study was to evaluate the symptomatic and endoscopic responses as well as the toxicities in 158 patients with endobronchial lung cancer treated with high dose rate endobronchial brachytherapy (HDR-EB). Forty-three patients with stage III NSCLC were treated with 60Gy external beam radiotherapy (ERT) and three applications of 5Gy each of HDR-EB (group A). Seventy-four patients who did not receive previous RT were treated with 30Gy ERT and two applications of 7.5Gy HDR-EB with palliative intent (group B). Forty-one patients with recurrent tumor who were irradiated previously were treated with three applications of 7.5Gy HDR-EB, with palliative intent (group C). In group A, bronchoscopic complete (CR) and overall response rates (ORR) were 67% and 86%, respectively. Symptomatic improvement was obtained in 58% of patients with cough, 77% of patients with dyspnea and 100% of patients with hemoptysis. Two and 5-year survival rates were 25.5% and 9.5%, respectively and the median survival time (MST) was 11 months. In group B, the bronchoscopic CR and ORR were 39% and 77%, respectively and 28% and 72% in group C. The symptomatic response rates were 57% and 55% for cough, 90% and 78% for dyspnea and 94% and 77% for hemoptysis, with a MST of 7 and 6 months in Groups B and C, respectively. Eighteen patients (11%) died of fatal hemoptysis (FH) with the median time to this event of 7 months. Treatment intent (p<0.001), total BED (p<0.001) and the number of HDR-EB fractions (p<0.001) were significant prognostic factors for FH. HDR-EB provides effective palliation in relieving the symptoms of patients with endobronchial lung cancer, however, there is a risk of developing FH that is associated with a high BED and multiple HDR-EB applications.

Purpose: Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non-small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting., Patients and Methods: This noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m(2) on day 1 and gemcitabine 1,250 mg/m(2) on days 1 and 8 (n = 863) or cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 (n = 862) every 3 weeks for up to six cycles., Results: Overall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P

The combination of gemcitabine and cisplatin is one of the most active chemotherapy regimens against non-small cell lung cancer (NSCLC). This study was designed to evaluate the efficacy and safety of gemcitabine combined with cisplatin in a 3-week cycle regimen for patients with operable, early stage NSCLC. Gemcitabine at a dose of 1000 mg/m(2) on days 1 and 8 of each 21-day cycle for 3 cycles, followed by cisplatin at a dose of 75 mg/m(2) on day 1 was administered to patients with previously untreated, operable, early stage (IB-IIIA) NSCLC. A total of 47 patients (46 male, mean age 56.0+/-8.0 years) who met the eligibility criteria were enrolled. The pathological complete response rate was 5.3% of operated patients and 4.3% of total patients. At visit 4, 57.1% of the patients had partial response, 38.1%, stable disease and 4.8%, progressive disease. The main toxicities - leukopenia, neutropenia and thrombocytopenia - were usually clinically asymptomatic and did not require hospitalization. Non-hematological toxicities were minimal and manageable. Disease free and 12-month overall survival rates were over 70% and 80%, respectively. This study demonstrates that the administration of gemcitabine and cisplatin combination for 3 cycles is effective and tolerable for patients with operable, early stage NSCLC. Low toxicity profile and promising survival outcome suggest that this regimen has an encouraging activity in this subset of patients.