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The Ras-related C3 botulinum toxin substrate 1 (RAC1), a member of the Rho family of small guanosine triphosphatases, is critical for many cellular activities, such as phagocytosis, adhesion, migration, motility, cell proliferation, and axonal growth. In addition, RAC1 plays an important role in cancer angiogenesis, invasion, and migration, and it has been reported to be related to most cancers, such as breast cancer, gastric cancer, testicular germ cell cancer, and lung cancer. Recently, the therapeutic target of RAC1 in cancer has been investigated. In addition, some investigations have shown that inhibition of RAC1 can reverse drug-resistance in non-small cell lung cancer. In this review, we summarize the recent advances in understanding the role of RAC1 in lung cancer and the underlying mechanisms and discuss its value in clinical therapy. [ABSTRACT FROM AUTHOR]

OBJECTIVES: The impact of skip N2 metastases (i.e. N2 lymph node metastases without N1) on survival in surgically resected non-small lung cancer remains an intriguing and rarely investigated topic. The goal of our study was to elucidate (i) skip N2 influence on overall survival (OS) and time to recurrence (TTR) in patients with resected lung adenocarcinoma and (ii) its link with epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. METHODS: A retrospective analysis of 279 consecutive patients with lung pN2 adenocarcinoma, operated in two institutions between 2003 and 2013, was conducted. OS and TTR were calculated using the Kaplan-Meier method. Crude and multivariable-adjusted comparisons by skip N2 for OS and TTR were performed using the Cox method with shared frailty (accounting for the within-centre correlation). Associations between skip N2 metastasis, clinicopathological characteristics and EGFR and KRAS mutations were investigated using the Fisher exact test and Cramé r's V-test. RESULTS: The mean age at the time of surgery was 63 years (±12), and the median follow-up time was 36 months (min 3; max 101). Skip N2 was observed in 54 patients (19%). EGFR mutations were observed in 38 patients (14%); KRAS mutations were seen in 86 patients (31%). Patients with skip N2 metastasis were predominantly non-smokers (P = 0.001), underwent segmentectomy or limited resections (P = 0.004) and were not submitted to adjuvant therapy (P = 0.022). Moreover, there was a correlation between EGFR mutations and skip N2 (Cramé r's V: 0.25, P < 0.001). Indeed, EGFR mutations were significantly more frequent in skip N2 tumours (33%) compared with non-skip tumours (10%), P < 0.001. No correlation between skip N2 and KRAS mutations was observed (Cramé r's V: 0.05, P = 0.46). The multivariable-adjusted model showed a significant skip N2 protective effect on OS (hazard ratio, HR 0.503; P = 0.014; 95% confidence interval, CI: 0.291-0.8704) but not on TTR (HR 0.788; P = 0.446; 95% CI: 0.427-1.454). CONCLUSIONS: In our series, lung adenocarcinoma skip N2 metastasis demonstrated a favourable prognosis. The presence of EGFR mutations could have significance in the better survival and in the specific anatomic pathway of lymphatic metastases exhibited by skip N2 tumours. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Early clinical stage (T1 and T2) non-small cell lung cancer (NSCLC) is commonly treated with anatomic lung resection and lymph node sampling or dissection. The aims of this study were to evaluate the incidence and the distribution of occult N2 disease according to tumour location and the short- and long-term outcomes. METHODS: We performed a retrospective review of patients with clinical stage I NSCLC who underwent anatomic lung resection and lymphadenectomy. Mediastinal lymphadenectomy (ML) was defined as resection of at least 2 mediastinal stations, always including station 7 lymph nodes. Patients who had a lobe-specific lymphadenectomy were excluded. RESULTS: One thousand six hundred and sixty-seven consecutive patients met inclusion criteria and were included. Overall, 9% (146/1667) of the patients had occult pN2 disease. At multivariable analysis, adenocarcinoma histology and vascular invasion were independently associated with greater risk of occult pN2 disease. In left and right upper lobe tumours, station 7 nodes were involved in 5 and 13% of pN2 positive cases, respectively. Station 5 and station 2/4 nodes were involved in 29 and 18% of left and right lower lobe pN2 tumours, respectively. There was no postoperative mortality, and postoperative morbidity was 28%. The median overall survival was 77.4 months. N0 patients had a median overall survival of 83.7 months vs 48.0 months and 37.9 months in N1 and N2 populations, respectively (P < 0.001). CONCLUSIONS: Sixteen percent of pN2 patients had mediastinal lymph node metastasis beyond the lobe-specific lymphatic drainage. We recommend a complete lymphadenectomy be performed, even in clinical stage I NSCLC. [ABSTRACT FROM AUTHOR]

Background: Cough among patients with lung cancer is a common but often undertreated symptom. We used a 2015 Cochrane systematic review, among other sources of evidence, to update the recommendations and suggestions of the American College of Chest Physicians (CHEST) 2006 guideline on this topic.Methods: The CHEST methodologic guidelines and the Grading of Recommendations, Assessment, Development, and Evaluation framework were used. The Expert Cough Panel based their recommendations on data from the Cochrane systematic review on the topic, uncontrolled studies, case studies, and the clinical context. Final grading was reached by consensus according to the Delphi method.Results: The Cochrane systematic review identified 17 trials of primarily low-quality evidence. Such evidence was related to both nonpharmacologic (cough suppression) and pharmacologic (demulcents, opioids, peripherally acting antitussives, or local anesthetics) treatments, as well as endobronchial brachytherapy.Conclusions: Compared with the 2006 CHEST Cough Guideline, the current recommendations and suggestions are more specific and follow a step-up approach to the management of cough among patients with lung cancer, acknowledging the low-quality evidence in the field and the urgent need to develop more effective, evidence-based interventions through high-quality research. [ABSTRACT FROM AUTHOR]

Purpose The purpose of this study was to estimate the uncertainty in voluntary deep-inspiration breath-hold (DIBH) radiotherapy for locally advanced non-small cell lung cancer (NSCLC) patients. Methods Perpendicular fluoroscopic movies were acquired in free breathing (FB) and DIBH during a course of visually guided DIBH radiotherapy of nine patients with NSCLC. Patients had liquid markers injected in mediastinal lymph nodes and primary tumours. Excursion, systematic- and random errors, and inter-breath-hold position uncertainty were investigated using an image based tracking algorithm. Results A mean reduction of 2–6 mm in marker excursion in DIBH versus FB was seen in the anterior-posterior (AP), left–right (LR) and cranio-caudal (CC) directions. Lymph node motion during DIBH originated from cardiac motion. The systematic- (standard deviation (SD) of all the mean marker positions) and random errors (root-mean-square of the intra-BH SD) during DIBH were 0.5 and 0.3 mm (AP), 0.5 and 0.3 mm (LR), 0.8 and 0.4 mm (CC), respectively. The mean inter-breath-hold shifts were −0.3 mm (AP), −0.2 mm (LR), and −0.2 mm (CC). Conclusion Intra- and inter-breath-hold uncertainty of tumours and lymph nodes were small in visually guided breath-hold radiotherapy of NSCLC. Target motion could be substantially reduced, but not eliminated, using visually guided DIBH. [ABSTRACT FROM AUTHOR]

Purpose We investigated current trends in lung cancer surgery and identified demographic and social factors related to changes in these trends. Materials and Methods We estimated the incidence of lung cancer surgery using a procedure code-based approach provided by the Health Insurance Review and Assessment Service (http://opendata.hira. or.kr). The population data were obtained every year from 2010 to 2014 from the Korean Statistical Information Service (http://kosis.kr/). The annual percent change (APC) and statistical significance were calculated using the Joinpoint software. Results From January 2010 to December 2014, 25,687 patients underwent 25,921 lung cancer surgeries, which increased by 45.1% from 2010 to 2014. The crude incidence rate of lung cancer surgery in each year increased significantly (APC, 9.5; p < 0.05). The male-to-female ratio decreased from 2.1 to 1.6 (APC, -6.3; p < 0.05). The incidence increased in the age group of ≥ 70 years for both sexes (male: APC, 3.7; p < 0.05; female: APC, 5.96; p < 0.05). Furthermore, the proportion of female patients aged ≥ 65 years increased (APC, 7.2; p < 0.05), while that of male patients aged < 65 years decreased (APC, -3.9; p < 0.05). The proportions of segmentectomies (APC, 17.8; p < 0.05) and lobectomies (APC, 7.5; p < 0.05) increased, while the proportion of pneumonectomies decreased (APC, -6.3; p < 0.05). Finally, the proportion of patients undergoing surgery in Seoul increased (APC, 1.1; p < 0.05), while the proportion in other areas decreased (APC, -1.5; p < 0.05). Conclusion An increase in the use of lung cancer surgery in elderly patients and female patients, and a decrease in the proportion of patients requiring extensive pulmonary resection were identified. Furthermore, centralization of lung cancer surgery was noted. [ABSTRACT FROM AUTHOR]

Re-education of tumor-associated macrophages (TAMs) toward antitumor effectors may be a promising therapeutic strategy for the successful treatment of cancer. HangAmDan-B (HAD-B), a herbal formula, has been used for stimulating immune function and activation of vital energy to cancer patients in traditional Korean Medicine. Previous studies have reported the anti-angiogenic and anti-metastatic effects of HAD-B; however, evidence on the immunomodulatory action of HAD-B was not demonstrated. In the present study, immunocompetent mice were used to demonstrate the suppression of the in vivo growth of allograft Lewis lung carcinoma (LLC) cells, by HAD-B. In addition, HAD-B inhibited the in vitro growth of LLC cells by driving macrophages toward M1 polarization, but not through direct inhibition of tumor cell growth. Furthermore, culture media transfer of HAD-B-treated macrophages induced apoptosis of LLC cells. Results of the present study suggest that the antitumor effect of HAD-B may be explained by stimulating the antitumor function of macrophages. Considering the importance of re-educating TAMs in the regulation of the tumor microenvironment, the present study may confer another option for anti-cancer therapeutic strategy, using herbal medicines such as HAD-B. [ABSTRACT FROM AUTHOR]

Purpose: We conducted a comparative study to evaluate analgesic efficacy between paravertebral block via the surgical field (PVB-sf), in which the catheter was inserted into the ventral side of the sympathetic trunk in the paravertebral space by a thoracic surgeon under thoracoscopic visualization, and epidural block (Epi) using ropivacaine for post-thoracotomy pain relief. Methods: Lung cancer patients scheduled for lobectomy via thoracotomy were randomly allocated to receive either PVB-sf or Epi ( n = 36 per group). Before thoracotomy closure, 0.375% ropivacaine was administered as a bolus (PVB-sf, 20 mL; Epi, 5 mL), followed by a 300-mL continuous infusion of 0.2% ropivacaine at 5 mL/h. Postoperative pain was assessed using a visual analog scale (VAS) score at various time points, including the primary endpoint of 2 h after ropivacaine bolus injection. Sensory block area, vital signs, serum ropivacaine concentrations, and side effects were also evaluated. Results: The Epi group showed significantly lower VAS scores and blood pressure and a wider sensory block area than the PVB-sf group at all evaluation time points. While the mean serum ropivacaine concentration in the PVB-sf group was significantly higher than that in the Epi group until 1 h after injection of the ropivacaine bolus, there was no significant difference at any subsequent assessment point. The incidence of side effects was similar between the groups. Conclusion: The Epi was superior to PVB-sf for the management of post-thoracotomy pain in this patient cohort. The number of dermatomes anaesthetized by Epi was greater than that anaesthetized by PVB-sf. No difference in complication rates was observed between the two groups. [ABSTRACT FROM AUTHOR]

Background: The clinical validation of the EARL harmonization program for standardised uptake value (SUV) metrics is well documented; however, its potential for defining metabolic active tumour volume (MATV) has not yet been investigated. We aimed to compare delineation of MATV on images reconstructed using conventional ordered subset expectation maximisation (OSEM) with those reconstructed using point spread function modelling (PSF-reconstructed images), and either optimised for diagnostic potential (PSF) or filtered to meet the EANM/EARL harmonising standards (PSF). Methods: Images from 18 stage IIIA-IIIB lung cancer patients were reconstructed using all the three methods. MATVs were then delineated using both a 40% isocontour and a gradient-based method. MATVs were compared by means of Bland-Altman analyses, and Dice coefficients and concordance indices based on the unions and intersections between each pair of reconstructions (PSF vs OSEM, PSF vs PSF and PSF vs OSEM). Results: Using the 40% isocontour method and taking the MATVs delineated on OSEM images as a reference standard, the use of PSF images led to significantly higher Dice coefficients (median value = 0.96 vs 0.77; P < 0.0001) and concordance indices (median value = 0.92 vs 0.64; P < 0.0001) than those obtained using PSF images. The gradient-based methodology was less sensitive to reconstruction variability than the 40% isocontour method; Dice coefficients and concordance indices were superior to 0.8 for both PSF reconstruction methods. However, the use of PSF images led to narrower interquartile ranges and significantly higher Dice coefficients (median value = 0.96 vs 0.94; P = 0.01) and concordance indices (median value = 0.89 vs 0.85; P = 0.003) than those obtained with PSF images. Conclusion: This study demonstrates that automatic contouring of lung tumours on EARL-compliant PSF images using the widely adopted automatic isocontour methodology is an accurate means of overcoming reconstruction variability in MATV delineation. Although gradient-based methodology appears to be less sensitive to reconstruction variability, the use of EARL-compliant PSF images significantly improved the Dice coefficients and concordance indices, demonstrating the importance of harmonised-images, even when more advanced contouring algorithms are used. [ABSTRACT FROM AUTHOR]

Malignant pleural effusion (MPE), the presence of malignant cells in pleural fluid, is often the first sign of many cancers and occurs in patients with metastatic malignancies. Accurate detection of tumor cells in pleural fluid is crucial because the presence of MPE denotes an advanced stage of disease and directs a switch in clinical managements. Cytology, as a traditional diagnostic tool, has limited sensitivity especially when tumor cells are not abundant, and may be confounded by reactive mesothelial cells in the pleural fluid. We describe a highly sensitive approach for rapid detection of metabolically active tumor cells in MPE via exploiting the altered glucose metabolism of tumor cells relative to benign cells. Metabolically active tumor cells with high glucose uptake, as evaluated by a fluorescent glucose analog (2-NBDG), are identified by highthroughput fluorescence screening within a chip containing 200,000 addressable microwells and collected for malignancy confirmation via single-cell sequencing. We demonstrate the utility of this approach through analyzing MPE from a cohort of lung cancer patients. Most candidate tumor cells identified are confirmed to harbor the same driver oncogenes as their primary lesions. In some patients, emergence of secondary mutations that mediate acquired resistance to ongoing targeted therapies is also detected before resistance is manifested in the clinical imaging. The detection scheme can be extended to analyze peripheral blood samples. Our approach may serve as a valuable complement to cytology in MPE diagnosis, helping identify the driver oncogenes and resistance-leading mutations for targeted therapies. [ABSTRACT FROM AUTHOR]

Large-scale genomic characterization of non-small cell lung cancer (NSCLC) has revealed several putative oncogenic driver mutations that may constitute druggable therapeutic targets. However, there are little data to suggest that such gene alterations have clinical relevance. Over 12 consecutive months, tumor biopsy samples from 80 patients with stage IV NSCLC were analyzed for mutations in selected exons of 508 cancer-related genes using next-generation sequencing. From 85 specimens referred for genomic characterization, 80 (94%) specimens were successfully genotyped, and all had identifiable somatic alterations. Epidermal growth factor receptor ( EGFR) and TP53 genes contained the highest frequency of observed mutations (65% and 40%, respectively) in the stage IV NSCLC cases. Notably, patients with EGFR mutations showed a significantly shorter survival time compared with patients expressing wild-type EGFR (p = 0.0053). Moreover, of the 32 patients harboring EGFR mutations, EGFR-L858R mutant patients showed a significantly shorter survival time compared with patients with other EGFR mutations (p = 0.036). In conclusion, tumors from stage IV NSCLC patients harbor characteristic gene alterations, of which EGFR L858R in particular appears to be a poor prognostic factor for overall survival. [ABSTRACT FROM AUTHOR]

In this Industry Corner article, we describe the experience with nintedanib in combination with docetaxel, which was first approved in the European Union in 2014 for the treatment of patients with non-small cell lung cancer (NSCLC) of adenocarcinoma histology after first-line chemotherapy. In therapeutic indications such as NSCLC, where there is a clear unmet medical need, delayed patient access to new therapies following regulatory approval is a significant challenge. Although nintedanib in combination with docetaxel has satisfied the obligation of meeting a medical need, as noted by successfully receiving European Medicines Agency approval and passing several HTA evaluations, including the National Institute for Health and Care Excellence, and by demand for patient access to nintedanib via the CUP/NPP, patients across Europe are not gaining equal access to this new therapy due to varying reimbursement procedures. [ABSTRACT FROM AUTHOR]

E-cigarettes remain controversial because the scientific evidence of short term and long term effects on tolerance and the health value of a switch from tobacco to e-cigarettes is contested and controversial. Nevertheless the quality of e-cigarettes and e-liquids has improved. The main ingredients, propylene glycol, vegetable glycerine and nicotine are pharmaceutical-grade quality in most e-liquids. Flavors are almost all food grade. The high quality of ingredients has decreased the presence of impurities in e-liquids. The emissions of e-cigarettes do not contain solid particles or carbon monoxide. Nitrosamine content is at least one hundred times lower than in tobacco smoke. E-cigarette emissions in normal use do not contain any harmful constituents at significant levels except nicotine. UK public health authorities have stated that e-cigarette use is likely to be at least 95% less toxic than cigarette use. There are benefits from having a well-regulated legal market. In countries where e-liquid containing nicotine is not allowed, “do-it-yourself” liquids are common and have handling risks and may sometimes contain toxic impurities. Though e-cigarettes should never be assumed safe products for non-smokers, for smokers, the e-cigarette is at least 20 times less dangerous than the cigarette. Tobacco cessation specialists in countries where nicotine containing e-cigarettes are available increasingly provide counselling for e-cigarette use to stop smoking or to reduce smoking at the request of patients. Based on current knowledge, for patients with lung or other forms of cancer who would otherwise continue to smoke, e-cigarettes offer an alternative way to quit smoking while they undergo medical treatment. [ABSTRACT FROM AUTHOR]

The aim of the present meta-analysis was to evaluate the diagnostic value of diffusion-weighted imaging (DWI) in differentiating metastatic from non-metastatic lymph nodes in patients with lung cancer. A systematic literature search was performed to identify eligible original studies. The quality of included studies was assessed using 'quality assessment of diagnostic accuracy studies' (QUADAS-2). Meta-analysis was performed to pool sensitivity and specificity, to calculate the positive likelihood ratio (PLR), the negative likelihood ratio (NLR) and the diagnostic odds ratio (DOR), and to construct the summary receiver operating characteristic (SROC) curve. The homogeneity, threshold effect and publication bias were also investigated. Meta-regression analysis was performed to identify the sources of heterogeneity. A total of 10 studies with 11 datasets met the inclusion criteria, which comprised 796 patients with a total of 2,433 lymph nodes. The pooled diagnostic sensitivity was 0.78 [95% confidence interval (CI): 0.74-0.81] and the pooled diagnostic specificity was 0.88 (95% CI: 0.86-0.89). The PLR, NLR, and DOR were 7.11 (95% CI: 4.39-11.52), 0.24 (95% CI: 0.18-0.33), and 31.14 (95% CI: 17.32-55.98), respectively. The area under the SROC curve was 0.90. No publication bias was found (bias=-0.15, P=0.887). Notable heterogeneity was, however, observed, and patient selection, type of lung cancer, number of enrolled lymph nodes, reference standard, B-value and the type of scanner were the sources of heterogeneity (P<0.05). No significant threshold effect was identified (P=0.537). In conclusion, DWI has been revealed to be a valuable magnetic resonance imaging (MRI) modality, with good diagnostic performance for distinguishing metastatic from non-metastatic lymph nodes in patients with lung cancer. Therefore, DWI may be a useful supplement to conventional MRI techniques. [ABSTRACT FROM AUTHOR]

Invasive mucinous adenocarcinoma (IMA), formerly referred to as mucinous bronchioloalveolar carcinoma, is a rare variant form of invasive adenocarcinoma and is radiologically characterized by dense pneumonic consolidation, ground.glass opacity and nodules. By contrast, large, thin.walled cysts are rare. We herein report the case of a 75.year.old man with IMA presenting as a large, irregularly shaped cystic lesion. The histological diagnosis was based on specimens obtained during a bronchoscopy. The patient underwent lobectomy followed by anticancer chemotherapy for residual intrapulmonary metastases. Of note, the small metastatic nodules transformed into cystic lesions with thin walls and fused, forming a large, multiloculated cystic lesion. Typical pneumonic consolidation appeared in the pericystic parenchyma later during the clinical course. The available literature on this rare radiological manifestation was also reviewed and discussed. Clinicians should be aware of thin.walled cystic lesions as they may be an unusual radiological finding in IMA. [ABSTRACT FROM AUTHOR]

Plasminogen activator inhibitor-1 ( PAI-1) plays a crucial role in the process of lung injury, although its association with radiation pneumonitis ( RP) is unclear. We hypothesized that genetic variants in PAI-1 may influence the risk of RP. In this study, 169 lung cancer patients were genotyped for six single-nucleotide polymorphisms in PAI-1 using the Sequenom Mass ARRAY system. The risk of RP was evaluated by Cox proportional hazards analyses. The cumulative RP probabilities by genotype were assessed using Kaplan-Meier analyses. Univariate and multivariate analyses revealed that PAI-1:rs7242 GT/ GG was correlated with an increased occurrence of grade ≥3 RP (crude hazard ratio = 3.331; 95% confidence interval, 1.168-9.497; P = 0.024). Our results indicated that PAI-1:rs7242 in the 3′-untranslated region of PAI-1 can be a predictor of grade ≥3 RP before radiotherapy. [ABSTRACT FROM AUTHOR]

Pyropheophorbide- α methyl ester ( MPPa) was a promising photosensitizer with stable chemical structure, strong absorption, higher tissue selectivity and longer activation wavelengths. The present study investigated the effect of MPPa-mediated photodynamic treatment on lung cancer A549 cells as well as the underlying mechanisms. Cell Counting Kit-8 was employed for cell viability assessment. Reactive oxygen species levels were determined by fluorescence microscopy and flow cytometry. Cell morphology was evaluated by Hoechst staining and transmission electron microscopy. Mitochondrial membrane potential, cellular apoptosis and cell cycle distribution were evaluated flow-cytometrically. The protein levels of apoptotic effectors were examined by Western blot. We found that the photocytotoxicity of MPPa showed both drug- and light- dose dependent characteristics in A549 cells. Additionally, MPPa- PDT caused cell apoptosis by reducing mitochondrial membrane potential, increasing reactive oxygen species ( ROS) production, inducing caspase-9/caspase-3 signaling activation as well as cell cycle arrest at G0/G1 phase. These results suggested that MPPa- PDT mainly kills cells by apoptotic mechanisms, with overt curative effects, indicating that MPPa should be considered a potent photosensitizer for lung carcinoma treatment. [ABSTRACT FROM AUTHOR]

Objective: No definitive chemotherapeutic regimen has been established in patients with non-small-cell lung cancer (NSCLC) who failed second- or third-line treatment. The aim of this study was to evaluate apatinib, a VEGFR-2 inhibitor, in advanced NSCLC as salvage treatment. Methods: We evaluated the efficacy and toxicity of apatinib in patients with previously treated advanced NSCLC from 2014 to 2015 in Zhejiang Cancer Hospital. Survival analysis was performed by the Kaplan-Meier method. Results: Forty-two patients were included in the present study. Four patients achieved partial response, and 22 achieved stable disease, representing a response rate of 9.5% and a disease control rate of 61.9%. Median progression-free survival and overall survival were 4.2 and 6.0 months, respectively. The toxicities associated with apatinib were generally acceptable with a total grade 3/4 toxicity of 50%. Conclusion: Apatinib appears to have some activity against advanced NSCLC when utilized as salvage treatment. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to evaluate the chronological changes in epidemiological factors and surgical outcomes in patients with lung cancer who underwent surgery in a single Japanese institution. Patients and methods: A clinicopathological database of patients with lung cancer who underwent surgery with curative intent from January 1974 to December 2014 was reviewed. The chronological changes in various factors, including patient's age, sex, histological type, tumor size, pathological stage (p-stage), surgical method, operative time, intraoperative blood loss, 30-day mortality, and postoperative overall survival (OS), were evaluated. Results: A total of 1,616 patients were included. The numbers of resected patients, females, adenocarcinomas, p-stage IA patients, and age at the time of surgery increased with time, but tumor size decreased (all P<0.0001). Concerning surgical methods, the number of sublobar resections increased, but that of pneumonectomies decreased (P<0.0001). The mean operative time, intraoperative blood loss, and the postoperative 30-day mortality rate decreased (all P<0.0001). When the patients were divided into two groups (1974-2004 and 2005-2014), the 5-year OS rates for all patients and for p-stage IA patients improved from 44% to 79% and from 73% to 89%, respectively (all P<0.0001). The best 5-year OS rate was obtained for sublobar resection (73%), followed by lobectomy (60%), combined resection (22%), and pneumonectomy (21%; P<0.0001). Conclusion: Changes in epidemiological factors, a trend toward less invasive surgery, and a remarkably improved postoperative OS were confirmed, which demonstrated the increasingly important role of surgery in therapeutic strategies for lung cancer. [ABSTRACT FROM AUTHOR]

The senescence of the immune system and the risk of cancer increase with aging. Age itself entails changes in the immune system, which are related to a decrease in thymic output of naïve lymphocytes, an accumulation of chronic antigenic load, notably chronic viral infections such as cytomegalovirus (CMV), and replicative senescence of lymphocytes. These changes could eventually contribute to cancer risk and affect the response to cancer treatment. However, several confounding factors make it difficult to draw a picture of causal relationships. Studies in diverse human populations could contribute to clarify these complex relationships. Here, we summarize the current knowledge about the senescence of the T cells, the relationship with CMV infection, cancer, and cancer treatment. We also review the results of a series of studies performed in Cuba whose population is characterized by the unusual combination of long life expectancy and high antigenic load, including high seroprevalence of CMV, typical of tropical countries. Although immunosenescence affects almost all components and functions of the immune response, its most salient feature is a decrease in numbers and proportions of naïve CD8+ T lymphocytes and an accretion of terminally differentiated CD8+ T lymphocytes. These features were confirmed by the Cuban studies, but interestingly a clear gender effect also appeared. Moreover, as aging is a global phenomenon, a fast increase in elderly with malignancies is expected; therefore, the evaluation of patients immune status would support the decision of treating them with immunotherapy and predict the efficacy of such treatments, thereby improving benefits for the patients. [ABSTRACT FROM AUTHOR]

Esophageal symptoms are common during radiation and chemotherapy. It is unclear how often these symptoms persist after therapy.We retrospectively reviewed medical records of 320 adults treated for nonmetastatic breast cancer (84), lung cancer (109), or Hodgkin and non-Hodgkin lymphoma (127) who were disease-free at 10-14 months after therapy. Treatment included chemotherapy with or without nonmediastinal radiation therapy (150 patients), chemotherapy plus sequential mediastinal radiation therapy (MRT) (48 patients), chemotherapy plus concurrent MRT (61 patients), or non-MRT only (61 patients). Proton pump inhibitor use was documented. All treatment groups had similar prevalence of the esophageal symptom of heartburn before therapy. Rates were higher during treatment in those who received MRT with or without chemotherapy, but declined by 10-14 months after treatment. However, low baseline rates of dysphagia (4%) and odynophagia (2%) increased significantly after combined chemotherapy andMRT to 72% for dysphagia and 62% for odynophagia (P<0.01) during treatment and stayed significantly elevated over baseline with 27% of the patients having dysphagia and 11% having odynophagia at 10-14 months after treatment. The use of proton pump inhibitors by patients who hadMRT with chemotherapy was significantly increased during and after treatment (P=0.002). Dysphagia, odynophagia and the use of proton pump inhibitors were significantly more common both during and after treatment than before treatment in patients who received both chemotherapy and mediastinal radiation. Our data highlight the important challenge for clinicians of managing patients with lung cancer and lymphoma who have persistent esophageal problems, particularly dysphagia and odynophagia, at approximately 1 year after treatment. [ABSTRACT FROM AUTHOR]

Purpose: Using 4-dimensional dynamic-ventilatory scanning by a 320-row computed tomography (CT) scanner, we performed a quantitative assessment of parietal pleural invasion and adhesion by peripheral (subpleural) lung cancers.Methods: Sixteen patients with subpleural lung cancer underwent dynamic-ventilation CT during free breathing. Neither parietal pleural invasion nor adhesion was subsequently confirmed by surgery in 10 patients, whereas the other 6 patients were judged to have parietal pleural invasion or adhesion. Using research software, we tracked the movements of the cancer and of an adjacent structure such as the rib or aorta, and converted the data to 3-dimensional loci. The following quantitative indices were compared by the Mann-Whitney test: cross-correlation coefficient between time curves for the distances moved from the inspiratory frame by the cancer and the adjacent structure, the ratio of the total movement distances (cancer/adjacent structure), and the cosine similarities between the inspiratory and expiratory vectors (from the cancer to the adjacent structure) and between vectors of the cancer and of the adjacent structure (from inspiratory to expiratory frames).Results: Generally, the movements of the loci of the lung cancer and the adjacent structure were similar in patients with parietal pleural invasion/adhesion, while they were independent in patients without. There were significant differences in all the parameters between the two patient groups (cross-correlation coefficient and the movement distance ratio, P<0.01; cosine similarities, P<0.05).Conclusion: These observations suggest that quantitative indices by dynamic-ventilation CT can be utilized as a novel imaging approach for the preoperative assessment of parietal pleural invasion/adhesion. [ABSTRACT FROM AUTHOR]

Background and purpose Lung volumes are functionally heterogeneous but typically considered uniformly during radiotherapy planning. The present study aims to predict regional differences in radiation-induced lung damage based on pre-treatment CT information. Materials and methods For 42 lung cancer patients (including 15 from an external validation set), two 200 cc lung subvolumes (low-density (LD) and high-density (HD)) were auto-segmented in the ipsilateral lung of the planning CT 0. After non-rigid registration of 3 month follow-up CT scans, sigmoidal dose-density change (ΔHU = HU 3M − HU 0 ) response curves were determined for all subvolumes. Predictive factors for the sigmoidal response parameters D 50 and saturation level ΔHU max were analyzed. Results The baseline density difference between LD (mostly in the upper lobe) and HD (mostly in the lower lobe) was on average 102 HU. The saturation level ΔHU max,LD was significantly smaller than ΔHU max,HD ( p = 0.03). Expressed as mass density increase relative to the baseline density, saturation levels were 20.7% on average irrespective of baseline density, and they could be predicted in LD and HD subvolumes (AUC = 0.70–0.78). Intra-lung differences in D 50 were significantly smaller than inter-patient differences. Conclusions Limited amount of damage was observed in LD subvolumes, while the relative density increase of all subvolumes was well predictable. This could allow dose redistribution preferentially targeting low-density lung regions. [ABSTRACT FROM AUTHOR]

Introduction The National Lung Screening Trial recently reported that annual low-dose computed tomography screening is associated with decreased lung cancer mortality in high-risk smokers. This study sought to identify the factors patients consider important in making lung cancer screening (LCS) decisions, and explore variations by patient characteristics and LCS participation. Material and methods This observational survey study evaluated the Minneapolis VA LCS Clinical Demonstration Project in which LCS-eligible Veterans (N = 1388) were randomized to either Direct LCS Invitation (mailed with decision aid, N = 926) or Usual Care (provider referral, N = 462). We surveyed participants three months post-randomization (response rate 44%) and report the proportion of respondents rating eight decision-making factors (benefits, harms, and neutral factors) as important by condition, patient characteristics, and LCS completion. Results Overall, the most important factor was personal risk of lung cancer and the least important factor was health risks from LCS. The reported importance varied by patient characteristics, including smoking status, health status, and education level. Overall, the potential harms of LCS were reported less important than the benefits or the neutral decision-making factors. Exposure to Direct LCS Invitation (with decision aid) increased Veterans’ attention to specific decision-making factors; compared to Usual Care respondents, a larger proportion of Direct LCS Invitation respondents rated the chance of false-positive results, LCS knowledge, LCS convenience, and anxiety as important. Those completing LCS considered screening harms less important, with the exception of incidental findings. Conclusion Decision tools influence Veterans’ perceptions about LCS decision-making factors. As the factors important to LCS decision making vary by patient characteristics, targeted materials for specific subgroups may be warranted. Attention should be paid to how LCS incidental findings are communicated. [ABSTRACT FROM AUTHOR]

We investigate the role of physician agency in determining health care supply and patient outcomes. We show that an increase in health care supply due to a change in private physician incentives has a theoretically ambiguous impact on patient welfare. The increase can reflect either induced demand for ineffective care or a reduction in prior rationing of effective care. Furthermore, physician market structure matters in determining the welfare effects of changes in private physician incentives. We then analyze a change to Medicare fees that caused physicians to increase their provision of chemotherapy. We find that this increase in treatment improved patient survival, extending median life expectancy for lung cancer patients by about 18%. Consistent with the model, we find that while the treatment response was larger in less concentrated markets, survival improvements were larger in more concentrated markets. [ABSTRACT FROM AUTHOR]

Approximately 30% of early stage lung cancer patients are not surgical candidates due to medical co-morbidities, poor cardiopulmonary function and advanced age. These patients are traditionally offered chemotherapy and radiation, which have shown relatively modest improvements in mortality. For over a decade, percutaneous image-guided ablation has emerged as a safe, cost-effective, minimally invasive treatment alternative for patients who would otherwise not qualify for surgery. Although radiofrequency ablation (RFA) is currently the most extensively studied and widely utilised technique in the treatment of lung malignancies, there is a growing body of evidence that microwave ablation (MWA) has several unique benefits over RFA and cryoablation in the lung. This article reviews our institution’s clinical experiences in the treatment of lung malignancies with MWA including patient selection, procedural technique, imaging follow-up, treatment outcomes and comparison of ablation techniques. [ABSTRACT FROM PUBLISHER]

Background: The roles of carcinoembryonic antigen (CEA), cytokeratin 19 fragments (CYFRA21-1) and neuron-specific enolase (NSE) in metastases occurrence and poor diagnosis in specific histological classifications of lung cancer need further exploring. In this study, we investigated relationship between elevated levels of three biomarkers of CEA, CYFRA21-1 and NSE (individually and in combination) and metastasis, survival status and prognosis in lung cancer patients.Methods: Eight hundred and sixty eight lung cancer patients including adenocarcinoma (ADC, N = 445), squamous cell carcinoma (SCC, N = 215), small cell lung cancer (SCLC, N = 159) and other types (N = 49) were categorized into negative, moderate and high groups according to serum levels of biomarkers, and were then categorized into negative, single, double and triple groups according to any positive combination of three biomarkers. The cutoff values of three biomarkers for groupings were developed on the training group (N = 432) and verified in a validation group (N = 436). Clinical and laboratory characteristics were then assessed for correlation with occurrence of metastasis, survival status and prognosis between the two groups. Further correlation analyses were also conducted by different subtypes (ADC, SCC and SCLC) and tumor stages (I + II, III and IV) of lung cancers.Results: The consistent results between training and validation group confirmed the rationality of grouping methods. CYFRA21-1 levels had stronger association with metastases and survival status than CEA and NSE in all lung cancer patients. When stratified by subtypes, these significances only existed in ADC patients for CYFRA21-1. Cox regression analyses showed that CYFRA21-1 and NSE were independent prognostic factors for lung cancer patients. However, only CYFRA21-1 was an independent prognostic factor in ADC and SCLC patients subtypes. Cox-regression results also indicated that CYFRA21-1 could act as independent prognostic factor in different stages (I + II, III and IV) of lung cancer.Conclusion: CYFRA21-1 was more important in metastasis occurrence and in predicting poor prognosis in lung cancer patients than CEA, NSE and positive numbers of biomarkers. [ABSTRACT FROM AUTHOR]

Objectives: To report overall survival and local control for patients identified in the RSSearch® Patient Registry with metastatic cancer to the lung treated with SBRT.Methods: Seven hundred two patients were identified with lung metastases in the RSSearch® Registry. Of these patients, 577 patients had SBRT dose and fractionation information available. Patients were excluded if they received prior surgery, radiation, or radiofrequency ablation to the SBRT treated area. Between April 2004-July 2015, 447 patients treated with SBRT at 30 academic and community-based centers were evaluable for overall survival (OS). Three hundred four patients with 327 lesions were evaluable for local control (LC). All doses were converted to Monte Carlo equivalents and subsequent BED Gy10 for dose response analysis.Results: Median age was 69 years (range, 18-93 years). Median Karnofsky performance status (KPS) was 90 (range 25/75% 80-100). 49.2% of patients had prior systemic therapy. Median metastasis volume was 10.58 cc (range 25/75% 3.7-25.54 cc). Site of primary tumor included colorectal (25.7%), lung (16.6%), head and neck (11.4%), breast (9.2%), kidney (8.1%), skin (6.5%) and other (22.1%). Median dose was 50 Gy (range 25/75% 48-54) delivered in 3 fractions (range 25/75% 3-5) with a median BED of 100Gy10 (range 25/75% 81-136). Median OS for the entire group was 26 months, with actuarial 1-, 3-, and 5-year OS of 74.1%, 33.3, and 21.8%, respectively. Patients with head and neck and breast cancers had longer median OS of 37 and 32 months respectively, compared to colorectal (30 months) and lung (26 months) which corresponded to 3-year actuarial OS of 51.8 and 47.9% for head and neck and breast respectively, compared to 35.8% for colorectal and 31.2% for lung. The median LC for all patients was 53 months, with actuarial 1-, 3-, and 5-year LC rates of 80.4, 58.9, and 46.3%, respectively. There was no difference in LC by primary histologic type (p = 0.49). Improved LC was observed for lung metastases that received SBRT doses of BED ≥100Gy10 with 3-year LC rate of 77.1% compared to 45% for lung metastases treated with BED < 100Gy10 (p = 0.01). Smaller tumor volumes (<11 cc) had improved LC compared to tumor volumes > 11 cc. (p = 0.005) Two-year LC rates for tumor volumes < 11 cc, 11-27 cc and > 27 cc were 72.9, 64.2 and 45.6%, respectively. This correlated with improved OS with 2-year OS rates of 62.4, 60.9 and 46.2% for tumor volumes < 11 cc, 11-27 cc and > 27 cc, respectively (p = 0.0023). In a subset of patients who received BED ≥100Gy10, 2-year LC rates for tumor volumes < 11 cc, 11-27 cc and > 27 cc were 82.8, 58.9 and 68.6%, respectively (p = 0.0244), and 2-year OS rates were 66.0, 58.8 and 28.5%, respectively (p = 0.0081).Conclusion: Excellent OS and LC is achievable with SBRT utilizing BED ≥100Gy10 for lung metastases according to the RSSearch® Registry data. Patients with small lung metastases (volumes < 11 cc) had better LC and OS when using SBRT doses of BED ≥100Gy10. Further studies to evaluate a difference, if any, between various tumor types will require a larger number of patients. [ABSTRACT FROM AUTHOR]

Purpose: Our previous study suggested that some pulmonary artery (PA) dosimetric parameters were associated with mortality in unresectable non-small cell lung cancer (NSCLC) treated with definitive radiotherapy. The present study aims to analyze the impact of both PA and heart dosimetric parameters on survival of patients with NSCLC treated with definitive conventional fractionated radiotherapy (CFRT) in another independent research center and further determine whether the PA should be considered a dose-limiting organ at risk (OAR) for patients receiving thoracic CFRT.Methods: We performed a retrospective analysis of successive patients with medically inoperable or unresectable NSCLC treated with definitive radiotherapy or chemoradiotherapy from August 2010 to September 2014. Clinical and pathological information, PA and heart dosimetric factors, and follow-up data were collected from each patient's records and evaluated as potential prognostic factors for survival. Survival probabilities were estimated by the Kaplan-Meier method and compared by the log rank test. Cox proportional hazards regression models were performed to determine the independent predicators of survival. The optimal cutoff points of continuous dosimetric variables were determined by Youden index in receiver operating characteristic (ROC) analysis.Results: This study analyzed the records of 141 patients, 50.4% had adenocarcinoma, 71.6% had stage III disease, and 55% patients received concurrent chemoradiotherapy. Radiation dose ranged from 60 to 76 Gy in 30-38 fractions. Median follow up was 16.9 months. Median overall survival (OS) was 20.5 months (95% confidence interval [CI] 10.3-30.7 months), and 1-, 2-, 3-year OS rates were 75.2%, 58.2% and 56%, respectively. Univariate and multivariate analysis showed that Karnofsky Performance Status (KPS) score, Charlson's Comorbidity Index (CCI), T and N stage, PA invasion grade and the percentage of PA volume that received 40 to 55 Gy (PA V40-55) were significantly associated with OS. No significant associations were found between heart dosimetric factors and OS. Median OS of patients with PA invasion grade 0, 1, 2, and 3 were 41.8, 27.8, 12.7 and 7.5 months, respectively (P < 0.001). PA V40, V45, V50 and V55, using thresholds of 80%, 68%, 45%, and 32%, respectively, were independent predictors for OS.Conclusions: PA invasion grade and PA V40-55 appear associated with OS in patients with NSCLC treated with definitive CFRT. We propose that PA be considered as a dose-limiting OAR for such patients. [ABSTRACT FROM AUTHOR]

Purpose: As the major toxicity induced by pemetrexed plus carboplatin is severe hematologic toxicities, the aim of this study was to determine the risk factors for severe hematologic toxicities in lung cancer patients. Methods: We retrospectively investigated data from lung cancer patients who had received pemetrexed plus carboplatin, with or without bevacizumab. This observational study was carried out at Ehime University Hospital using electronic medical records dating from July 2009 to March 2015. Severe hematologic toxicities were defined as grade 3 or 4, according to the Common Terminology Criteria for Adverse Events, version 4.0. Results: Forty-two patients were included in the study. The incidence of grade 3 or 4 hematologic toxicities during the first cycle of chemotherapy and during all cycles was 19.0% and 16.1%, respectively. Multivariate time-depend generalized estimating equations logistic regression analysis revealed that regular use of non-steroidal anti-inflammatory drugs (NSAIDs) was significantly associated with an increased risk of severe hematologic toxicities during all cycles (adjusted odds ratio (OR): 8.32, 95% confidence interval (CI): 1.27–54.38; p = 0.03), whereas creatinine clearance of <45 mL/min was not significantly associated with an increased risk of severe hematologic toxicities during all cycles (adjusted OR: 0.91, 95% CI: 0.25–3.34; p = 0.88). Conclusions: The results suggest that severe hematologic toxicities in patients receiving carboplatin-based pemetrexed may be significantly induced by the inhibition of renal tubular pemetrexed secretion through drug–drug interactions between NSAIDs and pemetrexed rather than through glomerular filtration of pemetrexed, even with moderate to sufficient renal function. [ABSTRACT FROM AUTHOR]

Background: The time from a referral for suspected lung cancer is received at a hospital until treatment start has been defined as a quality indicator. Current Norwegian recommendation is that ≥70% should start surgery or radiotherapy within 42 calendar days and systemic therapy within 35 days. However, delays can occur due to medical complexity. The aim of this study was to quantify the proportion of patients who started treatment within the recommended timeframes; and to assess the proportion of non-complex patients for which there were no good reasons for delays.Methods: We performed a retrospective chart review of all patients diagnosed with lung cancer at a university hospital during 2011-2013. We defined "non-complex" patients as those who underwent ≤1 tissue diagnostic procedure and had no delays due to comorbidity, intercurrent disease or complications to diagnostic procedures ("Medical delays") of more than three days.Results: Four hundred forty-nine cases were analyzed; 142 (32%) had >1 tissue diagnostic procedures; 67 (15%) had medical delays >3 days; 262 (58%) were non-complex and 363 (81%) received treatment for lung cancer. Median number of days until surgery or radiotherapy was 48 (overall) and 41 (non-complex patients). The proportions who started surgery or radiotherapy within 42 days were 41% (overall) and 56% (non-complex). Corresponding numbers for systemic therapy were 29 days (overall) and 25 days (non-complex), and 64% (overall) and 80% (non-complex).Conclusion: Fewer lung cancer patients than desired started treatment within the recommended timeframes. Even among the least complex patients, too few patients received timely treatment. The reasons need to be identified and understood, and changes in the organization appear to be necessary in order to offer timely treatment to more patients. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to determine if preoperative quantitative computed tomography (CT) features including texture and histogram analysis measurements are associated with tumor recurrence in patients with surgically resected adenocarcinoma of the lung. Methods: The study included 194 patients with surgically resected lung adenocarcinoma who underwent preoperative CT between January 2013 and December 2013. Quantitative CT feature analysis of the lung adenocarcinomas were performed using in-house software based on plug-in package for ImageJ. Ten quantitative features demonstrating the tumor size, attenuation, shape and texture were extracted. The CT parameters obtained from 1-mm and 5-mm data were compared using intraclass correlation coefficients. Univariate and multivariable logistic regression methods were used to investigate the association between tumor recurrence and preoperative CT findings. Results: The 1-mm and 5-mm data were highly correlated in terms of diameter, perimeter, area, mean attenuation and entropy. Circularity and aspect ratio were moderately correlated. However, skewness and kurtosis were poorly correlated. Multivariable logistic regression analysis revealed that area (odds ratio [OR], 1.002 for each 1-mm2 increase; P = 0.003) and mean attenuation (OR, 1.005 for each 1.0-Hounsfield unit increase; P = 0.022) were independently associated with recurrence. The receiver operating curves using these two independent predictive factors showed high diagnostic performance in predicting recurrence (C-index = 0.81, respectively). Conclusion: Tumor area and mean attenuation are independently associated with recurrence in patients with surgically resected adenocarcinoma of the lung. [ABSTRACT FROM AUTHOR]

Background/aim: For the early stage of nonsmall-cell lung cancer, surgical resection provides the best survival, but the surgical risk generally increases with age because of the increased prevalence of comorbidities, especially cardiovascular disorders. The aim of this study was to compare survival and mortality rates of two groups with different ages, younger and older than 70 years, who went curative resection for nonsmall-cell lung cancer. Materials and methods: We analyzed the patients who underwent curative lung cancer surgery in the Department of Thoracic Surgery of Gaziantep University Research Hospital between January 1997 and November 2014. Patients were divided into 2 groups according to their ages. Results: A total of 497 patients were included in data analysis (381 were under 70 years old and 116 of them were =70 years old). The older group showed a 1.4-fold increased risk of mortality hazard ratio when the probability of survival was analyzed by histological type, lymph node involvement, disease stage, and age. Conclusion: There was no distinct increase in 30-day mortality rates of patients with nonsmall-cell lung cancer who were =70 years old, but the hazard rate for long-term survival was higher in the older group. Curative pulmonary resections due to lung cancer should be carefully performed in septuagenarians. [ABSTRACT FROM AUTHOR]

We analyze lung cancer mortality by age and sex in the United States, 1959–2013. It is already known that male lung cancer death rates exceed those of women and that tobacco use is the leading reason for the sex difference. We elaborate on this knowledge by showing that unlike most causes of death, lung cancer mortality patterns by age are a very good fit to a quadratic-Gompertz model, i.e., log mortality rates are quadratic by age, with the mode above age 70. With a little additional historical data on sex differences in tobacco use, the quadratic models help to paint a clear quantitative picture of behavior-led convergence in lung cancer mortality by sex. The shape of the sex-specific mortality curves have converged dramatically: since 1983, the sexes have had statistically indistinguishable shapes of their quadratic-Gompertz mortality curves. Female lung cancer mortality patterns have shown a transformation from a nonsmoking to a smoking pattern. The modal age of the quadratic-Gompertzian lung cancer death rates has potential application in countries at earlier stages of the global tobacco epidemic. Where the modal age is falling (year-on-year), we can infer that the local lung cancer epidemic is getting worse, and where it is rising, that it has begun to abate. [ABSTRACT FROM PUBLISHER]

Background: Diffusion-weighted imaging (DWI) derived apparent diffusion coefficient (ADC) has demonstrated inconsistent results in pulmonary nodule differentiation. Diffusion kurtosis imaging (DKI), which quantifies non-Gaussian diffusion, is believed to better characterize tissue micro-structure than conventional DWI. Purpose: To assess the feasibility of DKI in human lungs and to compare its diagnostic value with standard DWI in differentiating malignancies from benign pulmonary nodules. Material and Methods: Thirty-five pulmonary nodules in 32 consecutive patients were evaluated by DKI by using 3b-values of 0, 500, and 1000 s/mm2 and conventional DWI with b values of 0 and 800 s/mm2. Two observers independently evaluated and compared diagnostic accuracy of mean kurtosis (MK) and ADC values in differentiating malignancies from benign pulmonary nodules. The intra- and inter-observer repeatability (intra-class correlation coefficient [ICC]) were also assessed for each derived measures. Results: The diagnostic accuracy, and the area under curve (AUC) in differentiating malignancies from benign pulmonary nodule, were not significantly higher for MK (Obs. 1a: 85.70%, 0.87; Obs. 1b: 80.00%, 0.80; and Obs. 2: 82.80%, 0.91) as compared to ADC (Obs. 1a: 77.14%, 0.81; Obs. 1b: 80.00%, 0.85; and Obs. 2: 77.14%, 0.85 respectively). The intra- and inter-observer agreement (ICC) for malignant and benign lesions was substantial for each reading. Conclusion: The initial results of this study indicate the feasibility of DKI in human lungs. However, there was no significant benefit of DKI derived MK values over ADC for malignant and benign pulmonary nodule differentiation. [ABSTRACT FROM AUTHOR]

With 1.6 million deaths per year, lung cancer is one of the leading causes of death worldwide. One reason for this high number is the absence of a preventive medical examination method. Many diagnoses occur in a late cancer stage with a low survival rate. An early detection could significantly decrease the mortality. In recent decades, certain substances in human breath have been linked to certain diseases. Different studies show that it is possible to distinguish between lung cancer patients and a healthy control group by analyzing the volatile organic compounds (VOCs) in their breath. We developed a sensor based on photoacoustic spectroscopy for six of the most relevant VOCs linked to lung cancer. As a radiation source, the sensor uses an optical-parametric oscillator (OPO) in a wavelength region from 3.2 µm to 3.5 µm. The limits of detection for a single substance range between 5 ppb and 142 ppb. We also measured high resolution absorption spectra of the biomarkers compared to the data currently available from the National Institute of Standards and Technology (NIST) database, which is the basis of any selective spectroscopic detection. Future lung cancer screening devices could be based on the further development of this sensor. [ABSTRACT FROM AUTHOR]

Stage classification provides a nomenclature about the anatomic extent of a cancer; a consistent language provides the ability to communicate about a specific patient and about cohorts of patients in clinical studies. This paper summarizes the eighth edition of lung cancer stage classification, which is the worldwide standard as of January 1, 2017. This revision is based on a large global database, a sophisticated analysis, extensive internal validation as well as multiple assessments confirming generalizability. Practicing clinicians must be familiar with the stage classification system when managing contemporary patients with lung cancer. [ABSTRACT FROM AUTHOR]

Purpose: We examined the efficacy of poziotinib, a second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) in patients with lung adenocarcinoma with activating EGFR mutations, who developed acquired resistance (AR) to EGFR-TKIs. Materials and Methods: This single-arm phase II study included EGFR-mutant lung adenocarcinoma with AR to erlotinib or gefitinib based on the Jackman criteria. Patients received poziotinib 16 mg orally once daily in a 28-day cycle. The primary endpoint was progression-free survival (PFS). Prestudy tumor biopsies and blood samples were obtained to determine resistance mechanisms. Results: Thirty-nine patients were treated. Tumor genotyping was determined in 37 patients; 19 EGFR T790M mutations and two PIK3CAmutations were detected in the prestudy tumors, and seven T790M mutations were detected in the plasma assay. Three (8%; 95% confidence interval [CI], 2 to 21) and 17 (44%; 95% CI, 28 to 60) patients had partial response and stable disease, respectively. The median PFS and overall survival were 2.7 months (95% CI, 1.8 to 3.7) and 15.0 months (95% CI, 9.5 to not estimable), respectively. A longer PFS was observed for patients without T790M or PIK3CA mutations in tumor or plasma compared to those with these mutations (5.5 months vs. 1.8 months, p=0.003). The most frequent grade 3 adverse events were rash (59%), mucosal inflammation (26%), and stomatitis (18%). Most patients required one (n=15) or two (n=15) dose reductions. Conclusion: Low activity of poziotinib was detected in patients with EGFR-mutant non-small cell lung cancer who developed AR to gefitinib or erlotinib, potentially because of severe-toxicityimposed dose limitation. [ABSTRACT FROM AUTHOR]

Background: To understand whether patient-reported experiences with lung cancer may create teachable moments (TM) for their relatives as evidenced by shifts in their risk perceptions, affective response, and self-image and in turn, motivation to quit smoking.Methods: Patients at a comprehensive cancer center (n = 152) completed a survey within 6 months of lung cancer diagnosis to assess their cancer-related symptoms and openness and enumerated relatives who were smokers. Relative smokers (n = 218) then completed a survey assessing their risk perceptions, affective response, and self-image as a smoker related to the patient's diagnosis (TM mechanisms), and their motivation to quit smoking. Cross-sectional mediation and moderation analyses were conducted to explore the links between patient-reported experiences, and relatives' TM mechanisms, and motivation to quit smoking.Results: Relative-reported affect was a significant mediator of the association between patient-reported symptoms and relative smoker's desire to quit. Relatives' self-image was a significant moderator of the association between patient-reported symptoms and relative smoker's desire to quit, such that patients' reported symptoms were associated with relatives' desire to quit only when the relative smoker reported a generally positive self-image as a smoker. No evidence was found for moderated mediation. However, the link between symptoms and negative affect was moderated by perceptions of risk.Conclusion: Whether smokers experience a family member's lung cancer as a TM is influenced by multiple interrelated cognitive and affective factors that warrant further exploration. Clearer understanding of these factors could inform how to re-invigorate and sustain this motivation to promote concrete actions toward smoking cessation. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Recent results of a randomized clinical trial showed that a guided self-help intervention (based on problem-solving therapy) targeting psychological distress among head and neck cancer and lung cancer patients is effective. This study qualitatively explored motivation to start, experiences with and perceived outcomes of this intervention.Methods: Data were collected from semi-structured interviews of 16 patients. All interviews were audio-recorded and transcribed verbatim. Data were analyzed individually by two coders and coded into key issues and themes.Results: Patients participated in the intervention for intrinsic (e.g. to help oneself) and for extrinsic reasons (e.g. being asked by a care professional or to help improve health care). Participants indicated positive and negative experiences with the intervention. Several participants appreciated participating as being a pleasant way to work on oneself, while others described participating as too confrontational. Some expressed their disappointment as they felt the intervention had brought them nothing or indicated that they felt worse temporarily, but most participants perceived positive outcomes of the intervention (e.g. feeling less distressed and having learned what matters in life).Conclusions: Cancer patients have various reasons to start a guided self-help intervention. Participants appreciated the guided self-help as intervention to address psychological distress, but there were also concerns. Most participants reported the intervention to be beneficial. The results suggest the need to identify patients who might benefit most from guided self-help targeting psychological distress and that interventions should be further tailored to individual cancer patients' requirements. [ABSTRACT FROM AUTHOR]

Background and Aims: Infections related to pemetrexed have been reported in clinical trials. It is not yet clear whether this drug increases infection risk or not. This meta-analysis assessed the overall incidence and risk of severe infections (≥ grade 3) associated with the use of pemetrexed in non-small-cell lung cancer patients.Methods: The databases of PubMed, Embase, and the Cochrane Library were searched for relevant studies published up to December 2015. Eligible studies included randomized controlled trials (RCTs) of pemetrexed for non-small-cell lung cancer patients that reported grade 3-5 infection and febrile neutropenia. Summary incidence rates, relative risks (RRs) and 95% confidence intervals (CIs) were calculated by using either random-effects or fixed-effects models, according to the heterogeneity of the included studies.Results: Seven randomized controlled trials were included, comprising 1848 patients. The incidence of severe infection and febrile neutropenia due to pemetrexed was 5.7% (95% CI: 3.2-8.3%) and 1.3% (95% CI: 0.7-2.0%), respectively. The use of pemetrexed was associated with an increased risk of severe infection (RR 1.61, 95% CI: 1.07-2.44, P = .02) and febrile neutropenia (RR 4.28, 95% CI: 1.08-17.01, P = .04).Conclusion: The use of pemetrexed was associated with an increased risk of developing severe infections and febrile neutropenia in non-small-cell lung cancer patients. Frequent clinical monitoring and management of infections should be emphasized during pemetrexed treatment. More studies are needed to reveal the mechanism of the increased risk of severe infections. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor-tyrosine kinase inhibitor ( EGFR- TKI) is effective in lung cancer patients carrying sensitive EGFR mutations. In this study, we investigated if liver X receptor (LXR) agonist T0901317 could reverse the resistance of lung cancer cell lines A549 and H1650 to EGFR- TKI treatment. We found that T0901317 could make natural EGFR- TKI-resistant A549 human lung cancer cells sensitive to EGFR- TKI treatment and that this was dependent on LXRβ expression. However, T0901317 does not have a similar effect on another natural EGFR- TKI-resistant cell line H1650. [ABSTRACT FROM AUTHOR]

Objective: Patients with lung cancer experience different feelings and reactions, based on their family, social, cultural, and religious backgrounds, which are a source of great distress, not only for the patients but also for their family caregivers. This study aimed to evaluate the impact that lung cancer stage and quality of life (QoL) of lung cancer patients have on caregiver burden. Methods: This was a prospective cross-sectional study. Consecutive patient-caregiver dyads were selected and asked to complete the Hospital Anxiety and Depression Scale and the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36). Family caregivers also completed the Caregiver Burden Scale. Group-based modeling was used in order to identify patients with early- or advanced-stage cancer (IA to IIIA vs. IIIB to IV) plus non-impaired or impaired QoL (SF-36 total score > 50 vs. ≤ 50). Patient-caregiver dyads were stratified into four groups: early-stage cancer+non-impaired QoL; advanced-stage cancer+non-impaired QoL; early-stage cancer+impaired QoL; and advanced-stage cancer+impaired QoL. Results: We included 91 patient-caregiver dyads. The majority of the patients were male and heavy smokers. Family caregivers were younger and predominantly female. The burden, QoL, level of anxiety, and level of depression of caregivers were more affected by the QoL of the patients than by their lung cancer stage. The family caregivers of the patients with impaired QoL showed a higher median burden than did those of the patients with non-impaired QoL, regardless of disease stage. Conclusions: Caregiver burden is more affected by patient QoL than by lung cancer stage. [ABSTRACT FROM AUTHOR]

Circulating tumor cells (CTCs) are established cancer biomarkers for the "liquid biopsy" of tumors. Molecular analysis of single CTCs, which recapitulate primary and metastatic tumor biology, remains challenging because current platforms have limited throughput, are expensive, and are not easily translatable to the clinic. Here, we report a massively parallel, multigene-profiling nanoplatform to compartmentalize and analyze hundreds of single CTCs. After high-efficiency magnetic collection of CTC from blood, a single-cell nanowell array performs CTC mutation profiling using modular gene panels. Using this approach, we demonstrated multigene expression profiling of individual CTCs from non-small-cell lung cancer (NSCLC) patients with remarkable sensitivity. Thus, we report a highthroughput, multiplexed strategy for single-cell mutation profiling of individual lung cancer CTCs toward minimally invasive cancer therapy prediction and disease monitoring. [ABSTRACT FROM AUTHOR]

Objective. To evaluate the involvement of glutamate metabolism in peripheral blood mononuclear cells (PBMC) in the development of neurological complications in lung cancer and during chemotherapy. Methods. The prospective study included 221 lung cancer patients treated with chemotherapeutics. Neurological status and cognitive functions were evaluated at baseline and after 6-month follow-up. Glutamate level, the activities of glutaminase- (GLS-) glutamate synthetizing enzyme, glutamate dehydrogenase (GDH), and glutamate decarboxylase catalyzing glutamate degradation were analyzed in PBMC and in sera of lung cancer patients by means of spectrophotometric and colorimetric methods. Results. Chemotherapy of lung neoplasms induced increase of glutamate content in PBMC and its concentration in serum increased the activity of GDH in PBMC and decreased activity of glutaminase in PBMC. The changes in glutamate metabolism markers were associated with initial manifestation of neurological deficit in lung cancer patients and with new symptoms, which appear as a complication of chemotherapy. Moreover, the analyzed parameters of glutamate control correlated with a spectrum of cognitive functions measures in lung cancer patients. Conclusion. We have demonstrated dysregulation in glutamate and glutamate metabolism controlling enzymes as promising indicators of risk for chemotherapy-induced neurological complications in lung cancer patients with particular emphasis on cognitive impairment. [ABSTRACT FROM AUTHOR]

Introduction. A possible association between lung cancer and bullous lung disease has been suggested and recently supported by the results of genetic studies. Case report. A previously healthy 43-year-old man, smoker, was diagnosed with bullous lung disease at the age of 31 years. He was followed up for 12 years when lung cancer (adenocarcinoma) was found at the site. In the meantime, he was treated for recurrent respiratory infections. Conclusion. There is the need for active approach in following up the patients with pulmonary bulla for potential development of lung cancer. [ABSTRACT FROM AUTHOR]

Introduction. Pseudomesotheliomatous lung carcinoma is a special, rare entity characterized by large pleural growth and minor invasion of lung tissue. Clinically, radiologically, macroscopically and even histologically this tumor can be misdiagnosed as malignant pleural carcinoma. Case report. We represent a 64-year-old male patient, former smoker. Due to difficulties in the form of dry cough, feeling of discomfort and pain in the right hemithorax, fatigue, heavy breathing, sweating, fever up to 39.6°C the patient was treated as with combined antibiotic therapy (macrolides, cephalosporins and penicillin), but without improving of his condition. Chest radiography showed a shadow of pleural effusion by the height of the front end of the third right rib. Chest MSCT showed the extremely thickened pleura apically and to the posterior along the upper right lobe in addition to existence of massive pleural effusion. Subpleural condensation of parenchyma ranging about 30 mm was described in the upper right lobe. Cytological analysis of the pleural effusion showed the presence of malignant cells impossible to differentiate whether they were metastasis of adenocarcinoma or malignant pleural mesothelioma. By histochemical and immunohistohemical analyses of a pleural sample, pseudomesotheliomataus lung adenocarcinoma was diagnosed. Conclusion. Pseudomesotheliomataus carcinoma of the lungs can be a diagnostic problem. Its diagnosis is based on recognition of histopathological characteristics which enable its discernment from the epithelial variant of malignant pleural mesothelioma. [ABSTRACT FROM AUTHOR]

Purpose: We herein evaluated the status of circulating tumor cells (CTC) dislodged from the tumor during surgery in patients who underwent pulmonary resection for non-small cell lung cancer (NSCLC) to assess the clinical implications. Methods: Tumor cells in the peripheral arterial blood before surgery (Before) and immediately after lung resection (After) and in the blood from the pulmonary vein of the resected lung were detected using a size selective method. The clinicopathological characteristics and the prognosis were then analyzed according to the CTC status: no tumor cells detected ( N), single tumor cell or total number less than 4 cells ( S), and existence of clustered cells ( C). Results: According to the CTC status, the patients were classified into the following three groups: Before- C and After- C, Group I ( n = 6); Before- S or N and After- C, Group II ( n = 9); and Before- S or N and After- S or N, Group III ( n = 8). Group III showed a high rate of p-stage IA, smaller tumor size, lower CEA level, lower SUVmax level, and a higher relapse-free survival rate than the other groups. Conclusions: CTCs were detected in patients after undergoing lung resection, some of which may have been dislodged by the surgical procedure. The presence of clustered CTCs after the operation indicated an unfavorable outcome. [ABSTRACT FROM AUTHOR]

Purposes: The aim of this study was to evaluate whether sublobar resection could achieve recurrence and survival rates equivalent to lobectomy in high-risk elderly patients. Methods: We conducted a retrospective multicenter study that including all consecutive patients (aged >75 years) who underwent operation for clinical stage I non-small cell lung cancer (NSCLC). The clinicopathological data, postoperative morbidity and mortality, recurrence rate and vital status were retrieved. The overall survival, cancer-specific survival and disease-free survival were also assessed. Results: Two hundred and thirty-nine patients (median age 78 years) were enrolled. Lobectomies were performed in 149 (62.3 %) patients and sublobar resections in 90 (39 segmentectomies, 51 wedge resections). There were no differences in the recurrence rates following lobar versus sublobar resections (19 versus 23 %, respectively; p = 0.5) or the overall survival ( p = 0.1), cancer-specific survival ( p = 0.3) or disease-free survival ( p = 0.1). After adjusting for 1:1 propensity score matching and a matched pair analysis, the results remained unchanged. A tumor size >2 cm and pN2 disease were independent negative prognostic factors in unmatched ( p = 0.01 and p = 0.0003, respectively) and matched ( p = 0.02 and p = 0.005, respectively) analyses. Conclusions: High-risk elderly patients may benefit from sublobar resection, which provides an equivalent long-term survival compared to lobectomy. [ABSTRACT FROM AUTHOR]

Purpose: Lung transplant recipients are known to be at risk of a postoperative malignancy. In Western countries, skin cancer and post-transplant lymphoproliferative disorder (PTLD) are the most common malignancies in this cohort. We conducted this study to evaluate the characteristics of postoperative malignancies in Japanese patients following living-donor lobar lung transplantation (LDLLT) or cadaveric lung transplantation (CLT). Methods: We reviewed the medical records of 120 Japanese patients who underwent either LDLLT ( n = 62) or CLT ( n = 58) between April 2002 and July 2015. Results: Postoperative malignancy developed in 11 patients (9.2 %), as PTLD in 7, breast cancer in 1, gastric cancer in 1, glioblastoma in 1, and adenocarcinoma of unknown primary in 1. Twenty-six (21.7 %) of the 120 transplant patients had a history of malignancy pre-transplant; however, the postoperative malignancies were all de novo without any recurrence of the original disease. The malignancies developed after LDLLT in six patients (9.7 %) and after CLT in 5 patients (8.6 %). Three of the four patients with solid organ malignancies had distant metastasis at diagnosis. Three patients died of PTLD and one patient died of gastric cancer. Conclusions: PTLD occurred after both LDLLT and CLT. There was no case of skin cancer in this series of Japanese patients, suggesting ethnic differences. Solid organ malignancies in lung transplant recipients tended to progress rapidly. [ABSTRACT FROM AUTHOR]