Virtual Library

Background:
Lung cancer is one of the commonest cancers worldwide. The pathological profile varies among different geographical regions. In India squamous cell carcinoma or adenocarcinoma has been reported as the common histological type in all the series. Odisha is socioeconomically behind some states of India. There is no epidemiological published data on lung cancer from this part of the country. The aim of the study was to analyse the epidemiological, clinical and pathological profile of lung cancer patients at a newly established tertiary level Government hospital in Odisha.

Methods:
We analysed 87 lung cancer cases registered at our centre over a period of initial 18 months in the department of Pulmonary Medicine of this newly opened Government Institution. They were evaluated for their epidemiological, clinical and pathological profiles. The data were recorded in Excel spreadsheets and subjected to appropriate statistical analysis.

Results:
Average age was 57 years with a male: female ratio of 2.6:1. About 48% of patients were smokers. Non-small cell lung cancer (NSCLC) was the predominant pathological variant in about 92 % and small cell lung cancer (SCLC) in only 3% of the cases. Among the patients with NSCLC, adenocarcinoma was the commonest histological subtype after the pathology review.

Conclusion:
Adenocarcinoma now be the commonest histological subtype. Prevalence of lung cancer among non-smokers is also high in the eastern part of India. Most of the patients present at an advanced stage with poor outcome, probably due to lack of awareness and limited resources in this part of the country.

Background:
Based on a 20% reduction in lung cancer deaths in participants of the National Lung Screening Trial (NLST), CT screening for lung cancer is now widely recommended in the US. However concerns remain regarding the cost-benefits of screening due to overall low detection rates, over-diagnosis and high false-positive rates. Using the spirometric data available from the ACRIN-biomarker sub-study of the NLST (n=18,714), we examined the effect of Chronic Obstrucitve Pulmonary Disease (COPD) status on lung cancer detection in the NLST screening participants. Specifically we compared lung cancer incidence, histology and stage shift in those with and without COPD based on baseline pre-bronchodilator spirometry.

Methods:
Baseline spirometry results were available for 18,475 (99%) of the total cohort of 18,714, (6,436 with COPD and 12,039 with no COPD). Spirometry results were available for 758 (99%) of the 768 histology-confirmed lung cancer cases diagnosed over the 7 year follow-up period. After lung cancer cases were sub-grouped by spirometry-defined COPD (GOLD 1-4, n=401) and no baseline COPD (n=357) it was possible to compare the number of cancers, histology and stage according to screening arm. Differences in lung cancer incidence rates were compared by incident rate ratios, while prevalence, histology and stage shift, were compared by chi-square frequency tables.

Results:
In this NLST-ACRIN Biomarker sub-study, we found the demographic variables were comparable to those from the full NLST study. Regardless of screening interval, we found the lung cancer incidence was 2 fold greater in those with COPD compared to no COPD (P<0.0001). In those with COPD, we found a signficant reduction in adenocarcinomas and bronchioloalveolar carcinomas. After stratification by COPD status, when comparing CT versus CXR screening arms, we found no excess lung cancers and comparable lung cancer histology. However, a clinically significant stage shift favouring increased early stage (+17) and reduced late stage cancers (-23) was found (P=0.05). In contrast, in cancer cases with no COPD, we found an 18% excess of lung cancers in the CT arm (+29) which were of a BAC/AC histology. After correction for this overdiagnosis from these excess cancers, the stage shift no longer favoured early stage over late stage. Figure 1



Conclusion:
These data suggest that in those with COPD at baseline, CT screening (vs CXR) was associated with no excess cancers, no histology shift but a clinically significant stage shift favouring early over late stage cancers. In those with no COPD, CT was associated with excess cancers and a marginal stage shift.

Background:
We sought to estimate the relative effectiveness of CT and CXR versus no screening in the context of a comparative cost-effectiveness analysis of lung cancer screening. CXR is considered ineffective because no randomized population trial (RPT) has shown a lung cancer mortality reduction. In the Mayo Lung Project, however, CXR screening produced a significant survival advantage which was not attributable to overdiagnosis or other screening biases (JCO 20:1973-83; 2002). The lung portion of the Prostate Lung Colon Ovary (PLCO) Cancer Screening Trial reported no lung cancer mortality reduction with CXR versus no screening, and it is considered to be a negative trial. The National Lung Screening Trial (NLST) was the first lung cancer screening RPT to report a mortality reduction comparing CT to CXR, but lacked an unscreened control. Survival from these trials has not been reported.

Methods:
To compare effectiveness of CXR and CT versus no screening, we calculated mortality, survival, and stage distribution in an intent-to screen analysis of PLCO and NLST data. Only lung cancers diagnosed within 7 years of randomization in PLCO were considered to match the median 6.7 years follow-up in NLST. Kaplan-Meier survival was compared by the log-rank test. Incidence, mortality, and stage distribution were compared with Fisher’s exact test. All p-values are two-sided.

Results:
In PLCO, 154,897 participants were randomized to either four annual CXRs over 3 years or to no screening. Within 7 years of randomization, 1072 and 1022 lung cancers were diagnosed, respectively (RR=1.05; 95%CI 0.96-1.14; p=0.271). 5-year survival was 27% and 18% (p<0.001). Mortality analysis revealed 764 and 811 lung cancer deaths in CXR and control groups (RR=0.94; 95%CI 0.85-1.04, p=0.244). The CXR group had significantly more stage IA cancers (RR 1.70; 95%CI 1.33 – 2.16; p<0.001) and fewer advanced stage IIIB and IV cancers (RR=0.87; 95%CI 0.76 – 0.99; p=0.044). NLST randomized 53,452 participants to either three annual CTs or CXRs over 2 years. There were 1089 and 969 lung cancers in the CT and CXR groups respectively (RR=1.12; 95%CI 1.03-1.22; p=0.007). 5-year survival was 49% and 33% (p<0.001). Mortality comparisons revealed 449 and 528 lung cancer deaths in the CT and CXR groups (RR=0.850; 95%CI 0.751-0.964, p=0.012). There were significantly more stage IA cancers (RR 2.16; 95%CI 1.82 – 2.56; p<0.001) and fewer advanced stage IIIB and IV cancers in the CT versus CXR groups (RR=0.74; 95%CI 0.63 – 0.87; p<0.001).

Conclusion:
Based upon similar lung cancer incidence, improved survival, and a more favorable stage distribution (particularly a reduction in the number of advanced cancers) in PLCO, CXR screening is superior to no screening, and overdiagnosis does not account for this advantage. While CXR screening is superior to no screening, CT is more efficacious than CXR in NLST. As CT is more expensive, has a higher false positive rate, and is more likely to detect overdiagnosed cancers than CXR, CXR may still be cost-effective compared to CT. Accordingly, a cost-effectiveness analysis employing NLST and PLCO data is ongoing.

Background:
Lung Cancer screening with low-dose computed tomography (LDCT) has been shown to reduce lung cancer mortality in high-risk individuals. Critics raise concern over the potential for unnecessary surgical procedures for benign disease as a result of screening. We have up-dated our surgical outsomes in a large clinical lung cancer screening program to assess the number of surgical procedures done for benign disease.

Methods:
We retrospectively reviewed our surgical outcomes of consecutive individuals who underwent LDCT lung cancer screening from January 2012 through March 2015 using a prospectively collected database. All patients met the National Comprehensive Cancer Network (NCCN) Lung Cancer Screening Guidelines high risk criteria.

Results:
There were 2,043 screened individuals during this interval with clinical follow-up at Lahey Hospital and Medical Center. Thirty-nine of the 2.043 (1.9%) had surgery. Twenty-eight (72%) had lung cancer, 25/28 (89%) had early stage and 3/28 (11%) had advanced stage lung cancers. Four (10%) had non-lung cancer malignancies. Seven of thirty-nine (18%) were found to have benign disease. There were no in hospital or 30 day mortalities in those who had surgery and only one (2.56%) major surgical complication.

Conclusion:
The incidence of surgical intervention for non-lung cancer diagnosis was low (0.56%) and is comparable to the rate reported in the National Lung Cancer Screening Tria; (0.62%). Surgical intervention for benign disease was rare (0.34%) in our experience.

Background:
Lung cancer (LC) is the leading cause of cancer in the U.S. with 85% caused by smoking. There is recent strong evidence that LC mortality is decreased by 20% with low-dose computed tomography (LDCT) screening for healthy individuals with an elevated risk for lung cancer. Previous studies have shown that those at higher risk (i.e., older smokers) are less interested in being screened despite awareness of risk.

Methods:
The aims for this study were, among older smokers: 1) Identify the demographics, smoking history, knowledge, and attitude factors associated with willingness to have a CT scan and 2) Provide a predictive model of factors to explain willingness to have a CT scan. This was a cross-sectional national survey study with 549 older adult (≥ 45 years) current and former smokers (≤ 2 years quit).

Results:
There were no significant differences between current and former smokers on all variables. After controlling for age, gender, ethnicity, income and education, all perception and belief variables significantly associated with agreement to have a LDCT scan were included in a logistic regression analysis to develop a predictive model for agreement to have a LDCT scan. Figure 1 Figure 2





Conclusion:
Older smokers are interested in LC screening and overall, their attitudes are positive. Eleven variables had a significant association with the decision to have a CT scan. In the final model, four beliefs were significant predictors of whether older smokers would agree to a scan. The strongest predictor was “believes that early detection of LC will result in a good prognosis,” followed by perception of accuracy, belief that they are at high risk for LC, and belief it will decrease worry about LC. An effort needs to be made to improve smokers’ knowledge of the potential benefits and risks when they are making decisions about participation in screening.

Background:
Current guidelines for repeat CT imaging of small nodules detected during screening are a function of the size and consistency of the nodules and the round it was detected. They attempt to balance the frequency with which a change would genuinely occur (i.e. the frequency with which a nodule of a given size is a cancer) with the ability to actually measure the change should it have occurred. Recently the American College of Radiology has established a new set of guidelines for this purpose called LungRads. This study analyzes the change in nodule volumes and doubling times for small nodules if the LungRads guidelines are followed.

Methods:
The LungRads protocol focuses on providing categories for nodules based on their degree of suspiciousness and provides suggestions for follow-up. They also provide criteria so as to determine when growth is genuine —that is, the change in size is beyond what could have occurred solely as a result of measurement error. Genuine growth defined as increase in diameter of >1.5 mm. For purposes of estimating change in nodule volume and doubling times associated with them, we used the time intervals in LungRads for follow-up and derived the doubling times necessary for a nodule to reach the definitional growth threshold. We assumed a spherical model for the nodules and used a simple exponential growth rate. We focused on solid nodules where the range of growth rates is known to be large and they are most accurately measured.

Results:
For LungRads Category 2, where 6 month follow up CT is recommended, in order for a 4 mm nodule to grow sufficiently so as to pass the size threshold where change could be detected, it would need to have a doubling time faster than 129 days, anything slower would not achieve the necessary size change and it would only then be rescanned 6 months later at an annual repeat scan and it would then potentially reach a size of 8.0 mm. For category 4A, LungRads recommends repeat scanning in 3 months. According to the protocol, a 6 mm nodule would need a doubling time of 92 days for detection otherwise at one year it will reach a size of 15.1 mm.

Conclusion:
The change threshold for growth and time intervals between scans can have serious consequences downstream in terms of how large a tumor might become before it can reliably be diagnosed. The ability to better define the threshold for when change has occurred will always be beneficial as it will allow not only the very fast growing tumors to be diagnosed but those with more typical doubling times as well. The LungRads protocol keeps the smallest size category of tumors from growing beyond 15 mm when workup is initiated.

Background:
Recent clinical screening trials using highly sensitive low-dose computed tomography (LDCT) demonstrated an increased detection proportion of stage I lung cancers and improved overall survival of lung cancer patients as the result of early detection. However, lung cancer screening trials also showed high repeat screening rates and false-positive rates causing unnecessary second-line invasive procedures and surgery. New strategies are still needed to improve the specificity of lung cancer screening. The airway fluid, bronchoalveolar lavage (BAL), is commonly used for the evaluation of lung nodules and diagnosis of lung cancers. Proteins in the BAL fluid may serve as potential biomarkers for cancer detection. In this study, we examined the protein profile, particularly the signature of glycoprotein in normal and lung cancer patients.

Methods:
We collected BAL fluid after cellular components were harvested for cytological examination in the cytology laboratory. Protein profile and N-glycoproteins were analyzed using the solid-phase extraction of N-glycoprotein (SPEG) and liquid chromatography tandem mass spectrometry (LC-MS/MS). Sixteen BAL samples, including four cases each of benign lung disease, adenocarcinoma (ADC), squamous cell carcinoma (SqCC), and small cell carcinoma (SCLC), were analyzed.

Results:
A total of 1013 unique peptides from 457 glycoproteins were identified and quatified. Among them, 286 proteins were identified in BAL of ADC, 363 in squamous cell carcinoma (SqCC), 298 in SCLC and 330 in benign BALs. In addition to common proteins found in all groups, we identified 113 unique proteins that were differentially expresssed in benign disease, ADC, SqCC and SCLC, respectively. The levels of Napsin A, periostin, Galectin-3-binding protein (G3-BP) and myeloperoxidase (MPO) in cancer and benign BALs were further validated using independently collected BAL specimens by ELISA assays (Table 1). Table1. Detection of Proteins in BAL from lung cancer and benign lung disease by ELISA assays.

Protein	Benign* (n=7)	ADC* (n=18)	SqCC* (n=9)	SCLC* (n=6)	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)	P value
Napsin A	55±39	295±104	102±34	50±28	83.3	66.7	88.2	57.1	<0.05
Periostin	255±104	4002±218	3496±1765	1772±1119	73.68	71.43	87.5	50.0	<0.05
G3-BP	168±29	290±70	240±65	132±65	47.4	11.8%	69.2	23.1	>0.05
MPO	3227±2948	0.08±0.03	1.6±0.7	0.1±0.06	33.3	100	100	83.3	<0.05**

* protein concentration was expressed as ng/mg total BAL protein. ** for benign lesions.

Conclusion:
Our study demonstrates that potential protein biomarkers in BAL fluid can be identified and quantified. They have the potential to improve the specificity of lung screening tests and to reduce unnecessary surgery in patients with benign lung nodules.

Background:
Hundreds of biomarkers are being developed for the screening and early detection of lung cancer. The vast majority, however, even after extensive internal validation, will likely fail during external validation. For biomarkers to reach the clinic, therefore, it’s imperative that external validation studies focus on the most promising candidates. Towards this end, various strategies have been proposed to rank order and prioritize biomarker candidates. These strategies range from simple, highly intuitive ideas to highly sophisticated statistical analyses. To our knowledge, however, none of these strategies has itself been validated externally, which is an important consideration given that each strategy involves making subjective decisions. Here we conducted an independent validation test to assess the performance of the “vote-counting strategy”, a straightforward, commonly used strategy that ranks biomarkers on the basis of three highly intuitive criteria: the number of supporting studies in the literature, the combined sample size in the supporting studies, and the average fold change difference associated with the biomarker.

Methods:
We obtained vote-counting biomarker rankings from two recent meta-analyses that together surveyed over 180 miRNAs reported to distinguish lung tumor tissue from normal. We compared the rankings of 50 top candidates and 22 unranked miRNAs to our RT-qPCR results obtained from 45 tumor-normal pairs. We tested for a statistically significant Pearson correlation (r) between biomarker performance and the rankings according to each of the three ranking criteria.

Results:
We found that the number of supporting studies in the literature was indeed a statistically significant predictor of biomarker performance (r = 0.44, n = 50, p = .0006). Our results also suggested that markers supported by two studies in the literature had approximately a 50% chance of being confirmed, markers supported by 3 studies about a 67% chance, and markers supported by 6 studies about a 90% chance. Our unranked markers showed only a 5% chance of being confirmed. At the same time, we found that the combined sample size in the supporting studies was not a predictor of biomarker performance (r = 0.11, n = 50, p = 0.29). We also found that the mean fold change associated with each biomarker was not a predictor (r = 0.12, n = 47, p = 0.22) because large fold-change differences were also associated with large amounts of variability between studies.

Conclusion:
Considering that vote counting has obvious limitations (such as selection bias, not counting negative votes, and the variation in how different studies define significance) counting the number of supporting studies in the literature appears to work remarkably well for ranking biomarker candidates. On the other hand, using total sample size or mean fold change in the supporting studies to rank biomarker candidates appears to provide little, if any, added value. Our results also indicate a need for external validation testing of the current strategies being used to rank biomarkers across studies.

Background:
The bone resorption biomarkers cross-linked N-telopeptide of type I collagen (NTx) have been shown to aid in the diagnosis of metastatic bone disease from lung cancer (MBDLC). Patients with MBDLC are often treated with zoledronic acid (ZA). ZA reduces the levels of NTx and also lowers the risk of skeletal adverse events in patients with MBDLC.

Methods:
Patients with MBDLC at initial diagnosis were included in this study. Serum NTx (sNTx) was measured once a month using the OSTEOMARK[TM] sNTx assay (Alere Medical). MBDLC was assessed by monthly physical examinations and bone scintigraphy every 3 months for 12 months. Progression of bone metastases during the follow-up period was defined as when the number of bone metastases as assessed by bone scintigraphy had increased from the previous follow-up measurement. The optimal cut-off value of sNTx levels indicative of progression of bone metastasis was evaluated by performing a receiver operating characteristic (ROC) curve analysis. In this ROC analysis, we evaluated the change rate of sNTx per month. The change rate per month was defined as “The change rate of sNTx between at the minimum levels of NTx and at the worsening bone metastasis / the number of month from the minimum levels of sNTx to the worsening bone metastasis’’

Results:
Twenty patients were enrolled between June and December 2010. The sNTx concentration at baseline was 19.8 ± 5.8 nmol bone collagen equivalents (nM BCE)/L. In the 16 patients receiving ZA, the levels of sNTx showed a significant decrease after the first month of treatment (baseline vs. 1 month of treatment: 21.3 ± 5.5 vs. 13.6 ± 2.7 nM BCE/L; p < 0.01). During the follow-up period, 13 of the patients treated with ZA experienced worsening bone metastasis. There were statistically significant differences in the levels of sNTx at baseline (20.3 ± 4.8 nM BCE/L), at the lowest levels after the administration of ZA (11.8 ± 2.9 nM BCE/L vs. baseline; p < 0.001), and at the point of measurable disease progression (14.1 ± 4.6 nM BCE/L vs. baseline; p < 0.05). In the ROC analysis, the optimal change rate of sNTx per month was 4.0% (sensitivity: 53.8%, specificity: 100%, area under the curve = 0.564).

Conclusion:
The administration of ZA significantly decreased the levels of sNTx within one month of the initiation of therapy. However, the levels of sNTx was slightly elevated when the bone metastasis has been aggravated during ZA treatment. The serial measurements of sNTx might prove to be useful in selecting drug treatment and evaluating drug efficacy for bone metastasis.

Background:
Previous studies have shown that plasma free amino acid (PFAA) profiles are altered in cancer patients compared with healthy controls. A multivariate index based on PFAAs was generated from a Japanese dataset and has been previously demonstrated to be clinically valuable for discriminating patients in the early stages of lung cancer. However, it remains unclear whether similar PFAA profile changes occur in cancer patients from other populations. Therefore, this study aimed to validate the performance of this index in discriminating lung cancer patients from controls in the Korean population.

Methods:
Samples were collected from a total of 142 Korean subjects (72 lung cancer/70 controls) for this study. PFAAs were quantified by high-performance liquid chromatography-electrospray ionization-mass spectrometry, and the clinical performance characteristics of the amino acid multivariate index were evaluated across cancer stages and histological types.

Results:
The concentrations of several PFAAs were significantly decreased in the Korean lung cancer patients compared with the controls. Significant decreases in threonine, citrulline, histidine and tryptophan and increases in proline, isoleucine, phenylalanine and ornithine were observed, which are similar to the PFAA changes reported by a previous Japanese study. The area under the receiver-operator characteristic curve (AUC of the ROC) for the index was 0.80, and similar performances were demonstrated for the different histological types.

Conclusion:
These results suggest that the amino acid multivariate index previously developed from a Japanese dataset has the potential to aid in the early detection of lung cancers of different histological types in Korean patients.

Background:
Worlwide, lung cancer is the primary cause of cancer death. Today 75% of patients are diagnosed in a locally advanced or metastatic inoperable stage, and a new tool for early detection of lung cancer is urgently needed in order to improve the outcome. Circulating microRNAs have emerged as stable, non-invasive and promising biomarkers for diagnosis, prognostication and prediction in cancer. The purpose of this study was to identify circulating microRNAs for detection of early stage lung cancer, capable of discriminating lung cancer patients from those with chronic obstructive pulmonary disease (COPD) and healthy normal individuals.

Methods:
We profiled the expression of 756 unique microRNAs in sera from 38 patients with NSCLC, 16 patients suffering from COPD and 16 healthy volunteers, to explore the potential of the microRNAs as diagnostic biomarkers. For validation of our results, we analyzed serum from an independent cohort of high-risk individuals enrolled in the IELCAP screening trial (n=161) using RT-qPCR

Results:
Focusing on microRNAs upregulated in sera from lung cancer patients, we identified a unique set of 6 microRNAs with significantly higher abundance compared with sera from COPD patients and healthy normals. Validation of the 6-miR signature demonstrated a sensitivity of 86% and specificity of 79.3%

Conclusion:
Considering their accessibility and stability, circulating microRNAs can be a diagnostic tool for clinicians in the future, and may lead to increased fraction of lung cancers diagnosed in an early curative stage. The 6-miR signature may be a basis for a screening study and can easily be implemented in the clinic to identify those who should be further examined for lung cancer

Background:
In Chile, Lung Cancer (LC) has the second high mortality rate/100,000 for cancer, after to stomach cancer. During 2012, in the country the LC incidence for male was 17.1 with a mortality of 17.0, while for female the incidence was a 10.2, with a mortality of 8.8. In the same period, the Antofagasta region (North of Chile) showed a rate mortality of 31.6 for both gender, with a rate of 44.2 and 17.4, for men and women, respectively. According to this point of view, early detection and screening are imperative in order to increase survive to 5 years. Non invasive biomarkers, as complementary tools, might contribute with the early diagnosis of LC. In this context, free-circulating DNA (fcDNA) levels have been described as a potential tool to detect in comparison with controls.

Methods:
Volunteers enrolled, were classified as LC free subjects (C), Pre Neoplastic Lesions (PNL) and Lung Cancer (LC), according to results of Quantitative Automatic Cytology (QAC) in sputum specimen, DR70 tumor marker, and Auto fluorescence Bronchoscopy (AFB). Free circulating DNA (fcDNA) was isolated from serum of the three groups of volunteers, quantified by qPCR and amplified. The amplified fcDNA was co-hybridized against genomic DNA from total blood, using microarray-HGC.

Results:
The LC patients showed significantly higher levels of fcDNA (average, 16,13 ng/mL) than volunteers cancer free (CF) (p < 0.01) (average 2,692 ng/mL) and with Pre neoplastic Lesions (PNL) (p < 0.001) (average 1,961 ng/mL). Additionally, four recurrent and significant deletions were detected in 2p, 7q, 11q and 17p of LC volunteers. Non significant alterations were detected in PNL. Genes located in segments with CNAs were related in immune response, xenobiotic metabolism and oxidative phosphorilation and associated to , cell proliferation, cell cycle regulation, apoptosis, differentiation and cellular adhesion and migration, all functions relevant to neoplastic progression.

Conclusion:
. In conclusion; fcDNA levels were significantly associated to LC but not to PNL related to LC, fcDNA concentration could be a non invasive and complementary tool to diagnosis of LC, molecular characteristic of fcDNA suggest that its might be used as biomarker associated to malignancy of LC, as a non invasive and complementary tool for the diagnosis of LC. Supported by INNOVA CORFO Chile: Grants 07CN13B48 and 11IDL2-10634.

Background:
Early studies of volatile organic compound (VOC) testing in lung cancer suggested similar profiles for all stages of lung cancer, raising the possibility that in-situ cancer might be detectable by VOC profiling. It was hypothesized that a metabolic predisposition to cancer was being detected in VOC profiles, rather than VOCs arising from tumour bulk. In situ SCC can be detected in lung as well as the larynx allowing VOC profiles to be compared to advanced cancer. Because many lung cancer patients can develop Larynx cancer (and vice versa) profiling to determine the possibility of VOC testing in post treatment surveillance could provide useful data.

Methods:
Prospective pilot study. Breath samples were collected using the E-Nose Cyranose ®per established protocols prior to biopsy. Data were reduced to principal components for canonical discriminant analysis to determine differences between groups. Accuracy (CVV) was calculated using leave one out cross validation. All cases and controls had autofluorescence or Narrow Band Imaging bronchoscopy or microlaryngoscopy as well as CT chest. Histological confirmation was obtained. Control patients had negative larynx and bronchus on scopes. All patients had a smoking history.

Results:
Patients were as follows:

	Bronchus	Larynx
	N	Age	M/F	Current smokers	N	Age	M/F	Current smokers
In situ	8	67±9	6/2	0	10	61±10	9/1	4
Advanced	10	71±6	7/3	5	10	65±9	10/0	4
Control	10	63±9	7/3	2	10	62±10	9/1	4

Factor analysis p values for advanced cancer compared to control were 0.05 for larynx and 0.08, NS for bronchus. Values for in situ for both sites compared to control were NS, but were significant when compared to advanced cancer (0.04 and 0.009 respectively). Advanced cancer of larynx compared to bronchus showed p=0.001, CVV 80%.

Conclusion:
These results suggest that VOC signal as measured by eNose relates to tumour bulk as opposed to a systemic metabolic predisposition to cancer, (which might have allowed in situ cancer to be detected). Whilst the inability to detect in situ SCC was disappointing, the clear differences between VOC profiles for advanced cancer suggest the Squamous cell carcinoma has different metabolic profiles in the 2 sites, and further study may allow development of VOC breath testing for surveillance of bronchial SCC after larynx cancer. It suggests that whereas SCC arises in the aerodigestive tract “field” there are different inputs into the tumour development at each site.

Background:
There are about 3 million workers at high potential risk of silica exposure in India and around 17 lakh in mining industry.[]But unofficialy figure for Rajasthan alone, over 2.5 million that are engaged in unorganized mine sector. The problem of silicosis is much more severe in the unorganized sector of industries like slate pencil cutting, stone cutting, and agate industry.The flaw here is because most industries belonging to the unorganized sector do not fall under the purview of Factories Act and Mines Act.

Methods:
Present study used the data from published report of detection of Silicosis by National Institute for Miner's health an autonomous Institute under Ministry of Mines, Government of India. ARAVALI a NGO based in Jaipur arranged for medical investigations (through Dang Vikas Sansthan (DVS), Karauli based voluntary organization, one of the ARAVALI‟s field host organization since 2008), of persons which had the history of work in stone mines. That included detailed work history, respiratory symptoms, history of treatment, chest radiography, sputum examination and pulmonary function test. The medical records evaluated by three specialists experienced in the evaluation of chest radiographs as per ILO classifications of radiographs for Pneumoconiosis, 2000. The report has published in three different time, first were in 2011 (101 miners),[] second 2014 (314 miners)[] and third 2014 (157 miners)[]. These reports cover stone miner from two districts of Rajasthan, named Karauli (first two reports) and Dhaulpur (third report). Reports include around 18 villages from Dhaulpur and 38 villages from Karauli. Thirty-four X-ray qualities were poor, and nine has no history of mining were not clinically evaluated for Silicosis. So, total 529 mine worker were clinically assessed for silicosis as per ILO classification of radiographs by the Institute. Cox regression is used for exploring the relationship between the onsets of silicosis among mine workers.

Results:
Bivariate analysis of the study shows that 58 % of the mine workers those diagnosed for silicosis were previously treated for TB. TB treatment, working duration in mines (16-30 years) and (30+ years) were found to be risk factors for Silicosis. The corresponding adjusted hazard ratios were 1.299(95 % C.I. 0.895, 1.886), 5.605(95% C.I. 3.485, 9.016) and 3.689(95% C.I. 2.73, 4.984). By age 40, maximum miners get silicosis found in life table analysis.

Conclusion:
Sandstone miners affected with silicosis but getting treatment of TB. After 15 years of work in mine, miners get affected with silicosis and by age 65 all miner get affected with silicosis if he continued to work.

Background:
Recently, Tomasetti and Vogelstein proposed that the variation in cancer risk among tissue is explained by the number of stem cell division, and this was widely interpreted as “bad luck” due to random mutations arising during DNA replication in normal non-cancerous stem cells. Smoking is widely considered as the main aetiological risk factor for the lung cancer and the aim of our study is to evaluate the hypothesis comparing the differences in proportions of the two main histological subtypes in smokers and never smokers in a patients with early stage primary lung cancer to determine the impact of smoking on the development of squamous and adenocarcinoma.

Methods:
Data were retrospectively analysed from a prospectively collated database at our institution over a 7 year period. Histological data were extracted and compared for the two main historical subtypes of squamous and adenocarcinoma (subtyped according to the new IASLC adenocarcinoma classification). Frequencies were compared using Fishers exact or Chi square tests as appropriate to the data.

Results:
A total of 2170 patients underwent surgical resection for lung cancer at our institution from March 2008 to November 2014 of which 436 (20%) patients were never smokers. The mean age (SD) was 66 (12) years and 48% were female. The relative proportion of patients with squamous carcinoma was significantly different between smokers 323 (27.0%) and never-smokers 16 (5.7%) with P <0.001 with a risk ratio of 4.70 (95% CI 2.9 to 7.6). However the relative proportions between patients with adenocarcinoma were similar between smokers 578 (48.3%) and never-smokers (54.4%) P=0.06 with a risk ratio of 0.89 (0.79 to 1.00).

Conclusion:
Our results suggest that smoking remains an important aetiological risk factor for the development of primary lung squamous cell carcinoma. For adenocarcinoma, the relative proportions between smokers and never-smokers were similar (in fact lower for smokers) supporting Tomasetti and Vogelstein hypothesis of random mutations arising during DNA replication in normal non-cancerous stem cells– or simply put as “bad luck”.

Background:
There has been an increased utilization of radial and convex probe endobronchial ultrasound with application in the nodal staging of the mediastinum for bronchogenic carcinoma. Prior work has demonstrated that vascular invasion (Vi) is associated with upstaging and a worsened prognosis in those patients with non-small cell carcinoma. Utilization of endobronchial ultrasound has been promulgated to improve the sensitivity of transbronchial needle aspiration (TBNA), but also to avoid vascular puncture. As such, imaging of the pulmonary vasculature is routinely performed and may allow insight and confirmation of CT imaging of vascular invasion.

Methods:
We present the case of a patient presenting with scant hemoptysis where the CT scan was interpreted as possible invasion of the right pulmonary artery (Fig 1). The literature was reviewed as to the effect of vascular invasion on upstaging patients with lung cancer and he underwent a diagnostic procedure.

Results:
Bronchoscopy and endobronchial ultrasound were performed to allow nodal TBNA to permit pathologic diagnosis and staging of the patient’s identified lung mass. During the procedure, ultrasound of the pulmonary vasculature revealed extensive invasion and mass effect from the central tumor mass (Fig 2). Using these synergistic techniques, the patient was upstaged to T4 and was referred for consultation with medical and radiation oncology. Fig. 1: Figure 1 Fig. 2: Figure 2





Conclusion:
Vascular invasion has previously been demonstrated to result in upstaging and a poorer prognosis. Critical to the workup, then, is not only diagnostic pathology, but also rapid and accurate staging and a decision regarding appropriateness of surgical resection. We believe our case illustrates that with the synergistic use of convex or radial endobronchial ultrasound during initial bronchoscopy, vascular invasion may be accurately confirmed resulting in improved decisions in patient care.

Background:
There has been an increased utilization of tomographic imaging to aid in the acute evaluation of patients with chest complaints and in high-risk patients to screen for lung cancer with the recently reported National Lung Screening Trial (NLST). In particular, utilization of CT-angiograms in the emergency room may, increasingly, identify patients presenting with concurrent cardiac injury and imaging abnormalities concerning for lung cancer.

Methods:
We present the case of a 75 year old male with chest pain and a non-resolving pulmonary infiltrate concerning for lung cancer. Although the chest pain was felt to be secondary to the pulmonary abnormality, evaluation by the bronchoscopy and anesthesia services revealed severe hypertension and an elevated troponin. The procedure was cancelled and cardiology was consulted with cardiac evaluation, control of blood pressure, and subsequent bronchoscopy.

Results:
Although review of the literature revealed extensive study of preoperative risk stratification for surgery there was a paucity of studies regarding the performance of bronchoscopy in the setting of hypertension and possible silent ischemia, particularly in patients with concurrent elevated troponin levels. We use this case to review the current literature and propose recommendations in the setting of cardiac ischemia with a rapid pathway for evaluation and treatment to allow needed bronchoscopic diagnostic procedures.

Conclusion:
Bronchoscopy in patients with hypertension or chest pain, particularly in the setting of elevated troponins, is poorly studied and may result in an increased risk of silent ischemia. Consideration for additional cardiac evaluation or peri-operative use of beta-blockers is warranted. Additionally, prospective studies to determine the incidence of silent ischemia in patients, such as presented, should be considered.

Background:
Cavitary lung lesions are primarily due to pulmonary tuberculosis but they also can be associated with other etiologies such as lung malignancies, fungal infections. To exclude tuberculosis with ARB tests when these kind of lesions detected, is a generally accepted clinical approach. Rapid radiological progression in cavitary lesions are usually interpreted as tuberculosis while a slower progression is expected in malignancies.

Methods:
‘not applicable’

Results:
We presented this rare case because of a rapid radiological progression in a patient with lung cancer. Sixty-six year old male was admitted to our clinic with cough, weight loss, fever and fatigue. ARB test was planned and nonspecific antibiotherapy was started because of the cavitary lesions in left upper lobe on CT which was performed in another centre one week before admission to our clinic. ARB test was negative and control CT was planned. CT revealed prominent progression of the lesions. Although tuberculosis was the initial diagnosis because of this rapid progression diagnostic bronchoscopy was performed. Endobronchial lesion in the left upper lobe was detected and pathological examination revealed squamous cell lung cancer.

Conclusion:
Although cavitary lesions can be observed in lung cancer, such a rapid progression as observed in our case suggests infections, especially pulmonary tuberculosis rather than malignancies. We presented this case to be useful for the clinicians in cavitary lung lesion assessment process.

Background:
There has been increasing awareness of the more indolent course of cancers manifesting in nonsolid nodules, especially among those where the nodule is solitary or dominant. There have been reports of virtually 100% cure rates upon resection and most recently, the recommendation from the ACR in their Lung-RADS screening guidelines is for those nonsolid nodules less than 2 centimeters to be followed by annual screening without additional evaluation. In order to further evaluate the aggressiveness of these types of cancers in the screening setting, we determined how frequently they were the cause of death (COD) within the NLST.

Methods:
We searched the NLST database to identify all participants who had a diagnosis of lung cancer after a positive result on CT screening and whose death was attributed to lung cancer by the NLST endpoint verification process. Among them, 28 participants had at least one nonsolid nodule identified on CT in a screening round. Among these, all cases where the nonsolid nodule could not identified in the study year the cancer was first identified (cancyr) or in the location of the confirmed lung cancer were excluded. All images associated with the remaining 8 cases were downloaded from The Cancer Imaging Archive (TCIA) using the NLST Query Tool and reviewed by three radiologists (DY, DX, MH) to assess nodule consistency and location.

Results:
Among the 8 cases reviewed by the radiologists, only 5 cases had at least one nonsolid nodule. The remaining three cases had no CT evidence of a non-solid nodule (Table 1). Among the 5 cases with nonsolid nodules, 2 cases had another large solid nodule (average diameter of 54.5mm and 15 mm) in the same lobe which was the probable lung cancer that was the cause of death. In another case, the nodule was less than 5 mm in diameter and stable for 3 years, and in another the cause of death was small cell carcinoma which is not known to manifest as a nonsolid cancer. One case manifested on baseline scan with multiple nonsolid and part-solid nodules which all grew on successive annual scans. Table 1. Lung cancer deaths with non-solid nodules in NLST database

Case	Any NS nodules	Size of largest NS	Multiple/solitary	Stage/Cell-type	Comments
128534	Y	29 x 19	Solitary NS Solitary solid	IIIA/Squamous cell	Large solid nodule (57 x 52)
134088	Y	27 x 20	Multiple NS Multiple solid	IV/Small-cell
212718	Y	26 x 26	Multiple NS Multiple PS	IV/BAC	Cancer reported in all lobes
116279	Y	5 x 4	Solitary NS	IV/Carcinoma NOS	NS nodule appears stable over 3 years
126576	Y		Multiple NS Solitary solid	IA/Adeno-mixed	Growing solid nodule, 15 mm
117025	N		Multiple solid	IV/Adeno NOS
208792	N		Solitary solid	IIIA/Squamous cell
218307	N		Solitary solid	IIIA/Squamous cell

*ns-nonsolid; ps-part-solid

Conclusion:
It seems unlikely that within the NLST, there were cases of lung cancer specific death that were attributable to cancers manifesting as a solitary or dominant nonsolid nodule. This lends further support that lung cancers manifesting as nonsolid nodules have an indolent course.

Background:
lung cancer is increasing rapidly in China. There are more and more peripheral small lung cancer (≤2cm) was found. CT-guided percutaneous fine needle biopsy becomes first of choice for pathological diagnosis of peripheral small lung tumor (≤2cm) and some central pulmonary lesions which could not be pathologically diagnosed by fiberoptic bronchoscopy. We developed CT-guided percutaneous fine needle biopsy (CT-NB) for detecting early stage lung cancer (size ≤2cm peripheral small lung cancer) since 1992. We discuss typical cases here.

Methods:
Case1: Man, aged 52, right lower lobe 1.5cm ball tumor, no typical malignant sign; unwilling to undergo surgery due to years’ coronary heart disease; CT-NB was performed and lung adenocarcinoma was diagnosed. Case2: Man, aged 63, right upper lobe 1.2cm ball tumor, with cardiopulmonary dysfunction; CT-NB was performed and found some inflammatory cells, but no malignant tumor cells found. Case3: Man, aged 40, heavy smoker, cough and blood-tinged sputum for one month, left lower lobe 3.5cm irregular mass, regional and subcarinal lymph node swollen, clinically progressed rapidly, suspected small-cell lung cancer (SCLC), T2N2M0; at least pneumonectomy was needed if want resected; CT-NB was performed and non-small cell lung cancer (NSCLC) was diagnosed, and SCLC was excluded.

Results:
For Case 1: right lower lobe resection and lymph node dissection was performed, postoperative diagnosis was adeno-squamous cell carcinoma, 1.5X1.3X1.3cm, lymph node negative, pT1N0M0 Stage I, early stage lung cancer. He was alive healthily more than five years postoperatively. For Case 2: considered as a benign disease; carefully follow-up for more than 5 years, no malignant sign. For Case 3: left pneumonectomy and lymph node dissection was performed; postoperative diagnosis was squamous cell carcinoma; pulmonary ligament lymph node positive, others negative, pT2N2M0 StageIIIA; radiation followed. He was alive healthily more than five years postoperatively.

Conclusion:
CT-NB is a very useful diagnostic method for peripheral small lung tumor (≤2cm) and some central pulmonary lesions with fiberoptic bronchoscopy failed. CT-NB could be used to confirm the diagnosis of lung cancer, to help make decision for surgically resection, to help cure more early stage lung cancer patients, to help improve the prognosis of lung cancer treatment. CT-NB could also be used to exclude lung cancer diagnosis, to avoid unnecessary surgery, especially for those aged, cardiopulmonary dysfunction, high risk patients. CT-NB could be used to confirm the pathological type of lung cancer before treatment applied, to help distinguish SCLC from NSCLC, to help select the best choice of treatment modality of chemotherapy and radiation according to patient’s age, cardiopulmonary function status, pathological type, and gene types.

Background:
Lung cancer is still one of the the most important and common mortality cause. Although, the presentation and course of the disease differ with the cell type, usually typical symptoms are seen. The most common symptoms include fatigue, weight loss, shortness of breath, and chest pain. These symptoms especially in smoking patients suggest lung cancer first. But in some cases paraneoplastic syndromes and symptoms of other systems caused by diffusing cancer come forward. Such findings are most common in small cell lung cancers (SCLC) among lung cancers. Because early metastasis and paraneoplastic syndromes SCLC can have very different clinical presentations.

Methods:
To emphasize this issue, we present a case of SCLC having only neurological signs.

Results:
60 years old male patient with a history of 70 pack years smoking, admitted to neurology clinic with vertigo, headache, nausea, and changes in consciousness. Because of the tumoral lesion in the left cerebellum seen in brain computed tomography, he was referred to brain surgery. Although, a preoperative thorax tomography revealed a mass lesion in left lung, he was operated for palliation of neurological symptoms and pathological diagnosis. Intraoperative frozen sampling diagnosed as small cell lung cancer. Patient is still followed by our department and radiation oncology.

Conclusion:
We present this case as a reminder of lung malignancies can be met by different presentations.

Background:
Huge dilatacion of the azygos vein (Aneurysms of the azygos vein) are rare and can sometimes mimic a paratracheal or posterior mediastinal mass. It is important to confirm the diagnosis with radiologic tools before performing invasive procedures, which carry the risk of hemorrhage. The usual diagnosis of a mediastinal mass by mediastinoscopy or percutaneous fine-needle aspiration or biopsy is very hazardous if there is a venous varix. Noninvasive thoracic CT scanning is a safe and better choice for diagnosis

Methods:
Here, we present a case in a 46-year-old symptomatic patient of an increasing azygos vein aneurysm that mimicked a growing paratracheal mass and posterior mediastinal mass. Review of images obtained using various modalities, including contrast CT scanner with out dynamic magnetic resonance image (MRI), revealed that the image findings were suggestive of azygos vein huge dilatation of the azigos vein ( aneurysm).

Results:
Using this method, an exact diagnosis can be reached without resorting to invasive procedures or with mini-invassiv thorax surgery.The main causes of a dilated azygos vein include portal vein hypertension, obstruction of the superior vena cava, hypertension in the right-heart chamber, Budd-Chiari syndrome, hypervascular tumor draining into the azygos system, posttraumatic pseudoaneurysm, kinking of the aorta, and pregnancy. In some cases, no definitive cause is found.

Conclusion:
We report a case of azygos vein varix mimicking a mediastinal mass in a patient with flebotrombosis of right femoral vena..

Background:
INTRODUCTION Prospective study from the work group in thoracic oncology in Hidalgo Mexico Lung cancer Still first cause of dead for cancer in wordlwide. Diagnosis, prevalence and therapeutic approach apperece directly with their clinic manifestation and deppends on economic an sociocultural patients behave. Being a non cover pathology by the State the patient has to pay all management and doctors visit. Eventhough hospital structure

Methods:
Retrospective study from january 2012 to december 2014 in Mexico including patients from public attendance and private all of them with autorized consecent We include 100 patients with massive pleural effusion, lung cancer risk factors like age more tan 50 years old, tabacco use with approximatly 30 annual package, Wood smoke 100 hr / year, work activity in mines, construction, masonry, or asbestos fibers at home or work. Sample include 54 male and 46 female. Diagnostic Thoracocentesis was done in all 100 patients with an amount of pleural effusion with range between 2.5 ml to 2500ml, aspect yellow to hematic an average of 248.6 ml. Only 8 patients (8%) Has oncologic diagnosis in pleural effusion; 40 patients (40%) with diagnosis in pleural tissue including 37 patients (37%) cáncer diagnosis and 3 patients (3%) tuberculousis. The rest 52 patients (52%) only mesothelial reaction in first thoracocentesis. From the 100 patients 60% do not return to confirm diagnosis or to reevaluate at 2 weeks with chest X ray and to explain first pathologic result arguing not having time, no money and no necesary if the first one was no cancer.

Results:
The present study shows how only in 8% can get in an oncologic diagnosis in pleural liquid in a thoracic reference hospital, on the other hand patients that had a complete protocol with a CT scan after thoracocentesis, and surgical intervention with thoracoscopy and pleural biopsy we can achieve an oncologic diagnosis in 29%, in patients with clinical features and risk factors for lung cancer. 29 patients that underwent single port thoracoscopy were previously rated for cardiovascular risk by a cardiologist, and for respiratory hazard by a pulmonologist. Surgical time varied from 1 to 2 hours, hospital stay was 2 to 5 days, those patients that persisted with high output from thoracic catheter tunneled were treated ambulatory and weekly consultation until chest tube withdrawal.

Conclusion:
Our study shows how a patient with a massive pleural effusion, with clinical data and risk factors for lung cancer, can get an oncological diagnosis by single port thoracoscopy as initial approach, with surgical staging, giving a quick resolution, and in selected cases offer a palliative treatment by a thoracic catheter tunneled and chemical pleurodesis, if indicated after making serial samples for histological study. Offering a resolutive treatment and a prompt diagnosis in a pathology that is increasing and with no satisfaying results in developing countries were a strict follow in many cases is no posible

Background:
Electromagnetic Navigation Bronchoscopy (ENB) is a relatively new minimally invasive bronchoscopic procedure that can be used to diagnose lung cancer, allowing bronchoscopists to (1) navigate towards peripheral lung lesions unreachable by a traditional bronchoscope, and (2) to utilize tools that can potentially obtain tissue samples large enough to perform advanced diagnostic and molecular testing. Here we share the experience of ENB at a large community-based hospital, aiming to better understand the diagnostic ability of ENB as well as possibly identify success factors for the biopsy methodology.

Methods:
Between September, 2012 and June, 2014, ENB was utilized in 138 cases to diagnose pulmonary lesions. Retrospective chart review was performed to access patient personal demographic information and disease-specific information. True positive diagnostic procedures were defined as those with a pathologically confirmed cancer diagnosis. True negative procedures were defined as those in which the lesions were not cancerous and had either resolved on radiological follow-up or have been stable over a period of 1 year. We assessed diagnostic yield percentages, lesion characteristics such as size and location, histological and staging characteristics of the tumor, outcomes of diagnostic tools, and size-tool correlation.

Results:
The ENB System carried an overall diagnostic yield of 75% with a sensitivity was 71.8% and specificity of 100%. 79% represented true positive results and 21% false negatives. Of the True Positives, 93% were non-small cell of which 73.6% were adenocarcinoma or had adenocarcinoma features. Of the latter, 82.1% of the adenocarcinomas diagnosed had enough tissue in the biopsy specimen for molecular testing. Of the negative results, 23% were later proven within 3-4 months of the initial biopsy and 77% after 3-4 months. The majority of cases attempted were stage I and II, with more success with lesions of larger tumor volume (greater than 500 mm[2]). Of the four tools used for biopsy sampling: lavage, brush, fine needle aspiration (FNA) and forceps, the brush had the highest true value percentage at 82.6%, followed by forceps at 80.7%. Lesions located in the right lung produced a greater percentage of true diagnoses with the right middle lobe giving an 87.5% yield while having the lowest percentage of false diagnoses at 12.5%. Risks for the procedure was 3.6% with 4 patients having pneumothorax and 1 patient with hemorrhage requiring intervention

Conclusion:
ENB can be successfully used to diagnose lung cancer in a community setting with a minimally invasive approach, and do so with reasonable accuracy and minimal risk. Moreover, tissue yields from this procedure were sufficient in over 80% of adenocarcinoma cases for molecular testing. Success factors include greater lesion size and the deployment of multiple diagnostic tools to enhance diagnostic yield. Further study is needed to determine other success factors.

Background:
Advances in systemic treatment have substantially improved the overall survival of advanced lung adenocarcinoma patients, and risk of brain metastases(BM) is higher. The survival of patients with symptomatic BM is poor. The identification of NSCLC patients with a high risk of developing BM would enable pre-emptive intervention to improve the outcome.

Methods:
A total of 53 biopsies of primary lung tumor adenocarcinoma stage IV treatment-naïve were analyzed for gene expression profiling using Affymetrix HuGene 1.0 ST and were processed in R using Bioconductor libraries. All patients were evaluated with brain MRI at diagnosis with a 3-month follow-up for BM development. Patients were classified into two groups: early-BM( < 6 months) and late-BM( > 6 months). A second independent cohort of 55 patients was analyzed to validate the gene expression signature (ClinicalTrials.gov: NCT00862173).

Results:
Samples were classified as early-BM(17) and late-BM(6), the remainder 30 never developed BM. Significant changes in gene expression of about100 genes were found. Eleven highly significant genes (B-stat > 12) were associated with process of cell-migrationCNN3(down-reg.) and adhesionCDH10(up-reg); anti-apoptosisBAG1(up-reg); immunological evasionSSX2(up-reg) and RAET1E(up-reg); signaling pathways related to RAS gene RAB9A(up-reg) and RAPGEF5(down-reg); mRNA-tRNA translocationDUS2L(up-reg); methylation controlNOC2L(up-reg); and members of the EGFR family EPGN(up-reg) and IGFR, IGF2BP1(up-reg).

Conclusion:
We describe an 11-gene signature that may predict the risk of BM which has the potential to classify patients and evaluate screening strategies that would facilitate pre-emptive interventional trials such as prophylactic cranial irradiation.

Background:
Various guidelines have proposed continuous surveillance for non-small cell lung cancer (NSCLC) after curative therapy. Yet the optimal postoperative surveillance strategy remains unclear.

Methods:
Patients who underwent complete resection for stage I-IIIA NSCLC were analyzed. Complete resection was defined as lobectomy and lobe-specific systematic nodal resection or more. We compared patterns of recurrence in patients with histology and early stage vs locally advanced NSCLC.

Results:
From 2002 to 2010, 745 patients were identified. 106 of 625 patients (17%) with stage I-II NSCLC and 74 of 120 patients (62%) with stage IIIA NSCLC developed recurrences. Local recurrences were significantly frequent in stage IIIA patients (45 [61%] vs 29 [27%] for stage I-II patients), whereas distant recurrences were about the same frequency in stage I-II and IIIA patients (91 [86%] vs 64 [86%]). Approximately 90% of recurrences had occurred within 3 years after surgery and recurrence rate within first year was significantly higher in stage IIIA patients (51 [69%] vs 52 [49%] for stage I-II patients; p=0.008). Squamous cell carcinoma (SqCC) patients had tendency to relapse earlier than non-SqCC patients (Figure 1). In particular, all recurrences in stage IIIA-SqCC patients had occurred within first 2 years . Although the risk of recurrence in stage IIIA patients was highest in the first 2 years, it remained consequential up to 6 years after surgery (Figure 2). Figure 1 Figure 2





Conclusion:
Stage IIIA NSCLC patients had significantly higher risk of recurrence and this risk was continued to 6 years after surgery. SqCC patients had tended to recur earlier. Surveillance strategies may need to account for stage- and histology-specific differences.

Background:
Previous studies show that adenocarcinomas is the main high risk factor of brain metastases (BM) in NSCLC, and 90% of BM developes in 3 years. In patients with completely resected stage IIIA(N2) pulmonary adenocarcinomas, we aimed to identify the risk factors of BM as the first site of failure in 3 years on the basis of the new lung adenocarcinoma classification and molecular biology information.

Methods:
Patients with IIIA(N2) pulmonary adenocarcinomas, who had undergone radical surgery in our hospital from January 2005 to July 2012 were retrospectively reviewed. We observed the correlation among clinical factors, the new lung adenocarcinoma classification, lymph node status, microenvironmental factors, gene mutation status and BM to find out the risk factors of BM. DNA of EGFR and KRAS was extracted and purified from primary tumors embedded in paraffin blocks. KRAS and EGFR mutation analyses were performed by using DNA sequencing. Main outcome measure was BM as the first site of failure in 3 years.The cumulative incidence of BM as the first site of failure were determined using the Kaplan–Meier analyiss. The log-rank test was used for univariate analysis, and Cox regression was used for multivariate analysis.

Results:
179 patients with completely resected stage IIIA(N2) pulmonary adenocarcinomas were included in this study. EGFR and KRAS mutations were found in tumors 41.3% and 11.7%, respectively. The most common EGFR mutations were deletions in exon 19 and the p.L858R point mutation in exon 21. The most common KRAS mutations were G-T or G-C point mutation in codon 12. Brain was the most common site of distant failure as the first failure, and 93.3% BM developed in 3 years after the complete resection. Multivariate analysis showed that the extra-capsular extension（ECE）, cN2 and KRAS mutations were significantly associated with the high risk of BM as the initial site of failure in 3 years, while EGFR 19 exon mutations were the low risk of BM. The risk of BM in patients with KRAS mutations were significantly higher than patients with EGFR 19 exon mutations or other EGFR mutaions (P=0.018). Figure 1



Conclusion:
In patients with completely resected stage IIIA(N2) pulmonary adenocarcinomas, ECE, cN2 and KRAS mutations were independent high risk factors for BM as the initial failure in 3 years. The EGFR 19 exon mutation may be a protective factor of BM. The new lung adenocarcinoma classification and tumor microenvironment were not statistically significant factors in our series.

Background:
In small-cell lung cancer little is known about harboring an ALK translocation [1, 2]. The aim of this study was to investigate the prevalence of ALK expression and rearrangement in patients with SCLC.

Methods:
In this retrospective series, archival tissue from 17 treatment naïve patients with SCLC and neuroendocrine tumors was analyzed to detect ALK expression by immunohistochemistry (IHC) in all samples. Cut-off value for positivity was similar as in non-small-cell lung cancer (NSCLC): focally strong staining of the tumor cells Fluorescent in-situ hybridization (FISH) with Vysis LSI ALK probe was performed in the IHC positive cases [3]. The ALK FISH positive cases were submitted for exome sequencing (NGS) (Illumina MiseQ).

Results:
Of the 17 patients 9 were male and 8 female. Of these 17 patients 12 had a SCLC, 3 a neuroendocrine tumor, and 2 a neuroendocrine carcinoma. Three specimens could not be analyzed. Six of 17 specimens were ALK IHC positive, of which one neuroendocrine tumor, one neuroendocrine carcinoma and 4 of the SCLC.

Conclusion:
The IHC expression of ALK suggests a possible role of ALK-TKI in the treatment of SCLC. Mature FISH and NGS data will be presented at the meeting.

Background:
Lung cancer is the leading cause of cancer-related deaths in Canada, for both men and women. Small cell lung cancer (SCLC) is one subtype of lung cancer, and accounts for 15-20% of lung cancer incidence. SCLC is an aggressive cancer and commonly develops resistance to drugs used to treat it, including platinum-based agents such as cisplatin. RBM5 is a lung cancer tumour suppressor gene that is generally downregulated in lung cancer, and deleted in some. RBM5 is an RNA-binding protein that has the ability to regulate the cell cycle and modulate apoptosis. We hypothesize that reintroduction of RBM5 into an RBM5-null SCLC cell will result in decreased cell proliferation and increased apoptotic-like cell death in the presence of cisplatin.

Methods:
A SCLC cell line with an endogenous RBM5 homozygous deletion, and two previously established stable GLC20 sublines (T2 and C4) that express different levels of RBM5, were used for in vitro mechanistic studies. Proliferation changes were monitored using an MTT assay and a cell counting assay. Cisplatin-induced cell death was monitored by assessing cell viability (by nigrosin staining), PARP cleavage (by Western blot), chromatin condensation and phosphatidylserine flip (by fluorescence microscopy).

Results:
Decreased proliferation was observed in the high (C4) but not the low RBM5 (T2) expressing subline, compared to either the parental GLC20 cells or the empty vector control subline. Increased cisplatin-mediated cell death, observed as PARP cleavage, was observed in both T2 and C4, compared to either the parental GLC20 cells or the empty vector control subline. Fluorescence microscopy results will be presented.

Conclusion:
These results suggest that the loss of RBM5 expression in SCLC cells leads to increased proliferation and survival of SCLC cells. We hope to demonstrate the potential role of RBM5 as a predictive marker for cisplatin sensitivity in SCLC.

Background:
Relapsed/refractory small cell lung cancer (RR-SCLC) has a poor prognosis with median overall survival of only 2-3 months. Objective responses to single agent newer chemotherapy agents range from 14-29%. One of the key mechanisms for the development of acquired resistance of cancer cells to chemotherapy is the induction of a heat shock response. Over-expression of Hsp90 and its co-chaperones in tumor cells results in up-regulation of ATP-dependent transporters such as ABCG2 and RLIP76. Such transporters act as drug-efflux pumps for chemotherapeutic agents including doxorubicin, thus mediating drug resistance. Ganetespib, a next generation Hsp90 inhibitor devoid of liver and ocular toxicities that limit other agents in its class, is now in phase 3 evaluation in NSCLC. Targeting Hsp90, ganetespib affects multiple drug resistance pathways. We recently demonstrated in vitro and in vivo that the addition of ganetespib (G) to doxorubicin (D) can indeed overcome drug resistance (Lai et al., Oncogene 2014). The primary objective of this clinical study is to determine the maximum tolerated dose and the recommended Phase II dose (RP2D) of G + D in subjects with advanced solid tumors. The secondary objectives are to determine the dose limiting toxicities (DLTs) and to assess if there is preliminary evidence of activity for the combination of G + D in RR- SCLC by determining the objective response rate and response duration. We will also aim to establish conditionally reprogrammed cancer cell lines from tumor tissue in subjects with RR-SCLC to allow ex-vivo molecular characterization and drug sensitivity testing.

Methods:
The dose escalation phase will follow a standard 3+3 dose escalation scheme with 2 dose levels of G administered weekly on Days 1, 8 of a 21-day cycle, in combination with fixed dose D at 50 mg/m[2] on Day 1. After 4-6 cycles of the combination, continuation of single agent G is permitted in patients deriving clinical benefit. The RP2D determined at the end of the dose escalation phase will be used to conduct a dose expansion study in subjects with RR-SCLC. Key inclusion criteria are refractory solid tumors (in dose escalation phase) and RR-SCLC (in dose expansion phase), age >18 years, ECOG PS 0-1, adequate organ/marrow function. Key exclusion criteria include LVEF < 50%, lifetime cumulative doxorubicin dose >150 mg/m[2], untreated, symptomatic brain metastases, serious cardiac illness, QTc >470 msec, strong inhibitors or inducers of CYP 3A4 or 2C19. DLTs are defined as grade 4 hematologic toxicities or > grade 3 non-hematologic toxicities including hypersensitivity reactions despite pre-medication and nausea, vomiting and diarrhea despite maximal medical therapy. Response assessment will be done using RECIST 1.1.

Results:
Clinical Trial Status: A total of 6 subjects have been enrolled thus far. With no DLTs observed in 5 subjects who have crossed the DLT evaluation period, the trial continues enrollment.

Conclusion:
Not applicable

Background:
The effect of second-line chemotherapy on overall survival (OS) might be confounded by subsequent therapies in patients with sensitive relapse of small cell lung cancer (SCLC). But there is no research in this viewpoint. Therefore, we aimed to determine the relationships between progression-free survival (PFS), post-progression survival (PPS) and OS after second-line chemotherapy in this population.

Methods:
Between January 1999 and November 2013, seventy-seven patients with sensitive relapse of SCLC who had received second-line chemotherapy following first-line platinum doublet chemotherapy were analyzed. We retrospectively collected individual data at Gunma Prefectural Cancer Center and National Hospital Organization Nishigunma National Hospital from medical records, and evaluated patient characteristics, treatment data, tumor shrinkage, PFS, PPS and OS.

Results:
The median follow-up time was 13.1 months (range 2.3-80.8 months). The response rate, the disease control rate, median PFS and median OS were 58.4%, 93.5%, 5.1 months and 13.7 months, respectively. The relationships of PFS, PPS and tumor shrinkage with OS were analyzed at the individual level. Spearman rank correlation analysis and linear regression analysis showed that PPS was strongly correlated with OS (r = 0.91, p < 0.01, R [2]= 0.96), PFS was moderately correlated with OS (r = 0.58, p < 0.01, R[2 ]= 0.28), and tumor shrinkage was weakly correlated with OS (r = 0.34, p < 0.01, R[2 ]= 0.12). Using multivariate Cox proportional hazards model with a stepwise regression procedure to explore prognostic factors for PPS, the number of regimens after progression beyond second-line chemotherapy and performance status (PS) at the beginning of third-line treatment were both significantly associated with PPS (p < 0.01).

Conclusion:
PPS has more impact for OS than PFS in patients with sensitive relapse of SCLC. Moreover, this study suggests that subsequent treatment and PS after disease progression following second-line chemotherapy may be important factors that influence OS.

Background:
We performed a feasibility study of maintenance irinotecan therapy in patients with extensive disease small cell lung cancer (ED-SCLC) who responded to the induction irinotecan plus cisplatin (IP) therapy.

Methods:
The eligibility criteria included pts with ED-SCLC who responded to four cycles of induction IP therapy, ECOG performance status (PS) of 0 to 1, age of 20 to 70 years and adequate organ functions. Pts received irinotecan monotherapy at 60 mg/m2 on days 1, 8 and 15 of a 28-day cycles until disease progression. The primary endpoint was the proportion of treatment success (TS) at 6 months. Using a binomial design, a lower activity level (p0) of 0.25 and a target activity level (p1) of 0.50, the preplanned accrual of 28 patients was sufficient (alpha, 0.10 and power, 0.90).

Results:
Between August 2012 and August 2013, 22 pts were enrolled. However, accrual was discontinued because of the three grade 3 pneumonitis events (3 of 22 patients, 13.6%). Patient characteristics of the 22 eligible pts were as follows; the median age was 65 (54-70) years; 12 pts had a PS of 0, and 16 pts were male. The median number of cycles delivered was four (range, 1–31). Four of 22 (18.2%) patients achieved TS at 6 months. Median progression free survival and overall survival from the start of the maintenance irinotecan therapy were 3.2 months and 15.9 months, respectively. Grade ≥3 toxicities included neutropenia (4.5%), hyponatremia (4.5%), pneumonitis (13.6%) and cholangitis (4.5%). No treatment-related deaths occurred. Figure 1



Conclusion:
This trial was early terminated due to the unexpected toxicity, but maintenance irinotecan therapy was still active for a subset of ED-SCLC.

Background:
Aldoxorubicin is a novel prodrug that binds to albumin in the circulation. Doxorubicin is cleaved in low pH environments, allowing administration of 3.5-4-fold higher doses than standard doxorubicin and 10-fold greater cumulative doses. Patients with metastatic small cell lung cancer (SCLC) who have failed prior chemotherapies have a poor prognosis with response rates (ORR) of 5-20%, progression-free survival (PFS) of 2-4 months and overall survival of 6-10 months. Topotecan is the standard therapy for these patients.

Methods:
Open label study, 132 patients, (1:1 randomization) to receive either aldoxorubicin (230 mg/m[2], IV infusion, Day 1, every 3 weeks) or topotecan (either 1.5 mg/m[2]/day IV, Days 1-5, every 3 weeks or 4 mg/m[2] IV infusion on Days 1, 8, and 15 every 28 days). Key inclusions: confirmed SCLC, relapsed or refractory to ≥ 1 prior chemo, ECOG 0-2, measurable tumor (RECIST 1.1). Key exclusions: >375 mg/m[2 ]prior doxorubicin, prior topotecan, active CNS mets, lab abnormalities (ANC <1500/mm[3], platelets <100,000/mm[3], Hgb <9 gm/dL, LFTs > 3 or 5x ULN), serious myocardial dysfunction, anion gap >16 meq/L or arterial blood pH < 7.30. Key stratifications: relapse < 90 days versus > 90 days; ECOG 0-1 versus 2. Primary endpoint: PFS (analysis after 110 events); assume PFS for topotecan = 3.5 months, aldoxorubicin = 6.5 months. Secondary endpoints: OS (analysis after 110 deaths; assumes OS for topotecan = 6 months, aldoxorubicin = 8 months), ORR, disease control rate, adverse events, tolerability, lab abnormalities. Study sites: Up to 40 sites in the US, Hungary, Spain, and Italy.

Results:
Not applicable.

Conclusion:
Not applicable.

Background:
To observe the clinical efficacy of Compound Kushen Injection combined with EP regimen chemotherapy for the treatment of small cell lung cancer SCLC).

Methods:
98 cases of small cell lung cancer patients were chosen and randomly divided into experimental group and control group. 49 patients in experimental group were treatment with Compound Kushen Injection combined with EP regimen chemotherapy. 49 patients in control group received EP regimen chemotherapy alone. Both groups were repeated every 4 weeks and 3 cycles. All patients completed efficacy evaluation after treatment 3 cycles.

Results:
There was no significant difference in short-term effect between the two groups( P＞0.05). The gastrointestinal reactions(represented as vomiting, anepithymia and diarrhea) and bone marrow depression(the toxicity on hemoglobin, leukocyte and platelet) in experimental group were alleviated compared with those in control group. There was significant difference between the two groups (P＜0.05). The median survival time was 462d in experimental group while 268d in control group( P＜0.05). KPS score after chemotherapy in all experiment groups was significantly higher than that in control group( P＜0.05).

Conclusion:
Compound Kushen Injection combine with EP regimen chemotherapy shows precise therapeutic effect on SCLC, reducing adverse drug reactions, increasing median survival time and improving the life quality of patients.

Background:
Pembrolizumab (pembro) is a selective anti-PD-1 antibody that blocks the interaction between programmed death-1 (PD-1) on T-cells and PD-L1 and PD-L2 on tumor cells. We report safety and clinical activity of pembro combined with chemotherapy in patients with advanced small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) progressing after ≥ 1 line of chemotherapy (NCT02331251).

Methods:
Patients were treated with pembro 2 mg/kg on day 1 every 21 days with either irinotecan on day 1 every 21 days or gemcitabine with or without vinorelbine on days 1 and 8 every 21 days until progression or toxicity. Eligibility included at least 1 measurable tumor lesion, Karnofsky Performance Status (KPS) of 70-100%, and adequate organ function. Tumors were assessed every 3 cycles using RECIST 1.1 and immune-related response criteria (irRC) and unconfirmed best overall response (BOR) was evaluated.

Results:
Eight lung cancer patients have been enrolled at the time of submission. Median age was 52.5 (range 33-74) and median KPS was 80%. Histology was adenocarcinoma (62.5%), including one with an EGFR T790M mutation and three SCLC (37.5%). One SCLC patient is on pembro plus gemcitabine 1,000 mg/m2, one NSCLC patient is on gemcitabine 1,000 mg/m2 and vinorelbine 25 mg/m2, and the remaining six patients were treated with irinotecan 250-300 mg/m2. Two NSCLC had prior exposure to nivolumab for ≥ 2 months. The maximum tolerated dose (MTD) was exceeded for irinotecan 300 mg/m2, and subsequently all patients receiving irinotecan are currently dosed at 250 mg/m2. Any grade drug-related treatment adverse events (AEs) occurred in 88% of patients; the most common (n>1) were skin rash, fatigue, diarrhea, anorexia, and extremity edema. No infusion-related reactions were observed. Dose limiting toxicities (DLTs) with pembro plus irinotecan were fatigue and nausea/vomiting. DLT with gemcitabine and vinorelbine was hypoxia. No grade 3 AEs were observed thus far with pembro plus gemcitabine. Five patients are currently evaluable for BOR. Two of two SCLC on pembro plus irinotecan have partial response as BOR and continue on study. One NSCLC patient on pembro plus gemcitabine and vinorelbine had stable disease, and two NSCLC patients had PD as BOR.

Conclusion:
In patients with previously treated SCLC and NSCLC, pembro plus chemotherapy appears to be safe to administer with a toxicity profile similar to the individual components of the regimen utilized. Establishment of the recommended phase 2 dose is ongoing for these treatment arms. Since the median follow-up is ~2 months, updated results including any new lung cancer patients enrolled, median progression-free survival (PFS), and overall survival will be presented at the WCLC.

Background:
Although small cell lung cancer (SCLC) is initially chemo sensitive, most patients rapidly relapse. Prognosis of late line treatment for relapsed SCLC patients is generally poor. The efficacy of paclitaxel regimens for relapsed SCLC patients has been reported in some articles. But no specific study has been reported to our knowledge, about nab-paclitaxel administration for relapsed SCLC patients.

Methods:
By using the database of two hospitals, we underwent a retrospective analysis to evaluate the efficacy and safety of nab-paclitaxel regimens for relapsed SCLC patients. The data of patient characteristics, treatment efficacy and adverse events were collected from the medical records.

Results:
Fourteen patients (3 women and 11 men) with relapsed SCLC were administered weekly nab-paclitaxel or carboplatin plus nab-paclitaxel between February 2013 and July 2014 in our hospitals. The median age was 71 years old. Eight patients had comorbid pulmonary disease (5 had interstitial lung disease, 2 had chronic obstructive pulmonary disease, and 1 had both diseases). Five patients were administered nab-paclitaxel regimen as second line chemotherapy, five patients were as third line and four patients were as fourth or fifth line. Five patients achieved partial response, and four patients had stable disease. The response rate was 36%, and disease control rate was 64%. Most common toxicities were hematological adverse events such as neutrophil count and anemia. Severe neutropenia (Grade 3 or 4) appeared to some patients, but all patients were restored by treatment. The main non-hematologic adverse events were neurotoxicity and constipation, and these events were mild.

Conclusion:
The administration of nab-paclitaxel regimens to highly treated patients with relapsed SCLC demonstrated modest response rate and disease control rate. All adverse events were manageable, so that nab-paclitaxel regimens were well tolerated. Further clinical trial to evaluate the efficacy and safety of nab-paclitaxel regimens for relapsed SCLC patients is warranted.

Background:
The prognosis of recurrent or refractory small cell carcinoma of lung is poor with conventional therapies; one of the issues is the presence of brain metastasis. Topotecan is a topo-isomerase inhibitor with very good penetration to CNS system. The efficacy of topotecan in metronomic doses over a period of time is extremely well tolerated and effective. Topotecan is an approved drug for recurrent or refractory small cell carcinoma of lung. Temozolomide in metronomic dosing or in repeated small dosing can be an effective alternative to conventional dosing without the side-effects and has been shown to be effective in Neuro-endocrine tumors and Small Cell Carcinoma of Lung shows neuro-endocrine differentiation as well as the presence of unmethylated MGMT.

Methods:
This is a two arm Open Label Single Institute Phase II Study reviewed and approved by Institutional Review Board. Written Informed Consent was obtained from all patients. The study was conducted to find the safety and efficacy of this regime. All patients had recurrent small cell lung cancer that was sensitive or refractory to first line platinum therapy. Patients with brain mets were eligible. All patients had to have minimal functional reserves; had to be greater than the age of 18 years; Karnofsky scale > 60. Response evaluation by RECIST criteria Version 1.1 was used. Patients were treated with Topotecan 1mg per day along with Temozolomide 20mg in morning and in the evening, no food allowed 1hr before and 1hr after. The comparator arm was oral topotecan at standard dosage of 2.3mg/m[2] in Day 1 to Day 5. Patients were evaluated for toxicity every 3 weeks and for efficacy after every 12 weeks. There were 21 patients in each arm. Palliative medication and Best Supportive Care was offered to both the groups.

Results:
In the experimental arm vs comparator arm, response rate was as follows: · Complete response – 9.5% vs 0% · Partial response – 33.3% vs 23.8% · Stable disease in – 38.1% vs 28.6% Median Survival time was 38 weeks vs 25.9 weeks in the Intent to Treat population arm. (Log rank P=0.0104). Quality of Life had slower deterioration in patients with metronomic chemotherapy. Principal toxicities seen were mainly hematological toxicity in the standard arm 33% vs 4%; Grade IV thrombocytopenia in 7% vs 4%; Grade III/IV anemia in 25% vs 10%; Infection Grade III/IV in 16% vs 6%; Vomiting 6% vs 1%; Diarrhea 6% vs 0%; Dyspnea 9% vs 4%. Pain 6% vs 4%; Toxic death occurred in 6% in comparator arm.

Conclusion:
Metronomic Chemotherapy is associated with prolongation of survival and Quality of Life benefits in Relapsed Small Cell Lung Cancer.

Background:
The role of PCI in the management of Small Cell Lung Cancer (SCLC) pts is still debated. Several studies showed its effectiveness in terms of progression (PFS) and metastasis free survival (MFS), but advantages for overall survival (OS) are not always reported. The aim of our analysis is to retrospectively evaluate the current clinical impact of PCI in patients affected by SCLC.

Methods:
From April 1989 to May 2014 a total of 182 pts with SCLC underwent radical concomitant or sequential CHT-RT on thoracic disease +/- PCI in two different Italian Institutions. Thirty-eight pts were female, while 144 were male. Mean and median age were respectively 62.6 (range 38-86) and 63 years. Only 5 pts had “extended disease”, while the other 177 had T1-T4 N0-N2 limited stage SCLC. Seven pts underwent surgery followed by adjuvant CHT-RT on mediastinal nodes while 8 pts didn’t received any RT for primary disease; the remaining 167 pts received concomitant/sequential CHT-RT with radical intent. After receiving CHT or CHT-RT for thoracic disease, 66/182 pts received PCI, while 118/182 pts underwent regular clinical/radiological follow up. Most of patients were routinary followed in out-patient clinic every three months and they were also submitted to neurocognitive questionnaires. All PCIs were planned using opposite lateral fields with 2D technique or virtual off-line simulation; all pts received 25-30 Gy in 10 fractions within two weeks. Three- and 5-year OS,PFS and Brain mts free survival (BrMFS) were analyzed; univariate and multivariate analysis (using Kaplan Meier and Cox Regression tests) were performed due to identify patient, tumor and/or treatment related prognostic factors

Results:
: We retrospectively analyzed our cohort of patients using Kaplan Meier curves for survival and Cox regression tests for univariate and multivariate analysis. At a mean follow up of 32 months, no difference in terms of OS, PFS and brMFS was found comparing population referring to the 2 different centers. In the analyzed population 3- and 5-year OS were respectively 28.2 and 18.4%, while PFS were 22.4 and 18.9 respectively. Finally 3- and 5-year BrMFS were 56.3 and 50.2%. By multivariate analysis PCI and clinical response to primary thoracic treatment remain as independent variables being protective in terms of OS, PFS and BrMFS. Concomitant CHT-RT and RT on thoracic disease are positive factors just for PFS (respectively with p<0.014 and p<0.025). No G3 or G4 acute/late toxicities were found.

Conclusion:
PCI after primary thoracic CHT-RT with radical intent was confirmed as a “treatment-key” in the management of SCLC having also an optimal toxicity profile. Our data confirmed that PCI will be encouraged in all fit patients due to its potential benefit in terms of OS, PFS and BrMFS. Pts with Limited Stage SCLC having experienced a good response to primary CHT-RT treatment on thoracic disease seems to be the optimal candidate to PCI.

Background:
To evaluate our experience in radical radiochemotherapy (RCT) twice daily in limited disease small cell lung cancer (SCLC) in term of effectiveness and toxicity.

Methods:
A retrospective review was performed to determine the local recurrence and survival rates for patients with SCLC localized disease undergoing RCT according Turrisi regimen between October 2004 and August 2014. All patients were treated with 3DRT, with a median dose of 45 Gy (150cGy twice daily), combined with chemotherapy based in cisplatinum-VP16. 73% received preventive cranial irradiation (ICP). 22% of patients underwent induction QT based in platinum-VP16. The primary objective was overall survival (OS); secondary objectives were progression free survival (PFS), local progression free survival (LPFS) and toxicity. OS was analized with Kaplan-Meier test.

Results:
44 elegible patients were recruited (82% male, median age 62, with good performance status). The clinical stage was 89% E.III and 11% E.II. At a median follow-up of 18 months, the median OS was 21 months (95%CI: 16.3-25.4) and median PFS was 12.6 months (95%CI: 10.2-15). OS at 2 and 5 years were 38.6% and 24.8% respectively. LPFS was 14 months (95%CI: 10.5 -17.6) and systemic progression free survival was 14.2 (95%CI:10.1-18.2). During the RCT we reported anaemia (2%G3), neutropenia (7%G3, 16%G4), esophagitis (2%G3), dyspnea (2%G2), pneumonitis (7%G2). Induction QT did not improve the OS and PFS.

Conclusion:
In our experience radical radiochemotherapy twice daily is a feasible treatment option for small cell lung cancer, showing long-term survival with no inferiority results compared with the published and acceptable toxicities.

Background:
Several clinical studies have demonstrated the efficacy and safety of the adjuvant chemotherapy for patients with small cell lung cancer (SCLC) , particularly in patients with stage　Ⅰ disease. But it is unclear which chemotherapy regimen is the most efficacious for SCLC patients who underwent surgery, due to the rarity. The objective of this study was to analyze the efficacy and safety of adjuvant chemotherapy for patients with SCLC retrospectively.

Methods:
From January 2002 to September 2014, we retrospectively analyzed the clinical data of 23 patients with SCLC who received surgery in our institute. Seventeen patients received adjuvant chemotherapy. Six patients was observed with no chemotherapy after surgery, due to old age or poor condition（n=4）, patient refusal（n=1）, early post-operative relapse（n=1）.

Results:
The chemotherapy regimens were cisplatin and etoposide（PE）in 8 patients, and carboplatin and etoposide （CE） in 9 patients. Median time from surgery to starting chemothetapy was 1.5 months, and median follow-up time was 39.5 months. 12 pts （70%） received full cycles of chemotherapy. The recurrence was observed in 2 of 8 pts who received PE therapy and 2 of 9 patients who received CE therapy in April 2015. The median recurrence free survival (RFS) of patients who received adjuvant chemotherapy was not reached, and the RFS of patients with no chemotherapy was 7.62 months（Log-rank test P value 0.0007）. No treatment related death was observed.

Conclusion:
The adjuvant chemotherapy for patients with small cell lung cancer may be safe and efficatious.

Background:
Concurrent chemotherapy and thoracic radiotherapy (TRT) is the recommended treatment of LD-SCLC. The treatment often causes severe toxicity. Many patients have comorbidity due to old age and smoking, and it is unclear whether these patients tolerate and benefit from the treatment as much as more fit patients. Studies have shown that comorbidity is a negative prognostic factor in many cancers (including lung cancer), but this has not been investigated in LD-SCLC patients receiving chemo-radiotherapy. We investigated whether comorbidity was a prognostic factor or associated with severe toxicity in a randomized trial comparing two schedules of TRT in LD-SCLC (n=157).

Methods:
Patients received four courses of cisplatin plus etoposide and were randomized to receive concurrent TRT of either 45 Gy/30 fractions (twice daily) or 42 Gy/15 fractions (once daily). Responders were offered prophylactic cranial irradiation of 30 Gy/15 fractions. The Charlson Comorbidity Index (CCI) was used to assess comorbidity from hospital medical records. The CCI rates common conditions associated with increased 1-year mortality with scores of 1, 2, 3 or 6 based on severity - and a total score (“CCI-score”) is calculated. Toxicity was assessed using the CTCAE v3.0. We adjusted for treatment arm and established baseline prognostic factors in lung cancer (gender, stage of disease, appetite loss, weight-loss, age and performance status (PS) in the multivariate analyses.

Results:
157 patients were analyzed (100%). Median age was 63 years, 52% were men, 16% had PS 2, 72% stage III, 30% weight-loss >5% last 3 months and 46% received twice-daily TRT. The most common grade 3-4 toxicities were pneumonitis (n=4; 3%); esophagitis (n=50; 32%) and neutropenic infections (n=64; 41%). 4 patients (3%) died from pneumonitis. 63 patients (40%) had CCI-score 0; 54 (34%) CCI-score 1; 23 (15%) CCI-score 2; 13 (8%) CCI-score 3; 3 (2%) CCI-score 4 and 1 patient had CCI-score 5 (1%). Most common comorbidities were chronic obstructive pulmonary disease (n=60, 38%), peptic ulcer disease (n=19, 12%), previous myocardial infarction (n=17, 11%) and diabetes (n=17, 11%). Median overall survival (OS) for the whole population was 22.7 months. There were no significant associations between CCI-score and median OS in univariate (CCI-score 0: 30.6 months; CCI-score 1: 15.1 months; CCI-score 2: 23.0 months; CCI-score 3: 23.0 months and CCI-score 4-5: 9.3 months, p=0.18) or multivariate analyses (HR: 0.97; 95% CI 0.79 – 1.18, p=0.74). Patients with comorbidity had a shorter survival than others in the univariate (CCI-score 0: 30.6 months, CCI-score ≥1: 18.8 months, p=0.047), but not in the multivariate analysis (HR: 1.27; 95% CI 0.82–1.98, p=0.29). Patients with comorbidity did not experience significantly more grade 3-4 pneumonitis (CCI-score 0: 3%, CCI-score ≥1: 2%, p=1.0), esophagitis (CCI-score 0: 38%, CCI-score ≥1: 28%, p=0.17), neutropenic infections (CCI-score 0: 41%, CCI-score ≥1: 40%, p=0.92) or deaths from pneumonitis (CCI-score 0: 2%, CCI-score ≥1: 3%, p=0.65). There were no other significant associations between CCI-scores and overall survival or toxicity.

Conclusion:
LD-SCLC patients with comorbidity had similar survival and toxicity as others, suggesting that they should be offered similar treatment as those without comorbidity.

Background:
In elderly patients with LD-SCLC, the role of irinotecan has been unclear and the timing of TRT combined with chemo-therapy has not been fully evaluated. Furthermore, no standard treatment has been established for them. We report a phase I/II trial of induction chemotherapy of carboplatin and irinotecan followed by sequential TRT in this population.

Methods:
Patients with untreated, measurable LD-SCLC >70 years with performance status (PS) 0 to 2 and adequate organ function were eligible. Treatment consisted of induction with carboplatin on day 1 and irinotecan on days 1 and 8 every 21 days for four cycles. TRT of 54Gy in 27 fractions was then administered sequentially. Carboplatin dose was escalated from AUC of 4 to 5 (Levels 1 and 2, respectively)　with a fixed dose of irinotecan at 50 mg/m[2]. The primary objective of the phase II portion was evaluation of efficacy.

Results:
A total of 41 patients were enrolled [median age 75 years, range 70-86 years; 31 male, 10 female; PS 0/1/2: 22/18/1]. At Level 1 (n=6), one patient experienced dose-limiting toxicity (DLT) as Grade 3 hypertension. At Level 2 (n=6), two patients experienced DLT as Grade 4 thrombocytopenia. Therefore, level 1 was chosen as the recommended dose. The phase II trial was then expanded by 35 patients in the level 1 based on the Simon minimax design. In all cohorts, the median chemotherapy cycle was 4 (1/2/3/4 courses administered as 4/2/2/33); median radiation dose was 54Gy (range 36-60). Toxicities were generally mild, as expected.　Gr 3/4 leukopenia and thrombocytopenia were both observed in six (15%) patients. No Gr 3/4 diarrhea or esophagitis was noted. Although Gr 3 febrile neutropenia and Gr 3 pneumonitis were seen in two patients each, no treatment-related deaths occurred. There were five complete responses and 32 partial responses, for a response rate of 90%. With median follow-up of 80.4 months (n=41), median progression-free and overall survival times were 11.2 and 27.1 months, respectively.

Conclusion:
Induction chemotherapy with carboplatin plus irinotecan followed by sequential TRT was well tolerated and highly effective in elderly patients with LD-SCLC. Further confirmatory studies are warranted.

Background:
Treatment of small-cell lung cancer depends on the extent of disease. Concurrent chemotherapy and thoracic radiotherapy (TRT) is recommended if all lesions can be included in a radiotherapy field (limited disease – “LD”), while patients with more advanced disease (extensive disease – “ED”) receive chemotherapy alone. LD is defined as confined to one hemithorax, but some have excluded patients with contralateral hilar and supraclavicular lymph node metastases (LNM). When the latest revision of TNM was published, it was recommended that N3-disease should be considered as LD with the possible exception of supraclavicular LNM – and that TNM-stage should be reported in clinical trials of LD SCLC to further explore this. We assessed extent of disease according to TNM v7 in patients from a randomized phase II trial comparing two schedules of TRT in LD SCLC (n=157) and investigated whether N3-disease was a negative prognostic factor; and whether there were survival-differences between the different N3-subcategories.

Methods:
Patients received four courses of cisplatin plus etoposide and were randomized to receive concurrent thoracic radiotherapy of either 45 Gy/30 fractions (twice-daily) or 42 Gy/15 fractions (once daily). Responders were offered prophylactic cranial irradiation of 30 Gy/15 fractions. Extent of disease was assessed from CT scans obtained three weeks before chemotherapy commenced. N3-disease was categorized according to contralateral supraclavicular, ipsilateral supraclavicular, contralateral hilar and contralateral mediastinal LNM. Weight loss was defined as weight loss >5% the last 3 months prior to enrolment.

Results:
150/157 patients were analysed (96%). Median age was 63 (40-85); 51% were men; 15% had PS 2 and 46% received twice-daily TRT. 1% had stage I disease; 14% stage II; and 84% stage III. Median overall survival (OS) for stage I: not reached, stage II: 41.1 months, and stage III: 20.9 months (p=0.022). 17% had N0-disease; 5% N1-disease; 30% N2-disease; and 47% had N3-disease. Among those with N3-involvement, 40 % had contralateral mediastinal LNM, 16% contralateral hilar LNM, and 17% supraclavicular LNM (13% ipsilateral and 7% contralateral supraclavicular LNM). 43% had LNM to more than one N3-station. Patients with N3-disease had inferior survival compared with N0-2 disease (18.0 vs. 33.7 months; p<0.001). All subcategories of N3 had inferior median OS compared with N0-2 disease (median 33.7 months): contralateral mediastinal LNM (18.0 months; p=0.022), contralateral hilar (19.8 months; p=0.021), supraclavicular LNM (15.1; p=0.003) [ipsilateral supraclavicular LNM (15.1 months; p=0.009) and contralateral supraclavicular LNM (13.8 months; p=0.007)]. There were no significant differences in median OS between the different N3-categories (p=0.84). Multivariate analyses adjusting for established prognostic factors in lung cancer (gender, age, PS, weight-loss and appetite loss) and treatment showed that N3-disease (HR 2.30; 95% CI=1.51-3.48; p<0.001), supraclavicular LNM (HR 1.67; 95% CI=1.01-2.77; p=0.046) and contralateral mediastinal LNM (HR 2.34; 95 % CI = 1.55-3.51; p<0.001) remained significant prognostic factors.

Conclusion:
Patients with N3-disease had inferior OS to those with N0-2 disease. All subcategories of N3 had inferior OS in the univariate analyses, while supraclavicular and contralateral mediastinal LNM remained significant in the multivariate analyses. Patients with supraclavicular LNM had similar OS as other N3 subcategories.

Background:
We conducted a retrospective study to evaluate the prognostic factors of elderly patients with small cell lung cancer (SCLC).

Methods:
The records of elderly patients (≥65 years) with histologically-proven SCLC were reviewed. The patients’ information including demographic, clinical and laboratory parameters, staging status on the VALG staging system, and treatment modalities were registered. Univariate and multivariate survival analysis was performed by the Kaplan-Meier method and Cox proportional hazards model, respectively.

Results:
Between January 2004 and December 2012, 247 elderly patients with SCLC were analyzed, 129 patients initially presented with limited stage and 118 with extensive disease. The median age of the patients was 70.7 (range 65–83). The median follow-up period for all patients was 22.0 months (range, 1.0–84.0 months) and 39.9 months for surviving patients (range, 4.7–84.0 months). The overall median survival time (MST) was 17.3 months, and the 2-y and 3-y OS rates were 36.3% and 22.7%, respectively. The MST, 2-y and 3-y OS rates were 22 months, 45.0% and 30.5% in patients with limited stage, versus 13.4months, 26.5% and 13.7% in patients having extensive diseases, respectively. The the median PFS, 2-year and 3-year PFS rates were 10.0 months, 23.5% and 18.3% for the whole group, respectively. The median PFS , the 2-year and 3-year PFS rates were 13.0 months, 31.6% and 25.7%, respectively in the LD-SCLC group; and those of the ED-SCLC group were 8.2 months, 13.3% and 7.6%, respectively. Multivariate analysis revealed that disease extent (HR=3.034; p＜0.001) and the number of chemotherapy cycles (HR=0.486; p=0.003) were independent prognostic factors for the OS.

Conclusion:
Positive treatment was necessary to the elderly SCLC patients with good performance status. Fit elderly patients with SCLC could achieve a relatively prolonged survival.

Background:
Small Cell Lung Cancer has a aggressive clinical course and poor outcomes. Role of multi modality therapy and prophylactic cranial irradiation have been established in the last two decades. There is a paucity of studies on survival in SCLC in India and to our knowledge till date; only one study has been published from India. The current study is a retrospective review of outcomes in patients with SCLC in India

Methods:
All newly diagnosed small cell lung cancer cases from 2000 through 2014 who received treatment at Cancer Institute (WIA),Chennai were identified and clinical data from their hospital records, noted. The influence of various pretreatment factors on survival was investigated using Kaplan-Meier plots and Cox multivariate regression model. Only subjects who received intravenous chemotherapy were included in the analysis.

Results:
Forty seven subjects were included, 39 (83%) were males. Age distribution: Less than 50 years – 16 (34%), 50-59 years - 16 (34%),> 60 years – 15 (32%). Limited Stage: 21 (44.6%) and extensive stage: 26 (55.4%). Treatment outcomes in Limited stage disease (N=21): Sequential chemotherapy and radiation: N=11 (52.38%), median PFS was 8 months, 1 year OS was 72.9% (P<0.001) and 5 year OS was 0%. Concurrent chemotherapy and radiation: N=10 (47.62%), median PFS was 10 months, 1 year OS was 78.8% and 5 year OS was 26.3% (P<0.001). The improvement in overall survival when subjects received concurrent chemotherapy and radiation as compared to sequential chemotherapy and radiation was statistically significant (P<0.001). Treatment outcomes in Extensive stage disease (N=26); Chemotherapy alone: N=19 (73%),1 year PFS was 6.8% and 1 year OS was 9.1%, Sequential chemotherapy and radiation: N=7 (17%), 1 year PFS was 28.6% and 1 year OS was 53.6% (P=0.075). There were no survivors at 5 years in subjects with extensive stage disease irrespective of whether chemotherapy alone was used or sequential chemotherapy and radiation. In subjects with limited stage disease 9, (42.85%) received prophylactic cranial irradiation

Conclusion:
Subjects with limited stage disease who received concurrent chemo-radiation showed a better overall survival as compared to those who received sequential chemo-radiation. Subjects with extensive stage disease who underwent sequential chemo-radiation did not show any statistically significant improvement in overall survival as compared to those who received only chemotherapy. Concurrent chemo-radiation should be the preferred treatment approach in limited stage SCLC in spite of the significant increase in costs and side effect profile even in developing countries. Sequential chemo-radiation may not show any added advantage in extensive stage SCLC especially considering the added side effects as well as the burden on resources

Background:
Malignant mesothelioma (MM) is a highly aggressive tumor caused by asbestos exposure after a long latency. The neurofibromatosis type 2 (NF2) tumor suppressor gene is mutated in around 50% of MM cases, and encodes Merlin that regulates the Hippo tumor-suppressive signaling pathway. We previously reported occasional genetic or epigenetic alteration in the LATS2 and AJUBA genes in MMs, which encode components of the Hippo pathway. The LATS2 inactivation was shown to lead to constitutive activation of YAP, a prooncogenic protein and transcriptional coactivator, which enhances multiple cell cycle regulation genes including cyclin D1 (CCDN1). To further delineate the exact inactivation mechanism of this pathway and the roles of YAP in the development of MM, we established immortalized mesothelial cell lines and transduced YAP to determine whether or not YAP can confer the malignant phenotypes to these cells.

Methods:
Using retroviral transduction of HPV16 E6/E7 and hTERT genes, immortalized human omental mesothelial cell lines (HOMCs) were established. Three sublines (HOMC-B1, A4, and D4) with different morphologies were cloned by limiting dilution from the pool of immortalized cells. Retrovirus expression vectors of wild-type YAP (YAP[wt]) and mutant YAP (YAP[S127A])　were also synthesized. After retroviral infection of YAP expression vectors, transplantation of immortalized mesothelial cells was performed subcutaneously or intra-thoracically into nude mice.

Results:
We established immortalized mesothelial cell lines (HOMC) by transduction of HPV-E6/E7 and hTERT, and examined whether YAP activation induces malignant phenotypes in the cells. We found that transduction of both wild-type (YAP[wt]) and constitutively active-type (YAP[S127A]) YAP, but not other cell cycle-promoting genes including CCDN1 and FOXM1, enhanced HOMC-cell proliferation in vitro. We also tested whether or not YAP-transduced HOMC cells showed enhanced tumorigenicity in vivo after inoculation into nude mice subcutaneously or intrathoracically. We found that YAP[wt-] and YAP[S172A- ]induced tumors which displayed more aggressive phenotypes. Meanwhile, we also transduced YAP vectors into normal mesothelial cells but they were shown to be unable to immortalize them.

Conclusion:
YAP activation is frequently observed in MM cells. Although enforced expression of YAP[wt] or YAP[S127A] was insufficient to immortalize primary human mesothelial cells, the present study provides evidence for the crucial role of the disrupted Hippo pathway-activated YAP axis in the initiation of mesothelioma in vivo.

Background:
The use of nanomaterials-based therapeutic systems is rapidly growing and covering a several biomedical applications such as detection, diagnosis and treatment. Recently, nanodiamonds (NDs) have been demonstrated to have great potential as a multimodal imaging/therapy platform. NDs enhance the ability of the drug to cross the cell membrane, increase intracellular drug delivery to the cancer cells, improve treatment efficacy, and decrease toxicity to normal cells or tissues. NDs are attractive for use in drug delivery because of their rich surface chemistry, advantageous size, and ability to act as transmembrane carriers. NDs have also been shown to enhance therapeutic efficacy of doxorubicin (DOX), particularly in treating murine liver and mammary tumor models, and lung metastasis of breast cancer. Yet, nothing similar has been done to translate ND-DOX systems to other cancers such as malignant pleural mesothelioma (MPM). In our study, we aimed to investigate the efficacy of ND-conjugated DOX on MPM cell lines.

Methods:
Bare, uncoated nanodiamonds were pegylated and functionalised with DOX. NDs/Dox were washed three times then re-suspended in water. Nanoparticle Tracking Analysis (NTA), FTIR and PL spectroscopy and TEM imaging were performed to characterise the functionalisation. Human MPM cell lines such as REN and NCl-H2373 and human lung carcinoma cell line (NCl-H226) were used. LP-9 cell line, which resembles normal human mesothelial cells, was used as control. All cells were cultured and exposed to NDs, NDs/DOX or DOX alone. Cell cycle, cell viability, lysosomal mass/pH changes and mitochondrial membrane potential were examined using immunofluorescent staining techniques and data were collected and analysed with high content screening tools such as Cytell and IN Cell Investigator software.

Results:
Significant alterations of the examined biological markers were detected in human MPM cell lines such (REN and NCl-H2373) and human lung carcinoma cells (H226), while a slight changes were seen in the LP-9 cells. Interestingly, the MPM cells showed greater responses to NDs/DOX versus DOX alone.

Conclusion:
Our study demonstrates that NDs loaded with DOX exert significant inhibitory activities of human MPM cell lines and at concentrations that have minimal effects on normal pleura. Thus, ND-conjugated chemotherapy represents a promising, biocompatible strategy for enhancing chemotherapy efficacy and safety.

Background:
Empyema in relation to malignant pleural mesothelioma is a serious complication that may stop or delay the planned treatment. It may be secondary to surgery or non surgical , both are difficult to treat and are challenging to the thoracic surgeon as patients are usually too ill to tolerate therapy.

Methods:
We retrospectively reviewed the data of 443 patients with mesothelioma referred to the National Cancer Institute, Cairo between 2004 -2013. Extra pleural pnuemonectomy (EPP) was performed in 93 patients and radical pleurectomy / decortication in 12 . The remaining 338 patients received palliative chemotherapy or best supportive care. The frequency of empyema among those patients was 5.86% (26 cases). Full history and clinical examination was done for all patients, culture from the chest tube and or sputum culture was ordered for all, Computed tomography of the chest was done to evaluate empyema in all patients and bronchoscopy and biopsy to exclude stump recurrence was requested for patients with empyema secondary to EPP.

Results:
There were 23 males and 3 females , the right side was affected in 17 patients. Of the 338 patients with non operative therapy, 17(5%) developed empyema , 5 following repeated tapping of effusion ,8 with prolonged chest tube insertion and 4 after pleurodesis. Palliative pleurectomy was possible in 4 patients and was successful in 2. The remaining 13 patients were treated with second chest tube and repeated cavity irrigation with diluted bovidon iodine, 5 of them were improved within 2-3 weeks. Empyema secondary to EPP developed in 8 patients, 2 had early post operative empyema, one with stump dehiscence and one secondary to tube thoracostomy in the post pneumonectomy space. Surgery was successful in both. Of the remaining 6 patients, 5 had delayed bronchial stump fistula 1-3 years post pleuro pneumonectomy, All were re explored. Two patients were cured, the remaining 4 died from persistent sepsis. The last patient had infected mesh 3 years after surgery and was treated by re surgery and mesh removal. We had one patient with empyema following radical pleurectomy/ decortication due to residual space, wound depridement was done and the procedure was successful.

Conclusion:
Treatment of mesothelioma patients with empyema is challenging, every patient should be and evaluated and treated separately. In spite of high failure rate with surgery, it's considered the only treatment option, great effort by high volume thoracic surgeon should be offered to this group of patients.

Background:
The differences of radiological features for pleural mesothelioma from other diseases such as lung cancer and sarcomas or pleuritis et al. is not evaluated and the also the difference of features among the histological manufestation is also not clear.

Methods:
Four hundred and twenty four cases of pleural mesothelioma who were clinically diagnosed, were evaluated. The chest CT which patients first visited to hospital were classified into 7 category such as 1)uni-mass formation, 2)pleural rind, 3)slight thickening of pleura, 4)thickening of mediastinal pleura, 5)pleural effusion without pleural changes, 6)multi-mass formation and 7)specific type. Furthermore, evidence of pleural effusion and the radiological patterns of the histological differences were evaluated.

Results:
The number of mesothelioma who were definitely diagnosed was 383 cases and 51 cases were not diagnosed mesothelioma but lung cancer, sarcoma or pleuritis or benign asbestos pleurisy et al. were diagnosed histologically. For mesothelioma cases, 230(60.1%) cases showed epithelioid histology, 62 cases(16.2%) biohasic type and 86 cases(22.5%) were sarcomatoid type and 5 cases(1.3%) were specific type and 89.6% showed pleural effusion. For the radiological patterns for 383 cases, pleural rind pattern occupied 42.2% and multi-mass formation 14.1%, pleural effusion without pleural changes 12.9% and uni-mass formation occupied 8.6%. As for the histological features, biphasic type showed only 2 cases(2.9%) uni-mass formation and 13.2% showed thickening of mediastinal pleura and sarcomatoid type only 4.4% showed pleural effusion without pleural changes. Other 51 cases who were not diagnosed mesothelioma such as lung cancer et al. showed 30.9% of uni-mass formation, pleural rind 21.8% and pleural effusion without pleural changes 18.2%. And 80.4% of them showed pleural effusion.

Conclusion:
Pleural mesothelioma shows various types of radiological manifestation and also other diseases such as lung cancer or sarcomas or benign pleuritis show similar patterns. Therefore, we try to make differential diagnosis when we suspect pleural mesothelioma by chest CT.

Background:
The pathological diagnosis as mesothelioma is difficult even if experienced pathologists do. Also the diagnosis of imaging including CT has no conclusive evidences as mesothelioma. Accordingly comprehensive diagnosis based on discussion by several pathologists and/or radiologists is necessary. However most of diagnostic specialists are too busy to have a meeting at designated date and venue. New remote diaignostic system will solve those problems and the accurate diagnosis as mesothelioma can be made.

Methods:
The remote pathological diagnosis consists of scanning of tissue slide by scanning equipment (NanoZoomer®), transmission of the digital data to cloud system (Google) by Internet. We have developed a new system named “LOOKREC” including pathological data and imaging data (chest X-P,CT and so on). The pathologists and radiologists as a member of special diagnostic group obtain a special account and access to the data on cloud by Internet. The diagnotic opinions made by individuals are entered into the discussion sheet and the organizer will decide a final diagnosis including whether mesothelioma or not, which type of mesothelioma, based on individual diagnostic opinions.

Results:
In Japan, the annual number of occurrence of mesothelioma is over 1200. The compensation or relief system for mesothelioma patients has been established ten years ago, and the accurate diagnosis is always required for adequate management of those systems. The number of mesothelioma showing diagnostic problems is about 10% of all mesothelioma cases. The cases with some difficulties of differentiation between early epithelioid mesothelioma vs reactive mesothelial hyperplasia, pleuritis, localized methelioma vs lung cancer will be presented and the points of differential diagnosis will be discussed.

Conclusion:
The new remote diagnostic system using Internet has been developed. It is expected that diagnostic accuracy will be improved when the observation of pathological findings as well as imaging and effective disccussion on the web will be done by pathologists and radiologists.

Background:
Patients with neurofibromatosis type 2 (NF2) are predisposed to schwannomas and meningiomas. Somatic NF2 mutation has also been reported in patients with sporadic schwannomas and a variety of cancers. In particular, approximately 35–40% of patients with malignant pleural mesothelioma (MPM) carry inactivating mutations of NF2. In addition to NF2, BRCA1-associated protein-1 (BAP-1) has also been identified as a key genetic alteration in mesothelioma. Recently, a new familial cancer syndrome associated with germline mutations in BAP1 was proposed, which includes MPM, ocular melanoma, and other cancers. However, NF2 mutations do not usually cause mesothelioma synchronous with schwannoma. We here report two cases of MPM synchronous with vestibular schwannomas and analytical finding on NF2 mutations

Methods:
Case 1 was a 65-year-old man with epithelioid MPM. A unilateral acoustic neuroma was resected in 2010 because the patient experienced progressive hearing loss in the right ear since 2000. In April 2012, right pleural fluid was detected on chest X-ray and a thoracoscopical examination was performed. Epithelioid MPM was diagnosed pathologically. Case 2 was a 72-year-old man with epithelioid MPM synchronous with unilateral acoustic neurinoma. The patient presented with DOE and hearing loss in the left ear that had progressed over the past month. Chest X-ray showed pleural effusion, and a biopsied specimen with thoracoscopy revealed epithelioid MPM. Brain MRI and CT showed a mass that was highly suspected to be acoustic neurinoma between the left cerebellopontine angle and the opening of the internal acoustic meatus. We performed whole-exome sequencing on DNA in tumor tissue and blood and immunohistochemical analysis of NF2 gene encoding protein merlin.

Results:
Both patients were diagnosed with synchronous acoustic neurinoma and epithelioid MPM. NF2 gene mutations were identified in both tumors of MPM and acoustic neurinoma in Case 1. And in Case 2, diagnosis of acoustic neurinoma was depended on typical findings of brain MRI/CT, for which surgical resection was not performed because of advanced stage of MPM. Tumor tissue of MPM in Case 2 showed positive result of NF2 mutation. Both patients had a history of asbestos exposure.

Conclusion:
Although the role of NF2 mutation as a possible disease-causing mutation in MPM and synchronous occurrence with schwannoma remain unclear, both cases showed the possible role of NF2 mutation in asbestos-related neoplasm. We will show the pedigree of the patients’ families.

Background:
Malignant pleural mesothelioma (MPM) is a highly aggressive asbestos-induced cancer arising from the mesothelium lining the thoracic cavities. The definitive diagnosis of MPM in most instances depends on the availability of a biopsy. A number of biomarkers have been proposed to assist in making the MPM diagnosis but none of them has yet reached the accuracy required for routine clinical use. Among the candidates is the secreted extracellular glycoprotein Fibulin-3 (FBLN3) (Pass et al, NEJM 2012; 367(15)). In this study, we have further investigated the potential of FBLN3 to serve as a biomarker for MPM.

Methods:
Cellular and secreted FBLN3 was measured (ELISA) in MPM and normal mesothelial cell lines, plasma of xenograft tumour-bearing mice, plasma from two independent series of MPM and non-MPM patients, and in malignant and non-malignant pleural effusions. The diagnostic and prognostic potential of FBLN3 was assessed by receiver operating characteristics curve analysis and the Kaplan-Meier method, respectively.

Results:
FBLN3 levels were significantly higher in MPM cells than in mesothelial cells, with a strong correlation between secreted and cellular levels. Human FBLN3 was also detectable in the plasma of tumour-bearing mice, suggesting that MPM cells were the origin of circulating FBLN3. Plasma FBLN3 levels found in MPM patients were lower than previously reported (Pass et al, NEJM 2012; 367(15)), but were comparable to those appearing in subsequent validation studies (Creaney et al, Thorax 2014; 69(10), Corradi et al, Anticancer Res 2013; 33(12)). Plasma FBLN3 was significantly elevated in MPM patients from a Sydney cohort, but far less in a Vienna cohort and the diagnostic accuracy of FBLN3 was insufficient in both cohorts [63%, (95%CI: 50.1-76.4) and 56% (95%CI: 41.5-71.0), respectively]. FBLN3 levels found in pleural effusions were comparable to those reported in previous studies, but the difference between cases and controls did not reach significance. In our series low levels of pleural effusion FBLN3 were again associated (p=0.002) with prolonged survival. In multivariate analysis taking histological subtype, age and gender into account FBLN3 remained significant with a hazard ratio of 9.92 (95%CI: 2.14–45.93).

Conclusion:
FBLN3 is overexpressed in MPM cell lines and may point to a potential oncogenic role for this protein. In contrast to the initial report linking FBLN3 to diagnosis in MPM, the levels of FBLN3 measured in plasma and pleural fluid of our series of MPM patients lacked diagnostic accuracy. However, the potential prognostic value of FBLN3 levels measured in pleural fluid was confirmed and in line with previous validation studies. These data underline the importance of validation studies for newly proposed biomarkers.

Background:
Malignant pleural mesothelioma (MPM) is a rare aggressive cancer of the pleura. The most well established risk factor for this disease is exposure to asbestos. The current standard of care for patients suffering from MPM is a combination of cisplatin and pemetrexed (or alternatively cisplatin and raltitrexed). Most patients however, die within 24 months of diagnosis. New therapies are therefore urgently required for this disease. KAT5 (also known as Tip60) is the catalytic subunit of the NuA4 histone acetyltransferase complex which is involved in transcriptional activation of select genes. This complex may be required for the activation of transcriptional programs associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair. KAT5 has also been linked with the development of cisplatin resistance. KAT5 may therefore be a significant element in MPM with respect to responses to cisplatin based therapy and could represent a novel candidate target for intervention.

Methods:
KAT5 has 4 variant mRNAs. Primers were designed to distinguish between all variants, and a panel of MPM cell lines was screened for KAT5 expression by RT-PCR. Levels of KAT5 were subsequently examined in a cohort of snap-frozen patient samples isolated at surgery comprising benign, epithelial, biphasic, and sarcomatoid histologies by RT-PCR. The effects of a small molecule inhibitor of KAT5 (MG-149) on cellular proliferation were examined.

Results:
Semi-quantitative densitometric analysis showed that the expression of KAT5 is dramatically increased in MPM for all mRNA variants. When separated according to histological subtype, significant differences were also observed between the various histologies. A small molecule inhibitor of KAT5 exists and treatment of cells with this small molecule inhibitor (MG-149) resulted in a significant inhibition of cellular proliferation (p < 0.001) in the NCI-H226 cell line. We continue to assess this compound by other methodologies to confirm its potential utility in the treatment of MPM.

Conclusion:
KAT5, a lysine acetyltransferase associated with cisplatin resistance in cancer is significantly altered in MPM. A small molecule inhibitor of this protein shows significant anti-proliferative effects in MPM cell lines. Targeting this protein may have important future implications for the management of MPM.

Background:
Mesothelioma is a mesodermic tumor localized in the pleura in 70-90% of the presentations. In most cases the diagnosis is made by computed tomography-guided biopsy or thoracoscopy. Characteristically mesothelioma includes papillary structures which make it difficult to distinguish from adenocarcinoma on hematoxylin and eosin stain, making this entity its main differential diagnosis. Immunohistochemical studies in biopsy specimens aids in the obtaining of a precise diagnosis. Notwithstanding it is often difficult to distinguish between both entities, in which case, electron microscopy is the gold standard as it allows to observe the abundant long thin microvilli (characteristic of the mesothelium) in tumor cells. Sometimes patients have only pleural effusion cytology which makes the diagnosis more challenging.

Methods:
Twenty-five pleural effusion cytology samples were studied to evaluate electron microscopy and its efficacy for diagnosis, as well as by immunohistochemistry for the diagnosis of either lung adenocarcinoma or mesothelioma.

Results:
Five pleural effusion samples with the histological diagnosis of mesothelioma and twenty with the histological diagnosis of adenocarcinoma, all with confirmed biopsies by immunohistochemistry. Of the five pleural effusion samples with histological diagnosis of mesothelioma, cytology in electron microscopy showed morphological characteristics of mesothelioma (long thin microvilli, dense junctions, desmosomes and tonofilaments ) in two samples (40%), and three were acellular (60%). Of the twenty pleural effusion samples with histologically confirmed diagnosis of adenocarcinoma (short microvilli, secretory vacuoles and intracytoplasmic lumens), eight were confirmed by electron microscopy (40%), eleven were acellular (55%), and one showed reactive mesothelium (5%).

Conclusion:
Pleural effusion cytology by electron microscopy showed that cells maintained their morphological features, either of mesothelioma or of lung adenocarcinoma, and can help in the diagnosis; however this is limited to the presence of cells in the pleural effusion

Background:
Malignant Pleural Mesotelioma (MPM) is a tumour with extremely unfavourable prognosis. Early diagnostic is rarely possible and chemotherapy has limited value in prolongation of survival. Pemetrexed with platinum is the standard 1[st] line chemotherapy. In the Czech Republic, the incidence of MPM is influenced mostly by former industry processing asbestos for roofs, other parts of buildings and isolation materials. Any work with asbetos is prohibited in the mean time.

Methods:
Treatment with pemetrexed and cisplatin was evaluated in a prospective study. Data of consecutive patients from 9 centers were prospectively collected from January 2008 till February 2015. Altogether 181 patients (47 women, 134 men) were evaluated. Mean age was 62 years, 71 pts were non smokers, 47 smokers, 61 ex smokers. Professional/ non-professional exposure was reported in 44/ 18 pts. Histology: 119 epithelial, 20 mixed, 12 sarcomatoid, not specified in 30 pts, TNM st.: I/II/III/IV in 19/32/48/78 pts, not assessed in 4 pts, PS: 0/1/2 in 39/130/12 pts.

Results:
Median of treatment was 18.5 weeks. Most frequent side effects (Gr 3, 4): leucopenia in 22, neutropenia in 15, anaemia in 15, trombocytopenia in 6, nausea/vomiting in 19, fatigue in 8 pts. Therapeutic response: CR in 5, PR in 47, SD 85, PD in 21 pts, overall disease control was 75.6 %. The median of overall survival (OS) was 19.8 months (16.2; 23.4), 1 year survival 67.9% (48.3; 71.5). Median of progression free survival (PFS) was 9.1 months (7.6; 10.7). Differences of survival were compared according to sex, smoking history, age, PS, TNM stage, treatment associated AE occurrence, type of exposure and histology. Significantly different results were achieved according to PS,TNM, exposure, AE and histology.

Conclusion:
Treatment of MPM with pemetrexed and cisplatinum in routine practice is effective and well tolerated. Prognosis is still poor and it is influenced by several clinical markers. Longer survival can be expected in PS 0, TNM I/II, unknown asbestos exposure, epitheloid histology and no treatment associated AE. Supported by national grant IGA MZ ČR NT/13569

Background:
The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against multiple cancers. Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody currently being investigated in clinical trials. The phase Ib study (NCT01772004) is an open-label, parallel group expansion trial in patients with metastatic or locally advanced solid tumors that includes a cohort of patients with advanced, unresectable mesothelioma.

Methods:
This trial cohort is enrolling patients with histologically or cytologically confirmed unresectable mesothelioma (pleural or peritoneal) that has progressed after treatment with either a platinum-pemetrexed–containing regimen or a platinum-based regimen followed by pemetrexed (or vice versa). Eligible patients must have available tumor archival material or fresh biopsy, and an ECOG performance status of 0 or 1 at trial entry, and disease with at least 1 measurable lesion that has not been irradiated. Exclusion criteria include prior therapy with immune checkpoint drugs, a known history of autoimmune disease, or recent anticancer treatment (within the 28 days prior to study start). Up to 50 eligible patients will receive avelumab at 10 mg/kg as an infusion Q2W. Treatment will continue until disease progression, unacceptable toxicity, or any criterion for withdrawal occurs. Treatment may be continued despite progression according to RECIST 1.1 if the patient’s clinical status is stable and, according to investigator opinion, there is no need to start salvage therapy. The primary objective of the trial is to assess the safety and tolerability of avelumab. Select secondary objectives include: assessment of best overall response (BOR) and progression-free survival (PFS) according to RECIST 1.1; assessment of immune-related BOR and immune-related PFS (using the modified Immune-Related Response Criteria); and assessment of overall survival. Association between tumor PD-L1 expression and efficacy will be evaluated. Changes in soluble factors and immune cell profiling will be characterized and immunomonitoring will occur at each visit. Tumor assessments will be performed every 6 weeks until progression. Tumor tissue from the most recent biopsy or surgical specimen will be collected prior to the initiation of trial treatment, and fresh biopsies may be optionally collected on day 43 and at the end-of-treatment visit. At each visit during the treatment phase, adverse events will be assessed and graded according to NCI-CTCAE v4.0. Enrollment in this study began in September 2014. *Proposed INN.

Results:
not applicable

Conclusion:
not applicable

Background:
Advanded malignant peritoneal mesothelioma (AbM) is a rare and aggressive neoplasm. The natural course of the disease is different from pleural mesothelioma. The optimal ctx duration for AbM remains undetermined. Ctx of AbM is commonly reported case by case. Efficacy of Pemetrexed (Pem)+cisplatinum (DDP) ctx has been demonstrated previously. A major obstacle to sustained Pem/DDP for AbM is renal safety beside neurotoxicity. At present, there are sparse data regarding renal safety in AbM pts receiving sustained ctx >6 cycles of Pem+platinum.

Methods:
We evaluated long-term renal safety of Pem (500 mg/m[2])+DDP (75 mg/m[2]) in AbM prospectively. Ctx was given on d1 and repeated on d22 until disease progression or toxicity. Pts with impairment of renal function (Crea-Cl <60 ml/min) switched to carboplatin AUC5 (carbo). Pem ctx was stopped with a decline of Crea-Cl <45 ml/min. The trial was in accordance with the local ethics. Folic acid 400 μg po/d and vitamin B12 1000 μg i.m. qw 9 wks was administered to prevent severe AE. All pts received best supportive care with pre and post hydration as well as antiemetics including 5-HT3 antagonists and dexamethasone according to local standard of care. Study endpoints were long term renal safety in patients receiving sustained therapy of Pem + DDP followed by carbo and/or Pem-mono.

Results:
Between 2002 and 2014 staging revealed AbM in 19 pts. Initial ctx was Pem/DDP in 18 pts, except one who died prior to Tx. Ctx with Pem was given a mean of 12 cycles (range 1 to 37) with a mean of 259 d(range 21 to 1151). Mean dose of DDP was 678 mg(range 130 to 1335). Mean S-Crea(Crea-Cl) was 0,79 mg/dl(113 ml/min) prior and 0,95 mg/dl(97,4 ml/min) at the end of Pem/DDP. Pem/DDP was administered >6 cycles in 8 pts up to a max. of 10 cyles. DDP was stopped due to a decline in S-Crea in 6 out of 18 pts (33%). Renal tox was the reason for DDP cessation in all pts with >6 cycles, except 1. Five pts switched then to carbo due to renal tox with S-Crea(Crea-Cl) of 1,1 mg/dl(83 ml/min) prior and 1,2 mg/dl(79 ml/min) at the end of Pem/carbo. No renal toxicity was observed in those 4 pts with Pem-mono (max 10 cycles) subsequently after platinum ctx with S-Crea(Crea-Cl) prior 1,25 mg/dl(69 ml/min) and 1,14 mg/dl(72,5 ml/min) respectively.

Conclusion:
Sustained treatment for AbM is feasible but limited by renal tox of DDP, while subsequent Pem +/- carbo did not lead to additional deterioration of renal function, allowing sustained ctx for AbM.

Background:
Asbestos had been stopped to use in Japan since the late 1970s. Asbestos exposure will increase the risk of mesothelioma and the interval between initial exposure and subsequent biological consequences is assumed more than 40 years. Iwakuni is part of the Seto Inland Sea industrial area and one of the oldest petrochemical industrial complexes in Japan is located. The incidence of mesotheliomas is expected to rise over the next decade. Treatment for mesothelioma includes surgery, chemotherapy, radiation therapy and their combination. Recently, cisplatin in conjunction with pemetrexed has shown advantageous results in reducing tumors, but pleural mesothelioma is still incurable fatal disease except specific case. In this study, we reviewed the clinical features of 26 patients with malignant pleural mesotelioma treated in our institute.

Methods:
Between January 2006 and December 2014, 26 patients were histologically diagnosed as malignant pleural mesotelioma. Retrospective review was performed and demographic, clinical, pathologic, treatment and survival data were collected. Overall survival were estimated by the Kaplan-Meier analysis. Surgery includes two patients treated by trimodality therapy (chemotherapy + extrapleural pneumonectomy + radiation therapy) and a patient treated by pleurectomy combined with hyperthermic therapy. Other four patients were treated by extrapleural pneumonectomy alone.

Results:
In the studied population,21 of 26 patients were male.the mean age of diagnosis was 72y.Each number of histological subtypes(epithelial,sarcomatoid and biphasic) were 15,6,and 5.The number of patients who treated with surgery were 8,with chemotherapy were 17 and best supportive care was 1. The median survival time of the 27 malignant pleural mesotelioma patients was 13.4 months. According to histological subtypes,the MTS of epithelial,sarcomatoid and biphasic were 21.4 months,6.5 months and 11.6 months The MTS of surgery and chemotherapy were 21.4 months and 13.2 months.One year survival rate were 85.7% and 47.6%. The MTS of the patients with and without pleural plaque were 13.4 months and 15.0 months. Female gender, epithelial subtypes, treatment of surgery and patients without pleural plaque showed relatively favorable outcome.

Conclusion:
Because of the appearance of effecrive chemotherapies,such as Pemetrexed sodium hydrate,better survival has been observed in patients treated by chemotherapy. However, long-term survival was seen only in patients treated by surgery. Surgery allows us to accurately stage patients and provide data that may be useful in better patient stratification. Surgery should be selected for the operable patients with c-stage I-II and epithelial disease. We have to detect malignant pleural mesothelioma in early stage and treat in appropriate means.

Background:
Malignant pleural mesothelioma (MPM) is an aggressive tumor in the pleural lining of the lung. Median OS with frontline chemotherapy of pemetrexed/cisplatin (pem/cis) is ~12 months. There is no established second line therapy. Pem/cis has been shown to enrich cancer stem cells (CSCs) in tumors. Focal adhesion kinase (FAK) inhibitors have been found to decrease CSCs in mesothelioma models. The use of a FAK inhibitor in a maintenance setting after frontline chemotherapy may therefore extend survival of MPM patients. Furthermore, approximately 40% of MPM tumors exhibit disruption of the NF2 tumor suppressor gene by mutation and/or deletion resulting in lack of expression of functional merlin protein. Mesothelioma cell lines that lack merlin are more sensitive to FAK inhibitors than those with wild type merlin. This Phase 2 study will determine if defactinib (VS-6063), an oral inhibitor of FAK, provides superior clinical benefit compared with placebo as maintenance treatment in patients with MPM following frontline pem/platinum therapy.

Methods:
COMMAND is a multinational, randomized, double-blind, placebo-controlled trial. Approximately 370 patients with PR or SD following ≥4 cycles of frontline pem/platinum therapy will be enrolled. Patients will receive defactinib 400 mg BID or matched placebo. Randomization will be stratified by merlin status, as determined by immunohistochemistry. Primary endpoints include OS and PFS. An adaptive enrichment design at the interim analysis (projected to occur in Q2 2015) may restrict patients to those with low merlin protein expression if greater benefit is observed among this subpopulation. Secondary endpoints include patient-reported outcomes, objective response and safety and tolerability. The study is currently enrolling across 15 countries. Clinical trial: NCT01870609.

Results:
Not applicable

Conclusion:
Not applicable

Background:
Naftopidil, an antagonist of the α1A/1D-adrenoceptor, was developed as a drug for the treatment of benign prostate hyperplasia and hypertension, and has recently been shown to exert antitumor activity in a variety of cancers. We previously discovered that naftopidil induces apoptosis of malignant pleural mesothelioma (MPM) cells in an α1-adrenoceptor-independent manner, as this was not reproducible using other α1-adrenoceptor-inhibitors such as prazosin. The present study was conducted to assess whether naftopidil is useful for the treatment of MPM.

Methods:
Cell viability of cultured NCI-H2052 human cells was evaluated using MTT. TUNEL staining was performed to detect in situ DNA fragmentation as a marker of apoptosis using an in situ apoptosis detection kit. Caspase activity was measured using a caspase fluorometric assay kit. NCI-H2052 cells were treated with naftopidil (100 μmol/L) and were subcutaneously inoculated into the right flank of BALB/c-nu/nu mice under pentobarbital-induced general anesthesia. Naftopidil was diluted with a physiological salt solution and injected intraperitoneally twice a week, starting 1 week after inoculation; the salt solution alone was used in control mice. The longer (L) and shorter (S) lengths of the induced tumors were measured using calipers, and tumor volume (V) was calculated according to the following equation: V = (L × S[2]) × 1/2.

Results:
Naftopidil reduced NCI-H2052 cell viability in a concentration-dependent manner and significantly increased the number of TUNEL-positive NCI-H2052 cells compared to untreated cells. Naftopidil activated caspase-3 and -8, but not caspase-9. Naftopidil did not affect the expression of FasL protein in NCI-H2052 cells. Notably, however, it did significantly increase the concentrations of extracellular FasL protein in a bell-shaped, time-dependent manner. Intraperitoneal injection of naftopidil significantly inhibited NCI-H2052 xenograft tumor growth compared to tumors in control mice. All mice injected with naftopidil survived 8 weeks after the first injection, and the drug had no effect on their mean weight.

Conclusion:
The results of the present study suggest that naftopidil induces apoptosis of NCI-H2052 cells by stimulating the secretion of FasL, a ligand of the death receptor Fas. This in turn activates caspase-8 and the effector caspase-3, leading to the inhibition of NCI-H2052 xenograft tumor growth in vivo. This supports the concept that naftopidil could be developed as a therapeutic agent for the treatment of malignant pleural mesothelioma.

Background:
Malignant mesothelioma is an aggressive tumour of the pleura or peritoneum and strongly related to asbestos exposure. Malignant pleural mesothelioma is the most common and occurs with a latency of up to 40 years. Long pathogenic fibres fail to clear through the lymph system and are retained in the pleura of the exposed individuals. During the long latency period, mesothelial cells remain exposed to paracrine signalling from inflammatory cells recruited to the fibre-retaining areas. However, the mechanism of malignant transformation is not well understood. Several studies have identified changes in defined signalling pathways in mesothelial and stromal cells, but the relationship between different cell types has not been explored.

Methods:
To examine the pro-oncogenic role(s) of different cell populations, the effect of primary fibroblasts from human mesotheliomas and fibre-activated macrophages on cellular signalling in normal untransformed mesothelial cells was monitored using imaging and immunoblotting techniques.

Results:
Paracrine signalling from activated fibroblasts or macrophages increased the levels of proliferation and motility in normal mesothelial cell cultures. Activation of pro-oncogenic signalling was demonstrated in the cultures subjected to ‘cross-talk’ with pro-inflammatory cells, including ‘horizontal transfer’ from activated fibroblasts. Normal mesothelial cells, co-cultured or treated with conditioned media from fibre-activated macrophages, also displayed signs of epithelial-to-mesenchymal transition. The levels of growth modulators and survival rates were also altered in these cells.

Conclusion:
Thus, non-mesothelial cells instigate pro-oncogenic alterations in cellular signalling in target mesothelial cells. Further integral examination of the aberrant signalling pathways, especially at early stages of neoplasia, will provide new insights into the mechanisms underlying malignant transformation of the mesothelium.

Background:
Even though pleurodesis is the gold-standard procedure to manage recurrent malignant pleural effusion (RMPE), little is known of its impact on the quality of life (QOL), adverse events, and systemic inflammatory consequences. Our main objective was to evaluate the impact of pleurodesis on the QOL of patients with RMPE and the adverse events related to the procedure. The secondary objectives were to evaluate systemic consequences of pleurodesis and to identify predictors of QOL improvement after pleurodesis.

Methods:
Retrospective study including data from patients who underwent pleurodesis from 2005 to 2014 at our Institution. QOL was measured through WHOQoL-Bref instrument, pain visual analog scale, and British Medical Research Council dyspnea scale. Adverse events were systematically registered and classified according to the NCI–CTCAEV.4.0. Blood tests were collected before, 2, 5, and 10 days after the pleurodesis. To compare continuous variables we used paired-T test or Wilcoxon test. To find predictors we built linear regression models. We considered as significant tests which p<0.05.

Results:
257 patients (77% female) with mean age of 69 years-old(± 13.01) were included. The most frequent primary malignancies were breast cancer (56%) and lung cancer (25%). The sclerosing agents used were talc (38%), silver nitrate (36%), and iodopovidone (25%). Clinical recurrence was observed in 8% of the patients and mean survival was 8 months. The physical domain of QOL as well as pain and dyspnea scores were the most abnormal results at baseline and were also the variables which improved the most 30 days after the procedure (p<0.001 for all 3 parameters). Female gender, low pleural fluid lymphocytes count, and the use of silver nitrate were associated with QOL improvement. Adverse events occurred in 43% of the patients, and in 16.3% we observed severe events (Grade 3 or higher). Hypoxia, renal failure, and pain were the most frequent. We observed significant variation in the following blood tests: C-Reactive Protein (rise), hemoglobin (decrease), platelets (rise), alkaline phosphatase (rise).

Conclusion:
Pleurodesis is associated with improvement of the QOL of patients with RMPE; nevertheless, it is also associated with high number of adverse events and systemic metabolic effects.

Background:
Typical and atypical carcinoids represent about 2% of all lung tumors. Unlike most lung tumors, survival of patients with typical bronchial carcinoids is generally long but and is dependent on stage. We report the findings from the Ochsner/Louisiana State University (LSU) Neuroendocrine Tumor (NET) Program.

Methods:
A database with all patients who were seen at the Ochsner/LSU NET Program was queried for all bronchial NET patients. We included those who had confirmed pathological bronchial carcinoid and those who had at least one visit to our clinic. Typical and atypical bronchial carcinoids were defined by most recent WHO classification. Excluded were patients with large and small cell NETs, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, and inaccessible patient records.

Results:
One-hundred sixty-nine patients were included from January 1996 - March 2015. The mean age at diagnosis was 53 (range 12-92). There were 154 (91%) Caucasian, 10 (6%) African-American, and 5 (3%) other. Females represented 67% of all patients. 51% percent (86/169) were well differentiated, 12% (21/169) were moderately differentiated. Eighty-five percent and fifty-three percent were positive on PET and octreotide scanning, respectively. One-hundred fifty-five patients had adequate staging information. Overall survival and survival by stage and differentiation status is shown below. There was a statistically significant difference in survival by Ki-67 index.

Overall Survival
N	Median	5-year	10-year
169	243 months	88%	74%
Survival by AJCC 7 Stage
	N	5-year	10-year
I*	65	98%	91%
II*	23	95%	87%
III*	27	84%	66%
IV	40	73%	49%
Survival by Differentiation Status
	Median	5-year	10-year
Well (n=86)	243	88%	81%
Moderate (n=21)	119	80%	42%
Survival by Typical/Atypical
	Median	5-year	10-year
Typical (n=109)	243 months	89%	80%
Atypical (46)	126 months	84%	59%

* A and B stages are grouped Figure 1



Conclusion:
Overall, patients with bronchial carcinoids experience high 5 and 10-year survival rates. As expected, there were significant survival differences between nodal status, differentiation status and typical versus atypical. Interestingly, there was a statistically significant difference in survival between low, low-intermediate and high-intermediate Ki-67 values. Our analysis showed that survival rates were much better for Ki-67 index value ranges from 0-2% versus >2-10% versus >10-20%. As with gastroenteropancreatic NETs, Ki-67 index could become a valuable prognostic indicator for bronchial carcinoids.

Background:
To evaluate the treatment of post-radiotherapy recurrent mediastinal nodal metastasis.

Methods:
Post-radiotherapy thoracic cancer patients with mediastinal lymph node recurrence were enrolled in this study. Patients were randomized into the Radiation (+/- Chemotherapy) or the chemoablation group. Patients randomized to the chemoradiotherapy group received additional radiotherapy, second-line chemotherapy, or both. Patients randomized to the chemoablation group received CT-guided percutaneous chemical ablation. Clinical remission was assessed at one month by contrast CT. Reirradiation dose ranged from 2200-3600 cGy depending on dose limiting constraints in consideration of prior radiotherapy dose. The RECIST criteria were used in the evaluation of response to therapy. The median length of follow-up is six months.

Results:
Thirty-one patients were enrolled in the study. In the chemoradiation group, all patients underwent CT imaging at one month follow-up. Among these patients, 7 had progressive disease (PD), 5 had stable disease (SD), and 4 had partial response (PR). The six-month survival rate was 12.5%. In the chemoablation group at one-month follow-up, 12 patients had SD and 3 patients had PR and the six-month survival rate was 46.6%.

Conclusion:
Our results suggest that chemoablation therapy as salvage treatment after post-radiotherapy relapse is efficacious and safe.

Background:
Follicular dendritic cell sarcoma (FDCS) is defined in the WHO as a neoplastic proliferation of spindle/ovoid cells with morphological and immunohistochemical features of follicular dendritic cells. It is a rare tumour with no clear aetiology, often misdiagnosed and difficult to characterise. Occasionally it occurs in association with the hyaline-vascular type of Castleman disease which, in such cases, is considered its precursor lesion. Most cases are reported in lymph nodes, however several cases with extranodal presentation have been described. Despite the fact that metastasis are common in the lung, only 7 cases have been reported as primary pulmonary FDCS. Surgical excision with chemotherapy is the treatment of choice giving transient, partial response in some cases. We report our experience within the last 15 years of 6 cases of FDCS arising in the mediastinum and in the lung.

Methods:
The study included 7 patients referred to Royal Brompton Hospital between 2001 and 2014 with a diagnosis of FDCS. Criteria for inclusion were morphological and immunohistochemical: fascicles/whorls of spindle to ovid cells with features resambling follicular dendritic cells and the expression of one or more specific markers (CD21, CD23 and CD35). We performed a broad immunohistochemical panel and we looked for the presence of Castleman’s disease and the type of inflammatory infiltrate in the background. Clinical information were obtained from hospital records and clinicians.

Results:
After review, we identified 6 cases consistent with the diagnosis of FDCS, four males and two females between 25 and 61 years old. One case was excluded because of equivocal expression of specific markers. Three patients presented with a mediastinal mass and one having two recurrences within the study period. Two patients presented with a lung mass and one with a radiological pleurally based mass infiltrating the lung and chest wall. Clinical presentation was mainly with cough and chest pain due to the location of the tumour.Histologically all cases showed an atypical spindle cell proliferation with storiform pattern within a mixed inflammatory stroma. Mitotic rate was generally low except in case of recurrences. In three cases Castleman’s features were present in the background.Five out 6 cases (83.3%) expressed CD21, CD35, p53 and cyclin D1, 3 cases (50%) expressed CD35, S100, lysozyme and bcl2 and 2 cases (33.3%) expressed KP1, PGM1, CD45, CD4, CD30 and bcl6. All were negative for keratins. Four cases (66.7%) were initially misdiagnosed as pleomorphic malignant tumour.Background showed a variably amount of B and T cells, with T cells expressing CD4 and PD1. Follow up data were available for 4 patients: one died after 5 years, 2 were alive with no recurrence after one year and one is alive after 8 years and two recurrences.

Conclusion:
FDCS is a rare tumour and should be considered in cases with a malingant spindle cells proliferation negative for the most common markers. Our series also showed Cyclin D1 expression in this tumour which has not previously been reported. This may raise the possibility for a new more effective therapeutic approach but further studies are needed.

Background:
Bronchopulmonary carcinoids are low grade malignant tumours and increased incidence has been noticed worldwide. Our aim was to study preoperative characteristics, surgical approaches and outcome in bronchopulmonary carcinoid patients treated at a institutional cancer center.

Methods:
Twenty patients with bronchopulmonary carcinoids were surgically treated at department of surgical oncology, IRCH, AIIMS between December 2006 and December 2014. Preoperative variables, postoperative outcome and histopathological features were analyzed retrospectively. All patients underwent a detailed clinical evaluation followed by CECT of chest and bronchoscopy with biopsy of the suspicious lesion. After preoperative optimization, all patients were treated with upfront surgery. Adjuvant chemotherapy was given in patients with lymph nodal metastasis. Patients were followed up at three monthly interval with Clinical examination, chest X ray and serum chromogranin in cases of suspected recurrence. Because of cost factors Dotanoc scans were done only in cases with radiological suspicion of recurrence.

Results:
Patient’s median age was 40 years (range 18-62 years). All patients were symptomatic and median duration of symptoms before presentation was 18 months (range 6-72 months). Eight patients were treated with antitubercular drugs after presumptive diagnosis outside based on symptoms and Xrays. All the patients had lobar or main bronchial involvement which was detected on bronchoscopy and biopsy. Ninteen patients underwent complete pulmonary resection with mediastinal nodal dissection and surgical approach included eight pneumonectomies, four bilobectomies, five lobectomies, two sleeve resections. After a median follow up of 15 months, all patients were alive with no local recurrence or distant metastasis. On Histopathology all the resections margins were free of tumor and lymph nodal involvement was found in one patient.

Conclusion:
Delayed presentation and misdiagnosis are major concern in our scenario because of high prevalence of tuberculosis and despite a small number of cases our study emphasises the need for early bronchoscopy in patients with persistent symptoms. Aggressive surgical resection with technical approach of lung preservation may provide optimal survival results

Background:
primary cardiac tumors are very rare pathological entities with an incidence (autopsy and surgical biopsies reports) ranging between 0,3% - 0,7 %. The main histopathological type of primary malignant cardiac tumors is represented by angiosarcoma, usually located within right atrium. The diagnosis may be delayed due to nonspecific symptomatology. Most cases are presenting with metastases to the lung in the moment of diagnosis and a median survival is less than one year (between 6 and 11 months).

Methods:
not applicable

Results:
Case report: we present the case of a non-smoker 19-year-old man, with right atrial angiosarcoma, with pericardial involvement and difuse limphohaematogenous pulmonary metastasis. The symptomatology consisted in: cough, difuse chest pain, progressive dyspnea, night swets, low grade fever and hemoptoic sputum. Chest X-ray revealed a diffuse micro nodular pattern, a resting pulseoxymetry with mild hypoxemia, no ECG abnormalities. No abnormalities on the clinical examination. The differential diagnosis included mainly: miliary tuberculosis (high incidence of tuberculosis in Romania) and Pneumocystosis. Bronchoalveolar lavage shows no fast acid bacilli, no Pneumocystis cysts, no neoplastic cells and HIV was negative. No inflammatory syndrome, normal WBC, no anemia and normal biochemistry. According to this data we decided to start antituberculous treatment and the patient was programed for thoracic CT scan. The clinical status rapidly deteriorated with worsening of dyspnea, respiratory failure and hypotension. Chest X-ray revealed enlargement of cardiac opacity and on ECG a micro voltage with an alternance in the QRS complex was identified. An echocardiography was performed in emergency and a massive mass of tissue occupying almost the entire right atrium with pericardial invasion and cardiac tamponed was identified. A median sternotomy with pericardial drainage , pericardial and tumor biopsy where performed. The patient died one week later with palliative care. The autopsy showed a right massive atrium tumor with myocardium, epicardium, and papillary muscle invasion, difuse lung nodular and micronodular metastases. The hystopatological / immunochemistry exam diagnosed a moderately differentiated angiosarcoma expressing CD 34, CD31.

Conclusion:
Tardive diagnoses of a massive right atrium angiosarcoma with bilateral pulmonary metastasis. Particularity of the case: rare cardiac malignant tumor revealed by respiratory symptoms dues to diffuse pulmonary micronodular metastases

Background:
Surgical resection of lung metastasis from colorectal cancer is beneficial for improving the prognosis of patients when no other metastatic lesions exist. However, the efficiency of multiple time resection of lung metastases has not yet been established. We investigated the characteristics and prognosis of multi-time lung resection cases in order to identify the appropriate indication for this procedure.

Methods:
Ninety-nine patients underwent resection of lung metastases from colorectal cancer between 1993 and 2013 at our institute. Among these patients, we investigated 26 cases who underwent lung resection more than twice.

Results:
With regard to the initial stage of disease, one case was stage I, 4 were stage II, 15 were stage III, and 6 were stage IV. Twenty-two patients underwent lung resection twice, and 4 patients underwent lung resection three times. The median follow-up time was 85 months (range, 36–215 months). Twelve cases died of colorectal cancer recurrence. Eight cases died due to metastases to multiple organs including the liver, lymph nodes, and lung. Two cases died of multiple lung metastases, one died of liver metastasis, and one died of mediastinal nodal metastasis. The overall survival curve from second lung resection is shown in the figure (Kaplan-Meier curve, log-rank test). The 5-year overall survival rate was 46.2%, and the 5-year disease-free survival rate was 44.1%. Three out of 4 cases who underwent lung resection three times died within a year after the operation. Figure 1



Conclusion:
A second lung resection seems to be feasible, while a third may not. Precise evaluation of metastatic lesions in other organs before operation and systemic therapy for preventing multiple metastases may be important.

Background:
Alveolar soft part sarcoma (ASPS) is a rare tumour that was initially described by Christopherson et al. in 1952. It accounts for 0.5 - 1% of all soft tissue sarcomas. It most commonly presents in the 15 - 35 year age group with slightly higher incidence in females than males by a ratio of 3:2.

Methods:
We describe a case of a 55-year old woman who had a right mastectomy, adjuvant chemotherapy and radiotherapy 3 years prior to her presentation to our service with a left sided supraclavicular mass that was causing shoulder pain and left upper limb paraesthesia. The patient did not present Horner's syndrome.

Results:
Preoperative PET-CT showed a 5.8 x 4.5 x 5.5cm mass, moderately FDG avid (SUVmax 6.7), arising from the 1st rib. An MRI of the brachial plexus showed no vertebral body involvement, no vessel infiltration, but suspicion of left T1 nerve sheath involvement (Fig 1.). The patient underwent a CT-guided biopsy that classified the lesion as sarcoma. After being discussed at the local sarcoma MDT the patient underwent en-block complete resection of the tumour and of the posterior part of the first rib. Histology showed morphology typical of an ASPS which had arisen from the first rib and extended into the overlying soft tissues. There was nuclear expression of TFE3 and the (PAS+) tumour cells also unusually expressed CD68 and HMB45 as well as vimentin and NSE. Figure 1



Conclusion:
Cases of primary intraosseous ASPS are rare. To our knowledge this is the second description in the medical literature of an ASPS arising in a rib causing Pancoast syndrome. Chemotherapy and radiation have not proven beneficial in the treatment of ASPS, although new drug trials are ongoing. Even with en bloc surgical excision and adjuvant therapy, 5-year overall survival ranges from 20% for patients with metastatic disease to 88% for patients with local disease only at the time of presentation.

Background:
Primary pulmonary non-Hodgkin’s lymphoma (PPNHL) is a rare extranodal lymphoid neoplasm with few reports of Chinese patients. This study aims to analyze the demographic data, clinical features and radiographic presentation of Chinese PPNHL patients to obtain useful information for early diagnosis and differential diagnosis.

Methods:
A retrospective review of primary pulmonary non-Hodgkin’s lymphoma diagnosed at our hospital from February 2007 to April 2014 was performed.

Results:
This study included 34 PPNHL patients, comprising of 25 cases of mucosa-associated lymphoid tissue (MALT) lymphoma and 9 cases of diffuse large B-cell lymphomas (DLBCL). Cough and expectoration were the most common symptoms, accounting for 57.9% of the patients with symptoms. Nodules, masses and consolidations were the most frequent radiologic abnormalities and right lung is often involved. Pericardial effusion and bronchial abnormalities were found only in DLBCL cases. CT-guided percutaneous transthoracic biopsy was performed in most of the patients (73.5%) for diagnosis.

Conclusion:
The clinical features of PPNHL lack specificity. Imaging findings indicated that DLBCL patients tend to have an elevated incidence of pericardial effusion and bronchial abnormalities than MALT types. These discoveries provide assistance for the early diagnosis and differential diagnosis of these subtypes.

Background:
Lungs are the respiratory system that resides in the bottom of the chest cavity adjacent to the heart and mediastinum. Based on Jakarta Population-Based Cancer Registry 2005-2007, the incidence of lung cancer is ranked first in men and fourth in women. The frequency of lung cancer in Dharmais 1993-2007 is 4.29 % ranks third of all cancer incidence.

Methods:
Cross-sectional study began in 1993-2007. Inclusion criteria are patients newly diagnosed of lung cancer microscopically, inside or outside Dharmais. Classification using the WHO-ICD-O3. Determination of the sample with a precision formula with a total sample is 231.

Results:
Distribution by gender, 79.65% in males and 20.35% in women, higher in the age group above 59 years (52.72% male and 53.19% female).

Conclusion:
There are 14 variations of the main clinical features in men and 13 in women . The most common clinical picture of both men and women are cough, pain, and shortness of breath.

Background:
Teratoid Wilms’ tumor is an uncommon histologic variant of nephroblastoma, which is mainly characterized by a predominance of heterologous components within the tumor mass, and typically located in the kidney. Extrarenal forms of this neoplasm are extremely rare and have been previously described almost exclusively in pediatric patients.

Methods:
We herein describe the clinical, imaging, histological and immunohistochemical features of a mediastinal teratoid Wilms’ tumor in a 63-year old female. Diagnosis was established following surgical resection and histopathological evaluation of the tumor specimen, along with documentation of complete absence of a primary renal lesion.

Results:
Microscopic examination of representative tumor sections showed the typical WT architecture consisting of blastemal, mesenchymal and epithelial components (fig.1). More than 50% of the tumor’s volume was occupied by a variety of heterologous elements. Immunohistochemistry showed positive staining of the epithelial tumor cells for pankeratin (fig.2a), while the blastematous component stained positive for CD56 (fig.2b), CD99 (fig.2c) and WT1 (fig.2d). The patient received one preoperative course of carboplatin etoposide, as well as eight and four postoperative courses of carboplatin-etoposide and cyclophosphamide-doxorubicin, respectively. Disease progression was noted 15 months following administration of the first chemotherapy cycle, and the patient died 23 months after her initial presentation. Figure 1 Figure 2





Conclusion:
Identification of the typical triphasic WT histology along with a predominant heterologous differentiation –but without evidence of unequivocal heterotopic organogenesis- as well as documentation of complete absence of a primary renal neoplasm, are all required to establish the diagnosis of this extremely rare tumor.

Background:
to present a rare case of primary neuroendocrine carcinoma of the mediastinum treated by multimodal therapy.

Methods:
a 50-year-old man, non-smoker, with unremarkable past medical history, presented for asthenia, dyspnea and sub-sternal discomfort. A chest CT-scan showed a huge mass of 10,7x5,5x9,5cm in the anterosuperior mediastinum. The mass seems infiltrate both brachiocephalic veins, the superior vena cava, pericardium and both lungs (Fig.1a/b). PET-CT showed an intense hyperactivity of the mediastinal mass. CT-guided needle biopsy allows diagnosis of neuroendocrine carcinoma. After multisciplinary discussion, a multimodal approach was planned. The patient underwent 4 cycles of chemotherapy with cisplatin and gemcitabine. Since chest CT-scan showed a reduction of the tumor (7,4x5,6x9cm), a surgical resection was proposed. Figure 1



Results:
a median sternotomy was performed. On exploration, both lungs were marginally infiltrated. The pericardium was partially excised; the left anonymous vein was almost totally invaded by the tumor. The right anonymous vein was infiltrated at the confluence with the superior vena cava. After total caval clamping (clamping time: 27’), a partial section and reconstruction with bovine pericardium was performed (Fig.1c). The patient was discharged uneventfully on postoperative-day 9. The patient underwent 25 sessions of adjuvant radiotherapy. Currently, he’s free of disease after 30 months. Macroscopically the mass measured 9x8x3cm, looks whitish with tense-elastic consistency. Microscopically it showed clusters of small uniform cells, sometimes with cuboidal morphology, with nuclear pleomorphism and small nucleoli, arranged in trabeculae, nests and lobules and immersed in a hyaline stroma with foci of necrosis (Fig.2a). Perineural and vascular invasion were present. Immunohistochemistry showed the tumor cells were positive for chromogranin (Fig.2c), synaptophysin (Fig.2d), cytokeratins and negative for TTF1, FAP, PSA. The proliferation index Ki-67 was 10% (Fig.2b). Considering the radiological, morphological and immunophenotypic characteristics, the diagnosis was consistent with primary neuroendocrine carcinoma of the mediastinum. Figure 1



Conclusion:
mid-term survival was achieved after aggressive multimodal therapy.

Background:
Middle-aged and older women can present with dyspnoea and multiple well-demarcated rounded compact lesions of the lungs in different sizes, some very big. Investigation reveals no primary tumor but many years earlier an hysterectomi has been performed due to a big myoma, which was classified as benign. Biopsies of the lesions show the same picture. This is a very rare findings but we here present two cases seen recently by us.

Methods:
Two women with large probable metastases of the lungs were investigated.

Results:
Case 1: An exsmoking 74-year old woman was referred because of dyspnoea and pulmonary infiltrates. She had two lesions, one on each side approximately 2 cm in diameter. Laboratory tests normal .PET showed only minimal uptake. Needle puncture revealed leiomymatous cells with very low proliferation. Further questioning revealed that in 2008, an hysterectomy was performed because of a very large myoma, which was benign. Re-investigation of the myoma and of the biopsy from the lung lesion showed the same picture, and there were no signs of malignancy. Case 2: A neversmoking 68-year old woman was referred because of cough and pulmonary infiltrates. Multiple rounded lesions were seen on X-ray. Biopsy showed benign cells. In 1986 -29 years earlier - an hysterectomy had been performed because of pressure symptoms and a very large benign myoma was found.

Conclusion:
The diagnosis of "Benign metastasizing leiomyoma of the uterus" was established in the two cases. The name is an oxymoron; from the clinical view it must be regarded as a low-grade malignant leiomyosarcoma. Since its first description in 1939, around 100 case reports have been published. In rare cases, metastases in other organs than the lungs can also be found. Progression is usually extremely slow, no other organs are involved, and the main symptom is a slowly progressive dyspnoea, The prognosis in the short run (years) is very good, and specific treatment is lacking. If very big, surgical removal of lesions should be considered. We will just follow these patients since they have no symptoms.

Background:
Esophageal cancers are usually determined by examining the etiology of symptoms. Diagnosis in people without symptoms is rare and usually incidental. Although the most common symptom of esophageal cancer is dysphagia, in some cases clinical presentation can be different or misleading. Nevertheless, most esophageal cancers do not cause symptoms until they have reached an advanced stage. Here, we present an esophageal cancer case which suggests pulmonary malignancy with the clinical presentation.

Methods:
‘not applicable’

Results:
68-year-old male admitted our clinic with loss of appetite, weight loss and chest pain complaints. He had a smoking history of 30 packs/year. He was using LABA + ICS because of COPD. He told that his complaints had started 6 months before and gradually progressed. Because of the bilateraly suspicious hilar enlargement in chest X-ray, thorax CT examination was performed. In thorax CT, a conglomerate lesion, extending from subcarinal area to the posterior aspect of trachea, was observed. A clear distinction of lymphadenopathy/soft tissue could not be made. Diagnostic EBUS (endobronchial ultrasound) was performed to the patient under general anesthesia. During the process, a lesion protruded into the tracheal lumen with irregular surface was observed and biopsy was taken from this area. Also, EBUS guided biopsies were taken from the soft tissue lesions observed in thorax CT. In PET-CT of the patient, which was performed after this procedure, increased focal FDG uptake (SUWmax: 27.1) in the relevant field was observed without increased uptake elsewhere. Histopathological evaluations of these biopsies have been reported as esophageal squamous cell carcinoma. Subsequently, endoscopy was performed by gastroenterologists. In the course ofˈd(y)o͝oriNG endoscopy process, an ulcerated lesion, 1.5 cm in diameter and obstructing approximately 1/3 of the lumen, was observed on esophageal Z line at 44th cm from the incisors. The results of the biopsies taken from this area were also reported as esophageal squamous cell carcinoma. Thereafter, the patient was referred to Medical Oncology Department for oncologic treatment and follow-up.

Conclusion:
We shared this case in terms of being an informative example for local metastasis of esophageal malignancies presented with pulmonary symptoms which must be considered in differential diagnosis of intrathoracic masses.

Background:
Malignant melanoma, result of malignant transformation of melanocytes, metastasis mainly to regional lymph nodes, skeletal, and nervous systems. However, malignant melanoma can also metastasis to lung either. These metastases usually reach the lungs by tumor emboli to pulmonary arteries. Endobronchial spread of malignant melanoma to lungs diagnosed by bronchoscopy cases have limited number in literature. Here we share a malignant melanoma case spread endobronchially.

Methods:
‘not applicable’

Results:
62 years old male patient known to have malignant melanoma, was accepted to intensive care unit with respiratory distress and was intubated. In first evalution of his HRCT, consolidation and pleural effusion, constitute with large part of left lung’s atelectasis and less pleural effusion and partial atelectasis of neighbor parenchyma in right lung were seen. For both possible endobronchial metastasis causing airway obstruction and tumoral infiltration of parenchyma, bronchoscopy was performed through the endotracheal tube. Airway visualization revealed edema of the left main bronchus, concentrically significantly narrowed upper lobe, but segments were visible. Left lower lobe input was narrowed and segments were not visible. In entrance of left upper lobe there was an endobronchial lesion in brown- black color and slightly bulging form the mucosa like nevus. Transbronchial biopsy was taken from this nevus like formed lesion and left lung upper lobe apicoposterior. Both samples were reported as malignant melanoma by pathologist.

Conclusion:
We shared this case as an example of rare appearance of malignant melanoma with original images. We believe that this case report would be helpfull in terms of clinical practice.

Background:
We have previously reported on the importance of appropriate robot-arm settings and replacement of instrument-ports in robot-assisted thoracic surgery. Because the thoracic cavity requires a large space to access all lesions in various areas of the thoracic cavity from the apex to the diaphragm and mediastinum and the chest wall. Moreover it can be difficult manipulate the da Vinci[® ]Surgical System (Intuitive Surgical, Inc., Sunnyvale, CA) using only arms No. 1 and No. 2 depending on the tumor location. In this report, we show how robot-arm No. 3 can be used with maximum effectiveness in the da Vinci[®]-assisted thoracic surgery.

Methods:
Robot-arm No. 3 of the da Vinci® Surgical System was usually positioned on the same side of arm No. 2, and sometimes it was used as an assistant arm to avoid conflict with other arms in our previous report. We describe new effective application of robot-arm No. 3 for the da Vinci S®-assisted thoracic surgery. A 62-year-old man had an anterior mediastinal tumor suspected to be non-invasive thymoma. Instead of arm No. 1, arm No. 3 was placed in the 6th intercostal in the mid-axillary line inserted from reverse the side, rotating it behind the body of the da Vinci® Surgical System.

Results:
Robotic surgery enables access to tumors located throughout in the thoracic cavity. The time required for the da Vinci S ® -setting was 12 minutes and the console-time (the da Vinci S ®working time) was 75 minutes. Thymectomy was performed successfully, and the amount of bleeding was 68 ml, and there were no complications. The pathological findings were thymoma, Masaoka stage II.

Conclusion:
Arm No. 3 has wider range of motion than other arms because it has one more additional joint. That is the reason why arm No. 3 enables good operability and ability to reach remote lesions, such as in the apex, diaphragm, or costophrenic angle. Moreover, between the space of the camera-arm and arm No. 3 make enough working space than using arm No. 1 to avoid conflict between arms. This use of the da Vinci S ® arms should be helpful in robotic procedures for thoracic surgeons in manipulating the da Vinci S ® instrument arms. Our recent experience has taught us that arm No. 3 is extremely useful when used as the main arm instead of arm No. 1. This idea should facilitate the da Vinci S®-assisted thoracic surgery procedures as a new effective application of robot-arm No. 3.

Background:
Thymic carcinoma is a rare mediastinum malignant tumor based on thymic epithelial cells. The complete surgical resection is considered as a best treatment for thymic carcinoma. However, except completely resected cases, the effective therapy has not been established for the advanced or relapsed thymic carcinoma. The expression of excision repair cross-complementation group 1 (ERCC1) and class Ⅲ β-tubulin (TUBB3) protein are respectively expected as an indicator for the anticancer activity of the platinum-based and taxane-based chemotherapy.

Methods:
We examined the expression of ERCC1 and TUBB3 protein in 40 thymic carcinoma patients who underwent either the surgical resection or the core-needle biopsy. We also evaluated the expression of ERCC1 and TUBB3 protein in 50 patients who underwent the curative resection for the non-small cell lung cancer (NSCLC). We investigated whether the expression of ERCC1 and TUBB3 protein were associated with some overall survival and clinic-pathological factors of thymic carcinoma patients.

Results:
The expression of ERCC1 and TUBB3 protein were positive in eight cases (20%) in thymic carcinoma patients. ERCC1 was expressed in twenty-one cases (42%), while TUBB3 was in twenty-seven cases (54%) in the fifty NSCLC patients. In all thymic carcinoma cases, the 3 year-survival was 67.3%. Only complete resection was associated with the better prognosis (p=0.0341). Other clinico-pathological factors including the expression of ERCC1 and TUBB3 protein showed no effect on the overall survival.

Conclusion:
High expression of ERCC1 and TUBB3 might be associated with resistance to the platinum-based and taxane-based chemotherapy. Our results suggest a possibility of better antitumor effects of the platinum-based and taxane-based chemotherapy on the thymic carcinoma patients.

Background:
Malignant thymomas are rare tumours. The optimal therapy after subtotal resection is still controversial. Patients with locally advanced stages and postoperative residual tumours have a high risk of tumor recurrence. Adjuvant therapy using chemotherapy and/or radiotherapy brings contradictory results and this treatment can be limited by escalation of toxicity.

Methods:
Between 1994 and 2012 we assessed and retrospectively analysed a total of 36 patients. All patients underwent subtotal resection to various extent. Sixteen patients (44%) were treated with the standard adjuvant radiotherapy (RT) only (group A). In group B, twenty patients (56%) were treated with the sequence of chemotherapy (CT) and conformal radiotherapy (3D-CRT). The CT regimens consisted of doxorubicin + cisplatin + cyclophosphamide ± vincristine). The planned doses of 3D-CRT ranged from 50 to 60 Gy. Both of them, acute toxicities (acute eosophagitis-AE, radiation pneumonitis-RP) and late toxicities (lung fibrosis-LF, heart failure-HF), were classified according to CTC v 3.0. The manifestations of RP were softened by oxygenotherapy, antibiotics, corticoids and pentoxifylline (PTX). Pentoxifylline (400 mg) was administered orally tid in patients with severe manifestation of RP grade 3/4.

Results:
The median age at the time of diagnosis was 56 (range, 38 – 75 years). By Masaoka staging system, 8 patients were stage II (24%) and 28 stage III (76%). The number of applied CT regimens ranged from 4 to 8 cycles. The median 3D-CRT dose was 55.8 Gy (range, 43.2 – 66.6 Gy). Thirty-eight percent of all patients (14/36) had myastenia gravis. AE of grade 1/2 was observed in 1 (6%) and 2 (10%) patients and grade 3/4 in 2 (13%) and 3 (15%) patients in groups A vs B. RP of grade 1/2 was observed in 5 (31%) and 10 (50%) patients in groups A and B, respectively. RP of grade 3/4 was observed in 2 (13%) and 9 (45%) patients in groups A vs B. Median time to recover RP grade 3/4 was 4.7 months in patients without PTX vs 2.6 months in patients using PTX. Radiographic changes of partial LF was observed in 3 (19%) and 8 (40%) patients in groups A and B, respectively. HF was diagnosed only in one of twenty patients (5%) in group B. In this patient degenerative and fibrosis changes of the heart were observed, which resulted in non-congenital aortic valvular stenosis 31 months after 3D-CRT and CT. The patient is still alive with OOS 77 months since the time of the diagnosis. A better local control of the disease was observed in group B where the median time to tumor progression was 49 months in comparison with 21 months in group A (p=0.0001). Five-year survival rates were 43.7% (7/16) and 85% (17/20) in group A vs group B, respectively (p=0.0001).

Conclusion:
Intensive postoperative treatment leads to an improvement of the local control of this disease. The escalated acute toxicity, especially radiation pneumonitis, was not too serious and could be reduced with the benefit by application of pentoxifylline. Manifestation of late toxicities, predominantly lung fibrosis and heart failure, was acceptable.

Background:
Thymoma is a rare tumor with heterogeneous clinical outcome. We aim to assess if there is an arbitrary cutoff point of clinical significance to the histological subtypes of Thymoma

Methods:
this is a retrospective study including all eligible patients with Thymoma presenting to National cancer institute, Cairo University during the period from 2008 to 2015. Patients were divided in to two groups according to histological subtypes, first group: included patients with histological subtypes (AB+B1+B2) whereas second group included patients with histological subtypes (B3+C+ Thymic carcinoma). Endpoints were to compare the two groups with regard to clinical response to chemotherapy, progression free survival (PFS) and overall survival (OS) with concordance to standard clinicopathological factors.

Results:
26 patients were included in the study with 69% in the first group (mean age = 45.44 years± 14.1 SD) versus 21% in the second group ( mean age=41.63 ± 12.53 SD).Regarding clinical response to chemotherapy, 11.1% in the first group showed progressive disease as compared to 37.5% in the second group (p=0.51). Median PFS for all thymoma patients was 43.1 months (median ±SD = 43.1± 20.8). there was a trend towards better PFS in the first group where 2 years PFS in the first group was 68.4% versus 43.8 in the second group, p value= 0.09. Median OS for all thymoma patients was 76.7 months, (median ± SD = 76.7±29.8). 2 years OS was 72.6% in the first group versus 43.8 in the second group. (P- Value=0.24).

Conclusion:
although numerically better there was no statistically significant difference between the first and second groups with regard to clinical outcome. Collaborative studies including larger sample size are warranted.

Background:
Complete surgical resection is the best prognostic factor for thymomas. In advanced stage thymomas a complete surgical resection may require mutilating approaches, may not be performed because of anticipated technical difficulties or may just be considered not achievable.

Methods:
Retrospective analysis of patient files from April 2004 till March 2015 showed 239 patients who underwent a thymectomy in Maastricht University Medical Center. 15 patients (6.3%) underwent thymoma resection for Masaoka-Koga advanced stage III or IV. In all cases minimally invasive techniques were employed in patients-tailored stepwise treatment approaches.

Results:
A 66 years old male presented with a mediastinal mass with suspected invasion of the brachiocephalic vein and the ascending aorta (figure 1). Biopsy showed thymoma type B2/B3. Resection through sternotomy in a referral hospital was abrogated as invasion of the sternum was found. After the attempted resection the patient received chemotherapy (cisplatin-etoposid) however, the thymoma did not respond. In a multidisciplinary setting we decided on a bilateral robotic-assisted dissection and if successful, subsequent sternotomy for final removal of the giant mass. Minimally invasive dissection was started from the right side. With the help of the 10x magnification of the robot camera, the thymoma was freed from the sternum, the phrenic nerve and the major vessels. Macroscopic invasion of the pericardium and the brachiocephalic vein necessitated resection of the pericardium (12 x 4 cm) and the vein (3 cm). Complete inspection using the 30 degree robotic camera of both the right and left thoracic cavity revealed the absence of pleural metastasis, and no invasion of the phrenic nerve or the lung in the left thoracic cavity. An additional left-sided approach was therefore cancelled and sternotomy was performed to remove the specimen. Lymph nodes from the positions 4,5,6,7,10,11 as well as from the subclavicular area, were harvested. Pathological examination showed a thymic carcinoma/thymoma type B3, Masaoka-Koga stage III, and confirmed a R0 resection. All lymphnodes were negative for metastasis. Postoperatively, the patient was temporarily treated with an elastic sleeve because of oedema of the left arm. As of the histology of the tumor, the patient received postoperative radiotherapy.

Conclusion:
Complete surgical resection in advanced stage thymomas is be possible using a stepwise surgical approach including minimally invasive techniques.

Background:
Thymic tumors are rare entity with little information regarding outcomes after therapy with curative intent. We undertook a prospective analysis of all patients who underwent resection of thymic tumors at NCI hospitals. The optimal treatment includes surgical resection, chemotherapy, and radiotherapy.It is relatively uncommon(10%) but are highly aggressive.

Methods:
From 2008 to 2014, 13 patients (8 men, 5 women) underwent surgical resection of thymic tumor at a mean age of 47 years. Patient demographics, extent of surgical resection, and outcomes were compiled. Demographic variables, use of chemotherapy or radiotherapy, perioperative variables, recurrence rates, and long-term survival were analyzed retrospectively. The Masaoka stage and tumor diameter were recorded along with other variables that potentially influenced survival such tumor grade, site &number of metastatic disease.

Results:
The distribution of Masaoka stages at presentation was I in 6 (47%), II in 3 (23%), III in 1 (7%), and IV in 3 (23%). Neoadjuvant chemotherapy was administered to 3 patients (23%) whose tumors were deemed to be more locally invasive, two of them received neoadjuvant concomittant chemo-radiotherapy. Of the 13 patients in the surgical cohort, 8 (61.5%) were men. Mean age was 47 years (range: 21 to 58 years). No patient demonstrated an associated immunologic disorder such as myasthenia gravis. In all patients pathologic confirmation of thymic tumor was by CT giuded fine needle aspiration/biopsy as part of the diagnostic workup. Preoperatively, 3 of 13 patients (23%) received chemotherapy and 2 (15.5%) received radiotherapy. The decision to administer chemotherapy or radiotherapy preoperatively was individualized in each patient and based on the extent of tumor invasion. Complete tumor resection with pathologically confirmed negative resection margins (R0) was achieved in 12 patients (92.3%). The other 1 patient had microscopic residual disease (R1). Masaoka stage was I in 6 (47%), II in 3 (23%), III in 1(7%), and IV in 3 (23%). The most common approach to surgical resection was sternotomy, used in 11 patients (84.5%). Mean tumor size was 9.5 cm (range: 4.5 to 16 cm) for the 13 patients. Pulmonary wedge resection was done for only 2 cases,pleural resection 5 cases& lobectomy in only 1. No perioperative deaths occurred nor patients required tracheostomy for postoperative respiratory failure. The two patients who had unilateral phrenic nerve resection as part of their operation none of these patients underwent a diaphragmatic plication early in the postoperative course to improve respiratory insufficiency. Four patients received adjuvant chemotherapy or radiotherapy or both. Of those whose tumors were completely resected, 1 patient experienced a local recurrence. SurvivalMean length of survival in the entire group was 22.7 months (range: 14 to 36 months). At the last follow-up, 8 patients (61.5%) were alive without disease, 1 (7.5%) was alive with disease, and 4(31%) had died.

Conclusion:
Thymic tumor are amenable to surgical therapy, With increased use of computed tomography imaging, patients with early-stage disease are being identified more frequently, complete surgical resection appears to have favorable cure rates in these patients. Patients with locally advanced disease can experience long-term survival with a multimodality approach.

Background:
Mesothelin (MSLN), CA125 (also know as mucin-16, MUC16) and WT-1 are cancer-associated antigens currently under investigation as targets for tumor-specific immunotherapy, based on published observations that antigen-specific immune responses to these antigens prolong survival. In solid malignancies, we (Clin Cancer Res 2012, 2013) and others have published the role of MSLN in promoting tumor aggressiveness. Additionally, MSLN has been demonstrated to interact with CA125 in promoting invasion and metastasis, resulting in poor clinical outcomes. In this study, we investigated the individual and correlative expressions of MSLN, CA125 and WT-1 in both epithelioid and non-epithelioid MPMs.

Methods:
All available H&E-stained slides from patients who were diagnosed with MPM (1989-2010) were reviewed; tumors were classified according to the WHO classification. We constructed tissue microarrays (6 tumor cores/tumor) from 273 patients (epithelioid=224; non-epithelioid, including biphasic and sarcomatoid =49). MSLN, CA125, and WT-1 immunohistochemistry were performed, and total scores for each antigen were determined by assessing the combined intensity and distribution of the antigen expression.

Results:
Epithelioid MPMs demonstrated positive MSLN expression in 92% of patient samples (73% high-moderate expression), CA125 expression in 72% (19% high-moderate), and WT-1 in 94% (63% high-moderate) (Fig.1A). Triple positive antigen expression was recognized in 68% of patients; co-expression of two antigens was demonstrated in 23% of epithelioid MPMs (Fig.1B). In non-epithelioid MPMs, MSLN, CA125, and WT-1 were positive in 57% (16% high-moderate), 33% (2% high-moderate), and 98% (43% high-moderate) of patient tumors, respectively. Triple and double antigen co-expression were demonstrated in 29% and 33% of non-epithelioid MPMs, respectively. Only 1% of epithelioid and 2% of non-epithelioid MPMs demonstrated absence of expression of all three antigens: MSLN, CA125, and WT-1.Figure 1



Conclusion:
Our observation from a large cohort of MPM patients inclusive of all histological subtypes demonstrating greater than 98% positive expression of at least one of the three cancer-associated antigens in epithelioid and non-epithelioid MPMs, with strong antigen expression and high frequency of double and triple antigen expression, provides rationale to develop targeted therapies to these cancer-associated antigens for the treatment of MPM patients We are initiaiting a phase I clinical trial (NCT02414269) of mesothelin-targeted T-cell therapy for MPM patients at our center.

Background:
Patients with lung cancer are at increased risk of venous thromboembolism (VTE). Patient-related factors may help estimate an individual’s risk for VTE. Cardiovascular disease (CVD) risk factors increase the risk of arterial embolism, but it is less clear whether these factors increase the risk of VTE associated with lung cancer.We evaluated associations between major CVD risk factors and the occurrence of VTE in lung cancer patients using data from the Lung Cancer and Thrombosis Study conducted by the China VTE Study Group.

Methods:
A total of 632 hospitalized patients with newly diagnosed lung cancer were screened for VTE, and their major CVD risk factors were assessed at the baseline examination. Additionally, VTE diagnoses within the three months prior to recruitment were reviewed.

Results:
Eighty-six of the 632 (13.6%) experienced a VTE event, and 7.8%, 3.3%, and 16.6% of the patients also experienced diabetes, dyslipidemia and hypertension, respectively. Hypertension was more frequent in patients with VTE than in those without VTE (24.4% vs. 15.4%, P=0.04). Multivariate logistic regression analysis, including age, sex, smoking, body mass index, diabetes, dyslipidemia, hypertension and white blood cell count, found that hypertension (odds ratio [OR] 1.8; 95% CI 1.0-3.3; P=0.041) and leukocytosis (OR 2.7; 95% CI 1.5-4.8; P=0.001) were significantly associated with VTE in different tumor histology models and that hypertension (OR 1.9; 95% CI 1.1-3.4; P=0.029) and leukocytosis (OR 2.7; 95% CI 1.5-4.7; P=0.001) were also significantly associated with VTE in different tumor stage models. Leukocytosis was linearly associated with hypertension and VTE (P for trend = 0.006), and the ORs for VTE increased with leukocytosis (all P for trend < 0.05).

Conclusion:
Hypertension was associated with the risk of VTE in patients with newly diagnosed lung cancer, which may be mediated by the presence of inflammation.

Background:
Neoplastic obstruction of the airways occurs in about 30% of lung neoplasms, and is often associated woth end-stage, or advanced disease. Nonetheless, endoscopic treatment of the obstruction may improve quality of life and survival in selected patients. The primary objective is to evaluate the median survival and the predictors of mortality in patients undergoing endoscopic treatment of neoplastic airway obstruction. The secondary objective is to evaluate the morbidity of the procedure.

Methods:
Retrospective study, from January 2010 to December 2014. All data was collected until February 2015. We included patients with neoplastic obstruction of the trachea and bronchi, that underwent endoscopic treatment. Procedures were performed in the operating room under general anesthesia, through rigid bronchoscopy or suspension laryngoscopy.Age, sex, neoadjuant chemo-radiotherapy, adjuvant chemo-radiotherapy, ECOG status, ASA status, urgent procedures, need for mechanical ventilation, reintervention procedures, site of obstruction, type of stent and tumor histology were considered predictors for mortality.The median survival was analyzed by Kaplan-Meier curve. Prognostic factors of mortality were analyzed by Cox regression.

Results:
We included 42 patients (25M / 17F) with a mean age of 54 + 11 years, that underwent 68 endoscopic procedures. The most common histologic types were lung cancer (n = 15; 36%), esophagus (n = 11; 26%) and cystic adenoid carcinoma (n = 8; 19%). Twenty-five stents were placed. The silicone Y stent was the most common (n=14;56%). Eleven percent of patients required a tracheostomy. Complications occurred in 37.5% of cases; pneumonia (n = 10; 15%) and stent obstruction (n = 6; 9%) were the most frequent.The median survival was 221 days. The 30-day mortality was 14%, and overall mortality 40%. The predictors of mortality by Cox regression were re-intervention procedures (HR 5.9; p <0.001; 95% CI 2:25 to 15:45), mechanical ventilation before the procedure (HR 7:38; p = 0.015; 95% CI: 1.46- 37) and tumor hystology (HR: .23; p <0.001; 95% CI: .11 - .47). Individuals with esophageal cancer had a significant lower median survival, when compared with lung cancer and cystic adenoid carcinoma (94 vs 166 vs 346 days; p=0.002).

Conclusion:
The morbidity and mortality of patients submitted to endoscopic treatment of neoplastic airway obstruction is not negligible. Reintervention procedures, mechanical ventilation prior to treatment and tumor histology were significant predictors of mortality.

Background:
Lung cancer is getting more common and important especially in 6th-7th decade. Several recently published studies showed that eveluating the elderly patients with only Eastern Cooperative Oncology Group (ECOG) to manage the treatment is not eough. It is needed to consider this elderly group of patients precisely. In our study we aim to search the the clinical value of the comprehensive geriatric assessment of the elderly patients as a a parameter that can be used to guide the treatment decision.

Methods:
In our study 65 years old and over newly diagnosed 74 lung cancer patients in our hospital from April 2013 to April 2014 were included. In order to evaluate the comprehensive geriatric assessment, we applied the activities of daily living (ADL’s), instrumental activities of daily living ( IADLs), mini-mental test, mini-nutritional test, Yesavage depression scale and Charlson comorbidity index . Receiving treatment and the survival were assessed with 6 other tests and ECOG in single and multi variable analysis.

Results:
Men were 94.6 % of all patients. In this group 6.8% in small cell carsinoma, 90.5% in non-small cell carsinoma, 2.7 % in malignant epithelial tumour were diagnosed. According to ADL’s 86.5 % was independent and 13.5 % was semi-dependent as well as to IADLs 60.8 % was independent, 20.3 % semi-dependent and 18.9 % was dependent. %12.2 of the patients had malnutrition, %56.7 had malnutrition risk. The data provided that 54 % of all patients had severe dementia and 17.6 % has mild dementia. According to Yesavade depression scale 13.5% of patients were developed depression. Charlson comorbidity index provided the data that 2 % of patients had very high risk probability, 5% high risk, 42.5 % moderate, 25% low risk probability. It is found significant the relationship between the receiving treatment and results of ADL’s, IADLs, mini-mental test, Yesavage depression scale, and ECOG as well as ADL’s, IADLs, mini-mental test, Yesavage depression scale, ECOG and mini-nutritional test and the survival in single variable analysis (p<0,05). In order to consider which test will have more prominent role to receive the treatment ,multivariable analysis was performed and only IADLs was found significant as a determining factor for receiving or not receiving treatment (p=0,003). Yesavage depression scale was found more efficient to find out the factors affecting the survival in multivariable comparison analysis (p=0,011).

Conclusion:
The study published by Maione and collegues evaluating the relationship between functional status, comorbidity, life quality and the survival in 566 advanced stage non-small cell cancer patients showed that patients with beter IADLs ( p= 0.04) have better survival as similarly obtained from our study. Buccheri and his group reported the data from 133 heterogeneous bronchogenic cancer patients developed depression,have a worse survival comparing with the patients having no depression. The results of our study indicates that assessing with ECOG is not enough for considering the treatment,but how CGA is important to consider it as well. Improving the life quality and the survival of the advanced stage elderly patients with cancer, future research requires a more wide population

Background:
Chemotherapy-induced nausea and vomiting (CINV) is still a major adverse effect especially for patients treated with highly emetogenic chemotherapy (HEC). In clinical practice, 5-HT3 receptor antagonist, NK-1 receptor antagonist, and corticosteroids are widely used to alleviate emetic episodes during chemotherapy. With those drugs, acute-nausea and vomiting is successfully manageable. However, late-onset nausea and vomiting is sometimes difficult to be controlled and therefore, the promising drugs is needed. Olanzapine is an antipsychotic agent which is approved for schizophrenia and bipolar disorder in Japan. Recently, the combination therapy with olanzapine and the conventional anti-emetic drugs has been reported highly effective to prevent late-onset CIMV after HEC. However, it remains unclear whether olanzapine is really effective for patients who develop acute- or late-onset CIMV after HEC.

Methods:
All consecutive patients, who were treated with HEC and olanzapine at Jichi Medical University Hospital from January 2014 to December 2014, were included. “Antimetic Response” was defined as the absence of nausea and vomitting, no use of breakthrough antiemetic medications, or increased dietary intake (≧50%). The details of clinical information were reviewed from the medical records .

Results:
Among 18 patients treated with HEC and olanzapine as antimetic medication, 11 were males and 7 were females, with a median age of 60.5 years (42-74 years). Primary tumors were non-small cell lung cancer in 11 cases, small cell lung cancer in 5, malignant mesothelioma in one case, and embryonal carcinoma in one case. Olanzapine was used for preventing CINV in 8 patients with the previous experience of late-onset CINV and in 2 patients without, for treating late-onset CINV in 6 patients and acute onset CINV in 2 patients. "Antiemetic response" has been observed in 15 patients (83.3%). Among 8 patients previously experiencing late-onset CINV, "Antimetic response" was obtained in 7 patients(87.5%).

Conclusion:
Our results strongly suggest the olanzapine provides an additional effect on CINV uncontrolled with conventional antiemetic therapy, regardless of whether CINV is acute or chronic.

Background:
The aim of this study was to investigate the symptom distress, anxiety and depression in patients with NSCLC undergoing adjuvant chemotherapy after VATS lobectomy.

Methods:
A total of 62 patients undergoing adjuvant chemotherapy from January 2013 to December 2014 after VATS lobectomy were enrolled. The M.D. Anderson Symptom Inventory (MDASI) and the Hospital Anxiety and Depression Scale (HADS) were used to assess the patients, symptom distress, anxiety and depression condition.

Results:
The patients averagely scored 3.02 points in symptom items, and 2.58 points in interference items, with the scores being positively correlated with anxiety and depression respectively (P<0.01 for both). The patients mainly reported symptoms of alopecia, lack of appetite, dyspnea, etc.

Conclusion:
Symptom distress is commonly seen in patients with NSCLC undergoing adjuvant chemotherapy after VATS lobectomy. And symptom distress, anxiety and depression react upon each another. Therefore physicians should pay more attention to these patients, mental state and guide them to rationally release their emotions.

Background:
Febrile neutropenia is considered a severe complication of cancer chemotherapy, and one for which lung cancer is frequently associated with higher mortality rates than other solid tumors. The focus of this analysis was to identify risk factors most associated with in-hospital mortality and to describe their impact on mortality in patients with lung cancer.

Methods:
Hospitalization data from the University Health Consortium database inclusive of the years 2004-2012 from 239 US medical centers were analyzed. The study population included all adult patients with solid tumors who had neutropenia. Cancer type, presence of neutropenia, comorbidities, and further subgroups were based on ICD-9-CM codes. The primary study outcome was in-hospital mortality in lung cancer patients vs. other solid tumors. Further analysis concentrated on comparisons of the two groups with respect to number and type of comorbidities, occurrence of sepsis, pneumonia, or any infection, and ICU stay and influence of these factors on mortality. Differences between the groups were compared using chi-square test.

Results:
The analysis was based on 61,086 adult patients, including 11,111 lung cancer patients and 49,975 patients with other solid tumors. Overall 4290 (7.0%) patients died. Lung cancer was the tumor type associated with highest mortality (11.2%, compared with other solid tumors, 6.1%; p <0.0001) Lung cancer patients were older: 50% of lung cancer patients were over age 65, compared to 31.6% of patients with other solid tumors (p<0.0001). Lung cancer patients were more likely to have multiple (≥2) comorbidities than patients with other solid tumors (57.3% vs. 37.3% p<0.0001). The risk of mortality was directly related to the number of comorbidities (ranging from mortality risk of 0.9% for patients with 0 comorbidities to 35.2% for patients with 5 or more). The comorbidity-mortality relationship was observed in lung cancer patients as well as patients with other solid tumors, and the association persisted after adjusting for multiple covariates, including age. Even independent of number of comorbidities and age, lung cancer patients had higher mortality (Odds Ratio (OR)=1.38, 95%CI: 1.28-1.48). Four risk factors for mortality in addition to number of comorbidities were identified: pneumonia, sepsis, any documented infection, and ICU stay. Pneumonia occurred more commonly in the lung cancer patients (26.4% vs. 10.3%; p<0.0001). Comorbid pulmonary disease was strongly associated with development of pneumonia (OR=4.52, 95%CI: 4.30-4.74) and occurred more often in the lung cancer patients (52.1% vs. 24.0%; p<0.0001). With or without pulmonary disease as a comorbidity, lung cancer patients were more likely to have pneumonia than other solid tumor types (with – 36.0% vs. 22.8%, p<0.0001) (without – 16.1% vs. 6.4%, p<0.0001).

Conclusion:
Lung cancer patients presenting with febrile neutropenia are older, have more comorbidities, have a higher incidence of comorbid pulmonary disease, and are more likely to have pneumonia. These factors may help explain their higher mortality. In order to reduce the mortality of chemotherapy in lung cancer patients, careful pretreatment assessment and optimal supportive care during therapy are critical.

Background:
Co-morbidity is a key factor in determining prognosis and defining treatment in lung cancer. In the face of an ageing population and increasing prevalence of chronic medical conditions, lung cancer physicians will need to develop robust systems and services to ensure appropriate optimisation of co-morbidities during the diagnosis and staging pathway. The aim of this study was to provide a detailed description of co-morbidities and physiology in a UK lung cancer population.

Methods:
Prospective data was collected on all newly diagnosed lung cancer patients at the University Hospital South Manchester from November 2014 and February 2015. UHSM is a regional lung cancer centre and diagnoses over 200 lung cancers per year. Co-morbidities were assessed using the Charlson co-morbidity index. Performance status, MRC Dyspnoea Scale, BMI and physiological parameters for the cardiorespiratory and renal systems were also measured.

Results:
73 patients were diagnosed with lung cancer in the study period. Mean age was 70 years and 35 (48%) were male. 37 (51%) had radiological evidence of emphysema on staging CT of the thorax. Co-morbidities and physiological parameters for the patient cohort are presented in tables 1 & 2. Table 1: Charlson Co-morbidity Index

	n = 73 n (%)
0	9 (12%)
1-2	26 (37%)
3-4	16 (22%)
5-6	12 (16%)
≥7	10 (14%)
Chronic pulmonary disease	27 (37%)
Myocardial Infarction	14 (19%)
Cerebrovascular disease	13 (18%)
Diabetes without end-organ damage	10 (14%)
Congestive cardiac failure	7 (10%)
Peripheral vascular disease	7 (10%)
Moderate-severe CKD	5 (7%)
Dementia	3 (4%)
Diabetes with end-organ damage	3 (4%)
Connective tissue disease	3 (4%)
Chronic liver disease	2 (3%)
Lymphoma	1 (1%)

Table 2: Fitness and physiological parameters

PS 0-1	45 (62%)
PS 2-4	28 (38%)
MRC Dyspnoea Scale 1-2	38 (52%)
MRC Dyspnoea Scale 3-5	35 (48%)
BMI <20	17 (23%)
BMI 20-30	34 (47%)
BMI >30	22 (30%)
FEV1 % predicted, mean	77.1 ±26.7
FEV1:FVC	62.1 ±14.6
DLCO % predicted, mean	72.0 ±21.2
Shuttle walk distance, metres, mean	366 ±154
Lowest O2 sats during shuttle, %, mean	92 ±4.1
Peak VO2 % predicted, mean	71.7 ±17.8
Estimated glomerular filtration rate	75.4 ±18.9
Revised cardiac index ≥3	9 (12%)

Conclusion:
Chronic respiratory disease and disability is a major component of co-morbidity and physiological impairment in lung cancer patients. Cardiovascular disease and abnormalities in BMI are also highly prevalent. These results inform the need for rapid and reliable access to prehabilitation and dietetic services, robust cardiorespiratory physiological testing and specialist cardiovascular teams for all lung cancer physicians.

Background:
Palliative care is a medical specialty focused on improving the quality of life of patients and their families with life threatening illness by preventing or relieving suffering. An assessment of a thoracic surgery service was performed to identify the scope and frequency of care that was considered palliative and any implications the findings might have on the current thoracic surgery residency curriculum.

Methods:
A retrospective review of a prospectively collected database of general thoracic surgery procedures performed over a five year period at a single institution was performed. Procedures considered palliative were reviewed for demographics, diagnoses, palliative prognosis score, treatment, morbidity, operative mortality and survival. Excluded were referrals from thoracic surgery to other specialties for palliative procedures.

Results:
During the study period, 3842 procedures were performed of which 884 (23%) were palliative. Indications included pleural and/or pericardial effusion, dysphagia, hemoptysis, tracheobronchial obstruction, bronchopleural fistula and tracheoesophageal fistula. The majority was related to a malignancy. Only 127 patients (14%) had a palliative care assessment prior to thoracic surgery consultation. Mean survival following thoracic surgery intervention was 110 days for patients with malignancy.

Conclusion:
This investigation found that thoracic surgeons commonly care for patients when the intention is palliation. The majority of these patients have an associated malignancy, a poor performance status and a significantly decreased survival compared to the general population. Thoracic surgeons should be familiar with the concepts of palliative care and consideration should be given to expanding exposure to the principles of palliative care in the cardiothoracic residency training curriculum.

Background:
Lung cancer is the leading cause of cancer related morbidity and mortality in both the sexes in Nepal. It accounts for 15.4 % of total cancer as per hospital based Cancer Registry in Nepal. The purpose of this study was to review the patient characteristics and sociocultural factors and their influences in lung cancer cases presenting to the National Hospital and Cancer Research Center of Nepal.

Methods:
A retrospective cross-sectional study was done for the lung cancer cases from January 2009 to May 2014. 72 cases were identified by searching through inpatient records at the National Cancer Hospital but only 43 cases were selected for the analysis purpose due to lack of complete data in other remaining cases. Mean age, gender, ethnicity, locality, smoking habits, histological cell types and staging of the lung cancer patients at the initial presentation time were evaluated. Data were analyzed using SPSS statistical software.

Results:
The highest incidence of lung cancer is seen between 61-80 years of age (62.7%). There was no significant difference between the number of cases among male (51.16%) and female (48.83%). Majority of cases were from central part of the country near capital city (76.7%) whereas eastern and the entire western regions contributed to 7.1% and 16.2% cases respectively which clearly shows the lack of easy accessibility among patient for treatment at tertiary cancer center. People from Newar (39.5%) and Chettri (30.2%) ethnic origin were among the group with highest incidence of lung cancer in our study. 79.06% were smoker than compared to 20.93% who were non-smokers. 76.47% of patient started smoking at age between 10-20 years. 85.29% of the patients consumed local brand cigarettes which has either poor filter or no filter at all. 88.37% of the patients were diagnosed with Non Squamous lung Cancer (NSCLC) and 11.62% were diagnosed with Small Cell lung Cancer(SCLC). In NSCLC majority had squamous cell carcinoma (68.42%) and adenocarcinoma (31.57%). 86.84% of the patients were diagnosed with advanced stage III/IV lung cancer at the time of presentation to the hospital which shows significant delay in getting early diagnosis and treatment in majority of patient with the lung cancer.

Conclusion:
Because of the negligence for the simple cough patient tend to come to see the doctors late. The other reason for late presentation (stage III and IV) being the terrain and lack of diagnostic facilities in many parts of the country. Other important aspect of late presentation is treating the lung lesions as Pulmonary TB by the general physicians because of TB being one of the most common pulmonary diseases in the country. Such a study in larger scale would be beneficial for the implementation of awareness campaign, early detection, and treatment of the disease at the possible early stage.

Background:
Typically, resection of non-small cell lung cancer (NSCLC) is done solely for curative intent. Rarely, a patient may benefit from aggressive palliative resection when non-oncologic conditions pose a greater threat to health and quality of life. A 59 year old man with cT3N1M1 NSCLC suffered from fevers, and relentless cough productive of copious foul sputum secondary to tumor necrosis and abscess (Fig. 1). Infectious symptoms worsened despite intravenous antibiotics. Clinical staging also suggested adrenal metastasis. Figure 1



Methods:
Cytology of pleural fluid was positive and right upper lobectomy revealed pT3N1 poorly differentiated squamous cell carcinoma. The specimen opened ex vivo was consistent with necrosis and abscess (Fig. 2). Figure 1



Results:
The patient tolerated resection very well, and was home without complication in 8 days. Infectious symptoms promptly cleared. He underwent six cycles of carboplatin and paclitaxel, without significant toxicity. CT and bone scan revealed no evidence of disease 18 months post-resection.

Conclusion:
In some NSCLC patients whose greatest threat to health and quality of life is related to complications such as lung abscess, focusing on clearing the infection rather than strictly adhering to oncologic curative intent criteria may improve quality of life, alleviate symptoms and improve survival. In this particular case, the patient had a relentless cough of putrid sputum and fevers. He was not a candidate for curative resection due to adrenal metastasis and positive pleural cytology. A palliative resection could be justified, as his symptoms were severe, potentially able to be resolved with surgery, and no other treatment options were available. Following resection, the infection cleared, and symptoms resolved. He then tolerated chemotherapy with a favorable response and over 18 month survival.

Background:
In the screening of the possible etiology of pulmonary embolism rule out the presence of an occult neoplasia. Tumors more often associated with thrombotic phenomena are lung, pancreas and colon. The pulmonary artery sarcoma is a rare entity and its clinical diagnosis is complex.

Methods:
We report a case of a non-smoker 71 years old woman. In 1999 suffers first episode of thrombophlebitis. Since then presents several episodes of DVT in the lower limbs so it was anticoagulated with acenocumarol. In October 2014 she was admitted due to costalgia and fever and suspected diagnosis of pneumonia. She told a 3 months history of asthenia and progressive edema of the lower limbs. It is performed thoracic CT, with a massive pulmonary thromboembolism. The doppler sonography of lower limb show a chronic thrombosis. After clinical stabilization she was put under rivaroxaban. At 15th admission day, she starts with dyspnea with chest discomfort, and respiratory failure was found. In an urgent CT was shown a progression of the known embolism. Being a massive thrombosis refractory to treatment and progressive elevation of pulmonary pressure, surgeon was consulted, and is was performed a thromboendarterectomy and a pulmonary artery homograft replacement. In the pathology report, is reported a intermediate-grade sarcoma, suggestive of intramural primary origin and intimal type intimal grade. In January 2015 CT shows progression of local disease, and is discussed in the tumor board, considering unresectability of disesase, and it is proposed to start palliative chemotherapy

Results:
The pulmonary artery sarcoma is a rare disease, since its first description in 1923, there have been documented 200 cases. It can be classified according to their location relative to the vessel wall, or by histologic subtype. Usually located in the main pulmonary artery, diagnosis and complications arise from its intraluminal extension. Up to 50% of cases have pulmonary and mediastinal metastases at diagnosis and distant metastases in 16-19% It is an entity with very similar clinical and radiological features a thromboembolism, a fact that probably contribute to underdiagnosis. The symptoms are dyspnea (72-100%), chest pain (35-45%) and hemoptysis (15-24%), weight loss (21%), asthenia (10%) and fever (8%). The prognosis is poor, with survival reported between 6 months and 2 years (median 17 months) The treatment of choice is surgical approach, by pulmonary endarterectomy, lobectomy or pneumonectomy, with or without reconstruction of the pulmonary artery. In most cases R0 resection is not achieved. The role of radiotherapy (RT) and chemotherapy (CT) is not yet well defined. Regarding chemotherapy schedules, it have been used traditionally active drugs for the treatment of sarcomas

Conclusion:
The pulmonary artery sarcoma is a rare disease that should be suspected in patients with progressive or refractory pulmonary thromboembolism.

Background:
Cancer clinical trial (CCT) participation is critical to improving the care of patients with Non-Small Cell Lung Cancer (NSCLC), yet low participation in CCTs persists. Little is known about the specific barriers to CCT participation among patients with NSCLC. The On Q Care Planning System (CPS) is an electronic tablet based platform adapted to address potential barriers to CCT participation through algorithm-driven identification of and education about patient specific CCTs at the point of care. The primary objectives of this study were to 1) characterize knowledge, attitudes and beliefs about CCTs among patients with NSCLC and their providers and 2) evaluate the impact of the CPS on CCT participation.

Methods:
We performed a multi-site pilot implementation project of CPS as a clinical decision support and patient education tool. Patients were eligible if they had recurrent/metastatic NSCLC. The CPS contained clinical trial eligibility criteria for many CCTs in NSCLC open at the primary research site, as well as selected CCTs from surrounding cancer centers. Study aims were evaluated using patient and provider self-report surveys. Knowledge, attitudes and beliefs about CCTs for both patient’s and provider’s was captured through self-assessment surveys, using a combination of true/false questions and 1-5 Likert scale measures where 5 indicated highest level of agreement. Effect of CPS on CCT enrollment was measured by rate of enrollment in CCTs following the intervention, compared to historical rates of NSCLC CCT participation at our institution.

Results:
From April 2015 through July 2015, 9 providers (medical oncologists and nurse practitioners) and 79 patients with recurrent/metastatic NSCLC have been enrolled from 2 participating cancer centers. While providers reported being aware of open CCTs (mean score (m)=4.6), they felt that lack of adequate information about CCTs (m=3.0) and having time to review eligibility (m=2.6) were key barriers to CCT enrollment. Patients agreed that there were both the personal (m=3.7) and societal (m=4.1) benefits of CCTs. Similar to providers, key barriers to CCT participation for patients centered around lack of knowledge (concern about not knowing what drug they would receive (m=3.5) and that CCT agents would be too toxic (m=3.2)). Of the patients enrolled, 22 were at a point of new treatment or change in treatment and thus evaluable for rate of CCT referral and enrollment. In this subgroup, 21 (95.5%) received care plans with CCT recommendations. Following the study intervention visit, 8 (36.4%) of evaluable patients enrolled in a clinical trial. This compares favorably both with historical rates at our institution, where 13.8% of treatment eligible patients with lung cancer have been enrolled in CCTs, and with national averages which are less than 5%.

Conclusion:
CCT enrollment is critical to advancing the treatment of NSCLC, yet CCT enrollment in NSCLC remains low. For both providers and patients, the lack of readily accessible information about clinical trial eligibility and protocol details is a major barrier to CCT enrollment. The CPS is specifically designed to address these barriers. Indeed, in this pilot study, we showed a promising rate of CCT accrual with the use of the CPS. These findings should be validated in larger, randomized studies.

Abstract:
Background: Cetuximab, a chimeric monoclonal antibody targeting the epidermal growth factor receptor (EGFR), moderately increases survival in patients with advanced NSCLC. Our prior work suggested that EGFR gene copy number measured by fluorescent in-suit hybridization (FISH) could identify those patients most likely to benefit.Methods: Patients eligible for this NCTN multicenter open-label, phase III trial had histologically or cytological confirmed Stage IV NSCLC that was newly diagnosed or recurrent after previous surgery or radiation. Patients with controlled brain metastases were allowed entry. All patients were required to have tumor tissue available for EGFR FISH testing. Randomization was stratified by appropriateness for bevacizumab treatment, smoking status and M-substage. The co-primary objectives were progression-free survival (PFS) in EGFR-FISH positive (FISH+) patients and overall survival (OS) in the overall study population (OSP). Secondary objectives were OS in FISH-positive patients and clinical outcomes (PFS and OS) comparison among bevacizumab-appropriate (BA) and inappropriate (BI) patients.Results: The final accrual was 1,333 total and 1,313 eligible patients (control arm: 657 total, 275/382 BA/BI; cetuximab-containing arm: 656 total, 279/377 BA/BI). EGFR FISH status was determined on 976 patients, with 400 (41%) FISH+. Squamous carcinoma (SCCA) represented 24-25% of patients. PFS and OS were not significantly different in the OSP (HR (95%CI) =0.98 (0.87-1.09) and 0.94(0.84-1.06), respectively). There is some indication of benefit in PFS and OS (HR 0.91 (0.74-1.12) and 0.83 (0.67-1.04), respectively) in FISH+ patients, albeit not statistically significant. However, among FISH+ BI and SCCA patients, effect estimates for OS were 0.75 (0.57-1.00) and 0.56 (0.37-0.84), respectively. Cetuximab was generally well tolerated with a spectrum of adverse events consistent with prior reportsConclusion: The addition of cetuximab had minimal effect in unselected advanced NSCLC patients. In FISH+ patients there is a suggestion of benefit, predominantly in SCCA and BI. These data support using a new marker for determining who should receive an EGFR antibody inhibitor with chemotherapy.Support: NIH/NCI/NCTN grants SWOG: CA180888, CA180819; ECOG/ACRIN: CA180820; Alliance: CA180821; and in part by Bristol-Myers Squibb Co.

		N	PFS	OS
Analysis Group	OSP	FISH+	OSP	FISH+	OSP	FISH+
All Patients
	Cetuximab-Containing Arm, Median, 95% CI	656	199	4.6(4.2-5.2)	5.4(4.5-5.7)	10.9(9.6-12.0)	13.4(11.7-14.8)
	Control Arm, Median, 95% CI	657	201	4.5(4.2-4.9)	4.8(3.9-5.5)	9.4(8.7-10.3)	9.8(8.7-12.1)
	Hazard Ratio, 95% CI			0.98(0.87-1.09)	0.91(0.74-1.12)	0.94(0.84-1.06)	0.83(0.67-1.04)
	2-sided p-value			0.68	0.37	0.34	0.10
BA
	Cetuximab-Containing Arm, Median, 95% CI	279	86	5.6(5.3-6.1)	6.2(5.7-7.4)	12.7(10.9-13.4)	15.5(13.4-18.4)
	Control Arm, Median, 95% CI	275	80	5.9(5.5-6.6)	6.7(5.7-8.0)	11.6(10.5-13.8)	13.2(11.2-19.1)
	Hazard Ratio, 95% CI			1.05(0.88-1.25)	1.07(0.77-1.47)	1.04(0.86-1.25)	0.97(0.69-1.38)
	2-sided p-value			0.57	0.70	0.70	0.88
BI
	Cetuximab-Containing Arm, Median, 95% CI	377	113	4.1(3.6-4.4)	4.5(3.8-5.2)	9.2(8.2-10.9)	11.2(8.6-12.9)
	Control Arm, Median, 95% CI	382	121	3.8(3.1-4.2)	3.7(2.8-4.6)	8.2(7.3-8.7)	8.7(5.9-9.7)
	Hazard Ratio, 95% CI			0.93(0.80-1.07)	0.82(0.63-1.07)	0.88(0.76-1.03)	0.75(0.57-1.00)
	2-sided p-value			0.31	0.14	0.12	0.05
SCCA
	Cetuximab-Containing Arm, Median, 95% CI	160	55	4.2(3.7-4.6)	4.5(3.8-5.2)	9.6(8.2-11.5)	11.8(8.6-13.5)
	Control Arm, Median, 95% CI	161	56	3.7(2.8-4.3)	2.8(2.6-4.1)	8.0(7.1-8.9)	6.4(4.2-8.7)
	Hazard Ratio, 95% CI			0.88(0.70-1.11)	0.68(0.46-1.01)	0.85(0.67-1.08)	0.56(0.37-0.84)
	2-sided p-value			0.29	0.06	0.18	0.006

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Background:
This abstract is under embargo until September 9, 2015 and will be distributed onsite on September 9 in a Late Breaking Abstract Supplement.

Methods:


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Background:
Adjuvant chemotherapy for resected early stage NSCLC provides modest survival benefit. Bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor, improves outcomes when added to platinum-based chemotherapy in advanced stage non-squamous NSCLC. We conducted a phase 3 study to evaluate the addition of bevacizumab to adjuvant chemotherapy in early stage resected NSCLC. The primary endpoint was overall survival and secondary endpoints included disease-free survival and toxicity assessment.

Methods:
Patients with resected stage IB (>4 centimeters) to IIIA (AJCC 6th edition) NSCLC were enrolled within 6-12 weeks of surgery and stratified by chemotherapy regimen, stage, histology and sex. All patients were to receive adjuvant chemotherapy consisting of a planned 4 cycles of every 3 week cisplatin at 75 mg/m[2] with either vinorelbine, docetaxel, gemcitabine or pemetrexed. Patients were randomized 1:1 to arm A (chemotherapy alone) or arm B, adding bevacizumab at 15 mg/kg every 3 weeks starting with cycle 1 of chemotherapy and continuing for 1 year. Post-operative radiation therapy was not allowed. The study had 85% power to detect a 21% reduction in the overall survival (OS) hazard rate with a one-sided 0.025-level test.

Results:
From July 2007 to September 2013, 1501 patients were enrolled. Patients were 49.8% male, predominantly white (87.9%) with a median age of 61 years. Patients enrolled had tumors that were 26.2% stage IB, 43.8% stage II and 30.0% stage IIIA and 28.2% of patients had squamous cell histology. Chemotherapy options were utilized with the following distribution: vinorelbine 25.0%, docetaxel 22.9%, gemcitabine 18.9% and pemetrexed 33.2%. At a planned interim analysis, with 412 of 676 overall survival events needed for full information (60.9%), though the pre-planned futility boundary was not crossed, the Data Safety Monitoring Committee recommended releasing the trial results based on the conditional power of the logrank test. At the time of interim analysis, with a median follow-up time of 41 months, the OS hazard ratio comparing the bevacizumab containing arm (Arm B) to chemotherapy alone (Arm A) was 0.99 (95% CI: 0.81-1.21, p=0.93). The DFS hazard ratio was 0.98 (95% CI: 0.84-1.14, p=0.75). Completion of treatment per protocol was 80% on Arm A and 36% on Arm B. Statistically significantly increased grade 3-5 toxicities of note (all attributions) included: overall worst grade (67% versus 84%); hypertension (8% versus 30%), and neutropenia (33% versus 38%) on Arms A and B, respectively. There was no significant difference in grade 5 adverse events per arm with 16 (2%) on arm A and 19 (3%) on arm B.

Conclusion:
The addition of bevacizumab to adjuvant chemotherapy failed to improve survival for patients with surgically resected early stage NSCLC.

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Background:
EGFR mutant (M+) NSCLC is an archetypical oncogene-driven solid tumor, typified by high response rates when treated with a tyrosine kinase inhibitor (TKI), and median progression free survival of 10 months, commonly due to emergence of T790M. The genomic architecture and spectra of EGFR M+ tumours may provide insights to mechanisms of treatment failure and has not been well described to date.

Methods:
Paired tumor-normal exome/ transcriptome sequencing and SNP array was performed on 30 tbiopsies from 25 patients with TKI resistance (TKI-R) as well as multiple regions (n=46) of 8 treatment naïve (TKI-N), never smoker East Asian EGFR M+ NSCLC (L858R, n=5; exon 19 del, n=2; exon 20 ins, n=1). Genomic alterations were validated with targeted re-sequencing at a mean depth of 2000x. Alterations were identified and annotated using established pipelines.

Results:
Exome sequencing of 46 sectors (4-11 sectors/tumor) from 8 resected NSCLC (Stage IA, n=5; Stage IB, n=3), revealed a median of 52.5 validated mutations (Range: 15-112) per tumor. Primary EGFR mutations (including exon 20 ins) were identified as truncal events in all cases, with the notable absence of T790M even at sequencing depths of 2000x. Private mutations comprised 10-33% of all mutations per tumor, and in some cases harbored potential drivers of subclonal diversity including p53, AKT1 and ATXN1. For the 30 TKI-R tumors (T790M+, n=16; T790M-, n=14), exome sequencing revealed a higher mutation burden (median 80 vs 49 in TKI-N), while SNP array and expression data confirmed ERBB2 and MET as common co-existing resistance mechanisms. We next inferred the relevance of alterations and their hierarchical order (trunk, T; branch, B; private, P). In a TKI-N tumor where 11 sectors were subject to exome-sequencing, 39 of 112 mutations were truncal events – with MAP3K19 and PTEN splice site mutations co-existing with EGFR L858R mutation. Strikingly, when comparing the transcriptomic profiles of TKI-N and TKI-R tumors, all 8 evaluated sectors in this tumor clustered together with the TKI-R signature, suggesting that truncal co-mutations can contribute to primary TKI resistance. Finally, we attempted to curate novel genes in the 46 TKI-N sectors that may be implicated in TKI resistance by identifying genes in common with those altered in TKI-R samples with allele frequency > 0.25. We shortlisted approximately 150 recurrent genes or putative drivers – 85% of which were either trunk or branch mutations including TP53 (T,P), PTEN (B), LRP1B (B), GPRIN3 (B), MAP3K19 (T), ARID3A (P) and MED12 (P).

Conclusion:
Multi-region sequencing of 8 never smoker EGFR M+ NSCLC revealed a low mutation burden, with a significant proportion of alterations occurring as trunk or branch events. The different activating EGFR mutations were ubiquitous truncal events and T790M was not found in ultra-deep sequencing across 46 sectors. Mutation hierarchy provides a basis for patterns of TKI treatment failure: with co-occurring truncal events (e.g. MAP3K19, PTEN) potentially contributing to primary resistance, and the low incidence of private subclonal drivers consistent with the relatively high prevalence of T790M mutation in the setting of secondary resistance.

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Background:
The National Lung Screening Trial (NLST) has achieved a 7% reduction in mortality from any cause with low-dose computed tomography (LDCT) screening, as compared with the chest radiography arm. Other randomized trials are under way, comparing LDCT screening with no intervention in heavy smokers populations. None of these studies is designed to investigate the impact of smoking habits on screening outcome. In the present study, we have tested the effect of stopping smoking on the overall mortality of volunteers undergoing LDCT screening.

Methods:
Between 2000 and 2010, 3381 heavy smokers aged more than 50 years were enrolled in two LDCT screening programmes. Sixty-nine percent were males with median age of 58 years and median smoking exposure of 40 pack-years. Based on the last follow-up information, subjects were divided in two groups: current smokers throughout the screening period, and former smokers. The latter group included ex-smokers at the time of baseline screening (early quitters), and those who stopped smoking during the screening period (late quitters).The effect of smoking on mortality was adjusted according to the following covariates: gender, age, body-mass index (BMI), lung function (FEV1 %) and pack years at baseline.

Results:
With a median follow-up time of 9.7 years, and a total of 32,857 person/years (P/Y) follow-up, a total of 151 deaths were observed in the group of 1797 current smokers (17,846 P/Y) and 109 in 1584 former smokers (15,011 P/Y). As compared to current smokers, the Relative Risk (RR) of death of former smokers was 0.77 (95% CI, 0.60 to 0.99, p = 0.0416), corresponding to a 23% reduction of total mortality. Excluding 239 subjects who had stopped smoking from less than 2 years from the end-point of follow-up, RR was 0.64 (95% CI, 0.48 to 0.84, p = 0.0016), with a 36% mortality reduction. A similar risk reduction was observed in the subset of 476 late quitters (27 deaths, 4,777 P/Y), with a RR of 0.60 (95% CI, 0.40 to 0.91, p = 0.0158).

Conclusion:
Stopping smoking is associated with a significant reduction of the overall mortality of heavy smokers enrolled in LDCT screening programs. The benefit of stopping smoking appears to be 3 to 5-fold greater than the one achieved by earlier detection in the NLST trial.

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Abstract:
There are two clinical trial investigating the role of surgery in stage IIIA NSCLC.

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Abstract:
Introduction: Standard treatment of stage IIIA non-small-cell lung cancer consists of definitive concurrent chemoradiotherapy (CTx/RTx) protocols. Based on the broad heterogeneity of stage IIIA alone, there are selected patients (single mediastinal lymph node involvement, IIIA3 Robinson) where induction chemotherapy (CTx) followed by definitive surgery may be an alternative and valid approach preferably to test within prospective clinical trials with a close documentation of the toxicity/efficacy ratio. Patients and Methods: The medical literature (PUBMED) was reviewed looking for the search terms “induction chemotherapy“ and “stage III“ and “non-small cell lung cancer“. Furthermore large clincal trials were added that had been presented at important clinical conferences such as ASCO, WCLC and ESMO. Prospective phase-III clinical trials and prospective phase-II clinical trials were examined and cathegorized for efficacy and outcome parameters. We looked specifically for general patterns in the reporting of clinical trials results. Results: General outcome parameters for efficacy that have been reported were: 1) objective response rates 2) overall survival (median) 3) progression-free survival rates 4) complete resection rates (R0-resection) 5) pathological complete response rates (pCR) in the primary tumor and 6) pathological complete response rates (pCR) in the mediastinum. On the other hand important benchmarks for toxicity were 1) grade 3 and grade 4 maximum toxicity rates during induction 2) perioperative toxicity rates grade 3 and 4 3) treatment related death rates. Very few investigations have looked at patient reported outcome parameters such as symptom improvement or quality of life evaluation during the complete treatment protocol. Several groups have tried to improve outcome data by the use of 1) three-drug regimen as induction treatment 2) second- and third-generation platinum-based combinations 3) introduction of new molecular targeted agents (VEGF, EGF-R etc) especially looking closely at the pathological complete response rates induced by induction therapy 4) inclusion of different radiation schemas within a concurrent or sequential preoperative application protocols. Several reported trials have also tried to alternatively give a definitive CTx/RTx protocol with increased radiation doses and have not included a definitive surgical approach. These studies could not report data on pathological responses and some have alternatively looked at FDG-PET response to induction therapy as a surrogate marker for pathological response. Currently the treatment protocols with the highest reported pathological response (pCR) rates were based on cisplatinum and taxane (paclitaxel and docetaxel) combinations and induction protocols including concurrent cCTx/RTx regimen were those with the highest pathological efficacy in the mediatinum as well as in the primary tumor. Conclusions and Outlook: With the existing broad heterogeneity in patient selection within the different clinical studies performed it is currently difficult to give an overall recommendation about the most optimal treatment approach in this setting of stage IIIA NSCLC. Induction CTx could potentially serve as a backbone for including new treatment principles (eg. molecular targeted agents, immunotherapy, CTx/RTx protocols) into these multimodality treatment protocols and closely monitoring outcome by translational investigations and pathological response evaluations.

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Abstract:
The current IASLC/CAP/AMP guidelines indicate that testing for EGFR mutations and ALK fusions is recommended before instituting therapy in patients with advanced lung cancers with adenocarcinoma features. The guidelines indicate that the guidelines would be updated as other therapies become available for specific drivers. Since these guidelines were published, considerable information has become available on molecular changes that cause resistance to the first generation EGFR and ALK tyrosine kinase inhibitors (TKIs) and new 2nd and 3rd generation drugs to treat molecular resistance are in the clinic are likely to be approved in 2015. New drugs are also in development for other molecular drivers that have been reported in lung cancer including fusions that activate ROS1, RET, NTRK, and FGFR; mutations that activate KRAS, BRAF,HER2, and FGFR; and amplifications that activate MET, FGFR and HER2. It is also likely that some of these agents will approved in the near future. These developments bring into focus the most appropriate methods to test for molecular drivers in lung cancer. The techniques include direct sequencing, PCR testing for mutation hot spots, Next generation whole exome sequencing for mutations, translocations and amplifications, immunohistochemical testing for activated proteins or specific mutations, FISH testing for specific translocations, fusions, and amplifications. The sequential testing of one gene at a time is very inefficient especially with respect to the time it takes to complete testing, with the total cost and with respect to the amount of tissue necessary to complete the testing. Thus, multiplex testing is becoming far more common. However, in the US, the FDA’s companion diagnostic tests are one a time for specific tests for specific drugs. This one off policy is threatening the ability to perform one test for multiple analytes simultaneously. Hopefully, these issues can be resolved in the near future. What are the molecular changes that appear to be drivers for which there exist therapeutic TKIs? We can first discuss the development of resistance to 1st generation EGFR and ALK TKIs. About half of all patients who progress on a 1st generation EGFR TKI will have a secondary gatekeeper mutation, T790M that limits binding of 1st generation EGFR TKIs to the EGF receptor. 3rd generation EGFR TKIs such as AZD9291 and CO1686 (rocelitinib) have been shown to produce objective clinical responses in about 60% of patients with T790M who progress on a first generation EGFR TKI. These responses are associated with a median PFS of about 10 months. These drugs bind irreversibly to the T790M receptor and to activating mutations such as del19 and L858R but do not bind to the wildtype receptor. Therefore they have far less skin rash and diarrhea compared to the 1st generation inhibitors. Rocelitinb may cause hyperglycemia in up to a third of patients that is believed to be caused by a metabolite that inhibits IGFR. The use of oral anti-hyperglycemic agents such as metformin may be required for glucose control in these patients. Rocelitinib may also cause prolongation of the QTc on EKGs and thus monitoring is required. This side effect is rare but requires monitoring. AZD9291 may be associated with slightly more skin rash and diarrhea and uncommon reports of pneumonitis have been reported. The mechanism of resistance to these agents is under investigation but most often appears to be activation of alternative signaling pathways or phenotypic switching to a mesenchymal state. There are multiple tests available to detect the T790M mutation and many studies are evaluating its presence in circulating free DNA. Such analyses seem to be quite specific but less sensitive to analyses of tumor tissue. Testing for mutations in circulating free DNA is quite appealing because it does not require another tumor biopsy. Crizotinib which was the first agent approved for ALK positive cases, is also a potent ROS1 and MET inhibitor. ROS1 may be activated by fusion to other genes on the same chromosome and detected by FISH or Next generation sequencing. Crizotinib has been reported to produce objective response is about 60% of cases with ROS1 fusions with median progression free survival of about 16 months. Crizotinib has also been reported to produce objective responses in about 2/3 of patients with high MET amplification although the number of patients studied is very low. Additional studies are ongoing. Because MET amplification is frequent in patients who progress on 1st generation EGFR TKIs that do not have T790M, MET inhibitors are also being studied on this setting. Both ceritinb and alectinib have been approved for patients with ALK fusions who have progressed on crizotinib. It is clear that the two drugs have different activity among various resistance mutations for ALK. Thus, rebiopsy of tumor or testing of circulation free DNA may become standard in patients progressing on ALK TKIs as it is in patients progressing on EGFR TKIs. BRAF mutations occur in about 2% of advanced NSCLC patients and the V600E mutation is the most common. BRAF TKIs such as vemurafinib have been reported to produce frequent responses in NSCLC patients with V600E BRAF mutations. In melanoma the combination of BRAF inhibitors with MEK inhibitors has been more effective than BRAF inhibitors alone and this combination is being studied in NSCLC patient with BRAF mutations. HER 2 may be activated by either mutation or amplifications and the response to various HER inhibitors may vary by the method of activation. About 2% of patients have activation by amplification and about 2% by mutation (usually exon 20 insertions). The irreversible pan HER TKIs such as neratinib, afatinib and dacomitinib have not produced high response rates in these patients. However a phase 1 trial of the combination of niratinib with temsirolimus produced higher responses in both breast and lung cancers and a phase 2 study of the combination in lung cancers with HER2 mutations/amplifications is in progress. Other HER2 inhibitors have been reported to produce occasional responses but we await formal study of such agents. RET and NTRK fusions have been reported I about 1% of patients and there are sporadic reports of responses to specific TKIS. Formal studies are in progress but may not be reported for some time due to the rarity of the abnormalities and the fact that multiple TKIs are available. FGFR may be activated by amplification, fusion and mutations and there are both quite specific FGFR TKIs and multi-TKIs that have been studied in small numbers of patients. It is fair to say that response rates to specific FGFR TKIs are low in patients with squamous cell carcinoma patients with FGFR amplification. Additional studies with other biomarkers and other agents are ongoing. The most frequent oncogenic driver in lung cancer is KRAS. No specific TKI has been developed. Downstream inhibitors such as MEK inhibitors and FAK inhibitors have the most study to date. Response rates as single agents are relatively low and combination studies are in progress. In summary, the increased numbers of TKIs specific for various molecular drivers in lung cancer is becoming far more important not only a diagnosis but also at the time of progression. Future studies will focus on multiplex testing and testing of circulating free DNA.

Abstract:
Technologic and scientific development in medicine and the biomedical sciences has led to almost immediate transfer of knowledge and methodology applied initially in the research lab to the clinic, producing a profound impact in screening, diagnosis and treatment. These enormous amount of information and specialized skills in the medical practice have made it necessary to integrate multidisciplinary teams to improve quality of cancer care.Lung cancer is the most common neoplasia worldwide as well as the leading cause of cancer-related death, with more than 50% of patients presenting with stage IV disease at diagnosis (1). Therefore, lung cancer management usually requires the collaboration of surgeons, medical oncologists, radiation oncologists, pathologists, nurses, and other health care professionals (2). Given the fact that many patients will present with locally advanced or metastatic disease, only small amounts of tissue or cell preparations will be available for morphologic analysis, immunohistochemistry and molecular testing. Recommendations from academic centers and agencies are in favor of limiting the amount of immunohistochemical stains in order to save tissue for molecular assays, stressing the need to integrate pathologist to multidisciplinary teams, where clinical information is exchanged, and specific differential diagnosis and objectives established in a case-to-case basis (3). The traditional role of pathologist in lung cancer has been to establish histological diagnosis of malignancy, as well as proper taxonomic allocation according to widely accepted classification schemes. (4) This approach sets pathologist within single moment interventions early in the course of patient management, aside from opportunities to collaborate during the rest of care. However, the advent of personalized medicine, characterized by the identification of biological features in cells that predict benefit from specific targeted drugs, opened up the way for pathologist to actively participate with the team in the selection of treatment and patient follow-up. Overall, from 60-70% of NSCLC have specific mutations of well characterized oncogenic drivers, some of them with 1st line treatment drugs and many with targeted therapies under development. Current guidelines of advance stage disease recommend initial characterization of EGFR mutation status and ALK rearrangement, although there is building evidence to support testing of a number of actionable genes such as HER2, BRAF, MET, RET, ROS1, or other biomarkers with predictive capacity such as microsatellite instability (5). Multiple methods and technological platforms have been developed to identify gene mutations, and although most of them have very high specificity values, the sensitivity to detect a mutant clone from a background of wild type DNA is wide. Conventional Sanger sequencing will identify a mutation if it is present in 10-20% of the sampled cells, pyrosequencing increases the level to 1%, mutant-enriched polymerase chain reaction (PNA-LNA PCR, ARMS, etc.) can detect a mutant gene among as many as 10[3] wild-type alleles (0.1-1%) with comparative performance to next generation sequencing(6). These differences in analytical sensitivity do not only affect the number of EGFR mutated cases identified, but may also impact the clinical results obtained when using TKI therapy. For example, studies suggest that high EGFR mutation allele burden at diagnosis may be associated with increased progression-free survival and overall survival in patients treated with tyrosine kinase inhibitors, based in sensitivity differences between conventional sequencing and allele-specific PCR(7,8). In the light of these challenges, pathologist face the need to secure tissue availability and adequacy for testing in order to increase the diagnostic yield of molecular characterization. This demands the establishment of changes in sample management and processing, depending on the biological material to be tested. For example, rapid on-site evaluation may be performed in cytological specimens from fine needle aspirates. In the case of CT-guided transthoracic biopsies, one initial core may be submitted for frozen section or studied with cytological imprints to assess tumor viability. If proper cellular material is identified, this core may be entirely used for molecular testing and subsequent cores destined for histological processing. Once the tissue is paraffin-blocked, the tissue cuttings product of facing the block may be saved in a sterile, DNAase/RNAase-free tube for later use if necessary. It is established that patients will ultimately develop resistance to targeted therapies through different mechanisms, either the emergence of mutations in the target gene or the acquisition of mutations or over-expression of oncogenes that overcome this inhibition. Studies have proved that at tumor progression, a number of cases may have a morphological switch from adenocarcinoma to sarcomatoid carcinoma or small-cell carcinoma (9), requiring therapy adjustments. Re-biopsy allows molecular evaluation as well as morphologic analysis, however; it is an invasive procedure that not all patients may undergo. Alternative highly sensitive molecular methods may be used for patient follow-up without the need of invasive interventions. Blood sample-based PCR or NGS can detect circulating free DNA from the tumour (liquid biopsy), the concordance rate between tissue and plasma for EGFR mutation going from 58.3% to 93.1%, stressing the need of analytical improvement. Of especial interest is the fact that when examining the appearance of the T790M mutation in serial blood samples, this mutation could be detected in the plasma DNA before clinically evident disease progression. (10) NSCLC diagnostics is rapidly changing to combine a dual morphologic-molecular approach, where initial HE-slide examination is used to confirm malignancy and to allocate the tissue sample to a group of molecular test relevant to the cellular composition of the tumour. Continuous increase in the number of genes responsible of oncogenesis in lung carcinoma ensures the development of new targeted drugs as well as active communication from all the members of the multidisciplinary team. References 1) Aisner DL, Marshall CB. Molecular pathology of non-small cell lung cancer: a practical guide.Am J Clin Pathol. 2012 Sep;138(3):332-46. 2) Pan CC, Kung PT, et al. Effects of Multidisciplinary team care on the survival of patients with different stages of Non-Small Cell Lung Cancer: A National Cohort study. PLoS One. 2015 May 12;10(5):e0126547. 3) Lindeman NI, Cagle PT, Beasley MB, et al: Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Arch Pathol Lab Med 137:828-860, 2013 4) Cagle PT, Myers J.Precision medicine for lung cancer: role of the surgical pathologist. Arch Pathol Lab Med. 2012 Oct;136(10):1186-9. 5) Dacic S, Nikiforova MN.Present and future molecular testing of lung carcinoma. Adv Anat Pathol. 2014 Mar;21(2):94-9. 6) Young EC, Owens MM, Adebiyi I, et al. A comparison of methods for EGFR mutation testing in non-small cell lung cancer. Diagn Mol Pathol. 2013 Dec;22(4):190-5. 7) Kim HS, Sung JS, Yang SJ. Predictive efficacy of low burden EGFR mutation detected by next-generation sequencing on response to EGFR tyrosine kinase inhibitors in non-small-cell lung carcinoma. PLoS One. 2013 Dec 20;8(12):e81975. 8) Zhou Q, Zhang XC, Chen ZH. Relative abundance of EGFR mutations predicts benefit from gefitinib treatment for advanced non-small-cell lung cancer. J Clin Oncol. 2011 Aug 20;29(24):3316-21. 9) Sequist LV, Waltman BA, Dias-Santagata D. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011 Mar 23;3(75):75ra26. 10) Sorensen BS, Wu L, Wei W, et al. Monitoring of epidermal growth factor receptor tyrosine kinase inhibitor-sensitizing and resistance mutations in the plasma DNA of patients with advanced non-small cell lung cancer during treatment with erlotinib. Cancer. 2014 Dec 15;120(24):3896-901.

Abstract:
Remarkable progress has been made in the treatment of ALK-rearranged NSCLC with the initial approval of crizotinib. Multiple next-generation agents are impacting care as approved therapies in some regions of the world or in first- and second+-line clinical trials where early data are promising. Additional development of crizotinib and newer agents in ROS-1-positive NSCLC is quickly changing how patients are evaluated at diagnosis. Moreover, maturing data in BRAF-mutated NSCLC with BRAF and MEK inhibitors, along with early data in RET- and FGFR-positive NSCLC support broader and earlier testing in the care of patients with advanced NSCLC. The data for, and challenges of, selecting the best first-line (and beyond) options for patients with ALK, ROS-1, BRAF, RET, FGFR, or other altered NSCLC will be reviewed.

Abstract:
When more than one drug exists for the same target (e.g. erlotinib, icotinib, gefitinib and afatinib for EGFR mutant NSCLC), decisions in terms of which drug to commence targeted therapy with may be based on personal experience, side effects and cost. Until head-to-head trials in the same sensitive target population read out, any potential efficacy differences remain speculative. Other than to switch out drugs based on tolerability issues, the anti-cancer benefit from sequential use of different drugs in the same class/generation as a strategy separate from any benefit of ongoing target suppression post-progression with the same drug also remains largely unproven. However, as new generation drugs are developed, drugs directed against the same dominant driver now exist which have activity against both the initial form of the target and common acquired resistance forms (e.g. ceritinib and alectinib for ALK+ NSCLC, or rociletinib and AZD9291 for EGFR mutant NSCLC). While initial licensing strategies have focused on sequential use of such drugs after first generation drugs, studies are also underway looking to see if first line use of these next generation drugs could be more beneficial in the relevant molecularly selected population. As mechanisms of acquired resistance become better understood, specific actionable second drivers, co-existing with the initial sensitive form of the oncogenic driver, are now being identified (e.g. MET amplification with EGFR mutations). Preclinically, inhibition of both drivers is required to achieve cancer control in this setting. Clinically, trials of combination therapy are showing promise with determination of the exact predictive cutpoint in continuous variables such as MET emerging as a key issue. With more extensive molecular testing being deployed upfront, rather than in tiered testing strategies and separate from in the acquired resistance setting, multiple potential molecular drivers on each patient are now being reported to treating physicians. When some of these are known acquired mechanisms of resistance (e.g. MET or T790M in EGFR mutant), concern may arise re whether initial therapy will be effective. However, most diagnostic assays do not give information on the proportion of each molecular aberration. Consequently, a highly sensitive test can detect a small clonal fraction of a resistance mechanism that will later be selected out by use of the initial targeted therapy, but does not preclude an initial response. In contrast, germline abnormalities present in all cells, such as can occur with T790M, would preclude an initial response to the relevant targeted therapy. As such germline events are very rare, initial use of a targeted agent still makes most sense. While defined oncogenic drivers are often perceived to be mutually exclusive (e.g. EGFR and ALK), exceptions do occur. While there appears to be no specific growth advantage to having two oncogenic drivers in the same cell in the absence of a specific selection pressure, such examples of double drivers could reflect false positives, true positives where one of them is somehow non-functional (e.g. an ALK rearrangement detected by FISH, which is not transcribed), or true positives where each is present in a different cell population. Again, as proportional positivity is not a feature of most diagnostic assays, starting with monotherapy for the abnormality that is either easiest to target or has the lowest chance of being non-functional (e.g. a point mutation over a chromosomal abnormality), makes the most clinical sense. At acquired resistance, rebiopsy and reanalysis for changes in biology including the dominance of the other initial driver should be strongly considered. Perhaps the biggest challenge has been the proliferation of multiplex reports detailing a range of abnormalities in the same cancer, where the exact driver status and biological significance of the abnormalities remains unclear. Caution should be exercised in assuming that all changes are true drivers and extreme caution should be exercised if attempting to combine available targeted drugs that have not been combined before in the absence of a formal phase I study.

Abstract:
Paraneoplastic Syndromes (PNS) are a group of clinical disorders that are associated with malignant diseases that are not directly related to the physical effects of the primary tumour (Spiro 2007). The mechanisms by which PNS occur is not fully understood (Dalmau 2014) but is related to the production of polypeptide hormones or cytokines by the cancer itself or an immune response to the cancer. PNS may occur in 10% of patients with lung cancer and with the type of cancer influencing the nature of syndrome (Kanaji 2014). A wide variety of PNS have been associated with lung cancer with the most common syndromes being endocrine and neurological syndromes. This paper will only address these two groups of syndromes. Paraneoplastic Endocrine Syndromes include: Inappropriate Antidiuretic Hormone Secretion: hyponatremia is seen in 30-70% of patients with lung cancer with only 1-5% having symptoms and mostly associated with small cell lung cancer (SCLC); symptoms include confusion, seizure, reduced consciousness and coma (Spiro 2007). Hypercalcaemia: the incidence ranges from 2-12% in lung cancer; symptoms include nausea, vomiting, abdominal pain, constipation, polyuria, thirst, dehydration, confusion and irritability (Spiro 2007). Cushing Syndrome: production of adrenocorticotropic hormone(ACTH) is the most common explanation with approximately 50% being neuroendocrine lung cancers with 36%-46% carcinoid tumours and 8%-20% SCLC of cases; symptoms include weakness, muscle wasting, drowsiness, confusion, psychosis, oedema, hypokalaemia alkalosis and hyperglycaemia. hypertrophic osteoarthropathy (HOA) and finger clubbing: 90% cases in lung cancer Prevalence of 5-15% in lung cancer most common with squamous cell and adenocarcinoma. occurs due to proliferation of connective tissue beneath the nail bed with HOA causing distal expansion of the long bones; The Paraneoplastic Neurological Syndromes most commonly displayed are peripheral neuropathies and include Lambert-Eaton Myasthenic Syndrome, necrotizing myelopathy, cerebral encephalopathy, visual loss and visceral neuropathy. Symptoms include muscle weakness, cognitive and personality changes, ataxia, cranial nerve deficits or numbness. Classical and Non-Classical Symptoms have been defined (Graus 2004 Table 1) to aid in diagnosis. These syndromes are often associated with the presence of anti-Hu antibodies which are produced together with antigen-specific T lymphocytes and attack parts of the nervous system (Pelosof 2010). This syndrome is detected in 80% of cases before cancer is diagnosed (Honnorat 2007) and upto 20 per cent of those with SCLC have detectable antibodies although this syndrome will not necessarily develop (Darnell 2003). There is a reported 4-5% incidence in SCLC. Diagnostic Pathway Patients with lung cancer usually present with multiple symptoms with a time delay between symptom recognition and the ultimate diagnosis of lung cancer. The presence of a PNS may not necessarily preclude treatment with a curative intent which may help in the improvement of symptoms. Pathways of care commence with clinical evaluation, CT scan, blood screen and rapid evaluation for the next diagnostic test. It is at this point where a PNS may become apparent and can aid in the diagnosis of lung cancer. Where there are concerning symptoms for Paraneoplastic Neurological Syndrome and there is difficulty in identifying the underlying cancer: antibody screening can be considered but require considered interpretation as patients without cancer can harbour paraneoplastic antibodies, variation in the consistency of the presence of antibodies can be associated with different syndromes and the absence of antibodies may not exclude a syndrome; PET may identify neurological syndrome activity; electrophysiology may confirm the syndrome but are not always associated with cancer; MRI can assist in the diagnosis of limbic encephalitis as atrophy can be detected. Treatment As symptoms often present prior to the confirmed diagnosis it is important to treat the signs and symptoms of: Hypercalcaemia with: an increase in fluid intake; Bisphosphonates. Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) with: fluid restriction; chemotherapy (effective in 80% of SCLC cases); Demeclocycline; Vasopressin receptor antagonists (Conivaptan, Tolvaptan). direct inhibition of cortisol secretion to reduce circulating glucocorticoids (eg Ketoconazole); Octreotide (blocking the release of ACTH); bilateral adrenalectomy. Cushing syndrome by: Once the diagnosis of lung cancer has been established the optimal treatment for any PNS is to treat the disease. There is no randomised control trial data for treatment for PNS on which to base practice (Giometto 2012) but there is evidence that the anti-cancer treatments (surgery, radiotherapy, chemotherapy, biological therapies, immunotherapies, immunomodulation and immunosuppression including glucocorticoids) may be beneficial. One of the challenges is that irreversible neuronal damage may have already happened by the time the diagnosis has been established. Supportive Care The symptoms of PNS can have a major impact on the patient’s quality of life and on individual care requirements. It is recommended that a Health Needs Assessment (DoH 2011) is undertaken when symptoms first present, prior to starting any intervention and at the end of treatment. This assessment should take into account the patient’s physical, psychological, social, spiritual and practical needs and will enable interventions to be put in place to maximise the quality of daily life. When symptoms present the psychological and physical impact can be devastating as immobility, discomfort, cognitive dysfunction and loss of the ability to self-care can affect the patient and care providers. In the UK the role of the Lung Cancer Nurse Specialist (RCLCF 2014) is ideally placed to address these concerns not only when the diagnosis is first made but throughout treatment and beyond by providing psychological support and symptom management, home care coordination and referrals to other health professional such as Physiotherapists and Occupational Therapists. Once primary treatment has taken place the ongoing monitoring of response to treatment is required together with a comparison of presenting symptoms. Patients should know what to do if these reoccur and how they should access their clinical team. Conclusion The management of PNS is complex and in the absence of randomised trials there is available guidance to help with the management of Paraneoplastic Syndromes. The individual care of each patient should be tailored to the diagnosis, symptoms and holistic needs. References Dalmau J, Rosenfeld M (2014) Overview of paraneoplastic syndromes of the nervous system (Accessed 20[th] June 2015) http://www.uptodate.com/contents/overview-of-paraneoplastic-syndromes-of-the-nervous-system#subscribeMessage Darnell R, Posner J (2003) Paraneoplastic syndromes involving the nervous system. NEJM 349(16):1543-54. Department of Health (2011) Improving Outcomes: A strategy for Cancer. DoH Giometto B, Vitaliani R, Lindeck-Pozza E et al (2012) Treatment for Paraneoplastic Neuropathies. Cochrane Library (Assessed 30[th] June 2015) http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD007625.pub2/abstract Graus F, Delattre J, Antoine J et al (2004) Recommended diagnostic criteria for paraneoplastic neurological syndromes. Journal of Neurology, Neurosurgery and Psychiatry 75(8):1135-40 Honnorat J, Antoine, JC (2007) Paraneoplastic neurological syndromes Orphanet Journal of Rare Diseases 2.22 Kanaji N, Watanabe N, Kita N et al (2014) Paraneoplastic syndromes associated with lung cancer. World Journal of Clinical Oncology, 5(3), 197-223 Pelosof L, Gerber D (2010) Paraneoplastic syndromes: an approach to diagnosis and treatment. Mayo Clinic Proceedings 85:838–854. Roy Castle Lung Cancer Foundation (2013) Understanding the Value of Lung Cancer Nurse Specialists. RCLCF Spiro S, Gould M, Colice G (2007) Initial evaluation of the patient with lung cancer: symptoms, signs, laboratory tests, and paraneoplastic syndromes: ACCP evidenced-based clinical practice guidelines (2nd edition) Chest. 132:149S–160S. Figure 1

Abstract not provided

Abstract:
There were 35,371 deaths from Lung cancer in the United Kingdom in 2012 and it remains the leading cause of United Kingdom cancer deaths (Cancer Research UK 2014). Many patients can carry a high burden of symptoms, so the nature and scale of the disease can present significant challenges for the patients, their carer’s and for those who care for them within the National Health Service. As health care professionals we have a responsibility to provide an excellent service including communication and support of the highest standard. Lung Cancer Nurse Specialists (LCNS) are involved across all stages of the patient journey and have a distinctive role in communicating information and enabling patients with lung cancer to take an inclusive role in decisions around their care. They are mostly known as the patient’s keyworker, although the identified keyworker may change throughout the pathway according to the patient’s needs. Effective face to face communication along with regular telephone contact between the LCNS and the patient and carers can aid the development and implementation of individualised care plans. The LCNS should be available at all stages to complement care and facilitate best practice, responsible for the provision of information to patients and their families in a timely manner, within a supportive environment (NICE 2011). With an average annual new caseload of 122 patients per LCNS (UKLCC, 2012) there can be an overstrain on the level of support provided by the LCNS which can lead to inequity of access and inconsistent support (Leary et al, 2008). Yet consistent specialist support and advice are essential as individuals care needs and treatment options can be complex. With this in mind we have restructured the lung cancer service at Aintree Hospitalwith the development of a support worker role. Implementation of the role is competency led and training needs structured around specific pathways (Brummell et al, 2014). With correct delegation, such as being an access point for patients and health care professionals, the support worker can release the LCNS to enable a more effective use of LCNS skills, improving patient experience. United Kingdom Lung Cancer Coalition (UKLCC, 2012) recommends that all lung cancer patients should be able to access LCNS support and advocacy when they need it throughout their whole journey to support their holistic needs. Holistic care is total patient care that considers the physical, psychological, social, economic and spiritual needs of the person with his or her response to illness. Holistic Needs Assessment (HNA) helps form a base on which to navigate care needs of the individual. It provides a framework to discuss individuals concerns and how they are feeling, to identify and understand individual needs, enable care that is personalised, sign post to appropriate agencies, and enables patients to access, identify, appraise and interpret information. HNA should be performed at or near diagnosis and at the end of treatment and whenever health and social needs change. Indeed, work undertaken by Tod et al (2013) ‘Opening Doors to treatment’ explored the impact of LCNS’s on access to anti-cancer treatment. The report demonstrated why and how the LCNS has an impact in accessing treatment, with the communication and coordination aspects of the LCNS role being essential in realising the impact in increasing treatment access. This paper sets out to demonstrate as to why the LCNS in the UK is pivotal to navigating the care of the lung cancer patient. Brummell S, Tod A, Guerin M, Beattie V et al (2014) An evaluation of the role of the support workers in lung cancer. Cancer Nursing Practice. 14, 1, 22-27. Cancer Research UK (2014) Lung Cancer Statistics. [Online ]http:// cancerresearchuk.org/health-professional/cancerstatistics-by-cancer-type/lung-cancer/mortality [Accessed June 30 2015] Leary A, Bell N, Darlison L et al (2008) An analysis of lung cancer clinical nurse specialist workload and value. Cancer Nursing Practice. 7, 10, 29-33. National Institute of Clinical Excellence (NICE) (2011) Diagnosis and treatment of Lung Cancer. Department of Health. London. UK Lung Cancer Coalition (2012) The Dream MDT for Lung Cancer: Delivering High Quality Lung Cancer Care and Outcomes

Abstract:
Occupational therapists are integral members of the lung cancer multidisciplinary team, working with lung cancer patients in the inpatient hospital setting, hospital outpatient clinics and in the community. The focus of the occupational therapist is on enabling an individual’s participation in chosen everyday activities (Morgan DD and White KM, 2012). For people living with metastatic lung cancer, this focus is on enabling continued participation in the face of functional decline and increasing symptom burden. This focus can also encompass rehabilitation for people who have undergone curative treatment for their lung cancer, with the aim of facilitating a return to previous chosen and meaningful roles. Occupational therapists can assist people living with lung cancer prioritise their goals while managing the side effects of treatment. They also have a vital role in assisting the person living with lung cancer as their function changes with progressive disease. People living with lung cancer experience high symptom burden, which can include refractory breathlessness, fatigue and pain (Yang P et al., 2012). There is a growing body of evidence for occupational therapy interventions for people living with cancer to assist with symptom management and many of these interventions are applicable for people living with lung cancer (Morgan DD and White KM, 2012). Interventions utilised by occupational therapists when working with people living with lung cancer include task analysis, task modification, equipment prescription, priority setting and relaxation therapy. The occupational therapist is in a unique position to facilitate mastery of non-pharmacological interventions to assist in the management of refractory breathlessness and fatigue. It is important to teach techniques early in the lung cancer trajectory, to ensure mastery prior to the escalation of symptoms. This assists with preventing decreasing function and supports the engagement of the individual in valued activities (White KM, 2013). Occupational therapy management of breathlessness has been extensively researched in chronic lung conditions. The work of Migliore Norweg et al (Migliore Norweg A et al., 2005)focuses on interventions targeting improvement in everyday function for people living with COPD through mastery of breathing techniques and task modification. These interventions focus on managing breathlessness during activities that provoke breathlessness. Participation in pulmonary rehabilitation programmes is an established form of care for people with chronic lung disease. There is now a growing interest in the role of pulmonary rehabilitation to optimise function pre and post surgery for lung cancer (Pasqua F et al., 2013), as well as the role of exercise generally for people living with lung cancer (Bade BC et al., 2015, Lin Y et al., 2014, Cheville AL et al., 2012). The use of rehabilitation programmes for people living with cancer are being reported more frequently in the literature, and the occupational therapist is identified as a key team member (Silver JK and Gilchrist LS, 2011). Energy conservation techniques are useful in managing both fatigue and breathlessness. The occupational therapist completes a detailed assessment, including task analysis of how the person completes their everyday activities. This then informs interventions which can include behaviour and task modification, relaxation techniques, biofeedback, prescription of adaptive techniques and environmental modifications (White, 2013). Those living with advanced lung cancer may not have the time, energy or function to achieve full mastery of fatigue and breathlessness management techniques. Using adaptive equipment can be an effective and immediate way of improving function and assisting with symptom management for people living with advanced lung cancer. Conclusion Occupational therapy interventions aim to improve and optimise a person’s participation in everyday activities (World Federation of Occupational Therapy, 2010). Internationally, there are few occupational therapists that specialise in the field of lung cancer. This has led to a paucity of evidence and research into occupational therapy interventions that may benefit people living with lung cancer. Many interventions utilised by occupational therapists have a research base in non-malignant conditions and nursing literature. It is critical that occupational therapists build on this evidence and continue to research the efficacy of interventions used to optimise function for people living with lung cancer. The focus of occupational therapy interventions for people living with lung cancer is on enabling continued participation in valued and chosen activities in the face of functional decline and increasing symptom burden. References BADE BC, THOMAS DD, SCOTT JB & SILVESTRI GA 2015. Increasing physical activity and exercise in lung cancer: reviewing safety, benefits, and application. Journal of Thoracic Oncology, 10, 861-871. CHEVILLE AL, DOSE AM, BASFORD JR & RHUDY LM 2012. Insights into the reluctance of the patients with late-stage cancer to adopt exercise as a means to reduce their symptoms and improve their function. Journal of Pain and Symptom Management, 44, 84-94. LIN Y, LIU MF, TZENG J & LIN C 2014. Effects of walking on quality of life among lung cancer patients. Cancer Nursing, Epub ahead of print. MIGLIORE NORWEG A, WHITESON J, MALGADY R, MOLA A & REY M 2005. The effectiveness of differenct combinations od pulmonary rehabilitation on program components: A randomized controlled trial. Chest, 128, 663-672. MORGAN DD & WHITE KM 2012. Occuptional therapy interventions for breathlessness at the end of life. Current Opinion in Supportive and Palliatve Care, 6, 138-142. PASQUA F, GERANEO K, NARDI I, LOCOCO F & CESARIO A 2013. Pulmonary rehabilitation in lung cancer. Monaldi Archives for Chest Diseases, 79, 73-80. SILVER JK & GILCHRIST LS 2011. Cancer rehabilitation with a focus on evidence-based outpatient physical and occupational therapy interventions. American Journal of Physical Medicine and Rehabilitation, 90, S5-S15. WHITE KM 2013. Occupational therapy interventions for people living with advanced lung cancer. Lung Cancer Management, 2, 121-127. WORLD FEDERATION OF OCCUPATIONAL THERAPY 2010. Definitions of occupational therapy from member organisations. World Federation of Occupational Therapy. YANG P, CHEVILLE A, WAMPFLER JA, GARCES YI, JATOI A, CLARK MM, CASSIVI SD, MIDTHUN DE, MARKS RS, AUBRY M, OKUNO SH, WILLIAMS BA, NICHOLS FC, TRASTEK VF, SUGIMURA H, SARNA L, ALLEN MS, DESCHAMPS C & SLOAN JA 2012. Quality of life and symptom burden among long-term lung cancer survivors. Journal of Thoracic Oncology, 7, 64-70.

Abstract:
Due to toxicity during chemoradiation, patients are at risk for discontinuation of treatment and might not benefit optimally from this treatment.Small intervention trials are a possible tool to reduce toxicity within limited time. Toxicity and discontinuation of treatment were scored in 188 NSCLC patients treated with concurrent chemoradiotherapy. Literature based small intervention studies were performed for the reduction of toxicity Severe toxicity was seen in 33% of the patients; discontinuation of treatment in 20%. Esophagitis, gastro-intestinal toxicity and renal impairment were the most prominent toxicities. Intervention studies led to a reduction of nausea, weight loss, nephro toxicity and dysphagia CCRT for NSCLC is the treatment of choice at the cost of severe toxicity. Small intervention studies have shown to be benificial in reducing severe toxicity, enabling patients to accomplish CCRT en thus benifit optimal from this treatment.

Abstract:
Lung cancer survivors may suffer difficulty breathing, coughing, fatigue, anxiety, depression, insomnia and pain. Lung cancer survivors often experience a reduced quality of life. The good news is that quality of life can be improved with exercise and it should be considered for every patient. Exercise reduces the risk of lung cancer and is associated with reduced mortality. Exercise also lessens adverse symptoms and may improve quality of life, by enhancing physical and social function and lessening fatigue. The following are three of the more recent studies that have examined the benefits of exercise for lung cancer patients: 1. A 2012 study from Denmark looked at 25 patients with stage III/IV non-small cell cancer, and four patients with extensive disease small cell lung cancer. They participated in a 6-week supervised structured exercise and relaxation-training program. The researchers found that of the 23 patients, who completed the program, the majority adhered to the program and there were significant improvements in VO2 peak and 6-minute walking distance, as well as in muscle strength. The patients also reported a significant improvement in emotional well being. 2. In 2014, a larger study in Germany, included 40 patients with predominantly advanced NSCLC, who were receiving simultaneous or sequential radio chemotherapy or chemotherapy alone. The authors concluded, “ In this pilot study, endurance and strength capacity improved over time, indicating the rehabilitative importance of the applied intervention.” 3. In 2015, Dr. Gerard Silvestri, Dr. Brett Bade, David Thomas, and JoAnn Scott at the Medical University of South Carolina researched the benefit of physical activity and exercise for lung cancer patients. Their results were published in the Journal of Thoracic Oncology, June 2015. They found that physical activity should be considered as a therapeutic option for patients with lung cancer. They also concluded that exercise is safe, reduces symptoms, improves quality of life, increases exercise tolerance, and decreases length of hospitalization and post-surgery complications for lung cancer. Additionally, health care professionals should recommend exercise and encourage physical activity in patients at any stage of lung cancer. We can conclude from these studies and from my experience of working with this population that lung cancer survivors benefit from cancer exercise programs. These programs teach survivors how to exercise properly, and provide an exercise schedule. They can also provide a social and educational forum. Lung cancer patients may see even the idea of exercising as overwhelming, particularly if they suffer from shortness of breath, coughing or fatigue.The Medical University of South Carolina study found that patients with lung cancer want advice about physical activity from a cancer center physician before, during and following cancer therapy. The researchers also found that, when patients received this type of advice, there was a greater likelihood that the patients would comply with an exercise program. Why exercise during and after treatment or surgery? Exercise is a safe and inexpensive cancer therapy that reduces symptoms and improves quality of life. It improves strength, endurance, pulmonary function and flexibility, decreases the side effects of treatment and post-operative complications. Inactivity in cancer patients is associated with poorer outcomes and can cause the heart and muscles to regress and become less efficient. Being physically active not only helps prevent lung cancer in the first place, but it appears to also improve survival and quality of life for those already diagnosed. How much and what type of exercise is needed? The goal is to be able to exercise every day with a total of 150 minutes a week, the same as a healthy person. Lung cancer survivors should progress slowly, set goals, and listen to their bodies. Exercises can be performed initially in small increments of 10 minutes at a time depending on the fatigue level. Aerobic exercise is a great way to improve fitness. It not only improves cardiac function, but also improves the oxygen capacity. Aerobic exercises include walking, dancing, or any activity that increase the heart rate. Participate in enjoyable low intensity activities. Low intensity exercise such as walking is a safe way to begin. Aerobic exercise can be performed at a time that is convenient and there is no need to belong to an expensive gym. You can start by walking around a room in the house and slowly increase the distance walked. This can be done several times a day. You can use a pedometer to measure your steps and to help you set and attain goals. When sedentary one loses strength and gets weaker. Try to add movement to your day. You can take the stairs, park far from your destination, dance or whatever you enjoy that involves movement. Lung cancer patients may also benefit from strength training because it can strengthen weakened muscles. Fatigue can lead to sedentary behavior. Muscle mass will decrease if you sit or lie in bed a lot. By getting stronger it may be possible to return to work and take care of activities of daily living. Strength training can help you to improve balance, posture and increase bone strength. Patients with shortness of breath due to their cancer should perform stretching exercises daily to increase lung capacity. These can help to keep chest muscles loose and encourage deep breathing. Stretching can also help improve posture. Sitting down all day at a desk or driving can cause rounded shoulders and kyphosis, which can decrease lung capacity. It is also good to exercise prior to surgery and treatments and for those who are not surgical candidates. Exercise before surgery has multiple benefits such as improved quality of life, pulmonary capacity, endurance and strength coupled with reduced fatigue and surgical complications. Fitness level before surgery may predict risks of surgical complications and pre-surgery fitness levels may also predict how long lung patients may live beyond traditional markers of longevity. Despite limited lung capacity, exercise can help patients with lung cancer improve their quality of life by reducing fatigue, adverse symptoms and depression, while improving muscle strength, flexibility and mood.

Abstract:
The ability to identify and therapeutically target specific mutations (typically exon 19 deletions and L858R) in the Epidermal Growth Factor Receptor (EGFR) gene marked the beginning of personalized medicine for NSCLC. Phase III clinical trials with the EGFR tyrosine kinase inhibitors gefitinib, erlotinib and afatinib demonstrated superiority of these agents over chemotherapy establishing these agents as standard therapy for EGFR mutation positive NSCLC. However, resistance to therapy invariably occurs through multiple, heterogeneous mechanisms of which a secondary gatekeeper mutation in EGFR, T790M, is the most frequent, being identified in 50-60% of patients at the time ofprogression after initial EGFR TKI. EGFR T790M is thought to result in resistance by increasing the affinity for ATP rather than simple stearic hinderance. Recently novel irreversible inhibitors, structurally distinct to earlier generation compounds, have been developed that inhibit T790M while having relatively less potency against wildtype EGFR including rocelitnib (C01686) and AZD9291. Phase I/II studies have demonstrated responses to rocilitinib (CO1686) and AZD9291 in about 60% of patients with T790M positive disease. Preliminary data indicates the degree of response may correlate with the allelic frequency of T790, with greater degrees of responses in patients with higher proportions of T790M. Resistance to these compounds has been described clinically and includes loss of T790M, small cell transformation as well asdevelopment of tertiary mutations C7957 (resistance to AZD9291).

Abstract:
Recent advances in targeted therapies and the molecular analysis of tumor samples have led to recommendations that EGFR mutation testing be implemented as standard of care in non-small cell lung cancer (NSCLC) of non-squamous type. This is in large part because of substantial benefits provided to patients treated with EGFR tyrosine kinase inhibitor (TKI) therapy, particularly those patients whose tumors are positive for activating, sensitizing mutations in EGFR. Despite these benefits, resistance to EGFR TKIs inevitably develops in all cases. The most common molecular mechanism of acquired resistance in this setting, occurring in approximately 50% of cases, is the evolution of a secondary ‘gatekeeper’ mutation which results in p.T790M (T790M). This acquired mutation results in a reduction in affinity of EGFR for the TKIs, while preserving catalytic function of the tyrosine kinase domain, The testing for T790M at the time of progression on TKI has emerged as an important clinical practice, as new-in-class EGFR TKIs demonstrate activity against this subset of resistant tumors. Because T790M initially emerges as a sub-clonal event, technical elements involved in its detection become paramount. Most importantly, achieving a high technical sensitivity to allow for detection of a sub-clonal (low alleleic frequency) phenomenon is critical for assays designed to detect this mutation. Sanger sequencing, for example, lacks the technical sensitivity to adequately identify low variant frequency events, and therefore alternate mechanisms of testing are required. Additional factors requiring major consideration in detection of T790M include potential sampling bias (particularly for the small biopsies or fine needle aspirates that are typically acquired), heterogeneity between multiple progressing lesions, cellular components of post-treatment biopsies, and technical ability to perform tumor enrichment to enhance detection. Genomic alterations resulting in T790M are uncommonly detected prior to TKI therapy, likely owing to the technical sensitivity of assays used to query for the presence of this alteration. Studies employing extraordinarily sensitive assays have demonstrated the presence of T790M as a subclonal event prior to TKI therapy in many tumors. Thus clonal selection under the pressure of TKI is a major mechanism allowing this alteration to be identified in the setting of progression on targeted therapy using less analytically sensitive assays. The secondary implication of this finding is that assays employed for detection of T790M must be adequately sensitive, but not over-sensitive to allow for the appropriate identification of what can best be considered the dominant mechanism of resistance. Others have postulated that highly sensitive detection of T790M prior to therapy could be used to determine a combination therapy approach which effectively prevents the evolutionary advantages of this sub-clone. In the uncommon instance that this alteration is identified at a high level pre-TKI therapy using standard assay approaches (<5% of cases), it can be associated with a germline alteration leading to a genetic predisposition for lung cancer. Recently, there has been great interest in the potential to monitor for the emergence of T790M alterations in the periphery, either via circulating tumor cells or circulating cell-free DNA. This approach is particularly attractive as it reduces requirements for invasive tissue sampling and can allow for a continuous monitoring approach. While the technical elements of liquid biopsy testing have been diversely applied, with very little in the way of consensus on methodology, numerous studies have demonstrated the promise of liquid biopsy approaches for both primary mutation detection as well as evaluation for T790M. In some cases, peripheral detection of T790M was demonstrated substantially before radiographic evidence of progression, a key proof-of-principle that such monitoring could be utilized as an effective approach for disease monitoring. Similar approaches for chimerism analysis or BCR-ABL1 transcript monitoring in the setting of bone marrow transplant or TKI therapy for chronic myelogenous leukemia, respectively, have been very successful. Major challenges still exist for both tissue-based and peripheral blood-based detection of T790M. Determination of the ideal level of assay technical sensitivity required for prediction of response to T790M-directed therapies will be a critical component to the implementation of these drugs in the clinic. In addition, for tissue biopsies, techniques to enhance the tumor cellularity of tested material and to avoid sample bias will need to be further refined. Liquid biopsy techniques, though demonstrating extraordinary promise, are widely divergent in terms of methodologies employed, and further study in this technological space is needed. 1. Arcila ME, Oxnard GR, Nafa K, et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clinical cancer research : an official journal of the American Association for Cancer Research 2011;17:1169-1180. 2. Inukai M, Toyooka S, Ito S, et al. Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer. Cancer Res 2006;66:7854-7858. 3. Kim Y, Ko J, Cui Z, et al. The EGFR T790M mutation in acquired resistance to an irreversible second-generation EGFR inhibitor. Mol Cancer Ther 2012;11:784-791. 4. Majem M, Remon J. Tumor heterogeneity: evolution through space and time in EGFR mutant non small cell lung cancer patients. Transl Lung Cancer Res 2013;2:226-237. 5. Newman AM, Bratman SV, To J, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nature medicine 2014;20:548-554. 6. Oxnard GR, Paweletz CP, Kuang Y, et al. Noninvasive detection of response and resistance in EGFR-mutant lung cancer using quantitative next-generation genotyping of cell-free plasma DNA. Clinical cancer research : an official journal of the American Association for Cancer Research 2014;20:1698-1705. 7. Paweletz CP, Janne PA. Monitoring cancer through the blood. Cancer 2014;120:3859-3861. 8. Sorensen BS, Wu L, Wei W, et al. Monitoring of epidermal growth factor receptor tyrosine kinase inhibitor-sensitizing and resistance mutations in the plasma DNA of patients with advanced non-small cell lung cancer during treatment with erlotinib. Cancer 2014;120:3896-3901. 9. Tartarone A, Lerose R. Clinical approaches to treat patients with non-small cell lung cancer and epidermal growth factor receptor tyrosine kinase inhibitor acquired resistance. Ther Adv Respir Dis 2015. 10. Watanabe M, Kawaguchi T, Isa SI, et al. Ultra-Sensitive Detection of the Pretreatment EGFR T790M Mutation in Non-Small Cell Lung Cancer Patients with an EGFR-Activating Mutation Using Droplet Digital PCR. Clinical cancer research : an official journal of the American Association for Cancer Research 2015.

Abstract:
Acquired resistance to initial EGFR TKI invariably develops in patients with EGFR-mutant lung cancer after a median of 9-14 months. Though acquired EGFR resistance in NSCLC is a clinical condition that is treated and studied worldwide, there has until recently been a paucity of prospective data describing the best practices for managing these patients. In 2014, the first phase III trial studying EGFR-mutant lung cancer with acquired resistance was reported. Presented at ESMO 2014, the IMPRESS trial established platinum doublet chemotherapy as the standard second-line therapy for these patients, with no benefit to additionally continuing EGFR TKI at progression. And yet, even with standard second-line therapy established, there remain questions regarding how to manage patients with progressive disease (PD) on EGFR TKI, questions that will likely grow even more complex should newer agents reach the market. One way of framing this question is to consider the tools we have for managing acquired EGFR resistance, and then to consider how to best utilize them. The following outline provides a brief summary of therapeutic strategies that will be discussed further at WCLC 2015. · Continued TKI after PD - Feasible for a median of 3 months, especially in those with slow or asymptomatic PD (Lo et al, Cancer, 2015; Park et al, ESMO, 2014) · Retreatment with TKI after PD on chemo - 25% RR on a prospective phase II study of 20 patients, but responses were brief with a 3.4 month median PFS (Oh et al, Lung Cancer, 2012) · Afatinib – Limited activity in LUX-Lung 1 trial with 7% RR and 3 month median PFS (Miller et al, Lancet Oncol, 2010) · Afatinib / cetuximab – 29% RR and 4.7 month median PFS, with responses seen regardless of T790M status (Janjigian et al, Cancer Disc, 2014) · Cytotoxic chemotherapy – Cisplatin /pemetrexed has a 34% RR and 5.4 month median PFS after PD on gefitinib (Mok et al, ESMO, 2014) · Erlotinib & bevacizumab – May delay development of PD, but no prospective data for treatment of resistance (Seto et al, Lancet Oncol, 2014) · Erlotinib & crizotinib – Hypothetical option for MET-mediated resistance but requires dose reduction of both (Ou et al, ASCO, 2012) · Nivolumab – 82 patients with prior TKI and chemo treated on CheckMate 057, and there was no OS benefit seen compared to docetaxel (HR 1.18) (Paz-Arez, ASCO, 2015) · Erlotinib & nivolumab – 3 of 20 patients responded (15%) in the phase I study (Rizvi et al, ASCO, 2014) · Brain radiation – For CNS-only progression, radiation followed by restarting TKI can gain additional months of PFS (Weickhardt et al, JTO, 2012) · SBRT or surgical resection – An approach that is hypothesized to debulk a single resistant clone, thus delaying clinical resistance and prolonging the progression-free period (Weickhardt et al, JTO, 2012; Yu et al, JTO, 2013)

Abstract:
The introduction of EGFR TKIs has dramatically changed the natural history of advanced and/or metastatic NSCLC. The objective response rates of 50 to 70% are achieved and overall survival has improved from 4-5 months to over 30 months in EGFRm(+) NSCLC patients. However, unfortunately the patients are not cured of the disease and after a median PFS of 9 to 13 months, the disease comes back eventually with the emergence of acquired resistance(AR) to EGFR TKIs. Mechanisms of AR include target gene modification, activation of bypass tracks or histologic transformation, etc. In approximately 60% of patients, the mechanism of resistance is due to the acquisition of a gatekeeper T790M EGFR mutation. This T790M mutation leads to an enhanced affinity for ATP, thus reducing the ability of ATP-competitive reversible EGFR tyrosine kinase inhibitors, including gefitinib and erlotinib, to bind to the tyrosine kinase domain of EGFR. One strategy to overcome this mechanism of resistance mediated by target gene modification is through the use of more potent, novel, next-generation inhibitors. The ‘2[nd]-generation’ irreversible EGFR inhibitors such as afatinib and dacomitinib, covalent inhibitors of HER family kinases, showed preclinical activity against T790M in vitro. Both agents demonstrated excellent clinical activities in EGFR TKI-naïve patients with EGFR-mutant NSCLC in terms of response rate and progression-free survival as compared to cytotoxic chemotherapy. However, the results of treatment in patients with EGFR-mutant lung cancer who progress on an EGFR TKI are quite disappointing. Studies of afatinib monotherapy among patients with acquired resistance to erlotinib or gefitinib showed a response rate of only 7-8% and a progression-free survival of 3 to 4 months. This result may be due to the fact that physiologic doses of current generation irreversible EGFR TKIs do not fully inhibit EGFR T790M and dose escalation of 2[nd]-generation EGFR inhibitors is limited by on-target inhibition of wild-type EGFR, which leads to EGFR-mediated toxicity (skin rash and diarrhea). The so-called ‘3[rd]-generation’ EGFR TKIs are pyrimidine-based irreversible inhibitors and has mutant-specific activity including T790M mutation while sparing wild-type EGFR. There are several 3[rd]-generation EGFR TKIs under development, e.g., AZD 9291, CO-1686(Rociletinib), HM61713, ASP8273, EGF816, to name a few. The early clinical trials of the 3[rd]-generation EGFR TKIs have demonstrated a promising efficacy in patients with advanced EGFR-mutated NSCLC who have progressed on prior EGFR TKI therapy, including cohorts of patients with EGFR T790M-mutated NSCLC. For CO-1686, the reported overall response rate in the phase 1 study was 59%(27/46) in patients with centrally confirmed EGFR T790M-containing tumors. Median progression-free survival was 13.1 months. Likewise, initial results from the phase I trial of AZD9291 demonstrated a response rate of 61%(78/127) in patients with EGFR T790M positive tumors with median PFS of 9.6 months. Both AZD9291 and CO-1686 have recently been granted Breakthrough Therapy designation by the US FDA based upon results from early clinical studies. Early phase I/II results of HM61713 also showed encouraging anti-tumor activity with objective response rate of 55%(34/62) in T790M positive Korean NSCLC patients and global phase II trial is planned to launch. The early results of EGF816 and ASP8273, another irreversible 3[rd]-generation EGFR TKIs under clinical development, were recently reported and both agents demonstrated encouraging response rates of 50-60% in T790M(+) NSCLC patients after progression on a 1[st] or 2[nd] generation EGFR TKIs. Further studies are ongoing and mature results are awaited. In brief, many of the 3[rd] generation EGFR TKIs currently at various stages of development look so promising with encouraging clinical activities for T790M(+) NSCLC patients esp. in terms of response rate. In general these newer generation EGFR TKIs also have much better toxicity profiles as they spare the wild-type EGFR, e.g., less skin rash, diarrhea or paronychia compared with the 1[st]- or 2[nd]-generation EGFR TKIs though the toxicity profiles are slightly differerent one from another at some aspects. Since the follow-up is rather short we need longer follow up to confirm survival benefits. We certainly have made a significant progress in the management of advanced NSCLC with AR to EGFR TKIs, however, there are still several issues to be investigated to further improve the treatment outcomes, e.g., optimal timing and/or sequence of the 3[rd] generation EGFR TKIs, how to delay or prevent the emergence of resistance to 3[rd] generation agents, CNS progression, management of non-T790M-dependent AR to EGFR TKIs, etc. References Cong CR and Jänne PA. The quest to overcome esistance to EGFR-targeted therapies in cancer. Nat Med. 2013;19(11):1389-1400 Lovly CM and Shaw AT. Molecular Pathways: Resistance to Kinase Inhibitors and Implications for Therapeutic Strategies. Clin Cancer Res. 2014;20(9):2249–56. Jänne PA et al. AZD9291 in EGFR Inhibitor–Resistant Non–Small-Cell Lung Cancer, N Engl J Med. 2015 Apr 30;372(18):1689-99. Sequist LV et al. Rociletinib in EGFR-Mutated Non–Small-Cell Lung Cancer, N Engl J Med. 2015 Apr 30;372(18):1700-9. Park K et al. Updated safety and efficacy results from phase I/II study of HM61713 in patients (pts) with EGFR mutation positive non-small cell lung cancer (NSCLC) who failed previous EGFR-tyrosine kinase inhibitor (TKI). PASCO 2015 #8084 Tan D S-W et al. First-in-human phase I study of EGF816, a third generation, mutant-selective EGFR tyrosine kinase inhibitor, in advanced non-small cell lung cancer (NSCLC) harboring T790M. PASCO 2015 #8013 Goto Y et al. ASP8273, a mutant-selective irreversible EGFR inhibitor in patients (pts) with NSCLC harboring EGFR activating mutations: Preliminary results of first-in-human phase I study in Japan. PASCO 2015 #8014T