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Background:
Recently, tobacco was positioned "the essence of smoking is nicotine addiction" and conjunction with advanced of scientific research. However, not only the social situation and also tobacco-free (TF) campus has not been fulfilled in Japan. Therefore, we investigated the current state about smoking and analyzed for improvement the recognition and for change behavior in non-medical TF campus since 2010.

Methods:
The questionnaire for all faculty members(employees) in our campus was performed. Subjects in this survey conducted in 2012-13 who enrolled over 20 years of age was examined in 132 cases that consent were obtained.

Results:
Base of analyzed subjects' characteristics were male/female(%)=60.6/39.4, 44.6±11.6 yrs (mean±SD), respectively. Current smoking prevalence was 8.3% and Ex was 25.0%. The starting smoking age was 17.9±3.2 (Mean±SD, [Range 6;32]),opportunity(%) was “Out of interest/Incidentally/Because neighboring smoke”:11.7/10.2/8.6 were accounted for a large number (*multiple answers act). Tobacco products(connect with the Japanese government) sold in domestic market are required to have health warnings in Japanese, however, low level of recognition. This may be due to text size of tobacco package warning documents (Risk of Lung cancer, Secondhand smoke, etc.) are small, mild message and include educational problems. Currently, the people of quit smoking several decades has led to resmoking has been occasionally observed. After the Great East Japan Earthquake, resmoking rate was turned out to be themselves/blood relationship persons 1.9%/3.3%. Surprisingly found that awareness of TF within the campus, 10.8% was unknown and continuing smoke.

Conclusion:
The results revealed that stood out that lack of information on the status of tobacco and TF campus, and be considered sharing the critical issue. Road to TF campuses is difficult now in Japan, however, we should be make as the realization. Awareness of TF was poor, therefor the necessity of further education about stop smoking was indicated. Alongside we need a certain degree of understanding about resmoking status according to psychological damage factors of post-disaster, however, faculty members should be effort to critical that leads to a complete TF campus for youth-adult student in low-dose radiation exposure risk area. We would like to further advance a this research. For this purpose, the achieving completely TF campus, not only our university, we think need initiatives of the entire university in Japan. In addition, by resolving the current college students and faculty/staff problems, the younger generation, it aims to contribute to that improvement will be prevention and cessation education to (e.g. elementary and junior high schools), smoking current situation that is later than other countries.

Background:
To examine the effect of smoking on lung cancer risk in a large population-based cohort of women, many of whom started smoking as teenagers

Methods:
We followed 102,098 women, ages 30 to 50 years, completing a mailed questionnaire at recruitment to the Nigerian-Ethiopian Cohort Study in 2011/2012, through December 2013. We used Cox proportional hazard regression models to estimate relative risk (RR) of lung cancer associated with different measures of smoking initiation, duration, and intensity adjusting for confounding variables. We conducted analyses on the entire study population, among women who had smoked for at least 20 years, among non drinkers, and separately for each country

Results:
Altogether, 1,240 women were diagnosed with incident, invasive lung cancer. Compared with never smokers, women who smoked for at least 20 years and who smoked 10 cigarettes or more daily had a RR of 1.34 (95% CI, 1.06-1.70). Likewise, those who initiated smoking prior to their first birth (1.27, 1.00-1.62), before menarche (1.39, 1.03-1.87), or before age 15 (1.48, 1.03-2.13) had an increased risk. The increased RR associated with smoking was observed among nondrinkers of alcohol, women with and without a family history of lung cancer, pre-menopausal and post-menopausal women, and in both countries

Conclusion:
Our results support the notion that women who start smoking as teenagers and continue to smoke for at least 20 years have increased lung cancer risk

Background:
Many poor smokers in Northen Nigeria who started smoking at teenage, smoked for at least 15 years, have the least access to medical attention and who probably smoke more sticks and/or packets because of the cheap price of cigarettes may face a higher risk of entire DNA damage from lung cancer

Methods:
There were 98,500 men, ages 30 to 55 years involved in a community-based tobacco control/smoking cessation study through questionnaires in English and the local languages for two Nigerian geo-political zones which are the North western and North eastern with the most smoking prevalence in the country. The Nigerian Cohort Study was from 2007 through December 2013. Relative Risk (RR) of tobacco-related lung cancer associated with different measures of smoking initiation, duration, and intensity adjusting for confounding variables were estimated. There were also analyses conducted on the entire study population, among men who had smoked for at least 15 years, most of whom started smoking at youth. Study was separately for each geo-political zone.

Results:
From the entire number participating in the study, 19,200 men or about 20% were diagnosed with tobacco-specific lung cancer. Compared with never smokers, men who smoked for at least 15 years and who smoked 10 cigarettes or more daily had a higher Relative Risk (RR). On the other side, men who had smoked for at least 15 years, but were priviledged to periodic hospital visits or started smoking after teenage, had their lung cancer risk reduced and/or averted. The increased RR of DNA damage from lung cancer associated with smoking was higher amongst "I dont care" smokers in both geo-political zones in Northern Nigeria.

Conclusion:
Results here show that young initiation, poverty, high tobacco consumption, duration of smoking and inacesability to regular medical check up very well increases the risk of lung cancer leading to entire DNA damage.

Background:
Several studies have proved that over ninety percent of lung cancer cases are caused by tobacco. Smoking causes numerous cancers but surely has lung cancer on the highest. The alarming issue at the hand is that exposure to Environmental Tobacco Smoke-ETS may result to lung cancer among innocent non smoking employees in work places or elsewhere.

Methods:
Further from an earlier study where about 200 restuarant and bar non-smoking staff in four states in Nigeria-Lagos, Kano, Port-Harcourt and Abuja from were examined, we scaled up to conduct a similar expanded study among 450 non-smoking bar employees and regular non smoking bar users to reteirate our claims in 4 additional states. Level of ETS exposure was compared with survey results from participants. Duration of employment and level of exposure(number of hours daily) to Environmental Tobacco Smoke (ETS) for each person was also taken into account.

Results:
We discovered that participants exposed to workplace second-hand smoke were more likely to have any detectable level of NNAL (P=.005) and higher mean levels of NNAL (P < .001) compared with non-exposed participants. Increased levels of NNAL were also associated with hours of a single workplace exposure. Furthermore, some risks were noticed from non smoking daily bar users.

Conclusion:
Non-smoking employees left unprotected from workplace secondhand smoke exposure had elevated levels of a tobacco-specific carcinogen in their bodies. All workers—including bar and restaurant workers—should be protected from indoor workplace exposure to cancer-causing secondhand smoke. This calls for countries without a comprehensive National Tobacco Control Law to pass one as soon as possible in line with the WHO Framework Convention on Tobacco Control- FCTC.

Background:
Lung cancer is the leading cause of cancer death in the United States and other industrialized countries. The most important risk factor is still smoking. However, given the increased incidence of lung cancer in non-smokers, it is necessary to increase knowledge of the other risk factors. The Radon (Rn) is a noble gas and is the most important natural source of human exposure to ionizing radiation. Exposure to high levels of this radioactive gas are related to increased risk of developing lung cancer.

Methods:
We have conducted a survey on the website of the Brazilian National Health Surveillance Agency (ANVISA), LAMIN (Mineral Analysis Laboratory), CPRM (Geological Survey of Brazil), Ministry of Health and Pubmed The objective was to highlight the importance of measuring the concentration of this gas indoors and identify which steps should be taken for radiological protection.

Results:
We emphasize that lung cancer is a major public health problem and the exposure to Rn indoors should be considered as a risk factor in patients with non-smokers lung cancer. Buildings or houses with high concentrations of radon should be identified. However, currently, there is not in Brazil, a country with great potential of mineral extraction, any regulated recommendation for control of exposure to Rn.

Conclusion:
Exposure to indoor Rn should be considered as the main risk factor in patients with non-smokers lung cancer and second risk factor in smokers. Buildings or houses with high concentrations of radon should be identified. It is essential that regular reviews of radon levels are carried out at these sites

Background:
Our ongoing research is assessing stem cells alterations in cancer due to indoor radon exposure. Therefore, we performed a meta-analysis of previous studies on radon exposure and lung cancer to evaluate the strength of the statistical and radon-detection methods for determining exposure-response risk levels.

Methods:
Literature search used PubMed. Inclusion criteria: a), original case-control studies; b), use of alpha track detectors; c), report weighted average values of radon concentrations over time and/or cumulative exposure rates; d), include only lung cancer diagnosis by pathology and/or imaging; e), frequency-matched controls by age, gender and smoking status; f), enough samples and data for odds ratio estimation and variations; g), published in English. Data Extraction: Statistical data extracted from the selected studies. Studies selected were stratified by level of exposure to evaluate the dose-response relationships. Adjusted odds ratios (CI 95%) extracted for radon concentrations expressed in Bq/m[-3]). All data was later adjusted to WHO’s categories 0-99, 100-199, 200-299 and >300 Bq/m[-3]. Meta-analysis: For each study, analysis of the weighted linear regression of log-adjusted odds ratio was performed according to the average radon concentrations. Coefficients and 95% confidence intervals were calculated according to the various levels of radon concentration. Sensitivity analyzes: Separate meta-analysis was performed by grouping studies with similar characteristics

Results:
The log-OR for lung cancer risk was 1.22 higher at radon indoor levels >Bq/100[-3], being such levels more frequent in the homes of lung cancer cases. As for smokers, the 1.14 metanalytical measure indicates a log-OR of 3.19 (CI: 95%).

Conclusion:
This meta-analysis suggests a statistical significant higher risk of lung cancer in individuals exposed to indoor radon levels >Bq/100-3.

Background:
Tobacco consumption is increasing day by day world wide. In developed countries, the pattern of using tobacco is in the form of smoke where as in developing or underdeveloped countries both form (smoke & smokeless) of tobacco is in use. In developing countries like India, more than 2200 people are dying daily because of consuming tobacco in various forms, data issued by WHO & GATS. Dentist can play an important role in tobacco cessation , as they closely deal the patient of any gender and of any age groups. Smoking is very common among age of 20-45 years. Most of the dental problems arises during this age group and may be because of smoking. Dentist can counsel and motivate the patient by taking case history of the patient on Dental chair to quit this habit. He can use Carbon Monoxide analyser as a helping tool to tell the amount of carbon monoxide in patients lungs. CO analyser can be used as threating tool for smokers and later we can advice Nicotine replacement therapy according to the dependency on nicotine.

Methods:
Carbon monoxide analyser is a device which is used to measure the amount of carbon monoxide in smokers lung. It is of various types:- a) CO analyser with USB port which can be attached to Computer and printer ,b) Baby Carbon monoxide analyser. Benefit of CO analyser with USB port- it can be used in clinic and we can save data as clinic record and can give print out to the patient as their motivational agent. where as Baby CO analyser can be used for masses in camps. It immedidiately show the level of CO through their indicator lights. CO Analyser parts , it consists of D piece and instrument body. 1st step- ask the patient to take deep breath and hold it for 15 seconds then patient will blow the air slowly in D piece which is attached to anlyser , aiming to empty the lungs completely. The instrument will then display the level of Carbon monoxide by the relevant indicatror lights. CO is calculated in PPM. Normal Range - a) 0-6ppm- Normal (green light - less then 1 cigarette): b) 7-10ppm- Orange light (light smoker- 2-5 cigarette ) ; c) 11-15ppm- regular smoker (red light) ; d) 16-25ppm- red light with beep sound( chronic smoker). After this, we can do nicotine urine test by centrifugal method and prescibing the NRT products depending upon the investigation result. NRT is of differnt types- Gums, Patch, Nicotine nasal spray, Lozenges,Inhaler, etc.

Results:
CO anlyser can be helpful in knowing "SWOT" analysis of the patient. It will be a beneficial tool in counselling and helping the smokers to quit the habit. "SWOT - Strength, Weakness,Opportunity, Threatning analysis.

Conclusion:
By using CO analyser & NRT, we can help tobacco user to quit the habit by eliminating the exposure to 2nd hand smoke, prevent quiting among young and adults. Prevent initiation among youths at Dental clinics.

Background:
The role of haplotypes and the interaction of haplotypes and smoking exposure in the etiology of lung cancer have not been well characterized.

Methods:
We analyzed data from an Italian population-based case-control study among 1815 lung cancer cases and 1959 healthy controls in discovery phase and performed a validation using a case-control study comprising 2983 lung cancer cases and 3553 healthy controls of European ancestry for replication. Haplotype analyses and logistic regression were used to explore the casual haplotype and its association with lung cancer risk.

Results:
Sliding window haplotype analysis within chromosome 15, evaluating 4,722,250 haplotypes, and pair-wise haplotype analysis identified that rs16969968-rs588765 was the most significant haplotype associated with lung cancer risk (omnibus p = 8.35 × 10[−15] in discovery and 7.26× 10[−14] in replication), and improved the prediction of case status over that provided by the individual SNPs rs16969968 or rs588765 (likelihood ratio test p = 0.006 for rs16969968 and 3.83 × 10[−14] for rs588765 in discovery, 0.009 for rs16969968 and 4.62 × 10[−13] for rs588765 in replication, compared with rs16969968-rs588765). Compared to the wild type homozygous diplotype, the CA/CA homozygote exhibited an approximately 2-fold increase risk for lung cancer (OR = 2.12; 95% CI, 1.46 - 3.07 in discovery, and OR = 2.01; 95% CI, 1.51 - 2.67 in replication). Even among never-smokers, individuals with CA/CA homozygous diplotype had an increased risk of lung cancer with borderline significance in the discovery (adjusted OR = 1.75, 95% CI, 0.96 – 3.19) and statistical significance in the replication (adjusted OR = 2.10, 95% CI, 1.12 – 3.96), compared to those with combined genotypes (CG/CG + CG/TG). We also found that smokers with the CA/CA homozygous diplotype had a more than 13-fold increased risk for lung cancer in the discovery (adjusted OR = 13.42, 95% CI, 8.21 – 21.95) and 15-fold increased risk in the replication (adjusted OR = 15.52, 95% CI, 9.85 – 24.45), compared to nonsmokers with the combined genotypes (CG/CG + CG/TG).

Conclusion:
The rs16969968-rs588765 haplotype modifies lung cancer risk more than effects from individual variations at rs16969968 or rs588765, may be a marker of genetic susceptibility to lung cancer even among never-smokers, and has a joint effect with smoking exposure on lung risk.This knowledge may facilitate our understanding of lung cancer etiology and identifies a particularly high risk.

Background:
Social indicators of vulnerable populations are associated with increased rates of comorbidities and risk factors for cancer but not with screening attendance, as previously shown by the French EDIFICE surveys. The present work sought to determine whether living in poor economic social conditions is associated with specific behavior or beliefs that increase exposure to the risk factors for lung cancer.

Methods:
The 4th French nationwide observational survey, EDIFICE 4, was conducted by phone from June 12 to July 10, 2014 among a representative sample of 1602 individuals aged between 40 and 75 years, using the quota method. Individuals were questioned about their smoking habits. Tobacco addiction was evaluated in current smokers using the Fagerström Test for Cigarette Dependence (FTCD) score, which ranks participants into one of four groups: no dependence, low, moderate, and high dependence. Risk perception compared to the average-risk population was self-assessed. Data were analyzed according to the validated EPICES vulnerability score.

Results:
Vulnerable individuals (N=455) were more frequently current smokers than non-vulnerable individuals (N=941) (34.1% vs 19.9%; P≤0.01) and less frequently former smokers (25.9% vs. 35.8%; P≤0.01). Compared to the non-vulnerable population, current and former cigarette smokers in the vulnerable population were more likely to have started smoking before the age of 15 (33.8% vs. 25.5%, P≤0.05), and had a higher average consumption (16.6 pack-years [SD 16.25] vs. 13.59 pack-years [SD 16.44]; P≤0.01). Vulnerable individuals were also more likely to stop smoking for periods of less than 1 year or for 1-9 years (18.6% vs. 10.4% and 29.2% vs. 19.4%, respectively; P≤0.05) but were less likely to quit for longer periods (10-19 years, 17.6% vs. 27.1%, P≤0.05; 20-29 years, 17.2% vs. 22.5% and ≥30 years, 17.5% vs. 20.3%, not statistically different). Likewise, vulnerable individuals had higher average FTCD scores (3.24 [SD 2.38] vs. 2.55 [SD 2.16], P≤0.01) and were more frequently ranked as moderately or highly dependent on cigarettes (32.0% vs. 21.5%, P≤0.05). Respondents were asked about the number of cigarettes per day they considered to be associated with no risk of lung cancer; average replies were 3.01 (SD 5.40) in the vulnerable population vs. 1.93 (SD 3.90, P≤0.01) in the non-vulnerable population. The former were also less likely to spontaneously cite a number of lung cancer risk factors (unhealthy life-style 93.8% vs. 97.5%, active smoking 91.3% vs. 95.5%; passive smoking 60.4% vs. 72.0%; P≤0.01). But they were more likely to rank their own risk of lung cancer as higher than that of the average population (22.6% vs. 16.6%, P≤0.01) and to consider screening as more distressing than reassuring (25.9% vs 18.3%, P≤0.01).

Conclusion:
Because they develop a heavy, long-lasting consumption of tobacco and are less likely to quit smoking permanently, vulnerable individuals are more exposed to the tobacco-consumption-related risks of lung cancer. Paradoxically, they also appeared both less concerned and more anxious about the risks of lung cancer than non-vulnerable populations. These results highlight the urgency of implementing information campaigns, prevention messages, and smoking cessation support specifically targeting this vulnerable population.

Background:
It had been pointed out about the respiratory infectious disease that the tuberculosis patients had increased risk of lung cancers, and the lung cancer patients had increased risk of tuberculous infection. In recent years, primary lung cancer cases are increased, despite of decreasing of tuberculosis infection and, on the other hand, of increasing of chronic respiratory infectious diseases such as the pulmonary non-tuberculous mycobacteriosis or mycosis. A purpose of this study is to research the chronic respiratory infectious diseases as a background of the lung cancer treatment.

Methods:
From January, 2010 to December, 2014, 431 cases of radical operations for primary lung cancers were performed in our institute. A bacteriological search by the expectoration and bronchus absorption sputum was examined in 389 cases preoperatively. Among these cases, we retrospectively researched about the fungal infections and mycobacterial infections.

Results:
Among the 431 primary lung cancer cases, 19 cases of fungal infections were detected, 12 cases of non-tuberculous mycobacterium infections were detected, four were co-existing and none was tuberculosis. In the patient background of mycosis, gender was 15 cases of male and four of female, the mean age was 69.7±8.1 years old (53-88 years old), and mean smoking index was 1073 (0-2640). The histological types of the lung cancers were eight cases of squamous cell carcinoma, seven of adenocarcinoma, each one of small cell lung cancer, pleomorphic carcinoma and LCNEC. The pathological stages of the lung cancers were nine cases of stage I, five of stage II, four of stage III and two of stage IV. The detected species of bacteria were nine cases of Candida spp., eight of Candida albicans, two of Aspergillus fumigatus and one of Aspergillus niger. The patients had past history of tuberculosis in three cases, cancer in four, diabetes in 6 and continuous treatment by steroid in two. In the patient background of non-tuberculous mycobacteriosis, gender was 7 cases of male and 5 of female, the mean age was 71.7±10.2 years old (50-88 years old), and mean smoking index was 556 (0-1800). The histological types of the lung cancers were six cases of adenocarcinoma, three of LCNEC, two of squamous cell carcinoma, one of small cell lung cancer. The pathological stages of the lung cancers were eight cases of stage I, one of stage II, two of stage III and one of stage IV. The detected species of bacteria were 11 cases of Mycobacterium avium complex and one of Mycobacterium mucogenicum. The patients had past history of cancer in two cases and continuous treatment by steroid in two, but none of tuberculosis and diabetes. The five year survival rate of the lung cancer cases with the chronic respiratory infections was 63.0% and that without the chronic respiratory infections was 76.6%. The lung cancer cases with chronic respiratory infections showed tendency of poor prognosis, although there was no significant difference between two groups (p=0.087).

Conclusion:
The lung cancer cases with chronic respiratory infections had past history of coexisting disease, and showed tendency of poor prognosis.

Background:
Asbestos exposure is associated with dose-dependent risk of benign pleural disease, lung cancer and mesothelioma. While an association between asbestosis and lung cancer (even after adjustment for asbestos exposure) is well established [Reid et al, OEM 2005], the link between lung cancer and the presence of pleural plaque remains controversial.

Methods:
We followed 2,218 subjects exposed to crocidolite asbestos as miners (n=1286) or mine township residents, monitored with annual review, chest radiography (CXR) and outcome linkage to national cancer and mortality registry data over a 25-year period. Subjects were followed up from the date of their latest x-ray taken a year or more before the date of death, cancer incidence, or end of follow-up. Hazard ratios for lung cancer were estimated by Cox regression, with age as the underlying matching time variable, for sex, tobacco smoking, asbestos exposure estimates (time since first exposure and fibre/ml years), International Labour Organisation CXR readings for asbestosis (defined as profusion score > 1/0) and presence (and extent) of pleural plaques.

Results:
Mean age at follow up was 60.6 years, 1,575 (71%) were male, 328 (14.8%) had any pleural plaque and 359 (16.2%) had asbestosis. 103 (4.64%) lung cancers were recorded. 1568 (70.7%) were ever-smokers with a mean tobacco exposure of 39.3 pack years.

	HR	Lower 95% CI	Upper 95% CI	p-value
Log (yrs) SFE	1.77	.60	5.22	0.298
Ever smoker	18.1	2.5	132	0.004
Pack years	1.009	1.005	1.01	<0.0005
Female	0.75	.38	1.48	0.408
Profusion: 0/1	1.88	1.14	3.10	0.013
1/0	1.64	0.87	3.07	0.124
1/1	3.64	1.83	7.24	<0.0005
1/2	6.10	2.03	18.3	0.001
> 2/1	2.18	0.64	7.49	0.215
Log f/ml yrs	1.223	1.076	1.390	0.002
Any PP	1.048	0.601	1.826	0.869
SFE = since first exposure; f/ml = fibres / ml; PP = pleural plaque; HR = hazard ratio; CI = confidence interval

Table 1. Hazard ratios for diagnosis of lung cancer

Conclusion:
In our population, the presence of pleural plaque is not associated with an increased risk of subsequent lung cancer. This is contrary to a recent report that had smaller numbers of lung cancer and used death certificates [Pairon, AJRCCM, 2014]. As we have demonstrated previously, the presence of asbestosis and cumulative asbestos exposure both contribute to increased subsequent lung cancer risk, although previous tobacco smoke exposure remains the strongest risk factor.

Background:
LDCT lung cancer screening has been incorporated into most major American medical societies' screening guidelines and has recently been approved for reimbursement by the Centers for Medicare and Medicaid Services. However, its performance in a non-tertiary care community setting with a high prevalence of fungal infections has not been sufficiently studied.

Methods:
Beginning in April 2013, high-risk adults ages 55-80 with at least a 30 pack-year smoking history, including former smokers who had quit within the previous 15 years, were prospectively evaluated with an LDCT scan performed at our community hospital (Unity Point Health Medical Center in Quad Cities, Illinois). Standard National Lung Screening Trial exclusion criteria were followed with the exception of previous chest CTs being allowed up to 12 months rather than 18 months prior to study entry and extension of age of the studied population to 80 years. An oncology nurse navigator contacted and monitored all participants. The CTs were interpreted by a local radiology group with two radiologists spearheading the program and ensuring consistent interpretations.

Results:
As of April 2015, we have evaluated 176 participants, 86 of whom were men (49%). Median age of the studied population was 64 years (range 55 - 80). Screening adherence was 97% with a total of 36 participants (20%) having at least one follow-up LDCT. 40 participants (23%) had a positive baseline screening test. 1 patient had a baseline screening test positive for pneumonia and was subsequently diagnosed with stage IV non-small cell lung cancer (NSCLC). 135 patients (77%) had a negative baseline screening test. Benign appearing calcified granulomas were detected in 60 participants (34%) with a nearly identical relative distribution between those with negative and positive screening tests. Only seven follow-up PET-CT scans were necessary. One was performed for staging purposes after a histologically proven cancer diagnosis. Six were performed for evaluation of lesions felt to be highly suspicious on LDCT. Four of the six PET-CTs were positive and led to a diagnosis of malignancy. A total of five malignancies (2.8%) were detected as a direct result of the screening. Four were NSCLC, of which three were stage I and one was stage IV. One participant was diagnosed with Marginal Zone Non-Hodgkin Lymphoma of the lung. All biopsies that were performed were positive for malignancy. No unnecessary biopsies were performed. No biopsy-related complications occurred. Four out of five patients with detected malignancies are still alive and doing well. Two patients (1%) died during the follow-up. One patient died secondary to an advanced NSCLC detected by the screening program; the other death was due to an unrelated cause, pneumonia.

Conclusion:
To our knowledge, this is the first community hospital-based study evaluating the results of LDCT lung cancer screening in an area of the United States endemic for both Histoplasmosis and Blastomycosis. LDCT cancer screening in such a setting can be done effectively without significant false positive results due to fungal infections. A significant number of early stage lung cancers were detected without excessive testing or complications.

Background:
The overall 5 years survival for lung cancer patients is approximately 16%, a survival advantage is noted for early stage lung cancer, with 5-year survivals up to 65%. However, only 10% patients are diagnosed when the primary tumor is resectable. Our trial was conducted to improving the early stage lung cancer detection rate using low-dose CT.

Methods:
Eligible participants enrolled in our trial were local residents in 6 communities located in Xuhui District, Shanghai, China, aged from 45 to 70 years and with either of the following risk factors: 1) history of cigarette smoking ≥ 20 pack-years, and, if former smokers, had quit within the previous 15 years; 2) malignant tumors history in immediate family members; 3) personal cancer history; 4) professional exposure to carcinogens; 5) long term exposure to second-hand smoke; 6) long term exposure to cooking oil fumes. From November 2013 to November 2014, the high risk residents received free chest low-dose CT (LDCT) scans at Shanghai Jiao Tong University Affiliated Shanghai Chest Hospital. The findings of CT scan were identified by three experts. The shadows on the lungs were grouped accordingly. If imaging was highly suggestive of malignancy, the expert group would have further discussion. The residents would be assigned to undergo biopsy or surgical resection directly.

Results:
Up to January 2015, 2933 participants were received LDCT screening. According to the inclusion criteria, 2892 persons at high risk for lung cancer were included in our trail, and 41cases were finally excluded. Of the 2892 aged 45 -70 years old cases, the median age was 61years old. Of the included participants, 1151 cases were male, and 1741 cases were female. Pulmonary small nodules were found in 742 cases; small nodules detection rate was 25.66% (742/2892). 69 cases were suspected of lung cancer. Accounting for pulmonary small nodules was 9.30% (69/742), and was 2.39% (69/2892) of the total number of screening high risk population. 23 cases underwent surgery, with 22 lung cancer (10 males and 12 females) and 1 hamartoma, representing a positive lung cancer detection rate with low-dose CT screening of 0.76% (22/2892). 21 of the 22 cases resected lung cancers were stage I (95.45%) and 1 was stage II (4.55%), with 21 adenocarcinomas (95.45%) and 1 squamous lung cancer (4.55%).

Conclusion:
The application of low-dose CT screening prompted an increase detection rate of early stage lung cancers (stage I and II) in the high risk population.

Background:
The United States Preventive Services Task Force (USPSTF) and National Comprehensive Cancer Network (NCCN) recommend screening with Low-Dose Computed Tomography (LDCT) for asymptomatic patients at high risk of lung cancer. It remains unknown, however, how well these recommendations will translate to the medical community at large. Here, we report on the initial year of a statewide lung cancer-screening program implemented at Intermountain Healthcare.

Methods:
We developed a comprehensive lung cancer screening program open to patients aged 55-80 with either a 30 pack-year smoking history (USPSTF criteria) or a 20 pack-year smoking history plus a risk factor (NCCN criteria) who continue to smoke or have quit within the past 15 years. At the time of patient enrollment, a nurse coordinator was supposed to complete an electronic intake form that assessed patient screening eligibility, smoking history, symptoms, and environmental carcinogen exposure. Radiographic reporting and nodule evaluation were standardized.

Results:
From September 4, 2013 to October 1, 2014, 258 patients were referred to the lung cancer-screening program. Thirty-four patients were ineligible for screening based on the aforementioned guidelines while 17 patients declined screening. Of the 207 patients who met USPSTF or NCCN criteria, forty-five were not processed by the coordinator primarily due to physician office staff calling radiology directly. Of the 162 properly processed patients the mean age was 65.7 +/- 5.5 years, 50.6% (82) were active smokers, 45.7 %(74) had additional environmental exposures and 61.1% (74) reported symptoms at the time of intake. Of the 74 patients with symptoms 66 (89%) reported cough. Of the total of 207 who were screened 48.3%(100) had no nodules, 30.4% (63) had a nodule >6mm requiring follow up studies, 6.8% (14) had a nodule suspected of being cancer and 14.5% (30) had significant incidental findings. Eight of the 14 patients with suspicious lesions had been evaluated at the time of review. Three were found to have lung cancer (stages 1A, 2A and 4) and 2 others had a non-lung malignancy (renal, lymphoma). Three patients had benign lesions (2 hamartomas and 1 fibrosis).

Conclusion:
Despite vigorous attempts to standardize the process and broad discussion of the indications with physician groups, numerous patients who were ineligible were referred and several underwent screening when physician’s office staffs were able to bypass the coordinator step. Cough as a symptom needs further clarification as a significant majority of patients present with cough. The CMS recommendation for physician counseling is likely to have little impact as most physicians are not knowledgeable about the nuances of screening for lung cancer. For lung screening to realize its true potential these technical issues must be resolved.

Background:
In 2014 the University of Vermont Cancer Center obtained accreditation for the new Lung Cancer Screening Program from the American College of Radiology. During the first 6 months of the LDCT screening program, there were 100 participants in the program. Patient understanding of lung cancer screening did not seem to be clear.

Methods:
We conducted a preliminary survey to define the perceptions of the first 76 participants enrolled in the program. A 30 question questionnaire was done by telephone survey. Descriptive statistics were used.

Results:
Thirty-six participants (47%) responded to the survey. Referral of the majority of participants was done by less than primary care providers. 32Participants did not know about the program before they were told by their doctor. Although 92% of respondents knew they had a “lung X-Ray” done, 14% did not know why the test was done and only 28% knew they had undergone a LDCT of the lungs. All 36 patients knew they had received the results of the test and 26 (72%) had a follow-up appointment with their provider. Fourteen percent had further testing and 3 were diagnosed with early stage lung cancer. Only 25% received education material on lung cancer screening program. Eleven participants (30%) would have liked more information. Interestingly, 45% were not interested. Twenty-two percent incurred additional expenditure from $10 to $1200. Over 90% of the participants would agree to refer a family member to the program if this was an option. Most patients (75%) reported that the test did not affect their mood. The highest level of anxiety was in those who were diagnosed with cancer. Of the current smokers (N=20), only 17 (85%) were counseled to quit smoking. Of the 17 participants who received counseling, 9 followed the advice and sought help to quit, 2 did decrease smoking, and 7 did not follow the advice. Over 97% of patients (35/36) wanted to know what other anomalies were diagnosed on the LDCT. Interestingly, these 35 patients thought they would be more likely to quit if they had a better understanding of the damage done by tobacco.

Conclusion:
LDCT scan is an effective tool to diagnose early stage lung cancer and does not affect the mood of the majority of the participant, but it is still much underutilized mainly because of the knowledge gap among providers responsible for educating and referring at-risk patients. Most of the participants were satisfied with the program but there is a need to better educate the public and primary providers about the purpose of the study and the importance of smoking cessation. Finally showing participants the LDCT images of their lungs and counseling them about tobacco related changes in their lungs found during screening can be a power tool to help them quit smoking.

Background:
Detecting new or early lung cancer symptoms in people who have COPD is especially difficult as early signs of disease may be masked by existing chronic respiratory symptoms. Public awareness of lung cancer symptoms remains low despite recent media campaigns. A lack of knowledge and understanding of their condition and associated risks may account for patient symptom reporting delay. Over 60% of UK lung cancer patients are diagnosed at a stage where curative treatment is no longer an option. Early reporting and diagnosis can provide curative treatment options and improved outcomes. New, cost effective interventions that promote timely detection and diagnosis and that are acceptable to patients are required. Prospective Assessment of Incident Respiratory Symptoms (PAIRS-COPD) is a feasibility study that evaluated four-monthly telephone reviews of COPD patient’s respiratory symptoms, by a primary care nurse. This abstract presents findings that identify the intervention’s effectiveness in prompting symptom reporting and referral and explores participant’s perceptions of their chest condition and lung cancer risk.

Methods:
Mixed methods were used. Quantitative analysis of frequency of identification of indications for a chest X-ray was undertaken with COPD patients on a primary care register (n=77). A purposive sample (n=12) were selected for semi-structured telephone interviews (7 women and 5 men) to evaluate patient perceptions and experiences and acceptability of the intervention. Interviews were audio taped and transcribed. Thematic analysis was used.

Results:
Interviewees revealed that living with respiratory symptoms for protracted periods resulted in a high level of symptom tolerance. New symptoms were assumed to be an inevitable and expected part of their normal illness trajectory or of aging more generally. Awareness of prognostic implications and lung cancer risk was low. The interviewees reported the belief that decline was inevitable. This, combined with their worsening respiratory condition and high symptom tolerance, had made delay in reporting new or deteriorating symptoms inevitable. However, as a consequence of the intervention, symptoms recommended to prompt a chest X-ray by the National Institute of Clinical Excellence (NICE) were identified in 27% of the 77 volunteers over the 12-month study period. In 5%, criteria for an urgent lung cancer referral were met. Importantly, the interviewees described how the intervention was acceptable and accessible as it did not require additional travel and visits to the doctor. It successfully provided them with a more nuanced understanding of their chest condition, increased knowledge of early indicators of acute exacerbation and enhanced their self-management skills. The calls also heightened interviewees’ appreciation of their increased risk of lung cancer and awareness of the associated symptoms. They reported adopting more proactive help seeking behaviours.

Conclusion:
This study reveals how the PAIRS-COPD intervention can help COPD patients identify and report new symptoms that may otherwise be accepted or missed. In the study symptoms requiring further investigation and referral were uncovered surprisingly frequently. For a client group with a significant symptom burden, the lack of disruption was a primary reason for the acceptability of the intervention.

Background:
To evaluate the diagnostic accuracy of computed tomography (CT)-guided percutaneous lung biopsy for solitary pulmonary nodules.

Methods:
Three hundred and eleven patients (211 males and 100 females), with a mean age of 59.6 years (range, 19–87 years), who were diagnosed with solitary pulmonary nodules and underwent CT-guided percutaneous transthoracic needle biopsy between January 2008 and January 2014 were reviewed.

Results:
All patients were confirmed by surgery or the clinical course. The overall diagnostic accuracy and incidence of complications were calculated, and the factors influencing these were statistically evaluated and compared. Specimens were successfully obtained from all 311 patients. A total of 217 and 94 cases were found to be malignant and benign lesions, respectively, by biopsy. Two hundred and twenty-five (72.3%) carcinomas, 78 (25.1%) benign lesions, and 8 (2.6%) inconclusive lesions were confirmed by surgery and the clinical course. The diagnostic accuracy, sensitivity, and specificity of CT-guided percutaneous transthoracic needle biopsy were 92.9%, 95.3%, and 95.7%, respectively. The incidences of pneumothorax and self-limiting bleeding were 17.7% and 11.6%, respectively.

Conclusion:
Taking account of all evidence, CT-guided percutaneous lung biopsy for solitary pulmonary nodules is an irreplaceable, efficient, and safe diagnostic method associated with few complications.

Background:
miRNAs have shown exceptional promise as biomarkers of lung cancer; however, no miRNA signatures have yet reached the clinic. Towards developing a signature with a high likelihood of being validated externally for clinical use, we screened a panel of 50 miRNAs shown to be effective biomarkers in at least two previous studies for distinguishing human lung cancer samples from non-cancer samples.

Methods:
Sixty tumor-normal pairs (33 adenocarcinoma, 27 squamous cell carcinoma) were used to identify the best-performing combination of 4 miRNAs for distinguishing tumor samples from normal. The miRNA levels were measured by RT-qPCR using Taqman custom-made microfluidics cards and primer pools purchased from Life Technologies. All possible combinations of 4 miRNAs were tested, and best performance was defined as the highest median area-under the receiver operating curve (AUC) obtained from 1000 bootstrap replicates. A second, independent set of 68 tumor-normal samples (half adenocarcinoma, half squamous) was used as a test set, and bootstrapping was used to determine the 95% confidence interval for the AUC.

Results:
The median AUC for the top-performing panel of 4 miRNAs in our training set was 0.96. Several other miRNA combinations exhibited AUCs > 0.95 as well. In our test set, the top-performing panel (and only panel tested) exhibited an AUC of 0.97 (0.93, 0.99). This panel consisted of miRs 26a, 145, 183 and 486. miRs 145 and183 have previously been shown, when used individually, to be significant lung tumor biomarkers in at least 4 previous studies; miR-486 has been replicated 8 times.Figure 1



Conclusion:
Consistent with previous studies, we’ve identified a panel of 4 miRNAs that shows excellent potential for diagnosing lung tumors. Each of these miRNAs has been replicated as a biomarker of lung cancer in at least two previous studies, suggesting a high likelihood of achieving clinical validation. Several previous studies have also shown that these four miRNAs are potentially useful as biomarkers for diagnosing lung cancer using blood samples, and we are currently pursuing such validation studies.

Background:
Autoantibodies is an attractive diagnostic approach for early detection of malignant tumors. Our previous studies found a panel of 7 TAAs(p53，PGP9.5，SOX2，GAGE7，GBU4-5，MAGE A1，CAGE) was associated with lung cancer. We performed this large-scale clinical trial to validate their ability to aid early diagnosis of lung adenocarcinoma presenting with GGNs or solid nodules in Chinese population.

Methods:
The 7 TAAs were selected from 43 candidate TAAs from our previous studies. These samples including lung adenocarcinoma presenting with GGNs (n = 170) or solid nodules (n = 100) and healthy volunteers (n = 200). The sensitivity and specificity from 7 TAAs and the traditional cancer biomarkers CEA, NSE, and CYFRA21-1 were compared.

Results:
The sensitivity and specificity of autoantibody assay were 53% and 91% respectively, which were similar in different subgroups such as age, gender, smoker status and histological type. The sensitivity of autoantibody assay was 50% in lung adenocarcinoma presenting with GGNs. The sensitivity of autoantibody assay was 58% in lung adenocarcinoma presenting with nodules. The results were significantly higher than 27% when using the combination of CEA, NSE, and CYFRA21-1 to detect patients with lung cancer.

Conclusion:
Our study suggested that the 7 TAAs autoantibody panel might be helpful to aid diagnosis of lung cancer with GGNs or solid nodule. Large scale trial to validate our finding of patients with GGNs is ongoing in our institute.

Background:
Previous studies have demonstrated that volatile organic compounds (VOCs) in exhaled breath can distinguish between healthy and affected individuals, and can even discern between SCLC and NSCLC and within the subtypes of lung cancer (LC) and its mutations status. The current study assessed the differences in glucose metabolism on the volatile signature in LC through an oral glucose tolerance test (OGTT).

Methods:
This cohort included forty participants (22 control participants whom are at high risk for LC, 18 study participants whom have active, naïve lung cancer). Pre-OGTT and Post-OGTT blood glucose levels and exhaled breath samples were measured with a lay period of 90 minutes. A proton transfer reaction mass spectrometer (PTR MS) detected and measured the VOCs. The data was then analyzed using a series of feature selection methods to identify relevant inputs for multilayer perceptron (MLP) models to distinguish LC patients from controls, with and without the consideration of the glucose effect.

Results:
The feature selection method “infogain” revealed a combination of 14 masses (m/e) that were different between the two groups without considering the glucose effect. All the average values of these masses were higher in the LC group except for m/e 52, which was higher in the high-risk group. These 14 masses enable us to distinguish between the two groups with an average accuracy of 91.67% for three internal validation tests of a MLP (threshold set at 0.45). The analysis of the effect of glucose revealed that several m/e increased more for the control group whereas others increased more for the LC group. Moreover, three feature selections, each with a different combination of 4 masses, allowed the design of three MLPs that yielded 90% for K-fold cross-validation accuracy. Figure 1



Conclusion:
This study showed that breath analysis could discriminate between the high-risk and LC group. Furthermore, it demonstrated that glucose metabolism leaves a unique VOC pattern in the LC group. These findings may assist in the development of a non-invasive screening method for lung cancer.

Background:
Lung cancer is the leading cause of global cancer death in both males and females. Figures on disease outcome are disappointing despite advances in treatment since 86% lung cancer patients die within 5 yrs of diagnosis. However with early detection and treatment, 5-year survival improves from 20% stage III to 70% stage I disease. Breath chemical tests have been applied in respiratory disorders and we sought to determine if exhaled breath volatile compounds (VOC) could discriminate patients with lung cancer from pulmonary tuberculosis (TB) by comparing them against age matched controls.

Methods:
Subjects seen at outpatient respiratory clinics with CXR suspicious of lung cancer were recruited. Diagnosis of lung cancer or TB was established via bronchoscopic, CT lung biopsy or sputum cultures and exhaled breath was collected. Patients with other lung diseases but gender and age matched were recruited as controls. Analysis of VOC was performed by Thermal Desorption-Gas Chromatography mass spectrometry (TD-GC/MS) using Unity Series 2 Thermal Desorber (Markes International Limited) and 6890 GC system (Agilent Technologies), interfaced with 5973 MSD (Agilent Technologies). Data were analyzed by MZmine 2.11 for peak alignment and normalization, and OPLS for statistical clustering analysis. Additional univariate and receiver operating characteristic analysis were performed with SPSS.

Results:
Statistical clustering analysis OPLS Fig1 showed breath profile differences between lung cancer (n=17) and those with other lung diseases (CON, n=19). Fig2 indicated that breath profile of lung cancer patients was also different from those with Tuberculosis (TB). Specific VOC that contribute to these breath differences will be identified by TD-GC/MS. Individual breath VOC was reproducible in triplicates. Figure 1Figure 2





Conclusion:
These exciting preliminary results suggest that exhaled breath collected from subjects attending respiratory clinic may serve as screening test to aid the physician in the identification of patients with lung cancer and pulmonary tuberculosis from other respiratory diseases.

Background:
Periostin is an 836 amino acid, 93314 Da, protein secreted by airway epithelial cells that induces cell attachment and spreading and plays a role in cell adhesion. Specifically, it functions to enhance incorporation of BMP1 in the fibronectin matrix of connective tissues, and subsequent proteolytic activation of lysyl oxidase. Its expression is induced by the Th2 cytokine IL-13. Periostin serum levels have shown to be elevated in some asthmatic patients. Therefore, it is hypothesized that periostin may be useful as a surrogate marker for IL-13 up-regulation and to identify asthmatics more likely to benefit from IL-13 targeted therapy. The clinical utility of the assay is being explored in patients with uncontrolled severe asthma in Phase III trials of tralokinumab, an investigational anti-IL13 monoclonal antibody. An analytically robust investigational use only (IUO) immunoassay was developed to quantitate serum periostin on the ARCHITECT® immunoassay iSystem.

Methods:
The ARCHITECT® Periostin assay is a monoclonal antibody (mAb) sandwich two‑step immunoassay for the quantitative determination of periostin in human serum using Chemiluminescent Magnetic Immunoassay (CMIA) technology. Periostin is captured by microparticles coated with an anti-periostin mAb and detected with a mAb conjugated with acridinium. Chemiluminesence is triggered, and signal is measured as relative light units (RLUs), which directly reflect to the quantitative amount of periostin. ARCHITECT® iSystem has throughput of 200 tests per hour. The analytical performance of the assay was assessed for sensitivity, linearity, precision, endogenous and drug interfering substances, specimen handling/preanalytics, and periostin isoform reactivity. The assay was standardized using gravimetrically prepared periostin isoform 1 with protein concentration determined using an extinction coefficient established by amino acid analysis.

Results:
Prototyping was performed on ARCHITECT® iSR2000. Numerous antibody formats were evaluated for key analytical performance prior to final pair selection and completion of extensive analytical performance testing. Limit of quantitation is
Conclusion:
The IUO ARCHITECT® Periostin immunoassay is a robust and reliable test for the measurement of serum periostin. Periostin testing is in progress in Phase III trials for tralokinumab, an anti-IL-13 human IgG4 mAb.

Background:
The high false-positive rate associated with low-dose computed tomography (CT) lung cancer screening results in unnecessary testing, cost, and patient anxiety. We hypothesized that an algorithm incorporating clinical, radiographic, and serum biomarker data would be capable of differentiating benign from malignant pulmonary nodules.

Methods:
An institutional biorepository was used to identify 84 patients with ≤ 2 cm indeterminate pulmonary nodules identified on CT scan, including 50 patients with biopsy-proven, node-negative, non-small cell lung cancer (NSCLC) and 34 patients with benign, non-calcified, solitary pulmonary nodules. Clinical and radiographic data were collected from patient charts and imaging studies. Serum specimens were evaluated in a blinded manner for 55 biomarkers using multiplex immunoassays. Random forest analyses were used to generate a multivariate cross-validation prediction model incorporating clinical, radiographic, and serum biomarker data.

Results:
A total of 84 patients were identified with a median nodule size of 5 mm for benign nodules and 15 mm for NSCLC. Median smoking histories were 21 and 28 pack-years and patient age was 62 and 70 years, respectively. An algorithm incorporating serum biomarker profile (IGFBP-4, IGFBP-5, IL-10, IL-1ra, IL-6, SDF-1alpha, IGF-2), age, sex, BMI, COPD, smoking history, hemoptysis, previous cancer, nodule size, nodule location, spiculation, nodule type, and nodule count provided the optimal performance with a sensitivity 92%, specificity 65%, NPV 85%, and PPV 79%. This model performed with an overall accuracy of 81% with a cross-validated AUC=0.904.

Conclusion:
An algorithm incorporating clinical, radiographic, and serum biomarker characteristics may help differentiate benign from malignant pulmonary nodules. This model is currently being externally validated in a second-site patient cohort.

Background:
Lung cancer, with its high metastatic potential and high mortality rate, is the worldwide leading cause of cancer-related deaths. High-throughput “omics”-based platforms have accelerated the discovery of biomarkers for lung cancer, and the resulting candidates are to be evaluated for their diagnostic potential as non-invasive biomarkers. The evaluation of the biomarker candidates involves the quantitative measurement of large numbers of proteins in bodily fluids using advanced mass spectrometric techniques. In this study, a robust method based on targeted proteomics was developed for biomarker verification in plasma samples and applied to verifying lung cancer biomarker candidates.

Methods:
Sample acquisition: Blood samples were obtained from 72 patients diagnosed with non-small-cell lung cancer (NSCLC) (stages I-IV), and 30 healthy volunteers with the approval of the National Research Ethics Committee. Sample processing and Liquid Chromatography-Selected Reaction Monitoring (LC-SRM): Two most-abundant plasma proteins were depleted from each sample. Proteins were digested by trypsin to generate peptide mixtures. Peptides representing the potential biomarker proteins were selected. Stable isotope-labeled (SIL) peptides of the selected target peptides were synthesized to be used as internal standards, and spiked-in the processed plasma samples. A peptide banking system equipped with a local spectral library of synthetic peptides was used to facilitate automatic generation of LC-SRM methods. Multiplexed LC-SRM assays for >100 potential markers for NSCLC were generated to screen the plasma samples.

Results:
In the first set of screening for 190 peptides, a total of 60 peptides corresponding to 44 proteins were detectable by LC-SRM in the plasma. Among them, 17 proteins exhibited higher expression levels in the NSCLC patients compared to the control. For those proteins, additional peptides were prepared in order to increase the coverage of the protein sequence, and the number of samples were expanded (72 NSCLC and 30 controls). After differential analysis of the SRM results, 17 proteins were finally verified as potential diagnostic markers. The verified targets include ACTN1, ALDOA, ENO1, FLNA, G6PD, GPI, HSP90B1, ICAM1, ILK, LDHB, MSN, PGK1, PKM2, SPP1, TALDO1, THBS1, and ZYX. The expression levels were cross-validated by ELISAs if available. A novel plasma-based biomarker, ZYX, showed a potential of early diagnostics as its plasma level increases from the early stages (stages I and II). The overall pattern of the plasma levels of four ZYX peptides and the ELISA results were correlated. The role of ZYX in cancer has been recently discussed as a key player in epithelial-mesenchymal transition mechanism, and the association to lung cancer was reported in several studies. To the best of our knowledge, the potential use of ZYX protein as a tumor biomarker in plasma for lung cancer has been verified for the first time in this study.

Conclusion:
A targeted proteomics-based, analytical pipeline was designed for a large-scale biomarker verification and successfully applied to verifying a set of potential biomarkers for NSCLC. The robust workflow is critical to the early-stage screening where the attrition rate tends to be high (68% in this study). Several novel targets were verified as plasma-based NSCLC biomarkers, and ZYX showed a potential of early diagnostics.

Background:
There are estimated in the National Czech Cancer Registry since 1976 to 2010 among 203, 858 cancers a total of 16 622 lung cancers (LCs) in males associated with other neoplasms, presented 10 % of 166 239 (81,5%) newly registered LCs in males. They were 4,395 (2.6 %) primary and 12,227 (7.4 %) subsequent LCs; A total of 5,322 LCs in females, presented 14.1 % of 37,619 (18,5%) newly registered LCs in females, of which were 1,022 (2.7 %) primary and 4,300 (11.4 %) subsequent LCs. Their representation at the early clinical stages decreased gradually from 53% to 22 %, at the advanced stages increased from 20 % to 64 %; One third of subsequent neoplasms in early stage and one fifth in advanced stage evaluated replenish 51,2% of unknown stage in men and 47,4% in women. High proportion of LCs at unknown stages limited detailed analysis. Dichotomous question of early diagnosis is inquired.

Methods:
Miscellaneous group of 548 individuals (260 females and 288 males) with high risk of lung cancer was formed predominantly from South Moravia region of the Czech Republic, EU. They were enrolled since 2001 to 2010. Approximately one third (n=185) from the group had undergone surgery due to cancer of head and neck, gastrointestinal, gynecological including breast, urological and skin location (n=86) and due to pulmonary malignancy (n=99) . The follow up scheme for this subgroup represents four time yearly careful clinical investigation with monitoring of appropriate TM levels during first three years, then three time in the year during fourth and fifth years, and two time yearly follow up investigation during sixth to tenth year in connection with yearly paraclinical set of CT of thorax and USG of abdominal spaces on even-numbered, and X-rays of thorax and CT of abdomen on odd-numbered years, two-year period bone scan, endoscopy, and yearly laboratory screening tests – serology, hematology, and basic urine investigation. Another parts of the risk group are represented by persons (n=203) with high risk of lung cancer (uranium miners with long term professional exposure to Rn222, heavy smokers minimally 20 yrs with 1 to 2 packs cigarettes per day (n=60), pts with hemoptysis (n=15) and persons with other kind of risk (n=85). These were screened one time yearly by clinical, laboratory, and bronchoscopy examination and imaging alternately yearly X rays / thoracic CT scan and abdominal USG. Classification of malignant tumours TNM-7 and Program Microsoft Excel® were used to data analysis.

Results:
Among 548 persons from the risk group followed during ten years period they were found in 29 individuals (5,3%) counting 11 females and 18 males a total of 40 lung cancers. They were 14 primaries and 26 subsequent LC with two cases of triplicity. The early diagnosis in the stage (I, II) was established 32-times (i.e. 4/5) versus 8-times diagnosed advanced stage (III, IV) of disease (i.e. 1/5). Appropriate treatment was organized and follow up continues to evaluate survival.

Conclusion:
Early diagnosis in patients with lung cancer multiplicity seems attainable despite of certain limitation.

Background:
Each lung structure has a unique pattern of exhaled aerosols (aerosol fingerprint), whose deviation from the normal pattern may indicate an anomaly inside the airway. Therefore, an exhaled aerosol test can be used to detect and monitor lung diseases non-invasively. The key challenge is accurately interpreting the exhaled aerosol fingerprints and quantitatively correlating them to lung diseases.

Methods:
In this study, a novel integrated algorithm was developed to evaluate the feasibility of the exhaled aerosol tests. This algorithm has four steps: data generation via physiology-based modeling, image feature extraction using sub-regional fractal analysis, data classification using a support vector machine (SVM), and data quality assessment using principle component analysis.

Results:
By employing the 10-fold cross-validation method, we achieved 100% classification accuracy among four asthmatic models using an ideal 108-sample dataset and 99.1% accuracy using a more realistic 324-sample dataset. The fractal-SVM classifier has been shown to be robust, highly sensitive to structural variations, and inherently suitable for investigating aerosol-disease correlations.

Conclusion:
For the first time, this study quantitatively links the exhaled aerosol patterns with their underlying diseases and sets the stage for the development of a computer-aided diagnostic system for non-invasive detection of obstructive respiratory diseases. The proposed aerosol breath test is especially suitable for the use of screening to detect lung tumors at early stages, and to monitor tumor growth or therapeutic outcome of medical interventions.

Background:
Lung cancer is a major cause of death in the world and chronic obstructive pulmonary disease(COPD) are at risk for lung cancer. Both the diseases have common etiologies, including cigarette smoking. We aimed to clarify the effectiveness of lung cancer screening by chest X-ray and by low-dose computed tomography（LDCT）among patients with COPD tested by pulmonary function test(PFT) by using regional lung cancer mass screening.

Methods:
A total of 7,067 residents including 2,720 males and 4,347 females of Togane City, Chiba, Japan received lung cancer screening between May and July, 2011. All residents underwent chest X-ray and answered questionnaire, including smoking history , chronic respiratory symptoms and lifestyle-related disease for selecting COPD. We hypothesized that individuals with a positive smoking history with chronic respiratory symptoms or lifestyle-related disease considered COPD candidates and advised to undergo PFT. COPD candidates whose forced-expiratory volume in 1 second/ forced vital capacity less than 70 % were considered COPD who underwent LDCT. They were followed additional two years by high resolution CT for detecting lung cancer.

Results:
Chest X-ray showed normal in 6,749 and abnormal in 318(4.5%). Among participants with normal chest x-ray, positive COPD candidates were 1,686(23.9%) and negative COPD candidates were 5,381(76.1%), according to the questionnaire. 1,500 of 1,686 underwent PFT and diagnosed COPD in 171(2.4%). 151(2.1%) of them received LDCT. Six of 318(1.9%) cases with abnormal chest X-ray were finally diagnosed lung cancer (86/100,000). One case at initial time and three cases during follow-up periods were diagnosed lung cancer by LDCT in COPD patients (0.88 % per year).

Conclusion:
Chest X-ray and LDCT for COPD patients may be effective for lung cancer surveillance in community-based lung cancer screening.

Background:
American Society of Anesthesiologists (ASA) classification is an useful pre-operative evaluation system which helps clinicians in prediction of possible complications and risks due to surgery. In ASA classification, surgical candidates are divided into six groups according to their risk status. Following ASA classification, grading is done according to the severity of the operation. Grades are determined due to the severity and the duration of the operation. After determining ASA classes and grades, necessary tests are performed according to age groups to complete the pre-operative assessment. However, in this evaluation, randomly determined pathologies can dramatically change the assessment results in those cases without any symptoms. For this purpose, we retrospectively analyzed the results of the patients received pre-operative pulmonary evaluation during the last one year.

Methods:
Pre-operative pulmonary evaluation results of 520 cases were analyzed retrospectively who were referred to our clinic between January 2014-January 2015.

Results:
Through them, 6 (1.2%) patients (4 men, 2 women) with mass and/or nodule images in their chest radiographs, were histopathologicaly diagnosed with lung cancer. 3 of these cases were planned for inguinal herniorrhaphy, and other 3 cases for knee replacement surgery. The common points of these cases were being asymptomatic and included into ASA 1 - grade II group. The mean age of the patients was 71.1 (65- 87). Lung cancer diagnosis was proven by transthoracic needle biopsy in 3 cases, bronchoscopy in 1 case and thoracentesis + pleural biopsy in 1 case with pleural effusion. All of the cases are non-small cell lung cancer; 3 adenocarcinoma and 3 squamous cell lung carcinoma. 4 cases were found to be in stage IIIB and over, while the other 2 patients who were underwent lobectomy were in stage IB. Chemoradiotherapy was performed to the inoperable cases.

Conclusion:
Pre-operative tests conducted according to current ASA classification are still useful in terms of determining the possible complications and risks. However, in some cases, as in ours, examinations broader than recommended may be necessary. According to ASA classification; ASA group 1describes healthy person with no systemic problem accept for current surgical pathology, and grade 2 describes short timed operations (30 minutes - 1 hour) in which vital organs are affected minimum (inguinal herniorrhaphy, tonsillectomy, arthroscopy, cystoscopy, etc.). ASA recommends preoperatively complete blood count, serum electrolytes, blood glucose, blood urea nitrogen, creatinine tests for ASA group 1- grade II patients aged 61 years and older. Chest radiography is not routinely recommended in these patients with no obvious symptoms or signs. However, in our own clinical approach for pre-operative evaluation of patients aged over 65 years, chest radiograph is a preferred test. Considering that 6 asymptomatic lung cancer patients were determined by this approach, the benefits of pre-operative chest radiograph which is a cheap, fast and easy examination are remarkable in pre-operative pulmonary evaluation. We presented this case series in order to emphasize this subject.

Background:
Lung cancer incidence and mortality rates differ depending on race, ethnicity, and gender. African American (AA) men have significant higher incidence and mortality from lung cancer compared to white men (incidence 87.3 vs. 72.5; mortality 70.1 vs. 57.8 per 100,000). Lung cancer screening is an effective lifesaving tool. The National Lung Screening Trial (NLST) showed a 20 percent reduction in lung cancer mortality with low-dose computerized tomography (LDCT) versus chest X-ray screening, but the study population was 91% white and only 4.5% AA. Could the reduction in lung cancer mortality be even greater if the NLST population included a larger minority population? UI Health has a large community outreach that serves minority populations in Chicago (48% AA, 24% classified as “other”, 16% White, 7% Hispanic). In March 2015, UI Health began a comprehensive lung cancer-screening program.

Methods:
The program coverage and eligibility is broadly advertised to patients and primary practitioners in our community. Previously, low cost lung cancer screening was available but coverage was a concern for patients and practitioners. Lung cancer screening eligibility criteria used is set by the CMS (age 55-77, current smoker or one that have quit within the past 15 years, smoking history of > 30 pack-years) and the U.S. Preventive Services Task Force (including ages up to 80 for non-Medicare patient). American College of Radiology LungRADS system is used for standardized image reporting, and recommended management for positive screens. Data elements include age, gender, race/ethnicity, insurance type, LDCT findings, and treatment modalities for diagnosed lung cancer is collected in a secure registry.

Results:
In our first month, 13 patients have been screened between the ages of 56-76, 7 females/6 males. Race/ethnicity make-up: 54% AA, 31% White, 15% Hispanic. Estimated volume of LDCT screens is 200 per year. As yet, there are no significant findings requiring intervention. Of note, in the greater than 2 years that screening was an option but coverage was not clarified by CMS, fewer than 10 patients participated, suggesting that lack of coverage by CMS or commercial carriers was a barrier for our patients.

Conclusion:
Coverage by CMS and commercial carriers for LDCT screening has a significant impact on our patient population. Analysis from this study will assess if we can reach a large underserved group with a screening program and whether it will result in decrease of lung cancer mortality in this population.

Background:
National health surveillance with chest X-ray is performing in our country every two years. The present study was performed to evaluate the differences in clinical characteristics and survival outcomes of patients with non-small cell lung cancer (NSCLC) according to detecting the disease by health surveillance with chest X-ray (CXR) or presenting symptoms (SX).

Methods:
We identified 294 patients (male/female ratio: 226/68; mean age: 68.7 years old) in tertiary university hospital between Jan 2010 and Dec 2012. The patients were divided into two categories according to method of detection. The clinical characteristics and treatment outcomes were estimated according to CXR group and SX group.

Results:
CXR group was 102 patients and SX group was 192 patients. There were significant shift to early TNM stage distribution, cancer cell type, initial treatment modality and type of surgery in the CXR group compared with SX group (table 1). Median survival times were 35.2 months (95% confidence interval (CI): 24.1–46.3) in CXR group, and 14.2 months (95% CI: 12.1–16.3) in SX group. There were statistically significant differences in overall survival between CXR and SX groups (P=0.001) (figure1). Figure 1 Figure 2





Conclusion:
Lung cancer screening by national health surveillance with chest X-ray contributed to better clinical outcome in patients with NSCLC.

Background:
The recent large scale National Lung Cancer Screening Trial in the United States (NLST) demonstrated an increased detection of stage I lung cancers. This approach was associated with a 20% reduction of lung cancer-related deaths in the screening population. However, the current clinical guideline for the management of lung nodule is primarily based on studies of non-calcified solitary pulmonary nodules (SPN). Although several recent studies have addressed the issue of the management of semi-solitary and/or partially calcified lung nodules, the evidence-based study is still necessary. Clinically, the diagnosis of small pulmonary nodules involves the combination of radiological surveillance and the morphological examination of pulmonary cells, such as bronchoscopic sampling of the lesion, including bronchial brushing and/or transbronchial fine needle aspiration biopsy (TBNA) with or without ultrasound guidance. In this study, we correlated cytomorphological diagnoses of lung nodules with radiological characteristics, and compared them with findings of mediastinal lymph nodes (LN) fine needle aspiration (FNA) biopsy.

Methods:
A total of 300 lung and mediastinal LN cases over a one-year period were identified by a computer search, including 117 lung and 183 lymph nodes biopsies. All cases were divided into three categories: solitary, semi-solitary and partially calcified nodules/lesions according to radiographic image. The cytological diagnoses of all cases were correlated with radiographic findings.

Results:
In lung biopsies, the average sizes of the solitary, semi-solitary and calcified lesions were 1.952+/-2.225, 1.333+/-1.827, and 1.152+/-1.984 cm, whereas, in lymph nodes the average sizes of the solitary, semi-solitary and calcified lesions were 1.696+/-2.225, 0.909+/-1.041, and 2.788+/-3.371 cm. The cytological diagnosis was summarized in the table.

Lesions	Lung (n=117)			Lymph node (n=183)
	Malignant	Benign	Suspicious	Malignant	Benign	Suspicious
Solitary (lung n=88) (LN n=156)	58 (65.9%)	23 (26.1%)	7 (8.0%)	136 (87.2%)	20 (12.8%)	0
Semi-solitary (Lung n=23) (LN n=23)	8 (34.8%)	12 (52.2%)	3 (13.4%)	21 (91.3%)	2 (8.7%)	0
Calcified (Lung n=6) (LN n=4)	2 (33.3%)	3 (50%)	1 (16.7%)	4 (100%)	0	0
Total	68 (58.1%)	38 (32.5%)	11 (9.4%)	161 (88%)	22 (12%)	0

Conclusion:
In suspicious solitary and semi-solitary lung nodules, the malignancy was diagnosed as 65.9% and 34.8%, respectively. In suspicious solitary and semi-solitary lymph nodes, the malignancy was diagnosed as 87.2% and 91.3%, respectively. In lung lesions with partial calcifications (we only had very limited number of cases), approximately 50% were malignant lesions. In addition to radiological evaluation, the cytomorphological evaluation of semi-solitary and partially calcified nodules is still crucial for the accurate diagnosis and the appropriate clinical management of lung nodules patients.

Background:
The aim of the study is to introduce a more effective quantitative method(optimal identification index and reference value) for characterizing the AFB images within the region of interest and to explore the value of AFB in diagnosis of different types of lung cancer.

Methods:
Patients with one or more preinvasive bronchial lesions were entolled, followed-up by white light bronchoscope(WLB) and AFB. A quantitative analysis based on color space(red-to-green value, R/G value) was conducted and the result was compared with the final diagnosis obtained by the pathology of biopsy and/or by surgical pathology.

Results:
A retrospective analysis was conducted on 218 cases with 1,208 biopsies. 173 cases were diagnosed as positive by WLB associated with AFB, which included 151 true positive cases and 22 false positive cases. There were 45 cases in 151 true postive cases which included 13 false negative cases and 32 true negative cases. WLB associated with AFB was able to differentiate between benign and malignant lesion lymph nodes with a high sensitivity, specificity, positive predictive value and negative predictive value(92.1%, 59.3%, 87.3% and 71.1%, respectively). The quantitative method of R/G value allowed an more excellent discrimination and yielded a high sensitivity and specificity(82.3% and 80.5%), based on a cut-off level of 1.485.

Conclusion:
AFB associated with WLB is a promising method which allows characterisation and differentiation of benign and malignant lesions with a high sensitivity, specificity based on R/G value.

Background:
With the increase in survival of cancer patients over the past three decades, both as a result of improved treatments and earlier diagnosis, the likelihood of developing a second cancer has increased. The aim of our study was to assess the frequency of multiple malignancies in patients hospitalised at the Centre for Pulmonary Diseases in Olsztyn, Poland.

Methods:
We performed a retrospective review of medical records of 1112 patients hospitalised at our Centre between January 2013 and September 2014. We selected cases with at least two malignancies. We recorded the number and locations of the tumours in the patients and their relatives, risk factors and co-morbidities. The inclusion criteria were met by 56 patients (18 women and 38 men).

Results:
Among the patients with multiple primary neoplasms we identified 52 cases where at least one of the primary cancers was lung cancer and 4 cases where none of the primary cancers was lung cancer. The mean age at diagnosis of the first and the second cancer was 62,16 (SD 12,04) years an 67,20 (SD 9,68) years, respectively. The mean interval between the diagnosis of the first and the second cancer was 3,84 (SD 13,03) years. We identified 4 cases of triple primaries and 1 case of quadruple primaries. Regarding the sequence of diagnosis, lung cancer was the first malignancy in 11 cases (1 - non-small-cell carcinoma, 4 - adenocarcinoma and 5 - squamous cell carcinoma, 1 - undiagnosed), the second malignancy in 39 cases (4 - non-small-cell carcinoma, 12 - adenocarcinoma, 10 - squamous cell carcinoma, 7 - small-cell carcinoma and 6 - undiagnosed) and the third malignancy in 2 cases (1 - squamous cell carcinoma, 1- undiagnosed). The other malignancies diagnosed as the first ones and the second ones were:

	First	Second
Prostate cancer	6	4
Breast cancer	5	2
Vocal cord cancer	1	1
Renal cel carcinoma	4	1
Uterine cancer	4	0
Colorectal cancer	8	0
Skin cancer	3	0
Bladder cancer	2	3
Adrenal cancer	2	1
Lymphoma	1	3
Laryngeal cancer	3	0
Gastric cancer	1	1
Brain cancer	2	0
Tongue cancer	1	0
Salivary gland cancer	1	0
Ovarian cancer	1	0
Thyroid cancer	0	1

We identified the following co-morbidities: hypertension (28), COPD (17), coronary artery disease (8), atrial fibrillation (6), myocardial infarction (3) type 2 diabetes mellitus (4), thyroid diseases (4), chronic renal failure (2), peripheral artery disease (1), stroke (1) and connective tissue disease (1).

Conclusion:
· Lung cancer occur more frequently as the second malignancy. · Patients with multiple neoplasms make up 5,04% of all patients with lung cancer and the number seems to increase. · Generally synchronous neoplasms occur later (medium age; 67,31; SD 11,64), while metachronous neoplasms occur earlier (medium age of the first cancer: 60,12; SD 11,55 and the second one 67,17; SD 9,15), p=0,0014.

Background:
Peripheral pulmonary nodules (PPN) remain a diagnostic challenge for physicians. Minimally invasive biopsy methods for molecular analysis include endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA), navigational bronchoscopy (NB) and transthoracic needle aspiration under computer tomography (CT) guidance. Recently, a combined thoracic navigation system (TNS) allowing for NB and electromagnetic navigational trans-thoracic needle aspiration (N-TTNA) has become available allowing for all necessary procedures to obtain diagnostic and molecular analysis for NSCLC to be performed during a single procedural session.

Methods:
This study was a prospective single arm study examining the success in obtaining molecular tissue in NSCLC cases from the lymph nodes and/or PPN using a novel combined diagnostic approach with TNS (EBUS, NB and N-TTNA) in a single procedural setting. Consecutive patients who consented with a PPN undergoing bronchoscopy were enrolled. All patients underwent convex EBUS for full lymph node staging followed by NB and N-TTNA. All non-diagnostic biopsies were followed with radiographic interval imaging revealing a decrease in size or resolution or a surgical biopsy was performed. The primary outcome was successful acquisition and testing of tissue for molecular analysis.

Results:
Twenty-four subjects with PPN were enrolled in this study (9 male and 15 female) with a median age of 70 years (range 52-85). An EBUS with NB and/or N-TTNA was completed in 24/24 (100%) of the patients. In this cohort, there were seven cases of Adenocarcinoma in which adequate tissue for molecular analysis was obtained in all (100%) of the cases. PPN diagnostic tissue that was adequate for molecular testing was achieved in six out of seven patients (85%). Four patients had evidence of nodal disease on EBUS and all four (100%) nodal samples were adequate for molecular analysis. When a complete TNS is performed combining convex EBUS with the combined TNS procedure for complete staging, the overall diagnostic yield was 92%. No bleeding or hemoptysis events were encountered during the study. There were two (8%) subjects required small bore pigtail catheter placement secondary to pneumothorax.

Conclusion:
This is the first human study demonstrating the sampling adequacy for both nodal and parenchymal tissue sampling for NSCLC molecular analysis in a single procedural setting. Multicentered prospective studies are needed to confirm the utility of these findings in an era of expanding need for tissue acquisition in a minimally invasive setting.

Background:
To research the clinical value and complications of CT-guided percutaneous lung biopsy

Methods:
116 patients with pulmonary lesion were applied percutaneous lung biopsy, using the BRAND 18 G automatic puncturing pistol, under 64-slice spiral CT guiding.

Results:
114 patients succeed to get the biopsy of lung,2 cases failed due to sever pneumothorax,the achievement rate was 98.3%. Among them, 95 were diagnosed as malignant,91 cases being lung cancer (including 18 squamous cell carcinoma, 54 adenocarcinoma,2 small cell lung carcinoma,3 large cell lung carcinoma, and 4 are unclassified).The others contained 2 pleural mesothelioma,2 non-Hodgkin lymphoma,19 non-cancerous lesions (all of these cases,9 with tuberculosis,5 with organized pneumonia,2 with sarcoidosis, 2 with Vasculitis, 2 with inflammatory pseudo tumor).There were 26 patients presenting side effects or complications, the total incidence was 22.4%. Among these, 18 patients had pneumothorax (2 serious, ending puncture), 11 patients had lung bleeding, 2 patients with both pneumothorax and lung bleeding, 8 patients also had chest pain, nausea or other discomfort reactions.

Conclusion:
CTguided percutaneous lung biopsy has the advantages of security and accuracy ,was important method to identify pulmonary lesion.

Background:
Surgical resection is the accepted standard of care for patients with non-small cell lung cancer (NSCLC) at an early stage, patients have a favorable prognosis. Unfortunately, however, only about 25% of NSCLC patients are eligible for surgery, and once the surgical candidates are selected, mediastinal staging is mandatory because up to 50% of these patients have regional metastasis. Accurate nodal staging is crucial for determining optimal treatment strategies and optimizing prognoses. The aim of the present study was to use surgical and histological results to develop a simple noninvasive technique for improving nodal staging using routine preoperative PET/CT in patients presenting with localized and clinically resectable NSCLC.

Methods:
The institutional review board approved this retrospective study, and written informed consent to perform the initial and follow-up CT studies was obtained from all patients. Preoperative PET/CT findings (n=163 patients with resectable NSCLC) and pathological diagnoses after surgical resection were evaluated. Using PET/CT images, lymph node surface area (SA), the maximum standardized uptake value (SUV~max~), SA of SUV ≥2.5 (Figure) and ≥3.0 were drawn freehand and measured using caliper software. Receiver operating characteristic (ROC) curves were then used to analyze those data. Figure 1



Results:
Based on ROC analyses, the cut-off values for SA of SUV ≥2.5, SA of SUV ≥3.0, SUV ≥2.5 SA / node SA ratio and SUV ≥3.0 SA / node SA ratio for diagnosis of lymph node metastasis were 200 mm[2], 30 mm[2], 1.0 and 0.4. When the conventional SUV~max~ ≥2.5 was used for diagnosis, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy of nodal staging were 61.1%, 62.2%, 28.9%, 86.4%, 62.0% , respectively. SUV ≥2.5 SA / node SA ≥1.0 had the highest negative predictive value, and when a cut-off value of SUV ≥2.5 SA / node SA ≥1.0 was used for diagnosis, the sensitivity, specificity, PPV, NPV and accuracy were 61.1%, 73.4%, 36.7%, 88.2% and 70.9%, respectively.

Conclusion:
When diagnosing nodal staging based a lymph node SUV ≥2.5 SA / node SA ratio of ≥1.0, we achieved a higher performance level than was achieved using the conventional of SUV~max~ criterion. Furthermore, determination of this ratio from PET/CT images is a simple noninvasive procedure.

Background:
Conventional white light bronchoscopy (WLB) has been used for decades. Some technical advances in bronchoscopies are available for detecting lung precancerous and cancerous lesions currently. Our aim was to investigate the performance of autofluorescence bronchoscopy (AFB), AFB combined with white light bronchoscopy (AFB+WLB), narrow-band imaging bronchoscopy (NBI) and, additionally, to directly compare these new techniques with WLB alone.

Methods:
Pubmed, Embase, Web of Science, Ovid, ProQuest, Scopus and the Cochrane Library were searched for relevant articles. Eligible studies should study any of the new techniques with histopathology as a golden standard, and should have sufficient data to construct 2×2 contingency tables. We used random-effects bivariate models to pool sensitivity, specificity, diagnostic odds ratio (DOR) and the area under the receiver operating curve (AUC) with 95% confidence interval.

Results:
Fifty-three studies involving a total of 6543 patients and 18458 biopsy specimens were included. Single arm synthesis of the new techniques showed that the overall sensitivity of AFB, AFB+WLB, NBI and WLB was 87% (82%-90%), 88% (82%-93%), 96% (78%-99%) and 54% (46%-61%); overall specificity was 65% (58%-72%), 59% (48%-68%), 84% (70%-92%) and 79% (73%-84%); and AUC was 85% (81%-87%), 82% (78%-85%), 94% (91%-96%) and 72% (68%-76%) respectively. In direct comparison, AFB, AFB+WLB and NBI had higher overall sensitivity, DOR and AUC, but lower specificity than WLB alone, regardless of precancerous or cancerous lesions (see in Table 1). In exploratory subgroup analysis, the sensitivities of all techniques were relatively higher in studies with higher proportion of elder patients, or in those with higher proportion of ‘high risk’ patients who had prior/suspected lung cancer or head & neck cancer. Figure 1



Conclusion:
Based on this pooled analysis, the performance of AFB, AFB+WLB or NBI is superior to WLB alone for diagnosing both lung precancerous and cancerous lesions. Its application might be preferably encouraged in populations with higher risk for non-benign lesions.

Background:
Reactive oxygen species modulator 1 (Romo1) is a novel protein that is critical in mitochondrial reactive oxygen species (ROS) generation. It is increased in most cancer cell lines and is associated with resistance to chemotherapy in vitro. Recently, serum Romo1 has been suggested as a potential diagnostic marker for non-small cell lung cancer (NSCLC), and increased tissue Romo1 protein expression has been related with poor prognosis in patients following surgical resection for NSCLC. The clinical significance of pleural fluid Romo1 is unknown. We evaluated the clinical usefulness of pleural fluid Romo1 as a potential diagnostic and prognostic marker in patients with lung cancer-associated malignant effusion.

Methods:
Romo1 level was measured in pleural fluid using enzyme-linked immunosorbent assay in four groups: lung cancer-associated malignant effusion (n =24; 15 adenocarcinomas, 7 squamous cell carcinomas and 2 small cell lung cancers), tuberculous pleurisy (n = 14), parapneumonic effusion (n =15) and transudative effusion (n = 16). The discriminative power in lung cancer-associated malignant effusion and the association with survival of Romo1 was determined using receiver operating characteristic (ROC) curve and Kaplan-Meier survival analysis, respectively.

Results:
Pleural fluid Romo1 level was significantly higher in lung cancer-associated malignant effusion compared with other groups (all p < 0.001). In the ROC curve analysis, the optimal cutoff value for lung cancer-associated malignant effusion was 451.5 pg/mL with a sensitivity of 81.9% and specificity of 84.8%, with an area under the curve of 0.838 (95% confidence interval : 0.789 - 0892, p < 0.01). In addition, at the cutoff determined by median Romo1 level, high Romo1 expression was related with reduced overall survival in patients with NSCLC (p = 0.03). For all patients, pleural fluid Romo1 level was not related with age, gender, smoking status, tumor differentiation, histological type, glucose, protein, albumin and lactate dehydrogenase level.

Conclusion:
Romo1 discriminated lung cancer-associated malignant effusion from non-malignant effusions with considerable sensitivity and specificity. Also, high Romo1 level was associated with poor prognosis in lung cancer patients. Pleural fluid Romo1 could be a potential diagnostic and prognostic marker in patients with lung cancer-associated malignant effusion.

Background:
In recent years, the outcome of surgically treated early lung cancer patients have improved steadily. However postoperative recurrence following early stage lung cancer surgery can occur: 10-20% possibility of recurrence presents within 5 years after the initial operation. Numerous reports of various malignancies have revealed that 18-Fluoro-2-deoxy-D-glucose (18F-FDG) accumulation, evaluated by positron emission tomography, can be used to predict the prognosis of patients. Our purpose in this retrospective study was to determine if the maximum standardized uptake value (SUVmax) of a primary tumor predicts survival for patients of surgically treated early lung cancer.

Methods:
A total of 170 patients (99 males and 71 females) with curatively operated early lung cancer (p-stage I/II) were enrolled in this study between April 2010 and February 2015 at Japanese Red Cross Kyoto Daini Hospital. Lobectomy 160 cases, segmentectomy 20 cases, and wedge resection 4 cases. The FDG uptake of all primary lung tumor lesions diagnosed by conventional CT was evaluated by 18F-FDG PET/CT. The relation between SUVmax and patient survival was analyzed retrospectively. The postoperative survival rate was analyzed by Kaplan-Meier method, and the differences in survival rates were assessed by log-rank test. A probability value of <0.05 was considered significant. The optimal cut-off value of SUVmax for postoperative recurrences was determined using a receiver operating characteristic (ROC) curve.

Results:
The SUVmax of 170 patients ranged between 0 and 23.7. The median SUVmax was 3.5 for all cases, 3.5 for stage IA, 7.2 for stage IB, 8.2 for stage IIA, and 12.8 for stage IIB (P<0.01). Tumor recurrence occurred in 26 cases (15.3%). According to a survey by the ROC curve, the optimal cut-off value of SUVmax for postoperative recurrences was set at 3.75 with 81% sensitivity, 63% specificity. The survival between patients with SUVmax cut-off value 3.75 or more and patients with SUVmax less than 3.75 were statistically different. The 5-year survival for patients with SUVmax more than 3.75 was 76.6% and the 5-year survival for patients with SUVmax less than 3.75 was 90.6% (P=0.0196). However, the number of patients and the follow-up period were still not extensive enough to settle this important problem conclusively.

Conclusion:
The survival of patients with surgically treated early lung cancer might be predicted by evaluating their SUVmax using 18F-FDG -PET/CT. Among early lung cancer patients, there　are potentially advanced lung cancer. The present findings suggested that SUVmax of more than 3.75 in lung cancer patients is predictive of a higher likelihood of recurrence. We recommended close clinical follow-up of the early lung cancer patients with SUVmax more than 3.75 for early diagnosis of recurrence.

Background:
As the first failure, the rate of distant failure was much higher than local failure in patients with completely resected stage IIIA(N2) NSCLC . Brain was the most common site of distant failure as the first failure, and more than 90% Brain metastases (BM) developed in 3 years.We aimed to identify the risk factors of BM as the initial site of failure in 3 years and to define the highest-risk patients who are most likely to benefit from prophylactic cranial irradiation (PCI).

Methods:
The medical records of 301 consecutive patients with pathological stage IIIA (N2) NSCLC who underwent complete surgery were reviewed between January 2005 and July 2012. We observed the correlation between clinical, pathological, microenvironmental factors and BM to find out the risk factors of BM. 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. To assess the risk factors of BM as the first site of failure in 3 years, the log-rank test was used for univariate analysis, and Cox regression was used for multivariate analysis.

Results:
The 1-, 2-, and 3-year risks for patients developing BM as the initial site of failure were 9.3%，17.7% and 25.8%, respectively. Univariate analysis showed that adenocarcinomas (P = 0.000), multiple N2 stations (P = 0.025), multiple regions of mediastinal lymph node (MLN) involvement (P = 0.023), and highest MLN metastasis (P=0.023) were significantly associated with an increased risk of developing BM as the first site of failure in 3 years. Patients with the tumor budding >5 experienced increased BM in 3 years versus patients with the tumor budding ≤5 (P=0.068) Multivariate analysis showed that adenocarcinomas and multiple N2 stations were significantly associated with the high risk of BM as the initial site of failure in 3 years. In patients with adenocarcinomas and multiple N2 stations, the 3-year actuarial risk of BM as the initial failure was 43.5%. Figure 1



Conclusion:
In patients with completely resected stage IIIA (N2) NSCLC, adenocarcinomas and multiple N2 stations were independent risk factors of BM as the initial failure in 3 years. Patients with the tumor budding >5 had a tendency to experience more BM. Patients with adenocarcinomas and multiple N2 stations are at the highest risk of BM, and are most likely to benefit from PCI.

Background:
Protein kinase CK2 has long been associated with increased cell growth and proliferation in both normal and malignant cells. CK2α (a catalytic subunit) is highly expressed and pivotal for survival and proliferation in multiple malignancies; however, whether CK2α functions in small cell lung cancer (SCLC) malignant behavior and whether it is feasible to be used as a therapeutic target have not been evaluated.

Methods:
The expression levels of CK2α were analyzed in SCLC tissue microarray and cell line (NCI-H446) by immunohistochemistry and immunofluorescence. After knocking down the CK 2α level by specific siRNA sequence, biological consequences on proliferation, migration, invasion and apoptosis were evaluated.

Results:
CK2α was detected in 66.7% of cases with a trend towards a stronger CK2α immunostain in SCLC tissues compared to normal lung tissues. CK2α silencing had potent suppressive effects on SCLC proliferation, migration and invasion, resulted in abrogation of tumor-cell pseudopod formation, however, did not lead to cell arrest and apoptosis. Western-blot analysis confirmed elevated PML/Bcl-2 protein levels as well as reduced E-Cadherin protein level in the CK2α-silenced SCLC cells.

Patient Characteristics	No. of Cases	%
Gender (F/M)	9/31	22.5/77.5
Stage
Ⅰ	10	25
Ⅱ	21	52.5
Ⅲ	9	22.5
Tumor
T1/T2	36	90
T3/T4	4	10
N0	12	30
N1/N2	28	70
Normal Lung Tissue	10

Figure 1



Conclusion:
The results suggest that CK2α negative regulation of the protein levels of tumor suppressor PML/Bcl-2 and activation of the E-Cadherin pathway could be involved in SCLC malignant behavior. Depleting CK2α level may serve as a promising therapeutic strategy for human SCLC.

Background:
Background: Chemotherapy produces high response rates in extensive stage SCLC and a modest improvement in 5-year survival rates when combined with chest radiation in limited stage SCLC. Chemotherapeutic agents for SCLC have not changed in 20 years. Eribulin is a microtubule inhibitor that arrests cells in the G2/M fraction of the cell cycle with established activity in breast cancer. Radiobiological studies demonstrated that cells in the G2/M phase of the cell cycle are less efficient at repairing radiation induced DNA damage. Thus, we investigated the effects of eribulin, radiation and the combination on growth and cell cycle distribution in a panel of SCLC cell lines.

Methods:
Methods: Growth inhibition (GI) by varying concentrations of eribulin alone, radiation alone and the combination was assessed by MTS assay at 5 days post-treatment. Growth inhibition or fraction affected (FA) was determined by 1-(x/y) where x is the MTS signal for the experimental condition and y is the MTS signal for the untreated control cells. Our goal was to use a dose of radiation that alone induced a FA of about 0.5 allowing determination of the combination effects with eribulin. Changes in the G2/M distribution of cells treated with eribulin alone, radiation alone and the combination were evaluated at 24 and 48 hours post treatment by propidium iodine staining and analysis by FACS.

Results:
Results: Four of the eight SCLC cell lines were very sensitive to eribulin with half maximal growth inhibitory concentration (FA<0.5) of < 2nM. Four lines had 0.5 FA values > 2nM. 2 Gy radiation produced 32% to 58% growth inhibition in all 8 lines irrespective of their eribulin sensitivity. Low eribulin concentrations (≤ 1.25nM) and 2Gy radiation produced >70% growth inhibition in the 4 sensitive lines, which was significantly more growth inhibition than either alone. Eribulin concentrations of >2.5nM were required to increase growth inhibition over either alone in the 4 more resistant lines and the maximal GI was less in these lines (48%-70%) even at higher concentrations. With respect to G2/M, in the 4 most sensitive eribulin lines, there was a significant increase in the G2/M fraction following eribulin alone (0.625-1.25nM), radiation alone (2 or 3Gy) and a further increase occurred with the combination treatment. In these eribulin sensitive lines, 59% to 93% of the cells were in the G2/M phase by 48 hours. In 3 of the 4 less sensitive eribulin lines, higher concentrations of eribulin (>2.5nM) were required to increase the G2/M fraction to >50% and 2 or 3 Gy irradiation increased the G2/M fraction to 59% to 64%. The combination produced maximal G2/M fractions of 64%-79%. The one most eribulin resistance line never had more than 50% GI or > 40% of cells in G2/M at any concentration or radiation dose up to 4 Gy.

Conclusion:
Conclusions: SCLC cell lines are sensitive to eribulin and radiation and the combination produced significantly more growth inhibition and cell cycle arrest then either alone. The combination warrants further evaluation in in vivo models and potentially clinical trial study in patients with SCLC.

Background:
SCLC is an aggressive malignancy with limited treatment options. Based on in vitro data and results of a recent drug repositioning study, some medications approved by the FDA for the treatment of various non-malignant disorders were demonstrated to have anti-SCLC activity in preclinical models. Drug dose levels that demonstrated anti-cancer activity were similar to those used in the clinics. The aim of our study is to confirm whether use of these medications is associated with survival benefit in a large cohort of SCLC patients from a single institution.

Methods:
Consecutive patients with cytologically or histologically confirmed, metastatic SCLC evaluated between 2000-2013 at the National Koranyi Institute of Pulmonology were analyzed in this retrospective analysis. Patients that were prescribed statins, aspirin, clomipramine (a tricyclic antidepressant [TCA]), selective serotonin re-uptake inhibitors (SSRIs), doxazosin, and prazosin were identified. Next, we evaluated the associations amongst these various medications, clinicopathological characteristics (including gender, age, and Eastern Cooperative Oncology Group performance status [ECOG PS]), and overall survival (OS) in univariate and multivariate analyses with Bonferroni correction applied.

Results:
There were a total of 876 patients (508 men and 368 women) with a median age of 61 years (range, 33-86). 75% of the chemotherapy administered in the first line setting was platinum-based. Aspirin, statin, SSRIs, doxazosin, prazosin, and TCA were administered in 138, 72, 20, 14, 14, and 5 cases; respectively. Univariate analysis identified age, ECOG PS, and statin treatment as significant prognostic factors (p<0.001; p<0.001; and p=0.002; respectively). A statistically significant increase in OS was observed only in statin-treated patients when compared to those not receiving any of the aforementioned medications (median OS, 8.4 vs. 6.1 months; respectively). The administration of SSRIs, TCA, aspirin, prazosin, or doxazosin did not result in a statistically significant OS benefit (median OS, 8.5, 7.2, 6.8, 6.8, and 4.6 months; respectively). The multivariate Cox model showed that besides age and ECOG PS, statin treatment was an independent survival predictor (Hazard Ratio, 1.41; 95% confidence interval, 1.1–1.8; p=0.007).

Conclusion:
Statins appear to provide a statistically significant survival benefit in metastatic SCLC. Other classes of medications analyzed in this study did not validate the preclinical drug repositioning studies previously reported. Drug repositioning studies using only preclinical data or small numbers of patients should be treated with caution before application in the clinic.

Background:
NCCN recommends IP program as a first-line chemotherapy of ED-SCLC.Several clinical study conducted in colorectal cancer showed that the polymorphism of UGT1A1*28 gene can evaluate the risk of severe neutropenia and diarrhea occurred in patients receiving irinotecan chemotherapy. The purpose of this research is to analyze the distribution of UGT1A1 gene polymorphisms in Chinese Han patients with ED-SCLC，and to evaluate correlations between UGT1A1 gene polymorphisms and toxicity and efficacy of irinotecan in patients with ED-SCLC.

Methods:
Analysis of UGT1A1*28 and UGT1A1*6 gene polymorphisms were performed by peripheral blood gene sequencing. From June 2011 to Nov 2013, 67 cases admitted to hospital with ED-SCLC treated by irinotecan(CPT-11) based regimen were enrolled in this study. We observe the relationship of PFS , OS and AEs between different genotypes.

Results:
Figure 1 figure 1 the PFS and different gene type Figure 2 figure 2 the OS and different gene type The median PFS of wild type UGT1A1*28 (TA6/6) and mutant (TA6/7) was 9.9 months and 10 months respectively; the median PFS of wild type UGT1A1*6 (G/G) and UGT1A1*6 mutant (G/A) was 9.7 months and 9.9 months respectively. The median OS of wild type UGT1A1*28 (TA6/6) and mutant (TA6/7) was 13.9 months and 14.5 months respectively; the median OS of wild type UGT1A1*6 (G/G) and UGT1A1*6 mutant (G/A) was 13.8 months and 14.1 months respectively. No significant difference of PFS and OS was observed between different genotypes(p>0.05). The incidence of grade 3 and 4 delayed diarrhea and neutropenia in patients carrying UGT1A1*6 G/A was higher than that in the WT genotype(36.4% vs. 6.6% p<0.05; 27.2% vs. 4.4% p<0.05 respectively); The patients simultaneously carrying UGT1A1*28 TA6/7 and UGT1A1*6 G/A were prone to suffering 3 and 4 delayed diarrhea and neutropenia.





Conclusion:
Although UGT1A1 polymorphisms failed to predict the efficacy of CPT-11 in ED-SCLC, the prediction of adverse effect may worth attention.

Background:
Salvage chemotherapy (CT) for relapsing or refractory small cell lung cancer (SCLC) to platinum-etoposide remains disappointing. In vitro experiments are suggesting that valproic acid, by inhibiting histone deacetylases (HDAC), could increase apoptosis of SCLC cell lines exposed to doxorubicin, vindesine and bis(2-chloroethyl)amine. The primary objective of this phase II study is to determine if epigenetic modulation with valproic acid in addition to a doxorubicin, vindesine, cyclophosphamide (AVE) regimen may allow adequate improved 6-months progression-free survival (PFS) in refractory/relapsing SCLC.

Methods:
Patients (pts) with previously pathologically proven SCLC, either primary or secondary refractory to prior chemotherapy regimen including platinum derivatives and etoposide, Karnofsky performance status ≥ 60, adequate haematological, hepatic, renal, lung and cardiac functions were eligible. After central registration, pts received AVE (doxorubicin 45 mg/m², vindesine 3 mg/m², cyclophosphamide 1 g/m² every 3 weeks) plus daily oral valproic acid to obtain serum concentration in the range of the recommended values for the treatment of epilepsy (50-100 μg/ml). Response was assessed after 3 courses and responders continued treatment until best response, unacceptable toxicity or cumulative dose of doxorubicin > 500 mg/m². The trial was designed to show that 6-months PFS was > 18%, powering the trial to detect an increase to at least 39%. With this assumption, at least 43 pts assessable for PFS had to be registered (a 10%, b 10%).

Results:
From 11/2008 to 12/2013, 64 pts were registered of whom 6 were ineligible. The main characteristics of the 58 eligible pts were: male/female 38/20 pts, PS 60-70/80-100 17/41 pts, median age 60 years, 19 pts received two or more previous lines of CT. Seven pts did not receive any CT leaving 51 pts assessable for the primary endpoint. Objective response rate was 19.6% (95% CI 8.7%-30.5%). Median PFS was 2.75 months (95% CI, 2.46 to 3.61) and 6-months PFS was 6%. Median survival time was 5.9 months (95% CI, 4.7 to 7.5) with 6 and 12-months survival rates of 50% and 6%. As expected, toxicity was mainly haematological with 88% and 26% grade 3-4 neutropenia and thrombopenia, respectively.

Conclusion:
Despite an interesting response rate, the addition of valproic acid to AVE did not translate into adequate PFS in relapsing/refractory SCLC to platinum/etoposide. This regimen cannot be recommended for further investigation.

Background:
To investigate the dosimetric characteristics, feasibility and risk of Hippocampal avoidance prophylactic cranial irradiation (HA-PCI), in intensity-modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT).

Methods:
Sixteen patients with limited-stage small-cell lung cancer (LS-SCLC) achieved complete remission after chemoradiotherapy accepted HA-PCI. After image evaluation by fusing CT and MRI, hippocampal avoidance regions were created in the hippocampus. A 5 mm area around the hippocampus was plotted as radiation dose deduction area. Patients were randomly assigned to accept intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT). The prescription dose was DT25Gy per 10 fractions.The dose distribution of whole brain, hippocampus and hippocampal plus 5mm were calculated.

Results:
The mean value of Hippocampal volume in the sixteen patients was 2.76 cm[3](range 2.56cm[3]-3.01cm[3]). Using IMRT and VMAT, the mean value of radiation dosein hippocampus was 9.04Gy (range 8.92Gy-9.39Gy)and 10.32Gy (range 10.13Gy-10.82Gy), respectively, reduced by 66.03% and 61.17% compared with whole-brainirradiation.The mean dose in the avoidance regions for IMRT and VMAT was 13.57Gy (range 13.47Gy-13.67Gy),and 14.86Gy (range 14.33Gy-15.89Gy), respectively, reduced by 49.00% and 44.29% compare with whole-brain radiation.

Conclusion:
HA-PCI in IMRT and VMAT is feasible in clinical practice and can achieve adequate whole brain coverage, as well as reduce exposure dose in hippocampus. HS-PCI can protect patient's neurocognitive function.

Background:
The survival benefit of prophylactic cranial irradiation (PCI) in extensive stage small-cell lung cancer (ES-SCLC) reported by an EORTC randomized trial in 2007 has been questioned recently, as a Japanese study with similar trial design failed to show similar results. This retrospective cohort study aims to evaluate the uptake of PCI and its impact on the survival of ES-SCLC before and after publication of the EORTC randomized trial.

Methods:
All patients diagnosed with ES-SCLC without brain metastases and had stable disease or better after first line chemotherapy in the only two Singapore national cancer centers from 2003 to 2010 were identified using the institutions’ pathology registries. We linked the treatment records to the national death registry. We described the utilization of PCI and compared survival of patients diagnosed from 2003 to 2006 (pre-adoption cohort) with patients diagnosed from 2007 to 2010 (post-adoption cohort). Characteristics between pre and post-adoption cohorts were analyzed using chi-square test. Survival was determined from date of diagnosis to death using Kaplan-Meier method. Predictors for improved survival were determined using multivariate analysis.

Results:
71 patients were identified. The demographic and clinical characteristics were similar between the two cohorts save for more patients in the post-adoption cohort having second line therapy (49% versus (vs) 16%, P = 0.01) and receiving PCI (32% vs 10%, P = 0.04). There was no difference in overall survival between the two cohorts (Hazard ratio [HR] 0.70; 95% Confidence Interval [CI] 0.43 to 1.13, P = 0.148). Multivariate analysis showed that PCI (HR 0.47; 95% CI 0.24 to 0.91, P = 0.024) and thoracic radiotherapy (HR 0.49; 95% CI 0.28 to 0.86, P = 0.013) was associated with lower risk of death.

Conclusion:
There was an increase in the uptake of PCI for ES-SCLC since 2007. The use of PCI and thoracic radiotherapy has been shown to be predictors for improved survival in ES-SCLC who had stable disease or better after first line chemotherapy. A larger population based outcome study is warranted to confirm these observations.

Background:
Inactivation of proteasome function allows for increased apoptosis and the potential for enhanced antitumor effect by chemotherapy. Carfilzomib (C) and Irinotecan (I) potentially synergize by increasing camptothecin-induced apoptosis and interfering with topoisomerase-I degradation, preventing DNA damage repair. This report describes the initial phase I study of C + I in adults with relapsed, irinotecan-sensitive cancers including small cell lung cancer (SCLC).

Methods:
The primary endpoint was determination of the MTD of 28-day cycle 1 of I (D1,8,15) and C (D1,2,8,9,15,16) using a standard 3+3 Ph1 design. Toxicity and response were evaluated using NCI CTCAE (v4) and RECIST (v1.1). Pharmacodynamics endpoints (proteasome activity, topo-1 expression, and gamma-H2AX protein expression in PBMC) were assessed on C1D1 and C1D2.

Results:
16 patients were enrolled at 3 dose levels of C (mg/m2/d) using stepped-up dosing: 20 mg given C1D1 & C1D2 then increased to the dose indicated: 20/27 (N=4), 20/36 (N=9), 20/45 (N=3) and I dosed at 125 mg/m2d. Median age: 64 (range 56-78), 8 M/8F. Tumor types included: SCLC (N=13), non-small cell lung cancer (NSCLC) (N=2) and ovarian (N=1). 6 subjects completed 2 or more cycles of therapy, 4 subjects were not evaluable for dose-limiting toxicity (DLT) secondary to rapid progressive disease (PD) or withdrawal and were replaced. 2 DLTs were observed in cohort 3, Grade (Gr)4 thrombocytopenia lasting ≥ 7 days and Gr3 diarrhea lasting ≥ 7 days) and 1 DLT in cohort 2 (Gr3 diarrhea lasting > 7 days). Serious adverse events (SAEs) by dose level: 20/27: Gr3 Dysphagia and recurrent laryngeal nerve palsy, (unrelated); Gr3 peripheral motor neuropathy and Gr3 urinary incontinence, (unrelated); 20/36: Gr3 fatigue, multiple occurrences; Gr3 diarrhea with dehydration; Gr3 cholelithiasis with dehydration (unrelated); 20/45: Gr3 dehydration, Gr3 anemia, Gr2 anemia and Gr3 acute on chronic kidney disease. Common Gr3/4 AEs were: fatigue (19%), thrombocytopenia (19%), diarrhea (13%), anemia (6%), neutropenia (6%), and leukopenia (6%). One patient (25%), five patients (55%), and two patients (67%) experienced Gr3/4 AEs in cohorts 1, 2, and 3, respectively. The maximum tolerated dose was exceeded at 20/45. Antitumor activity (stable disease or better) was observed in 3 SCLC subjects to date, with updated follow-up to be reported.

Conclusion:
C and I is a well-tolerated combination with anti-tumor activity in heavily pretreated patients. The recommended phase 2 dose of Carfilzomib is 20/36 mg/m2/d in combination with Irinotecan 125 mg/m2/d. A phase 2 study in SCLC is ongoing through the Lung Cancer Research Team (LCRT). This study was supported by Onyx Pharmaceuticals, a subsidiary of Amgen Corporation. Clinical trial information: NCT01941316.

Background:
This study aims to evaluate the efficacy and safety of irinotecan/cisplatin (IP) and etoposide/cisplatin (EP) in extensive-stage small cell lung cancer (ES-SCLC) and the distribution of UGT1A1. Simultaneously, the relationship between UGT1A1 genotypes and patient outcomes were assessed.

Methods:
Patients with untreated ES-SCLC were randomly assigned to receive either IP or EP, and blood specimens were collected to test the genotypes of UGT1A1*28 and UGT1A1*6. The association of efficacy and toxicity of IP regimen with UGT1A1 genotype was analyzed.

Results:
Of the 62 patients enrolled from three institutions, 30 patients were in the IP and 32 patients were in the EP arms, respectively. Disease control rates (DCR) with IP and EP were 83.3% and 71.9%, respectively (P=0.043). Median progression-free survival (PFS) for IP and EP were both 6 months. Median overall survival (OS) for IP and EP was 18.1 and 15.8 months respectively, without significant difference. Grade 3-4 thrombocytopenia was more common with EP (18.8% versus 6.7%, P=0.035), while the incidence of diarrhea was higher with IP (70% versus 15.6%, P=0.008). The incidence of grade1-4 late-onset diarrhea of wild-type, heterozygous and homozygous UGT1A1*28 were 65.0%，85.7% and 66.7% respectively (P=0.037). UGT1A1*28 polymorphisms, Eastern Cooperative Oncology Group (ECOG) performance status, chemotherapy cycles were the essential factors affecting grade1-4 late-onset diarrhea in a logistic regression analysis.Figure 1Figure 2





Conclusion:
The efficacy of IP regimen was similar to EP regimen for untreated ES-SCLC. UGT1A1 polymorphisms was associated with late-onset diarrhea, however it has no influence on efficacy.

Background:
Small cell lung cancer (SCLC) is an aggressive malignant disease comprising approximately 14% of all lung cancers, with approximately 31,000 new diagnoses each year in the USA. SCLC has a very poor prognosis, particularly in patients presenting with extensive stage disease. Platinum-based combinations are standard first-line therapy for SCLC; however, relapse is almost universal (≥85%) and patients require further treatment in subsequent lines. Effective new targeted therapies are needed to improve the poor outcomes observed in SCLC. Alisertib is an investigational, orally available, selective inhibitor of Aurora A kinase. Alisertib has shown single-agent antitumor activity in preclinical in vivo models of SCLC and has demonstrated synergism with paclitaxel in this setting. Single-agent alisertib has demonstrated promising efficacy in patients with relapsed/refractory SCLC (Melichar B, et al. Lancet Oncol 2015;16[4]:395–405). Further, phase 1 and 2 evaluation of alisertib+paclitaxel in patients with relapsed ovarian cancer and breast cancer has suggested the antitumor activity of this combination (Falchook G, et al. Int J Gynecol Cancer 2013;23[8] Suppl_1:abstract; Coleman R, et al. Ann Oncol 2014;25[Suppl_4]:abstract 876O). Here we describe the design and objectives of an ongoing phase 2, randomized, double-blind, placebo-controlled study of alisertib+paclitaxel versus placebo+paclitaxel in patients with relapsed SCLC and previously treated with only one line of platinum-based therapy (NCT02038647).

Methods:
Approximately 166 adult patients with relapsed SCLC after standard first-line platinum-based therapy, measurable disease by RECIST v1.1, and Eastern Cooperative Oncology Group performance status 0 or 1 will be enrolled at approximately 80 sites in the USA and Europe. Patients will be randomized 1:1 (stratified by type of relapse [sensitive vs resistant/refractory] and presence of brain metastases) to receive 28-day cycles of either alisertib 40 mg or matched placebo PO twice daily on days 1−3, 8−10, and 15−17, plus paclitaxel 60 or 80 mg/m[2 ]IV, respectively, on days 1, 8, and 15, until disease progression or unacceptable toxicity. The primary endpoint of the trial is progression-free survival (PFS). Assuming a hazard ratio of 0.6 for PFS, a total of 138 progression/death events will be required to provide 85% power (two-sided alpha=0.05). Secondary endpoints include: overall and complete response rates; disease control rate; duration of response; overall survival; safety (NCI-CTCAE v4.03); alisertib pharmacokinetics; and symptom-related endpoints (symptom score, time to symptom relief, time to symptom progression). Evaluation of candidate biomarkers in tumor tissue specimens and in circulating tumor cells (CTC)/circulating tumor DNA, change from baseline in CTC numbers, and health-related quality of life (EORTC QLQ-C30/QLQ-LC13 instruments) are exploratory endpoints. As of 10 April 2015, there are 60 sites open in 6 countries with 90 patients randomized. The study continues to enroll patients.

Results:
not applicable

Conclusion:
not applicable

Background:
Small cell lung cancer (SCLC) is a rapidly progressive disease, characterized by rapid progression in spite of initial responsiveness to first-line chemotherapy. In this setting, an effective and safe maintenance therapy might result in improved disease control; to date, no maintenance strategy has been registered for SCLC yet. Since SCLC cells express a neuroendocrine phenotype, some tumors may express significant levels of somatostatin (SST) receptors; this feature might be exploited for new therapeutic approaches. The aim of our study is to investigate the activity of lanreotide, a SST analogue, as maintenance for patients with SCLC who have achieved a complete response (CR) or partial response (PR) to standard platinum-based chemotherapy (CHT) alone or combined with radiation therapy (RT) , in order to improve progression-free survival (PFS).

Methods:
In this prospective, open-label, multicenter, randomized phase III trial, patients with confirmed diagnosis of SCLC (limited or extended disease) expressing SST receptors (assessed by SST receptor scintigraphy) and with objective response (CR or PR) after CHT or CHT/RT are randomized (1:1) to one of the following arms: maintenance therapy/consolidation with 120 mg lanreotide, by deep subcutaneous injection, every 28 days up to progressive disease (PD) or one year (Arm A); or observation (Arm B). The patients were re-assessed every two months until documented PD during the first year after randomization, and then every three months. The planned enrollment period is 24 months, followed by a period of maintenance of 12 months and further 6 months for the completion of follow-up; the planned global period of the study is 3 years and a half.

Results:
This study is still ongoing; therefore, it is not possible to show its final results yet.. However, relevant preliminary data can be described. Currently, out of 76 expected patients, 53 were enrolled; of these, 11 patients (37.96%) in Arm A had limited disease and 18 (62.06%) extended disease. In Arm B, 11 patients had limited disease (45.83%) and 13 (54.17%) had extended disease. After one year of follow-up, among 29 patients randomized to Arm A, 1 patient died (3.45%), while 12 patients experienced PD (41.38%), and 16 are still on study (55.17%); among 24 patients randomized to Arm B, 2 deaths occurred (8.33%), while 11 patients experienced PD (45.83%) and 11 are still on study (45.83%). In Arm A, no significant adverse events were reported.

Conclusion:
This study will determine whether maintenance with lanreotide could prolong PFS of patients with SCLC expressing SST receptors and responsive to upfront CHT or CHT/RT. Moreover, the final results of this study might establish if this treatment could result in an improved overall survival rate after two years. To date, lanreotide has demonstrated an excellent safety profile in all the treated patients. On behalf of FONICAP (Forza Operativa Nazionale Interdisciplinare contro il Cancro del Polmone)

Background:
The optimal TRT dose/fraction for LS-SCLC remains debatable, and due to increasing number of population in Egypt and number of patients as well, so reducing the duration of radiation therapy is favored. This study was conducted using etoposide and cisplatin (EP) concurrently with accelerated hypofractionated thoracic radiation therapy to evaluate the response and toxicity of this protocol in the treatment of patients with limited-disease small cell lung cancer (LD-SCLC).

Methods:
Thirty patients with previously untreated LD-SCLC were enrolled into this study between June 2012 and February 2015. All patients received etoposide 100 mg/m[2 ]days 1 to 3 and cisplatin 25 mg/m[2 ]days 1 to 3 with start of accelerated hypofractionated thoracic radiation therapy on first day of the second cycle of chemotherapy of 55 Gy,2.5 Gy/ fraction over 30 days. Chemotherapy was given 4-6 cycles. Prophylactic cranial irradiation 25 Gy in 10 daily fractions was given for patient who achieved complete remission.

Results:
The median age was 61 years; 28 patients (93%) were men. ECOG PS was 0 in 6 (20%) patients , 1 in 20 (67%) patients and 2 in 4(13%) patients. Five (17%) patients achieved a complete response (CR), 22 (73%) patients achieved a partial response (PR), while 2 patients (7%) had progressive disease (PD) and 1(3 %) patients achieved stable disease; therefore, the overall response rate was 90%. The median survival time was 26.4 months and 1- and 2-year survival rates were 78% and 58.3%, respectively. The median progression-free survival (PFS) was 16.7 months, and 1- and 2-year PFS times were 60% and 41.4%, respectively. Among the hematologic toxicities neutropenia was the most prevalent toxicity and it was evident as grade 3-4 in 12 patients (40%). Grade 3-4 Asthenia was the most prevalent nonhematological toxicity, in 12 patients (40%); esophagitis occurred in 7 patients (23%). No treatment-related deaths (due to sepsis or bleeding) were reported in the study.

Conclusion:
Using etoposide and cisplatin concurrently with accelerated hypofractionated thoracic radiation therapy for the treatment of patients with LD-SCLC showed an encouraging outcomes and acceptable toxicity and warrants further research.

Background:
To report on the patterns of failure for medically inoperable early stage small cell lung cancer (SCLC) when stereotactic body radiotherapy (SBRT) manages the primary lung tumor.

Methods:
We queried our institutional IRB-approved SBRT registry for the period 2004-2014 for any early stage SCLC patients with a minimum of 6 months follow up. All patients had biopsy proven disease and were deemed medically inoperable after multi-disciplinary review. Routine staging consisted of PET/CT and MRI brain scans only. The treatment model consisted of SBRT to the primary followed by adjuvant platinum-based chemotherapy (CHT) and then prophylactic cranial irradiation (PCI). SBRT was delivered employing a stereotactic-specific LINAC with vacuum-bag based immobilization, and infrared-based X-ray positioning system+/- CBCT for image-guidance.

Results:
Of 747 definitively treated cancers over 10 years , 16 (2%) were SCLCs meeting study criteria. Patient characteristics revealed: median KPS was 80 (range 50-90), median age was 69 years (range 45-87), 50% of patients were female, median BMI was 28.2 (range 17.4-41.2). Tumor characteristics revealed: median tumor size was 3.25cm (range1.4-7.2 ), 4 (25%) tumors were “central” (per RTOG 0813 criteria), median PET-SUVmax was 10.3 (range 2.8-21.1). Median time to SBRT from diagnosis was 2.1 months (range 0.6-6.7). SBRT schedules were: 60 Gy/3 fractions in 25%, 50 Gy/5 fractions in 68.75%, 30 Gy/1 fraction in 6.25% of cases. Mean follow up was 15 months. Fifteen (94%) received at least 2 cycles CHT, of which 2 (12.5%) received CHT before SBRT. Nine patients (56%) received PCI and of the 7 (44%) that did not, 1 developed brain metastases prior, 1 refused, and 5 died of non-cancer issues before PCI . There was no grade 3 or higher toxicity; rate of grade 2 or less toxicity was 12.5%. Seven patients (43.75%) were alive at analysis and of the 9 deaths, 2 (22%)were cancer, 5 were non-cancer (56%), 2 unknown cause(22%). Local control was 100% with 13 patients (81.25%) without any failure. Crude rates of failure were one (6.3%) distant and regional nodal and two (12.5%) distant. Median survival was 39 months. Three-year actuarial overall and progression-free survivals were 50.5% and 76%, respectively.

Conclusion:
SBRT for stage I medically inoperable SCLC yields excellent local control. The absence of regional nodal failure lends support to PET for mediastinal staging. The primary pattern of failure is distant.

Background:
Prophylactic cranial irradiation (PCI) has led to improved overall survival (OS) for patients with small cell lung cancer (SCLC) that has responded completely to chemotherapy and thoracic radiotherapy. However, whether PCI is indicated for elderly patients remains unclear.

Methods:
We reviewed 658 patients with limited-stage SCLC treated in 1986-2009 at a single institution with definitive concurrent chemoradiation to a total radiation dose of 45-70 Gy. Variables investigated for possible association with OS included patient sex, age, ethnicity, Karnofsky performance status (KPS) score, year of diagnosis and treatment period (1986-1999 vs. 2000-2009), tumor size, radiation dose, cycles of induction chemotherapy, use of intensity-modulated-radiation-therapy (IMRT), and fractionation. Groups were compared with chi-square tests for categorical variables or medians tests for continuous variables. Kaplan-Meier estimates were constructed for overall survival (OS), disease-free survival (DFS), local-recurrence-free survival (LRFS), distant metastasis-free survival (DMFS).

Results:
Among 658 patients, 507 patients were <70 years old (Group A) and 151 patients were ≥70 years old (Group B). Median survival time was significantly longer in the younger group (25.6 months vs. 20.3 months, P=0.007), but no differences were found in DFS, LRFS, or DMFS time by age. Of the 151 patients aged ≥70 years (54 of whom received PCI and 89 did not), those treated in 2000-2009 (vs. 1986-1999) had better brain MFS than those treated in 1986-1999 (P=0.048); those who received PCI had better brain MFS than those who did not (P=0.033). Multivariate analysis showed that among patients aged ≥70, receiving PCI, not receiving induction chemotherapy, and local-regional control were associated with fewer brain metastases (for PCI, subdistribution hazard ratio [SHR]=0.40, 95% confidence interval [CI] 0.17-0.95, P=0.037; for induction chemotherapy, SHR=0.43, 95% CI=0.19-0.96, P=0.039; and for local-regional failure, SHR=0.996, 95% CI=0.993-0.998, P=0.001). Among patients ≥70, receipt of PCI seemed to have been associated with better OS for those with small-volume disease (primary+nodal disease <5 cm, P=0.0545) but not for those with larger-volume disease (P=0.7387).

Conclusion:
Patients aged ≥70 years with small-volume limited-stage SCLC seemed to show a benefit in OS from the use of PCI, but those with larger-volume disease did not. Improved brain MFS was associated with use of PCI, no induction chemotherapy, and locoregional control.

Background:
The standard of care for limited disease SCLC is chemo-radiotherapy. The recommended radiotherapy schedule is 45 Gy/30 F bi-daily (BD-RT) for patients in good performance status according to various guidelines. However, a large proportion of these patients are not able to fulfill the bi-daily schedule due to frailty. For these patients 45 Gy/25 F, once-daily (OD-RT) has been the standard of care at our institution. The aim of this study was to investigate the pattern of failure and survival after chemo-radiotherapy with the 2 different radiotherapy schedules.

Methods:
Records of 106 patients with limited disease SCLC treated from 2007 to 2013 with definitive chemo-radiotherapy in our institution were reviewed. The chemotherapy regimen was a platinum doublet with etoposide. The radiotherapy schedule for 69 patients was treatment OD-RT (45 Gy/25 F), whereas 37 patients were treated BD-RT (45 Gy/30 F). Log rank tests were used to compare overall survival (OS) and local failure free survival (LFS) between the groups.

Results:
In the OD-RT 23 patients (33%) were either alive or dead without evidence of recurrence, and 15 patients (41%) in the BD-RT. In the OD-RT 21 patients (30%) had locoregional recurrence only, 12 patients (17%) had locoregional and distant relapse, and 13 patients (19%) had distant metastasis only. In the BD-RT 8 patients (22%) had locoregional recurrence only, 8 patients (22%) had locoregional and distant failure, and 6 patients (16%) had distant relapse only. Statistically significant (p<0,05) differences in patient characteristics between the two groups were observed: fraction of Performance Status 0-1 93% vs 67%, fraction treated with PCI 78% vs 54% and mean age of 62 vs 67 years for the groups BD-RT and OD-RT respectively. No differences were observed in S-sodium, LDH or gender. The mean follow-up was 24 months. Median overall survival was 18 months in OD-RT and 24 months in BD-RT, and 2 year OS was 45% vs 43% respectively (p=0.23). Median local-failure free survival was 13 months in OD-RT vs 33 months in BD-RT, and 2 year LFS was 57% vs 40% respectively (p=0.19) Local failure free survuval: Figure 1



Conclusion:
In this study the locoregional control and overall survival was not significantly better in the bi-daily regimen with 45 Gy/30 F compared to once-daily treatment with 45 Gy/25 F. This was unexpected, because the two groups differed significantly in PS, PCI and age in favour of the bi-daily regimen. But the size sample was small and follow-up time short.

Background:
Metastatic bone disease is associated with increased morbidity as it may cause disabling pain and lead to other skeletal-related events (SREs), such as pathologic fractures, spinal cord compression or hypercalcemia of malignancy, with significant consequences on quality of life and overall functioning of patients, potentially affecting survival as well. The aim of the present study was to further explore the potential impact of bone metastases (BMs) and their therapeutic management on the overall prognosis of patients with small cell lung carcinoma (SCLC).

Methods:
A retrospective analysis of medical records of 363 patients with SCLC was performed. Clinicopathological features and survival data were correlated with the presence of BMs, their time point of development (early versus late onset) and their treatment modality (radiotherapy, bisphosphonates or both), in the entire study population and in the subgroups of patients with limited or extensive-stage disease (LD or ED-SCLC, respectively) at diagnosis.

Results:
Overall, 35.8% of our patients were diagnosed with BMs, either at diagnosis (early onset BMs, 26.7%) or at a subsequent time point (late onset BMs, 9.1%). Patients with early onset BMs had a worse survival time compared to those with late-onset BMs or those without BMs (log rank test, p=0.020; figure 1). No statistically significant associations were observed between OS and the presence of BMs in the ED and LD subgroups of patients (p=0.926 and p=0.144, respectively). Treatment modality of BMs had no impact on OS either (p>0.05). Multiple Cox regression analysis showed that increased age, poor performance status, presence of BMs and early onset BMs were independently associated with reduced OS. Figure 1



Conclusion:
The presence of early-onset BMs may represent an independent prognostic factor in patients with SCLC. In contrast, the type of modality employed for treatment of BMs had no statistically significant impact on survival in our study population.

Background:
Although the clinical significance of body composition has been recognized as associated with performance status and prognoses for solid tumors, no study has specifically evaluated baseline body composition in detail using computed tomography (CT) images for patients with small cell lung cancer (SCLC).

Methods:
We analyzed skeletal muscle mass and fat mass in 150 patients with pathologically proven SCLC between January 2010 and November 2014 in our institution. Cross-sectional areas of skeletal muscle (Hounsfield unit, HU ranges -29 to 150) and fat tissue (HU, -190 to -30) were measured on the level of 3rd lumbar vertebra using the baseline CT images. Data on clinical characteristics were retrospectively collected.

Results:
Mean age was 69 ± 9 years (85.3% were male). At the time of diagnosis, mean body mass index (BMI) was 22.1, with 40.7% of patients being overweight or obese (BMI ≥ 23). Only 16.7% overall were underweight as conventionally understood (BMI < 18.5). The overall prevalence of severe muscle depletion (sarcopenia) was 53.3% and was present in patients in all BMI categories (84.0% in underweight patients, 45.2% in overweight and obese patients). A much higher proportion of men (60.2%) than women (13.6%) met the criteria of sarcopenia.

Conclusion:
Wasting of skeletal muscle is a prominent feature of patients with small cell lung cancer, despite normal or heavy body weights.

Background:
Lung cancer is still one of the leading causes of cancer patients,which has a high incidence and poor prognosis. Hyponatremia is found in about 15% patients with small cell lung cancer(SCLC) at different disease stages. This study aims to analyze the association of hyponatremia with the prognosis of patients with SCLC.

Methods:
The clinical materials of 489 patients with SCLC treated in ZheJiang cancer hospital between January 2010 and December 2012 were retrospectively analyzed. Kaplan- Meier and Log-Rank test were used to analyze the data. Prognostic factors were analyzed by multivariate Cox proportional hazards model.

Results:
Hyponatremia occurred in 17.9%、13.3%、12.5% and 18.9% patients at 4 different clinical stages(before treatment, after 2 cycles of chemotheropy, after radiotheropy and after all the treatments). The serum sodium level was not significantly different among patients of different gender, age, BMI, KPS, hypertension and diabetes mellitus history, tumor stage, smoking history and tumor metastasis (P>0.05). Univariate analysis showed that hyponatremia significantly affected the survival of patients. Multivariate analysis showed that hyponatremia was the independent prognostic factor for SCLC. The relative risk of death of patients with hyponatremia was elevated by 1.297 times (95%CI:1.160~1.449，P<0.001), 1.366 times (95%CI:1.023~1.825,P=0.035), 1.77 times (95%CI:1.168~2.682,P=0.007) and 1.507 times (95%CI:1.167~1.944,P=0.002).

Conclusion:
Hyponatremia is an independent prognostic indicator for the survival of initially treated patients with small cell lung cancer(SCLC).

Background:
Amatuximab is a chimeric monoclonal antibody that binds to mesothelin, which is highly expressed in malignant mesothelioma and largely absent from normal tissue. In vitro studies indicate that amatuximab potentially has anti-tumor activity via antibody-dependent cellular cytotoxicity. Amatuximab was studied in a Phase 2 malignant pleural mesothelioma (MPM) trial which demonstrated that the safety profile of amatuximab in combination with P/C was consistent with that seen previously for the P/C regimen. Although PFS was not significantly different from historical results of P/C alone, the median OS was 14.8 months (as compared to 13.3 months for P/C). The post-hoc PK/PD analysis demonstrated that amatuximab trough concentrations were a significant predictor of both OS and PFS where higher concentrations were associated with longer OS (583 days; p=0.0202 ) and PFS (238 days; p<0.001).

Methods:
560 subjects with previously untreated, unresectable malignant pleural mesothelioma (MPM) will receive P/C and are randomized 1:1 to receive weekly amatuximab, 5 mg/kg or saline placebo IV in this global study. The primary endpoint of the study is to demonstrate whether amatuximab in combination with P/C has superior OS compared with P/C in subjects with MPM. The secondary endpoints are to compare amatuximab versus placebo with regard to PFS, ORR, duration of response, health-related QOL (LCSS-Meso), and the safety of amatuximab when administered with P/C. Clinical trial information: NCT02357147.

Results:
Not applicable

Conclusion:
Not applicable

Background:
Because the diagnosis is often made at a late stage, malignant mesothelioma (MM) prognosis is very poor, with a median survival of 6-12 months and a five-year survival of less than 5%. We found that germline BAP1 mutation is associated with a new cancer syndrome, including rare malignancies such as MM and uveal carcinoma (UV), and other cancers. We noted that some MM cases that we followed from BAP1 mutated families had prolonged survival. We carried out a pooled analysis of BAP1 mutated MM patients to test the hypothesis that they had a better survival compared to sporadic MM.

Methods:
: We included all published BAP1 germline mutated MMs with available data on BAP1 status, site of MM, age at diagnosis, gender, and age at death or status at end of follow-up, in addition to the BAP1 mutated MM cases from families that we are following. Twenty-three BAP1 MM patients were included. Using the Kaplan-Meier method and Wilcoxon test, we compared survival among BAP1 mutated MM patients with that of all MMs (N = 10 556) recorded in the US SEER data from 1973 to 2010.

Results:
In our BAP1 cohort, ten patients had peritoneal MM, ten pleural MM, and three MM in both locations. Thirteen patients had one or more malignancies in addition to MM. Actuarial median survival for the MM patients with germline BAP1 mutations was five years, as compared with less than one year in the SEER MM control group. Five-year survival was 47%, 95%CI [24-67%], as compared with 6.7% [6.2-7.3%] in the SEER MM control group. The small size of our BAP1 cohort did not allow for significant statistical comparisons. However, patients with peritoneal MM (median survival of 10 years, P=0.0571), or with a second malignancy in addition to MM (median survival of 10 years, P=0.0716), survived for a longer time compared to patients who only had pleural MM, or MM patients without a second malignancy, respectively. Figure 1



Conclusion:
MM patients with germline BAP1 mutations have an overall seven-fold increased survival, independently of sex and age. This better prognosis was associated with multiple cancer and/or peritoneal MM. Appropriate genetic counseling and clinical management should be considered for MM patients who are also BAP1 mutation carriers.

Background:
Malignant Pleural Mesothelioma (MPM) is an aggressive tumor characterized by chemoresistance. Most MPM tumor specimens have wild type p53 but show a deletion of INK4A/ARF locus (70-80%) which contains p14/ARF gene. The p14 lack increases MDM2 activity and subsequently down-regulates p53. The role of MDM2 is not only related to p53 control but it is also involved in regulation of cell proliferation, apoptosis and angiogenesis in p53 independent manner. Tumor necrosis factor (TNF)-Related Apoptosis-Inducing Ligand (Apo2L/TRAIL) is a promising agent for antitumor treatment because its ability to selectively kill cancer cells through the extrinsic apoptotic pathway. The aim of our study is to investigate, the anticancer effect of the MDM2 inhibitor, Nutlin 3a, in association with rhAPO2L/TRAIL in MPM in vitro and in vivo.

Methods:
In vitro apoptosis assay was performed using PI staining, positive cells were detected by flow cytometry. Cycle analysis was performed by PI staining and flow cytometry detection, DNA content was analyzed by MODFIT software. p53, p21 and survivin protein expression levels were detected by western blot analysis. TRAIL receptors levels were assessed by flow cytometry analysis. mRNA expression levels were evaluated by real-time PCR. In vivo experiments were performed in 32 SCID male mice, intraperitoneally injected with sarcomatoid MPM cells trasduced with lentiviral Luciferase vector and treated with Nutlin and/or rhAPO2L/TRAIL.

Results:
Nutlin 3a treatment provoked p21 induction and cell cycle arrest in p53 wild type cells (M14K epithelioid, MSTO-211H biphasic and ZL34 sarcomatoid) but had no effect in p53 mutated cells (ZL55 epithelioid). Interesting, apoptosis assay showed a synergistic cell death induction of Nutlin3a plus rhAPO2L/TRAIL in both p53 wild type and p53 mutated MPM cells with a greater effect in ZL34 cell lines that expressed higher mRNA and protein levels of MDM2. Nutlin 3a increased the expression of DR4/DR5 TRAIL death receptors and inhibition of survivin only in p53 wild type cells. As a consequence, western blot analysis of Caspase 8 activation showed that the MDM2 inhibitor induced an increase of extrinsic apoptosis signal only when p53 was functional. Finally, antitumor activity tested in ZL34 in vivo mouse model showed a strong inhibition of tumor growth in mice treated with Nutlin 3a plus Apo2L/TRAIL compared to Nutlin 3a or Apo2L/TRAIL used as single agents.

Conclusion:
The results demonstrate that the combination of Nutlin 3a plus Apo2L/TRAIL may be a promising strategy for MPM treatment independently to p53 status. Further esperiments are needed in order to clarify the role of p53 status as selection criterium for treatment and to explore p53-independent MDM2 functions.

Background:
Background: An evidence-based chemotherapy utilisation model for MPM suggests rates of use should be around 65%. Actual Australian rates are about 54%. Aim: To examine healthcare professional perceptions of chemotherapy use and barriers to it in MPM patients.

Methods:
Methods: Healthcare professionals caring for people with MPM were invited via email from professional groups, to complete a purpose designed online survey. Data were collected from January-July 2014. Descriptive data are presented.

Results:
Results: Surveys were completed by 102 doctors (Respiratory Physicians=53, Medical Oncologists (MO)=35, Other=15) and 19 nurses. Doctors mean age 47 (31-75) years, 74% male, 49% worked only in public system, 57% did not have lung cancer nurse specialist, and saw mean of 7 new patients with MPM annually. Nurses mean age 45 (29-68) years, all female, 53% worked only in public system, and saw mean of 12 (1-40) new patients with MPM annually. 74% of doctors and 53% of nurses believed >11% of MPM patients potentially eligible for chemotherapy do not receive it. Clinician barriers most commonly endorsed include: clinician nihilism 70%, 37%; non-referral to MO 47%, 63%; lack of cancer services 43%, 53%; no MDT review 40%, 32% for doctor, nurse respectively. 74% of nurses also indicated delayed diagnosis and 58% lack of clinician knowledge about treatment.

Conclusion:
Conclusions: Healthcare professionals’ estimates of potentially eligible patients with MPM who do not receive chemotherapy are consistent with or higher than evidence-based estimates. Barriers to chemotherapy access endorsed suggest strategies to increase knowledge of evidence-based treatment and address clinical nihilism are required.

Background:
There is no standard treatment for patients (pts) with MPM progressing during or after pemetrexed/platinum-based chemotherapy (PBC). Single agent chemotherapy is often administered in everyday practice, although its use is poorly supported by clinical trials. The aim of this retrospective study (NCI01865045) was to analyze the efficacy and toxicity of second (2nd) and third (3rd) line vinorelbine (VNR) in a large cohort of PBC-pretreated MPM patients.

Methods:
The clinical records of MPM pts consecutively treated in 8 Italian Centers with intravenous (iv) or oral (po) VNR as 2nd or 3rd line treatment following PBC were reviewed. Radiological response was assessed by modified RECIST criteria. Toxicity was reported according to CTCAEv4 criteria. Relative dose-intensity (DI) of VNR was calculated. Progression-free survival (PFS) and overall survival (OS) were estimated and correlated to clinical variables: age, gender, histological subtype, ECOG performance status (PS), line of VNR therapy (2nd vs 3rd) and outcome of first-line treatment.

Results:
From August 2001 to September 2014, 161 pts (M/F 120/41) were treated, 128 with iv and 33 with po VNR. Most of the cases included (92%) were treated after 2007. Histological subtype was epithelioid in 134, biphasic in 15, sarcomatoid in 8 and unspecified in 4 pts. Median age was 67 years (range 41-82). VNR was administered as 2nd or 3rd line treatment in 94 and 67 pts, respectively. Median number of VNR cycles was 3 (range 1-26), median relative DI was 88%. Main grade 3-4 toxicities were neutropenia in 9%, fatigue in 4% and constipation in 5% of pts. No toxic death occurred. A partial response was observed in 10 pts (6%), stable disease in 57 (35%), for an overall disease control rate of 41%. Median PFS and OS were 2.5 and 6.7 months, respectively. In multivariate analysis, only ECOG PS (0 vs 1-2) was significantly associated with improved PFS and OS. An analysis of molecular predictors of VNR response is ongoing.

Conclusion:
In this large retrospective patient cohort, 2nd and 3rd line VNR had modest but definite activity in PBC-pretreated MPM patients, with an excellent toxicity profile. Although inclusion in prospective clinical trials of new agents should be always considered in this setting, single agent VNR remains a reasonable option for palliation.

Background:
Malignant pleural mesothelioma (MPM) is an aggressive rare cancer affecting the pleura and is predominatly associated with prior exposure to asbestos. Treatment options are limited, and most patients die within 24 months of diagnosis. The current standard of care for MPM patients is a combination of cisplatin and pemetrexed (or alternatively cisplatin and raltitrexed), yet most patients die within 24 months of diagnosis. There is therefore an urgent unmet need to identify new therapeutic options for the treatment of MPM. Asbestos fibres contain of transition metals and their ability to both adsorb and accumulate these metals was one of the first mechanisms suggested for explaining the toxic and particularly carcinogenic effects of asbestos. One of the transition metals in asbestos fibres is iron, and therefore asbestos fibres may cause an alteration of iron homeostasis in the tissue. In addition, asbestos fibres have also been shown to have high affinity for histones, and therefore may result in high accumulation of iron around chromatin. Lysine Demethylases (KDMs) containing a JmjC domain require both Fe2+ and 2-oxoglutarate as co-factors to regulate gene expression by “erasing or removing” methylation on histones in chromatin. Members of this family are frequently found to have aberrant expression in cancer and currently are actively pursued as candidate pharmaceutical therapeutic targets. Given that asbestos increases iron levels, this may result in aberrant KDM activity, and these KDMs could therefore be novel candidate targets in mesothelioma. We therefore examined the expression of several JmjC containing KDMs in MPM and assessed their potential for therapeutic intervention in mesothelioma using existing small molecule inhibitors.

Methods:
A panel of MPM cell lines were screened for expression of KDM4A-D, KDM5A/B and KDM6A/B by RT-PCR. mRNA levels were subsequently examined by RT-PCR in a cohort of snap-frozen patient samples isolated at surgery comprising benign, epithelial, biphasic, and sarcomatoid histologies. IHC was performed for KDM4A on a cohort of FFPE specimens. The effects of treatments with small molecule inhibitors targeting these proteins on both cellular health and gene expression were assessed.

Results:
The expression of the various KDMs was detectable across our panel of cell lines. In primary tumours the expression of these KDMs were significantly elevated in malignant MPM compared to benign pleura (p<0.05), and significant differences were also observed when samples were analysed across different histological subtypes. Treatment of mesothelioma cell lines with various small molecule inhibitors caused significant effects on cellular health and on the expression of a panel of genes.

Conclusion:
The expression of KDMs are significantly altered in MPM. Small molecule inhibitors directed against these KDMs show potential therapeutic efficacy with significant anti-proliferative effects. We continue to assess the effects of these compounds on gene expression and cellular health to confirm their potential utility as novel therapies for the treatment of MPM.

Background:
Malignant pleural mesothelioma (MPM) is associated with poor prognosis and 5-year survival rate was only 23.1%.Tri-modality therapy (induction chemotherapy followed by pleural pneumonectomy and adjuvant radiation), bimodality therapy (induction chemotherapy followed by pleural decortication) and chemotherapy alone viable treatment option for MPM. These initial therapies are selected according to IMIG staging, performance status, and the severity of comorbidity. These treatment options all include platinum plus pemetrexed combination therapy, which is regarded as the standard regimen for advanced MPM. However, the majority of patients showed disease relapse even when treated with multimodality strategy and the treatment options for recurrent MPM are limited. Under these findings, the current study investigated the efficacy and safety of re-challenge platinum plus pemetrexed combination therapy for recurrent MPM.

Methods:
We retrospectively reviewed 36 patients pathologically diagnosed as MPM between April 2007 and April 2015. The patients who received re-challenge platinum plus pemetrexed combination therapy as second line therapy for recurrent MPM were eligible for this study.

Results:
Of these 36 patients, 15 showed disease relapse after receiving the first treatment. 7 patients received monotherapy or best supportive care after the relapse. After all, 8 patients received re-challenge platinum plus pemetrexed combination therapy. The characteristics of the 8 patients were as follows, male/female:6/2, median age:58 years (range 49-69), performance status 0/1:2/6, epithelioid/sarcomatoid/biphasic/unknown: 6/0/1/1. Prior therapy tri-modality/bimodality/chemotherapy alone:5/0/3, treatment free interval from the completion of initial therapy <90days/≧90days; 0:8. 1 partial response and 6 stable disease were observed in 8 patients, respectively. Median progression free survival and median overall survival was 8.3 and 17.3 months, respectively. In terms of toxicity, grade 3 leukopenia was observed in one patient. No grade 3-4 thrombocytopenia was observed. In addition, grade 2 erythema was observed in one patient. Over all, the combination therapy was well tolerated.

Conclusion:
The re-challenge platinum plus pemetrexed combination was active and well tolerable for recurrent MPM.

Background:
Malignant mesothelioma is a rare, but aggressive pleural or peritoneal tumor which is highly invasive and progresses rapidly. The median survival of patients with mesothelioma is between 9 and 13 months, and survival has not been significantly affected by most currently available therapeutic interventions. There are no approved therapies following first line treatment. VS-6063 is an oral inhibitor of focal adhesion kinase (FAK) currently being evaluated in a randomized phase 2 study in patients with malignant pleural mesothelioma who have stable disease or better after front line chemotherapy. VS-5584 is an oral dual inhibitor of PI3K/mTOR currently undergoing phase I testing in solid tumors. Previously reported literature has shown that dual PI3K/mTOR inhibitors have activity in patients with relapsed mesothelioma. In preclinical models, the combination of VS-6063 and VS-5584 have demonstrated synergy in tumor models of malignant mesothelioma supporting the potential exploration of this combination clinically.

Methods:
This is a multi-center, open-label, phase 1 trial in subjects with relapsed malignant mesothelioma. The study is comprised of two sequential parts: Part 1 (Dose Escalation of VS-5584 with a fixed dose of VS-6063) and Part 2 (Expansion). Patients receive VS-5584 orally on an intermittent dosing schedule and VS-6063 400 mg orally BID. Primary endpoints are to determine the maximum tolerated dose, recommended Phase 2 dose/schedule and to assess safety and tolerability of the combination in this patient population. Secondary endpoints include assessing the pharmacokinetics of VS-5584 and VS-6063 when co-administered. Exploratory endpoints include response rate and biomarker correlation with response and PD. The study is currently enrolling across 4 sites in the United States and United Kingdom. Clinical trial: NCT02372227.

Results:
Not applicable

Conclusion:
Not applicable

Background:
The incidence of Malignant pleural mesothelioma ( MPM) in Egypt showing a steady increase which mandate more intension. This study was conducted to study the clinico-epidemiological data and different treatment modalities offered for (MPM) patients and to evaluate their impact on survival

Methods:
Data was retrospectively collected from the medical files of 103 cases presented as MPM to Department of Clinical Oncology and Nuclear Medicine, Ain Shams University Hospitals from January 2011 to December 2013. Demographics, risk factors, morphological status and treatment received were described using frequencies. Survival outcome was described using Kaplan Meier curves stratified according to morphology and treatment received.

Results:
A steady increase in the number of cases was detected, from 30 in 2011 and 40 cases in 2013. Male/female ratio was 0.98 (p = 0.989). The median age was 58 years (range 28-85). About 60 patients (58.3 %) came from endemic areas. Only one patient underwent decortication surgery. About 70.9 %, 21.4 % and 5.8% of the patients received chemotherapy (CT) in 1[st] line, 2[nd] line and 3[rd] line respectively and median OS was 5 months (Range 1-48). Only 5.5%, 21.7% and 33.3% of the patients received Pemetrexed in 1[st] line, 2[nd] line and 3[rd] line CT respectively.Kaplan-Meier survival for sex, age, residence and the pathological types was insignificant. The median survival for epithelial versus non-epithelial pathological types was 6 and 5 months respectively (P= 0.165).The median survival for the patients who received 1[st] line, 2[nd] line and 3[rd] line CT versus best supportive care (BSC) was 3 and 8 months (P = 0.001), 12 and 5 months (P < 0.001) and 12 and 5 months (P =0.417) respectively.There was a significant difference (P = 0.001) between the median survival for patients who received CT (8 months, 95% CI 5.422-10.578) and those who were offered BSC ( 3 months, 95% CI 1.715-4.285). Another factor that affected the survival negatively was non-platinum based CT in the 1[st] line (2 months versus 9 months P =0.001). Cox regression analysis revealed that the factors that predicted better OS were patients being offered CT rather than BSC especially patients who received 1[st] and 2[nd] line of CT (P =0.004).

Conclusion:
MPM is a growing health burden in Egypt which is underestimated and need more support to offer new treatment modalities. The CT prolongs survival compared to BSC in patients with MPM. Moreover, using platinum based CT provides survival advantages.

Background:
Mesothelioma is a frequently "inflamed" tumor. We previously identified PD-L1 expression, a CD8 infiltrative pattern, and the presence of PD-1/PD-L1 immune checkpoints in about 1/3 of mesothelioma tumors, similar to the phenotype found in malignancies such as melanoma that benefit from immune checkpoint blockade (Kindler and Seiwert, ASCO 2014). Based on these data, we have initiated a single-center phase II trial (NCT02399371) of the anti-PD-1 antibody pembrolizumab in previously-treated mesothelioma patients. The rationale for this study is further supported by recent data from a phase IB multi-cohort study of pembrolizumab in PD-L1 positive solid tumors, in which an objective response rate of 28% and a disease control rate of 76% was observed in 25 pleural mesothelioma patients, who received 10 mg/kg pembrolizumab every 2 weeks (Alley, AACR 2015).

Methods:
Eligible patients have histologically-confirmed pleural or peritoneal mesothelioma, measurable disease, PS 0-1, disease progression on or after treatment with pemetrexed plus cis- or carboplatin, no more than 2 prior lines of cytotoxic therapy, normal organ function, and tissue available for correlative studies. Patients receive a flat dose of 200 mg pembrolizumab intravenously every 3 weeks. CT scans are obtained every 9 weeks. The primary objectives are: 1) to determine the objective response rate in A] an unselected population and in B] a PD-L1 positive population, and 2) to determine the optimal threshold for PD-L1 expression using the 22C3 antibody-based IHC assay. Secondary objectives include progression-free and overall survival, disease control rate, and toxicity. Correlative studies are intended to characterize the T-cell inflamed phenotype in mesothelioma via CD8, CD4, and PD-L1 staining, immune related gene expression signatures (Nanostring), and determination of other immune escape mechanisms including T-regulatory cells (FOXP3 expression), IDO expression, MDSCs, and other checkpoints/co-stimulatory signals by immunohistochemistry and/or flow cytometry. A single-stage binomial design will be used. Part A requires ≥ 3 responses in 35 patients. Part B, which uses PD-L1 pre-selection (optimal expression pattern and threshold determined in cohort A), requires ≥ 6 responses in 30 patients. Funded in part by a grant from the Mesothelioma Applied Research Foundation.

Results:
Not applicable.

Conclusion:
Not applicable.

Background:
Combination of surgical cytoreduction and hyperthermic intrathoracic chemotherapy (HITHOC) is performed for therapy of pleural malignancies within a multimodality treatment concept. We describe the perioperative management and our clinical experience.

Methods:
Between September 2008 and January 2015 a total of 23 patients with malignant pleural mesothelioma (MPM) and 27 patients with thymoma/thymic carcinoma with pleural involvement (Masaoka-stage IVa) were prospectively enrolled. Perioperative management, postoperative morbidity and mortality were analyzed.

Results:
Included were 17 female and 33 male patients with a mean age of 54.6 years (25 to 72 years). All patients received multimodality therapy depending on tumor stage, histology and their overall condition. Histologic subtype of patients with MPM was epitheloid (n= 19; 83%) or biphasic (n= 4; 17%). WHO-classification of thymoma patients was: B1 n= 2, B2 n= 10, B2/B3 n= 6, B3 n= 4 and C n= 5. All patients underwent radical surgical cytoreduction with pleurectomy/decortication (P/D; n= 25), extended P/D (P/D + resection of pericardium and/or diaphragm; n= 19) or extrapleural pleuro-pneumonectomy (EPP; n= 6) followed by HITHOC perfusion at 42°C for one hour. HITHOC was performed with an increasing concentration of cisplatin (100 mg/m[2] n= 14; 150 mg/m[2] n= 18; 175 mg/m[2] n= 2) or combination of cisplatin/doxorubicin (175 mg/m[2 ]/ 65 mg n= 16). Macroscopic complete resection (R0/R1) was achieved in 46 patients (92%). Severe chemotherapy-related complications were not observed. Operative revision was necessary in seven patients (14%). Postoperative renal insufficiency was observed in six patients (12%) with two patients requiring temporary postoperative dialysis (4%). Prolonged bronchopleural fistula was documented in five patients (11%) after lungsparing P/D or extended P/D. 30-day mortality was 4%, both after EPP.

Conclusion:
Surgical cytoreduction in combination with HITHOC can be performed with acceptable morbidity and mortality rates in selected patients. Patients should be evaluated interdisciplinary to determine their eligibility for this multimodality approach. Early clinical results may encourage the use of additional HITHOC to provide better local tumor control.

Background:
Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer that progresses in the thin layer of pleura. The inhalation of microscopic asbestos fibers primarily the main reason of the disease. Early symptoms of pleural mesothelioma often are confused with other respiratory ailments. Therefore, MPM can only be diagnosed in the advanced stage. Consequently, it is important to develop a new approach with high specificity and sensitivity for the differential diagnosis of MPM. Fourier Transform Infrared (FTIR) spectroscopy is a novel and non-invasive method that has potential to diagnose cancer with high specificity and sensitivity. Hence, we used ATR-FTIR spectroscopy coupled with chemometric methods to differentiate MPM from healthy individuals and lung cancer patients.

Methods:
FTIR spectra of the samples collected from patients diagnosed with malignant pleural mesothelioma (MPM), lung cancer (LC), and healthy control (C) were recorded in the 4000-650 cm[-1]spectral region. Recording the spectra and analysis of the spectral data were obtained with Perkin Elmer Spectrum One Program. Both unsupervised Principal Component Analysis (PCA) (The Unscrambler X 10.3, CAMO Software) and Hierarchical Cluster Analysis (HCA) (OPUS 5.5, BRUKER) were applied for differentiation MPM from other groups.

Results:
Cluster analysis of the samples demonstrated that MPM and lung cancer successfully differentiated from healthy controls at whole spectral region (4000-650 cm[-1]). Moreover, successful clusters of these three groups were obtained in the fingerprint (1800-650 cm[-1]) and 1500-800 cm[-1 ]regions. In addition, some special bands such as DNA band at 832 cm[-1 ]gave very successful differentiation by PCA from serum samples.

Conclusion:
These findings indicate that FTIR spectroscopic analysis of serum coupled with chemometric analyses enabled differential diagnosis of mesothelioma from lung cancer patients and healthy individuals. *This work was supported by the Scientific and Technical Research Council of Turkey (TUBITAK), SBAG-113S294 Research Fund.

Background:
Tumor Treating Fields (TTFields) are an anti-mitotic, regional treatment modality, which is based on low intensity alternating electric fields delivered non-invasively using a portable, home use, medical device (NovoTTF-100L, Novocure Ltd.). In-vitro, human mesothelioma cells were found to be highly susceptible to TTFields. When applied to the thorax, TTFields were found to be safe and efficacious in a clinical trial of 42 patients with advanced non-small cell lung cancer, where the only common device-related adverse event was mild to moderate skin reaction. Malignant pleural mesothelioma (MPM) is always fatal when unresectable, and existing therapies provide very limited clinical benefit. Since MPM normally progresses regionally within the thorax, the addition of a regional therapy to systemic chemotherapy is an appealing treatment approach. However, the use of radiation therapy as a loco-regional treatment is limited, due to significant pulmonary toxicity. TTFields may therefore serve as a potential non-toxic regional therapy in MPM.

Methods:
The STELLAR Clinical Trial Eighty (80) patients with unresectable and previously untreated MPM will be treated with pemetrexed and cisplatin or carboplatin in combination with TTFields. The patients will be followed up every 3 weeks (CT scan every 6 weeks) until disease progression. Objectives To test the efficacy and safety of TTFields combined with standard chemotherapy in this patient population. Endpoints The primary endpoint is overall survival (OS) and secondary endpoints are response rate, progression free survival and treatment-emergent toxicity. Statistical Considerations This is a prospective phase II, single arm, multicenter study for 80 patients. The sample size (71 + 12% loss to follow up) is based upon the asymptotic distribution provided by Lachin (2000) using the log of the hazard rate. The historical control is assumed to have an exponential distribution with a constant hazard rate of 0.03938 calculated from the median survival of 12.1 Months reported by Vogelzang et al. The sample size provides 80% power with a two sided alpha of 0.05 to detect an increase of 5.5 months in OS which is equivalent to a Hazard Ratio of 0.67 compared to the historical control data for OS. Major Eligibility Criteria Patients are 18 years of age or older with good performance status (ECOG 0-1). The patients must have pathological or histological evidence of MPM with at least one measurable or evaluable lesion according to modified RECIST criteria. The disease should be previously untreated and not amendable for curative treatment (surgery or radiotherapy). Untreated brain metastases and contraindications to any of the study treatments are exclusionary. Treatment Continuous TTFields at 150 kHz is applied to the thorax using the NovoTTF-100L System. The System is a portable medical device allowing normal daily life activities. The device delivers alternating electric fields to the thorax using 4 Transducer Arrays. The experimental treatment is administered on top of the standard of care chemotherapy – pemetrexed/platinum doublet.

Results:
not applicable

Conclusion:
not applicable

Background:
Overexpression of c-Met receptor tyrosine kinase has been highly associated with oncogenic progression of non-neoplastic mesothelial progenitor cells to malignant pleural mesothelioma (MPM). Moreover, activated c-Met receptor tyrosine kinase transduces signals that regulate tumorigenic activities including cell growth, migration, survival, and invasion of extracellular matrixes. A small molecule MET kinase inhibitor (BMS-777607) is an inhibitor of tyrosine receptor currently under clinical trials. Previous studies reported the effect of this inhibitor on cancer cells such as breast, hepatic and prostate cancer. However, its inhibitory effect on malignant pleural mesothelioma (MPM) cells has not yet been evaluated. In our study, we aimed to investigate the therapeutic usefulness of this small molecule on MPM.

Methods:
Human MPM cell lines such as REN and NCl-H2373 and a human lung carcinoma cell line (NCl-H226) were used. LP-9 cell line, which resembles normal human mesothelial cells, was used as control. These cells were cultured and exposed to BMS-777607 at concentrations 1uM, 5uM and 10uM. Cell cycle, cell viability, lysosomal mass/pH changes and mitochondrial membrane potential were examined using immunofluorescent staining methods and data were collected and analysed with high content screening systems such as Cytell and IN Cell Investigator software.

Results:
Both MPM cell lines and the lung cell line showed cell cycle arrest as examined by Cytell in significant dose-dependent manner with maximum effects seen at the highest dose (10 µM) of BMS-777607. Cell viability and other biological cellular markers were also altered upon exposure to this small molecule. Our results showed that BMS-777607 induces negligible changes of these markers examined in the normal mesothelial cells line (LP-9).

Conclusion:
Taken together, these findings indicate that inhibition of MET/RON signalling using a small molecule inhibitor such as BMS-777607 could significantly interrupt the cell cycle stages and alter other cellular compartments (i.e; lysosomal mass/pH, mitochondrial membrane potential) which lead to suppression of MPM cell viability, suggesting that such a targeting strategy may hold promise for the treatment of MPM.

Background:
Malignant mesothelioma (MM) is endemic in the population exposed to asbestos and has high healthcare cost with a limited life expectancy. The aim of this study is to evaluate the relationship between cost according to treatment type and prognosis in MM patients followed up from diagnosis to death.

Methods:
The demographics and healthcare costs of 239 patients with MM were obtained from hospital records in the tertiary university hospital between 2005 and 2014. Variance analysis and t-test were performed to compare the groups. The survival rates were estimated using the Kaplan-Meier method. To clarify health care cost in Turkey, the following information was given according to the national reimbursement price in April 2015. This study was supported by General Directorate of Health Researches, Republic of Turkey, Ministry of Health.

Results:
The mean age of the patients were 62.9±11.3 years and 125 (52.3%) of them were male. The median survival time was 9.0±0.8 months (95% CI: 7.3–10.7). Patients’ numbers according to treatment schema: 52 (21.8%) best supportive care (BSC); 3 (1.3%) BSC+palliative radiotherapy (pRT); 117 (49.0%) chemotherapy; 39 (16.3%) chemotherapy+pRT, 16 (6.7%) pleurectomy/decortication (P/D)+chemotherapy+RT; 4 (1.7%) P/D+chemotherapy; 8 (3.3%) extrapleural pneumonectomy (EPP)+chemotherapy+RT. BSC group had the lowest average cost with $1,355 (r:258-4,909) per patient. The average cost was $6,595 (r:1,621-21,371) for patients received only chemotherapy. When pRT added to chemotherapy, cost was increasing to $8,962 per patient. The average cost was $11,691 (r:6,567-19,064) per patient for P/D+chemotherapy+RT group. It decreased to $10,676 without RT. The highest average cost was seen in the group of EPP+chemotherapy+RT with $13,788 (r:6,168-19,577) per patient. The median survival times were 6 months (95%CI:5.3-6.7), 12 months (95%CI:9.8-14.2), 18 months (95%CI:11.5-24.5), 27 months (95%CI:7.6-46.4) for BSC, chemotherapy, P/D+chemotherapy+RT and EPP+chemotherapy+RT group, respectively. The median survival time was significantly different between BSC and chemotherapy groups (Log-Rank:10.607; p=0.001). The average cost of 6 months prolongation of lifetime was $5,239 in chemotherapy group and incremental cost was $873 per month gained. The median survival time was not different between chemotherapy and P/D+chemotherapy+RT groups (Log-Rank: 1.263; p=0.261). However, there was 6 months survival difference between the two groups. The average cost of 6 months prolongation of lifetime was $5,097 and incremental cost was $850 per month gained in EPP+chemotherapy+RT. The median survival time was significantly different between chemotherapy and EPP+chemotherapy+RT groups (Log-Rank: 8.082; p=0.004). The average cost of 15 months prolongation of lifetime was $7,194 and incremental cost was $480 per month gained in EPP+chemotherapy+RT group. There was a difference between surgical groups in terms of median survival (Log-Rank:4.421; p=0.036). The average cost for prolongation of lifetime was $2,097 and incremental cost was $233 per month gained.

Conclusion:
MM has a limited survival time despite antitumor treatment and treatment cost is relatively high by prolongation of lifetime. Treatment should be given to selected patients and EPP should be preferred to P/D as much as possible. It is clear that there is need well designed prospective studies for cost analysis of MM.

Background:
Sweden was one of the first countries in the world to ban asbestos, which happened in the early mid-seventies. The use of asbestos in Sweden was thus mainly in the 1960ies. The incidence of mesothelioma started rising from around 1975 and reached a little more tha 100 cases a year in 1985, in parallell to asbestos use 30 years earlier. It has been postulated that it should start sinking in the first decade of the 2000s.

Methods:
The incidence of pleural mesothelioma for both sexes have been taken from the ofiicial Swedish pulblication "Cancer Incidence in Sweden", the latest avialable figures of which is 2012.

Results:
Since 1984, a plateau has been reached, with around 100 cases of new pleural mesotheliomas occurring in Sweden every year, sometimes a little less, more often a little more. No tendency to declining figures can be seen so far. The median age st diagnosis has remained the same since the 1960ies, 54-70 years. Furthermore, the percentage of women is the same, 15-20 % of the total.

Conclusion:
The heaviest exposure took place in Sweden around 1965; after this date, in most working places people became more aware and the exposure was diminished, but continued until early 1970ies. It has been postulated that 40 years after exposure, the risk should decline, and if so those who were 20 years old in 1970 should by now have a decreasing risk, but there are no signs of this. Since the relative risk for men and women is about the same, it is unlikely that general environmental exposure to asbestos explains the lack of decline of the curve. Interestingly, the median age at diagnosis has remained the same though most of those exposed should by now have a fairly advanced age.

Background:
Primary chest wall soft tissue sarcomas are rare tumors of the thoracic wall. The objective of this study is to evaluate the impact of adjuvant radiation therapy on survival following surgical resection using the Surveillance, Epidemiology, and End Results (SEER) database.

Methods:
We queried the SEER database for all surgically resected histologically proven primary chest wall soft tissue sarcomas between 1998 and 2010. Exclusion criteria included pediatric sarcomas, multiple malignancies and unknown grade, stage or radiation therapy status. Chi-square tests were performed to identify covariates associated with receiving adjuvant radiation therapy. Coarsened-exact matching was used to generate a matched cohort of patients who received adjuvant radiation following surgery and patients who underwent surgery alone. Cox regression and Kaplan-Meier analyses were performed to determine covariates associated with overall survival.

Results:
A total of 570 patients were included in the cohort prior to matching based on the selection criteria. Histological type (p = 0.003) and tumor grade (p < 0.001) were independently associated with receiving radiation therapy. Cox-regression did not demonstrate reduced hazards of death for adjuvant RT. After coarsened-exact matching, Kaplan-Meier survival analysis of matched groups (105 surgery alone and 104 surgery + RT) showed significant 1-, 3- and 5-year overall survival difference (p = 0.034) in surgery + RT compared to surgery alone.

Conclusion:
In a matched large population cohort, adjuvant radiation therapy appears to improve overall survival following surgical resection of chest wall soft tissue sarcomas. Further trials are required to determine the efficacy of adjuvant radiation therapy in this population.Figure 1

Background:
Complete surgical resection is the treatment of choice in bronchopulmonary carcinoids. Previously published data showed no inferiority of sublobar versus lobar resection. Data on the extent of resection margins are lacking, thus we aimed to analyze resection margins in pulmonary carcinoids and correlated them with survival and recurrence.

Methods:
We retrospectively analyzed 85 patients that underwent surgery for atypical (AC) or typical (TC) pulmonary carcinoids. Patient charts were reviewed and clinicopathologic and survival data was collected. Pathology reports were reviewed for length of resection margins.

Results:
The median follow-up period was 42.3 months (range 0.3 - 172.2). There was no statistically significant difference in disease-free survival (DS) when comparing resection margins ≤2 mm to >2 mm (p=0.93, Hazard Ratio (HR)=1.7). When looking at AC alone, a worse DS can be seen if the resection margin was smaller than 2 mm (p=0.06, HR=15.8). In AC likelihood of recurrence was higher when the resection margin was ≤1 cm (Odds ratio=5.1, p=0.28). In TC this tendency was not present (Odds ratio=1.2, p=1).

Conclusion:
There is a trend towards a worse prognosis and higher likelihood of recurrence in smaller resection margins in AC in contrast to TC. Due to low sample size no definitive statements can be made based on this study, however respective data on these rare tumors cannot be drawn from tumor databases. The resection margin is the most critical issue for the treating surgeon and any information on this topic is of highest importance to the field.

Background:
Recently there has been some controversy about the value of percutaneous closed pleural biopsy (PCPB) as a diagnostic procedure for establishing the etiology of pleural effusion. Our objective was to assess the accuracy of percutaneous closed pleural biopsy as a diagnostic procedure for lung cancer and mesothelioma in patients with pleural effusion.

Methods:
We performed a prospective study of all individuals who underwent percutaneous closed pleural biopsy, using Cope needle or Abram’s needle in order to establish the etiology of pleural effusion, during a 8/year period in a refering hospital of respiratory diseases in Mexico City. The identification of patients who underwent closed pleural biopsy was obtained from the anatomopathological registries. The information of each patient was obtained by medical record review. In this study, when the pleural biopsy did not establish the definite diagnostic, we used as a gold standard other procedures such as thoracoscopy, open lung/pleural biopsy, fiberoptic bronchoscopy, adenosine deaminase and/or microbiological tests. All cases were followed up at least three months through medical record review and direct contact with the patient. With 2x2 table we determined the accuracy of PCPB.

Results:
A total of 1034 pleural biopsies were performed. Malignancy was identified in 466 (45.07%) of whom 252 (24.37%) had adenocarcinoma,105 (10.16%) mesothelioma, cancer not differentiated 28 (2.71%), epidermoid 5 (0.48%) small cells cancer 19 (1.84%), giant cells cancer 6 (0.58%), limphomas 11 (1.06%) and others malignancies 40 (3.87%). 116 (%) cases of pleural tuberculosis and 2 (0.19%) parapneumonicos. 378 (36.56%) biopsies were non/specific inflammatory. 171 (19.81%) were excluded to the analysis due to 72 (6.96%) obtaining no pleural tissue and in 99 (9.57%) we can not obtain case information. A total of 863 biopsies were analysed to asses the accuracy.

Indicator	Lung cancer and other malignancies	Mesothelioma
Sensitivity % (CI 95%)	77 (74-79)	81 (78-83)
Specificity % (CI 95%)	98 (97-99)	100
Positive predictive value % (CI 95%)	99 (98-100)	100
Negative predictive value % (CI 95%)	66 (63-70)	97 (96-98)
Likelihood ratio positive	38.5	81
Likelihood ratio negative	0.23	0.19
Prevalence % (CI 95%)	68 (65-71.3)	15 (13-17)

Conclusion:
This is a valid, available, accurate and precise diagnostic test which can be applied in patients with pleural effusion to establish cancer or tuberculosis diagnostic. The percutaneous closed pleural biopsy in this setting is useful in our practice due to produces big change from pre-test to post-test probability.

Background:
The treatment of pulmonary metastases of soft-tissue and bone sarcomas is challenging, as they are highly resistant to both chemotherapy and radiotherapy. Hence, while surgery is the treatment of choice, the treatment options are currently very limited for non-surgical patients. Therefore, the purpose of this study was to evaluate the safety and efficacy of percutaneous computed tomography (CT)-guided cryoablation for pulmonary metastases of soft tissue and bone sarcomas.

Methods:
Hospital records of patients who underwent cryoablation for metastatic lung tumors of soft-tissue and bone sarcomas were reviewed. Percutaneous cryoablation was performed using the Cryocare system (Endocare, Irvine, CA) and multi-slice CT fluoroscopy. CT scans were obtained immediately after the procedure; follow-up CT was performed on days 1, 7, 30, and 90, and subsequently at 6-month intervals. The procedural safety, local progression-free survival, and overall survival were assessed retrospectively.

Results:
Between 2002 and 2011, percutaneous cryoablation was performed on 20 patients (12 men and 8 women; median age, 46 years; age range, 17-83 years) for 56 metastatic lung tumors of soft tissue and bone sarcomas, during a total of 36 sessions. Of the 20 patients, 2 (10%) refused surgery and 18 (90%) were considered inoperable due to multiple tumors or insufficient pulmonary function. Of the 36 sessions, pneumothorax occurred in 12 (33%), transient hemoptysis in 11 (31%), and hemothorax in 1 session (3%). Of the 12 sessions with pneumothorax, 1 (8%) required chest tube insertion. No surgical intervention was required for any of these complications. With a median follow-up of 27 months, 2 tumors (4%) showed disease progression at the original cryoablation site. The local progression-free survival rates at 1 and 3 years after cryoablation were 95% each, and the 1- and 3- year overall survival rates were 77% and 49%, respectively. Four patients were alive over 5 years after cryoablation.

Conclusion:
Percutaneous cryoablation is a feasible and efficient treatment option for inoperable metastatic lung tumors of soft tissue and bone sarcomas.

Background:
Pulmonary carcinoid tumors represent only 2% of all lung tumors. Treatment generally involves surgery which many times is curative, however, once metastasis develops there are no standard treatment options. Radionuclide therapy with MIBG has been shown to be beneficial for gastroenteropancreatic neuroendocrine tumors. We sought to determine the efficacy of MIBG treatment for metastatic pulmonary carcinoid tumors at the Ochsner/Louisiana State University Neuroendocrine Program.

Methods:
All patients who had a diagnosis of a metastatic typical or atypical pulmonary carcinoid tumor and who underwent MIBG treatment at our institution were included. Tumor characteristics, demographic information, response rate and survival was captured. Patients without adequate records were excluded. All patients required MIBG avid disease on MIBG scintigraphy. MIBG treatment consisted on 200 mCi of [131]I MIBG delivered over one hour at 30 cc/hour. Follow up CT scans were used to determine response by RECIST 1.1.

Results:
Six pulmonary carcinoid patients were identified who had undergone MIBG treatment. The mean age at initial MIBG treatment was 66 (range 44-89) Females represented 83% of patients. There were five typical and one atypical carcinoid patient included. Two patients achieved a partial response, one patient had stable disease and three patients had progression following MIBG treatment. Overall survival for the entire cohort from the date of MIBG therapy is shown. Figure 1



Conclusion:
In our small cohort, MIBG treatment seemed to be beneficial in 50% of patients with MIBG avid disease with a partial response observed in 33% of patients. This treatment was well tolerated and offered an increased survival in an already heavily pretreated cohort. MIBG may offer some pulmonary carcinoid patients an additional treatment option. Further research should be directed at examining radionuclide therapy in pulmonary carcinoid patients.

Background:
Pulmonary resection for metastases from renal cell carcinoma (mRCC) is a treatment option that can provide long-term disease-free survival. Larger number and size of metastatic nodules, increasing number of lymph node metastases, shorter disease-free interval, and decreased preoperative forced vital capacity are negative prognostic factors in this setting. The potential role of surgery is illustrated by the results from a series of 278 patients with mRCC in which 51 percent underwent removal of all of their metastatic disease with curative intent, 25 percent underwent partial resection of their metastatic disease, and 24 percent were treated without surgery. Metastases were most frequently resected from the lung, brain, bone and soft tissue.

Methods:
Between 1989 and 2014, 73 patients (44 men, 29 women) underwent pulmonary resection of mRCC. Only patients who met the criteria for potentially curative operation, that means, control of primary tumor, ability to resect metastatic diseas were included. All patients received immunotherapy after surgical treatment.

Results:
Pulmonary metastases were bilateral in 15 patients and unilateral in 58 patients. 15 bilateral (9 staged) and 58 unilateral thoracotomies were performed. Wedge resection was performed in 68 and lobectomy in 5 patients. The overall 5-year survival was 72.8 % 10-year survival was 43,9% and 15-year survival was 20,9% among the patients, who had no other extrapulmonary metastases. The 5-year survival of curative resected patients with metachronous metastases was better then patiens with synchronous metastases. The overall 5-year survival was 31,3 % among the patients, who had extrapulmonary metastases.

Conclusion:
Surgical resection of isolated lung metastases in carefully selected patients is safe and effective. Metastasectomy nowadays is the best treatment option in cases with technical resectable metastases with as much as possible good prognostic factors.

Background:
The WHO 2015 classification for pulmonary carcinoids (PC) and high-grade neuroendocrine carcinomas (NEC) has in essence, not been changed compared to the previous one, despite known limitations in the diagnostic process such as 1) the need for resection material or large biopsies 2) reported inter-observer variability and 3) sporadic exposure in daily practice. Furthermore, nomenclature used in previous or different classification systems for neuroendocrine tumors may result in an aberrantly applied description of the WHO 2004 diagnoses. Here we evaluate if nomenclature established in daily pathology practice in the Netherlands is according to that advised by the WHO 2004 for PC, NEC and non-small cell lung cancer (NSCLC) with neuroendocrine differentiation established by immunohistochemistry (IHC).

Methods:
Written conclusions (diagnoses) of pathology reports (2003-2012) were retrieved from the Dutch Pathology Registry. Conclusions describing PC, NEC and carcinomas with neuroendocrine features/differentiation were selected by multiple queries on anatomic location, diagnosis and keywords (e.g. carcinoma + endocrine). All conclusions were screened in concordance with an experienced pathologist (JLD & RJS) and data on sampling method, diagnoses and origin of primary tumor were collected. Conclusions were excluded if established on autopsy cases or if it reported differential diagnoses, diagnoses of non-pulmonary/unknown primary, non-neuroendocrine or small cell lung cancer. We compared the retrieved diagnoses with the advised WHO 2004 nomenclature after which all diagnoses were clustered (e.g. typical/well differentiated/grade I carcinoid into “PC”). For statistical analysis the X[2] test was used.

Results:
4612 conclusions were eligible for analysis of which N=698 (15%) described a diagnoses that did not match the WHO nomenclature. Foremost non-WHO diagnoses were: (poorly differentiated) neuroendocrine carcinoma; high-grade neuroendocrine carcinoma/tumor; NSCLC neuroendocrine carcinoma; neuroendocrine tumor and low grade (well differentiated) neuroendocrine carcinoma/tumor (carcinoids). After discussion, we clustered N=2005 (43%) diagnoses into PC, N=1788 (39%) in high-grade NEC, N=763 (17%) in carcinoma with neuroendocrine features/differentiation and N=56 (1%) in neuroendocrine tumor n.o.s., respectively. Deviations from the WHO nomenclature occurred in 8% (N=157) of PC and 21% (N=377) of high-grade NEC and this occurred mainly on biopsy/cytology specimens (75% (N=399)). In (NSCLC) carcinomas with neuroendocrine features/differentiation diagnoses deviated from the WHO in 14% (N=108). Additionally, both the terms neuroendocrine “features” and “differentiation” were used to address positive neuroendocrine IHC staining (16% vs 25%) though differentiation was used slightly more often (p=0.001). Finally, 52% (N=1045) of PC diagnoses were established on biopsy/cytology specimens and a strong increase in diagnoses of large cell neuroendocrine carcinoma (LCNEC) on biopsy/cytology specimens was observed (<2008 N=174 vs. ≥2008 N=464, p<0.001).

Conclusion:
In daily practice 8% of PC, 21% of high-grade NEC and 14% of (NSCLC) carcinomas with neuroendocrine features/differentiation diagnoses deviated from the WHO 2004 nomenclature. This occurred mainly on biopsy/cytology specimens. Also, the diagnosis (NSCLC) carcinoma with neuroendocrine ‘differentiation/features’ was unclear and should be specified (i.e. IHC or morphologically based (or both)). Finally, often the diagnosis LCNEC was established on biopsy/cytology specimens whereas this is not advised by the WHO. Whether these findings are due to personal preferences or difficulties applying current classification to limited samples, require further investigation.

Background:
• Malignant pleural mesothelioma is known as disease of the poor prognoses. • Our purpose is to find useful CT findings for correct differentiation between Malignant Pleural Mesothelioma in the early stage (e-MPM) and Benign Asbestos Pleural Effusion (BAPE) to improve prognosis of MPM.

Methods:
• The BAPE group consisted of 36 patients diagnosed at Okayama Rosai Hospital since Jan 2000. In all BAPE patients thoracoscopic biopsies were conducted to exclude malignant diseases including MPM. • In e-MPM group, 66 patients who were diagnosed mesotheliomas with T1 or T2 (IMIG system) by the CT evaluation were studied. The e-MPM patients were selected from 2,742 mesothelioma death cases of Japanese vital statistics of 2003-05. • We evaluated CT scans taken at the time of diagnosis for each group. The evaluating items were presence of asbestosis, pleural plaque (PQ), rounded atelectasis (RA) and diffuse pleural thickening (DPT), as well as the grade and localization of pleural irregularities.

Results:
• In BAPE group (36 cases), the occurrence rate of asbestos-related lesions was significantly higher than in e-MPM group (66 cases) as follows; prevalence of asbestosis 17%/2% (*), PQ 92%/35% (**), RA 44%/0% (**) and DPT 25%/2% (**). (*P=0.0038 **P<0.001) • As for grade of pleural irregularity, no irregularity was found in 22%/9%, low-level irregularity in 72%/54%, high-level irregularity in 5%/23% and mass formation in 0%/14% of BAPE and e-MPM group patients, respectively. • As for localization (including overlap) of pleural irregularity, irregularity in mediastinal pleura was observed in 30%/74%, basal pleura in 91%/77% and interlobar pleura in 0%/55% of BAPE and e-MPM group patients, respectively. The mediastinal pleural thickening was minimal in BAPE group and found regressed in the follow-up CT scans.

Conclusion:
• In BAPE group the occurrence rate of asbestos-related lesions was higher than in e-MPM group. • Because the 5% of BAPE cases presented irregular pleural thickening, the differentiation with MPM was difficult in such case. • The mediastinal pleural thickening, which is considered to be a characteristic of MPM, was also observed in 30% of BAPE cases. However, the finding disappeared during observation. And no BAPE case with interlobar pleural irregularity was found. These findings can be useful for differentiation BAPE and e-MPM cases.

Background:
Primary malignant chest wall tumors are a heterogeneous group of tumors. They require special experience in designing resection and reconstruction. They account for less than 1% of all primary malignant tumors. This study is designed to clarify different factors contributing to the outcome of patients with primary malignant chest wall tumors in our institution.

Methods:
A retrospective study included 97 patients with pathology proven primary malignant chest wall tumors, treated at the national cancer institute, Cairo University, Egypt, during the period from 2002 to 2012. Computed tomography scan of the chest and upper abdomen was considered the primary staging tool for all patients. Magnetic resonance imaging was requested whenever indicated. Surgical resection and reconstruction was designed according to the site and extent of the lesion. resected. Adjuvant and neo-adjuvant therapy was given according to thoracic oncology committee decision. This study was approved by the ethical committee of our institution and informed patient consent was taken.

Results:
Primary malignant chest wall tumors represented 10.5% of all thoracic malignanciesin our institution. There were 46 males and 51 females, the median age was 41 years. Chondrosarcoma was the commonest tumor histology (20.6%). The mean tumor size was 9.3x6.2cm. Tumor multiplicity was found in 15.4% of patients. Bone resection was performed in 76 patients (78.3%), ribs resection was performed in 62 patients and the average number of resected ribs per patient was 2.57 ribs. Sternal resection was done in 9 patients. R0 resection was achieved in 73% of patients. There was one operative related mortality and 23% of patients suffered procedure related complications. Local recurrence developed in 45.3% of patients. The overall survival for the whole group at 1, 3 and 5 years was 67.1%, 37.2% and 26.1 % respectively and the median survival time was 26 months. Different prognostic variables were used to assess better survival including : age , sex, site , size pathologic subtype , tumor grade,, safety margin Good prognostic factors include female sex, age ≤ 40years, no rib resection, safety margin ≥ 1cm, when the least safety margin involve the soft tissue and not the bone, tumor size ≤ 6cm in diameter.

Conclusion:
rimary malignant chest wall tumors should be treated with highly qualified thoracic surgeon and achieving wide resection margins is of great importance to minimize local tumor recurrence that will have an impact on long-term survival.

Background:
The tumor related molecular markers in esophageal squamous cell cancer(ESCC) remains unknown and requires further investigation in order to promote effiicient and rapid development of therapeutic methods. The aim of our study was to evaluate if molecular markers of ESCC correlates with patients’ prognosis and the outcome.

Methods:
Protein expressions of EGFR, C-MET, HER2 were detected by immunohistochemistry (IHC) in 180 paraffin-embedded tissue samples from stage IIB-IIIC ESCC patients with esophagectomy at the Zhejiang Cancer Hospital between January 2007 and December 2012. Log-rank test was used for univariate analysis, and Cox’s proportional hazards model was used for multivariate analysis. Assessed factors were age, gender, somking, alcohol use , tumor location, stage, differentiation, venous or nerve invasion, radiation, chemotherapy and expressions of EGFR, C-MET, HER2.

Results:
The median survival of all patients was 46 months. Of the all 180 patients, the positive rates of EGFR, C-MET, HER2 were 94.4%, 87.2% and 11.1%, respectively. The high expression rates of EGFR and MET were 47.8% and 46.7%, respectively. On univariate analysis ( Tabel 1 ), stage and high expression MET were the statistically significant unfavorable factors for overall survival, meanwhile, a nonsignificant trend toward dcreased overall survival was found with non chemotherapy patients. The multivariate analysis indicated that independent prognostic risk factors included MET ( P=0.029 ) , chemotherapy (P=0.046) and late stage ( p=0.000 ) with very high statistical significance. In subgroub of the patients with MET high expression, tumor location ( p=0.029 ), non chemotherapy ( p=0.043 ) and late stage (p=0.014) had been the statistically significant unfavorable factors, analyzed by Cox proportional hazards model. In subgroub of the patients with C-MET low or negative expression, non chemotherapy ( p=0.043 ) and late stage ( p=0.014 ) had been the statistically significant unfavorable factors.

Table.1 Prognostic factors for overall survival in univariate analyses

Factors	Category	P-value
Age	≤65 (vs.＞65)	0.130
Gender	Male (vs. Female)	0.486
Smoking	Nonsmokers (vs. Smokers)	0.148
Alcohol use	Non use (vs. Use)	0.977
Tumor location	Upper and middle (vs. Lower)	0.193
Stage	IIA-IIIA (vs. IIIB-IIIC)	0.000
Differentiation	Well (vs. moderate and poor)	0.265
Venous or nerve in invasion	Non invasion (vs. Invasion)	0.613
Radiation	Non radiation (vs. Radiation)	0.957
Chemotherapy	Non chemotherapy (vs. Chemotherapy)	0.090
EGFR	>median (vs. ≦median)	0.347
C-MET	>median (vs. ≦median)	0.018
HER2	Positive (vs. Negative)	0.142

Conclusion:
In the Chinese population, HER2 expression rate was very low. The high expressions of HER2 and EGFR was not correlated with prognosis. High expression of C-MET may be prognostic factors for IIB-IIIC ESCC patients who underwent esophagectomy. ESCC with high expression of C-MET might be a poorer prognosis than those with C-MET low expression. In conclusion, C-MET is a important molecular marker in esophageal squamous cell cancer(ESCC) and further studies are necessary to explore the role of C-MET.

Background:
Surgery is still standard modality for the patients with pulmonary metastases from colorectal cancer in spite of recent remarkable development of chemotherapy. The aim of this multi-institutional retrospective study was to determine which pathological size is the best suited to pulmonary resection, and to evaluate the prognostic factors in the patients with small colorectal solitary metastasis.

Methods:
Patients and Methods Patients with pathologically solitary metastasis were recruited. The retrospective examined sample size was finally 561 who underwent complete resection at 46 facilities in Japan from 2004 to 2009.

Results:
No statistically significant difference was detected between with adjuvant chemotherapy and without in disease free survival (DFS) and overall survival (OS) (p=0.09 and p=0.79). Disease free survival (DFS) and overall survival (OS) calculated after initial pulmonary resection at 5 years were 71.0% and 41.7%, respectively. Tumors from 8-15mm in diameter showed the lowest incidence of recurrence in this series. Especially, relapse was occurred in all patients with pathological size 5mm (7/7, 100%) among the smallest group in the course of a median 279 days. Although significant difference was not found, a tendency was recognized with 15mm as the border by the recurrence proportion and the receiver operating characteristic curves for DFS. CEA abnormality, pathological size (more than 20 mm), and Disease free interval (more than 2 years) were the prognostic factors for DFS, whereas age (more than 70 years old), CEA abnormality, DFI (more than 2 years), and previous extrapulmonary treatment were the prognostic factors for OS in both univariate and multivariate analyses.

Conclusion:
Our multi-institutional retrospective study proposed that the optimum pathological size up to 15 mm was suitable to pulmonary resection in the patients with solitary metastasis from colorectal cancers, but the smallest nodules (less than 7 mm) had a possibility of re-recurrence within a median one year.

Background:
Primary mediastinal malignant germ cell tumours (MGCT) are a rare entity as typical localization of MGCT are gonads. As there is no concept of how to encode diagnosis of primary mediastinal MGCT (PMMGCT), they are usually reported as mediastinal tumor. The primary aim of the study was to evaluate the prognostic factors for survival of patients with PMMGCT.

Methods:
We analyzed data from patients’ medical records who had been diagnosed with a mediastinal tumor and encoded as C38 according to ICD-10. All of them had been diagnosed, treated and followed up in Cancer Center and Institute of Oncology in Gliwice Poland (COI). Patients’ medical records were analysed according to the national low regulation. We found 509 patients (pts) with mediastinal tumor diagnosis and reported as C38 according to ICD-10. The most frequently diagnosed tumors were mesothelioma - 32% of pts, and thymoma - 11% of pts. PMMGCT accounted for approximately 4% (19pts). 47% of them had seminoma and 53% non-seminoma diagnosed (the most frequent was tumor mixed). Median age was 28 years (range 19-41). Only 2 pts did not have any disease symptoms and the mediastinal mass has been discovered accidentally during periodic testing. The most frequent symptoms of disease were mediastinal pain and cough, in 79 and 74% of pts, respectively. The impact of the clinicopathological features was analyzed using the chi-squared test with Yates’ correction. Survival evaluation was performed using the Kaplan Meier estimate with log rank test.

Results:
Median tumor size was 15cm (range 6,5-20cm). All of pts received cisplatin based chemotherapy. In 53% of pts surgery was the primary treatment and the remaining pts started therapy with chemotherapy. 53% of pts experienced mediastinal radiotherapy. Total median dose was 40Gy (range 12-59,5Gy). All pts with seminoma achieved partial or complete response, disease progression was observed only in pts with non-seminoma tumors. 47% of pts had disease recurrence, including only one pts with seminoma. One pts had two high-dose chemotherapies followed by bone marrow transplant. 53% of the pts died due to disease progression or treatment complication, including one pts with seminoma. Median overall survival was 27,5 months with 5-OS of 53%. Pts with seminoma had smaller tumor size than pts with non-seminoma tumors, p=0.03. Pts with a smallers tumor lived longer, p=0.09, however, neither surgery nor radiotherapy had an impact on survival, p=0.5 and 0.2, respectively. Pts with no general disease symptoms lived significantly longer than those who had any disease symptoms, p=0.03. Pts with mediastinal pain at the time at diagnosis lived significantly shorter, p=0.02. Pts with seminoma lived significantly longer than pts with non-seminoma tumors, p<0.001.

Conclusion:
Primary mediastinal germ cell tumours occur mostly in males. Pts with mediastinal MGCT had poor prognosis, nonetheless. Pts with seminoma lived significantly longer than pts with non-seminoma tumors, p<0.001. Tumor size and general disease symptoms were the most important prognostic factors. The results of this study have many limitations, mostly due to the group of pts being small. That is why the results should be taken into consideration with caution.

Background:
Use of SABR to treat pulmonary oligometastases, and more recently, oligoprogression to delay the need to change systemic therapy, is increasing despite no randomized evidence. This project reviews the outcomes of treating pulmonary metastases from a large single institution.

Methods:
From a prospective SABR database, 180 pulmonary metastases in 120 patients were treated between 11/2008 and 12/2013. Indications for SABR were: 1) oligometastases, where the goal was to irradiate all sites of disease, 2) oligoprogression, where the goal was to irradiate only those tumours which were progressing while a systemic therapy strategy was controlling all other tumours, and 3) dominant areas of progression, where the goal was to irradiate dominant tumours, even if other tumours were progressing, usually in patients with indolent disease not on systemic therapy. Doses of 48-52 Gy in 4-5 fractions were delivered as per institutional policy depending on tumour location and histology. Since 2010 the dose for peripheral colorectal cancer (CRC) metastases was increased to 60 Gy in 4 fractions after a preliminary analysis revealed a higher local failure rate in those tumours.

Results:
Median age of patients was 66.5 years. Median duration of follow-up was 21.1 months. Median biological effective dose (BED) was 120 Gy~10~. We observed 1 (<1%) grade 5, 1 (<1%) grade 3 and 8 (7%) grade 2 radiation pneumonitis. 2 year local control (LC) of irradiated tumours was 81%. Non-CRC metastases had higher 2 year LC compared to CRC tumours (94% vs 70%, p=0.002). In 18 patients with non small cell lung cancer (NSCLC) pulmonary metastases, 2 year LC was 95%. In the subgroup of 59 patients with CRC metastases, delivering 60 Gy was associated with significantly higher 2 year LC compared to lower doses (88% vs 61%, p=0.011). In 79 patients with oligometastases treated with SABR, the 2 year progression free probability (PFP), progression free survival (PFS) and overall survival (OS) were 63%, 42%, and 73%, respectively. In 27 patients with oligoprogression treated with SABR, the 2 year PFP, PFS, and OS were 42%, 24%, and 70%, respectively. At 2 years, no change in systemic therapy was seen in 56% of the patients irradiated for oligoprogression, with a median time to changing systemic therapy of 30.8 months. In the 12 oligoprogression patients where a change of systemic therapy strategy occurred after SABR, the median time to systemic therapy change was 8.3 months.

Conclusion:
CRC metastases require higher SABR doses to optimize their LC. Outcomes for patients with oligometastases and oligoprogression treated with SABR seem favourable, but prospective clinical trials are needed to confirm these benefits.

Background:
Sunitinib is a potent oral tyrosine kinase inhibitor of VEGFR, KIT and PDGFR. In a single arm phase 2 study of sunitinib after at least one previous line of chemotherapy, a 26% of partial response rate (PR) was reported in thymic carcinoma (TC) and 6% in thymoma (T), with a median progression free survival (mPFS) of 7.2 months and 8.5 months, respectively. We investigated if off-labelled prescription of sunitinib in this population induced the same efficacy signal.

Methods:
We investigated the database of the French thymic malignancies network. We reviewed advanced T and TC patients (p) who were treated with sunitinib in order to evaluate patient’s outcome.

Results:
From October 2011 to January 2015, 28 patients of 7 institutions were identified (20 TC and 8 T). 32% of patients were females and median age was 49.7 y. Fifteen patients (54%) received sunitinib in ≥ 4[th] line of treatment. Two patients received sunitinib in 1[st] line treatment (1 T and 1 TC). The 37.5 mg was the initial dose of sunitinib in 16p. In the whole population, the PR rate was 21% (of 20p with TC, 4 (20%) had a PR; and of 8p with T, 2 (25%) had partial responses). Of note, PR to sunitinib was independent of treatment line (1p at 1[st] lines, 1p at 3[rd] line, 2 p at 4[th] line and 2p at ≥ 5[th] line). 3 TC p were c-KIT positive, without a clear relationship with response rate (1 PR, 2 PD). The mPFS in whole population was 103 days. For TC the mPFS was 87 days and 139 days for T. Sunitinib adverse events were manageable and tolerable. 8p stopped sunitinib due to toxicity. The median overall survival (OS) in the whole population was 175 days, with prolonged OS in T vs. TC (403 days vs. 166 days)

Conclusion:
Sunitinib is an active treatment in thymic epithelial malignancies irrespective of histological subtype, even in a heavy pre-treated population, and treatment line, supporting antiangiogenic therapies as an alternative treatment option for these patients.

Background:
To evaluate the utilization of positron emission tomography (PET) scan with fluorine-18 fluorodeoxyglucose (FDG) in the selection of the surgical approach for thymic lesions.

Methods:
Twenty-two consecutive patients with thymic pathology, underwent PET-FDG after being evaluated by computed tomography (CT), since 2011. The Standard Uptake Value (SUV) max of the lesion, as well as the SUV of the mediastinum, were estimated. The ratio SUVmax Lesion/Mediastinum was the caliber for selecting thoracoscopic thymectomy (TT) or thymectomy via median sternotomy (TMS), as the therapeutic procedure. If the ratio SUVmax L/M < 1, thoracocscopic thymectomy was preferable. If the ratio was, 1 < SUVmax L/M < 2, the selection was depended on the lesion’s dimensions (TT was preferred for lesions < 4 cm). If the ratio was SUVmax L/M > 2, a median sternotomy was the approach of choice.

Results:
There were 14 male and 8 female patients, with a mean age of 41.1 y.o. In 13 patients the ratio SUVmax L/M showed up > 1, while in 4 patients was higher than 2. The histopathology revealed 7 thymomas, 2 thymolipomas, 8 true thymic hyperplasias, 1 non seminomatous tumour, 1 silicone indused lemphadenopathy while 1 patient is waiting for TT and another one (type C thymoma by fine needle biopsy), for TMS. The mean SUVmax for thymomas was 3.02+-1.67, for thymolipomas was 1.48+-0.26, for true thymic hyperplasias was 1.82+-0.42, while the non seminomatous’ tumour SUVmax was 12.4. There have been performed 7 TTs, 1 Transcervical approach and 13 TMSs. R0 resection was achieved in all 21 patients, have undergone operation, so far. All patients had an uneventful postoperative course and the mean duration of hospital stay was 4 days for TTs and 7 days for TMSs.

Conclusion:
There is no imaging modality sufficient by itself to identify the nature of thymic lesions. The intensity of FDG uptake is useful for predicting the grade of malignancy, and high FDG uptake may reflect the invasiveness of the malignant nature in thymic epithelial tumors. The creation of a scale of “metabolic biopsy” with the use of the ratio SUVmax L/M, will allow the use of TT to a larger patient population, following of course, the surgical oncology guidelines for the removal of thymic lesions.

Background:
Surgery remains the center of treatment of resectable thymoma. Radiation and chemotherapy have been applied widely as adjuvant treatment. However, the optimal treatment strategy for advanced thymoma remains controversial. This study aimed to evaluate the efficacy of multimodal treatment for patients with advanced stage III, IV thymoma.

Methods:
A total 250 consecutive patients with thymoma were treated in our hospital from January 1985 to December 2013. Among these, 70 patients were staged as Ⅲ and Ⅳ. The overall survival (OS) was analyzed according to clinicopathological factors and types of treatment.

Results:
There were 32 patients with stage III (46%), 35 patients with IVa (50%), and 3 patients with IVb (4%). The 10-year OS rates of patients with III+IV, III, IVa were 76%, 89%, and 64%, respectively. Types of treatment were as follows: surgery alone in 23 patients (33%), surgery followed by radiation in 31 (44%), surgery followed by chemotherapy in 2 (3%), surgery followed by chemo-radio therapy in 8 (11%), chemo-radio therapy alone in 6 (9%). There was no significant difference in OS among the treatment groups. Twenty-eight (40%) patients coexisted with myasthenia gravis (MG). There were no differences in OS between those with and without MG. Significant difference in OS was observed between 49 patients who underwent R0/R1 resection and 21 patients who underwent R2 resection (P = 0.004). The disease-free survival was worse in patients with combined full-dose mediastinal and low-dose, entire thoracic radiation than in those with full-dose mediastinal radiation alone (P = 0.04).

Conclusion:
In this retrospective study, it was shown that the surgical resection should always try to leave no gross tumor behind to ensure better prognosis. Although the future comparative, prospective study seems difficult because of the limited number of new cases, the multimodal approach with maximal treatment intensity looks promising.

Background:
RASSF1 gene, located in 3p21.3, has eight exons and two promotor regions. RASSF1 is very famous tumor suppressor gene in various cancers. It was reported that DNA methylation on promotor region of RASSF1 in lung cancer, bladder cancer, and breast cancer and so on was higher, additionally low expression of RASSF1 was possible to cause to be poor prognosis. It is few reports about epigenome status in thymic epitherial tumors. We planned to explore DNA methylation in thymic epitherial tumors cyclopedically.

Methods:
①DNA and RNA were extracted from frozen specimen of B3 thymomas (8cases), thymic cancers (8cases), and thymic neuroendocrine tumors(NET)(3cases). ②DNA was treated by bisulfite conversion. ③DNA methylation level in 470000 CpG sites were measured by infinium methylation assay (Human methylation 450K; ILLMINA) exhaustively. ④DNA methylation on promotor regions of RASSF1 was measured by pyrosequencing（PyroMARK[TM]system;QIAGEN）.　⑤Expression level of mRNA was measured by Real time RT-PCR(Thermal Cycler　Dice® Real Time System Single; Takara), using TaqMan Gene Expression Assays (Hs00200394_m1；Applied Biosystems). Internal reference gene is GAPDH（Hs02758991_g1；Applied Biosystems). ⑥Expression level of protein was analysed by immunostaining. Anti-RASSF1a antibody（Anti-RASSF1a antibody [3F3] ab23950, Mouse monoclonal, abcam）was used by CSAⅡmethod（DAKO CSA II, Biotin-Free Catalyzed Amplification System）.

Results:
Significant difference of DNA methylation was recognized by analysis of infinium methylation assay. All 11 CpG sites were configured on 1α promotor region of RASSF1 in this assay. This assay showed DNA methylation level was highest in NET group. DNA methylation level were 70.9±4.9% in NET, 22.2±20.0% in thymic cancer, 14.3±12.3% in B3 thymoma. ( NET　vs　Cancer/B3　t-test：P<0.00001). Pyrosequencing showed DNA methylation level were 24.0±13.1% in NET, 3.0±0.5% in thymic cancer, 3.0±0.9% in B3 thymoma. Real time RT-PCR showed that relative expression level (/normal thymus) were 0.48±0.31 in NET, 1.02±0.82 in carcinoma, 2.13±2.93 in B3 thymoma ( NET　vs　Carcinoma/B3　t-test：P=0.16). Immunostaining of RASSF1 was scored by stain intensity and stain extend. Immunostaining scoring of RASSF1 showed expression inhibition rate were 66% in NET, 50% in thymic cancer, 14% in B3 thymoma.

Conclusion:
The infinium methylation assay showed that DNA methylation on promotor region of RASSF1 in NET is higher than B3 thymoma and thymic cancer. The pyrosequencing validated this result. It was tendency to suppress the mRNA or protein expression of RASSF1 in NET, compared to other tumors. It is possible that aberrant DNA methylation on promotor region of RASSF1 may be specific change in NET among thymic epitherial tumors. Now we collected 8 formalin-fixed paraffin-embedded samples of thymic NETs to perform pyrosequencing and immunostaining of RASSF1 gene.

Background:
Masaoka-Koga stage and the radicality of the surgical resection are the most important prognostic factors for thymomas. Infiltration of the phrenic nerve interests 10-40 % of invasive thymomas (stage III and IVA). We report the clinical and oncological outcome of patients operated on for invasive thymoma by a intention-to-treat “nerve sparing” technique.

Methods:
In the period 1992-2012 we have applied the “nerve sparing” surgery in all patients with invasive thymoma, and without pre-operative evidence of phrenic nerve paralysis. In that period we have operated on 72 stage III e 33 stage IVA thymomas. Thirteen out of them had a preoperative radiological evidence of phrenic paralysis (5 stage III and 8 IVA) and they were preliminary excluded. In 30 patients phrenic nerve was partially or completely surrounded by the thymoma and they underwent an attempt of ‘’nerve sparing’’ surgery. In twenty six cases the resection of the thymoma with a phrenic sparing procedure was possible. All patients underwent subsequent adjuvant radiation (45-60 Gy).

Results:
Twelve male and 14 female have been treated, with a mean age of 56 years (range 26-83). At the hystological analysis there were: 1 Type A, 5 Type AB, 10 Type B1, 5 Type B2, 5 Type B3. Myasthenia gravis and red cell aplasia were associated in fifteen and one case, respectively. Despite the attempt of preserving the phrenic nerve, in five patients phrenic palsy was observed in the immediate postoperative period. Three of them showed a complete phrenic nerve recovery, while in the other 2 cases nerve paralysis was irreversible. Mean follow up was 96 months (DS ±73) with an mean overall survival of 89 months (DS ±68). The mean disease free interval was 81 months (DS ±71). Three patients (11,5%) had a pleural recurrence (2 stage IVA, 1 stage III) requiring further surgical resection. Two patients (7,7 %) died (1 of systemic metastases and 1 for other cause).

Conclusion:
Preserving the phrenic nerve in case of invasive thymomas is feasible and if associated to adjuvant radiotherapy may also allow to achieve good long term disease-free results. In reason of the excellent local control of disease it should be proposed mainly to patients with invasive thymoma and myasthenia gravis or with a poor pulmonary function.

Background:
In general Indonesian population, mediastinal tumors are rare. However In Persahabatan Hospital Jakarta as National Refferal Hospital in Respiratory Diseases, mediastinal tumors are ranked second in thoracic malignancy after lung cancer, and thymomas are common type.

Methods:
An observational study was done in patients diagnosed as thymoma in Persahabatan Hospital between 2007-2012. Clinical stages, histological types, treatment modalities and survival were analyzed. Histological classification were done based on World Health Organization criteria, and stage of the diseases was determined by Mosaoka Staging System.

Results:
We found that the trend of thymoma cases was increased annually since 2007 to 2012 in Persahabatan hospital Jakarta Indonesia. Among 67 cases diagnosed with thymoma, 43 cases has a complete data and follow up, of which 30 cases were male (69.8%) and 13 female (30.2%) with median age 50 years old ( range 16 years old to 79 years old). Myastenia gravis were found in 23 of 43 cases (53.5%). During follow up, 1-year survival rate was 72.1% and 3-year survival rate was 58,1 % respectively. There was no significant difference in survival rate of thymoma based on age, gender and the presence of myasthenia gravis, but Masaoka Staging and histological type were corellated with the survival. Using the Log-Rank test comparisons, We found statistically significant differences between type A-B2 (p 0.009), type A-C (p 0.001), type AB-C (p 0.032) and type B1-C (p 0.018). Masaoka staging has significant differences between stage I - IV A (p 0.012), the I - IV B (p 0.007), II-IV A (p 0.002) and II-IV B (p 0.002). Multivariate analysis showed that the most influential factor on the survival rate in these series was staging,-based on Masaoka Staging system.

Conclusion:
The Masaoka staging system is the most important determinant of survival in surgically cases of thymoma.

Background:
Involvement of nurse navigators (NN) in oncology care is becoming increasingly common to facilitate more timely access to diagnostic services and treatment for patients. A lung cancer NN was implemented at the British Columbia Cancer Agency (BCCA) and this role involved developing pathways for triage and staging investigations, initiating molecular tests and coordinating new patient referrals. In the BC publicly funded health care model, reflex molecular testing is not available. The purpose was to evaluate referral practice, timelines and molecular testing for advanced NSCLC patients in cohorts with and without a triage nurse navigator.

Methods:
The study included all advanced NSCLC patients referred to the BCCA – Vancouver Centre in two separate 1 year cohorts for comparison; 2011 and 2014. Timelines between referral and systemic therapy/radiotherapy (XRT) treatments, availability of molecular testing and data on referral patterns were collected.

Results:
A total of 408 patients were included: 212 in 2011, 196 in 2014. Endpoints for medical oncology (MO) comparing 2011 to 2014: overall referral rates remained the same and the proportion of patients receiving systemic treatment increased, 57% vs 69% (p=0.05). Referral to MO consult 18 d vs 15.5 d (p=0.11), referral to systemic therapy initiation was reduced 48 d vs 38 d (p=0.016). Molecular testing: time from referral to EGFR result was reduced 34 d vs 20 d (p<0.001), EGFR results available at MO consult increased 6% vs 37% (p<0.001), rate of molecular testing increased 62% vs 91% (p<0.001), EGFR mutation positive (19% vs 26% p=0.26). For radiation oncology (RO) endpoints: RO consults 87% vs 80% (p=0.05), the same proportion of patients received XRT (91% vs 87%). Time from referral to RO consult 10 d vs 8 d (p=0.005), referral to XRT 18 d vs 11.5 d (p<0.001).

Conclusion:
Implementation of a NN at triage reduced the time period between referral and treatment for MO and RO. The proportion of patients provided with molecular testing increased and the rate of EGFR positive results remained the same, an indication that more patients received appropriate first line targeted therapy. Nurse navigator participation during triage activities suggests that physician, diagnostic and clinical resources are more appropriately allocated.

Background:
In 2013 the Holistic needs assessment (HNA) for newly diagnosed cancer patient, which highlights patient concerns and symptoms, was introduced in the UK. The use of the tool, in a leading cancer centre, identified a need for a multi-disciplinary education and support group to better address the management of patient symptoms and supportive care needs. The most common physical symptoms reported were; Fatigue/tiredness (74%), sleep (64%), walking/stairs (58%), breathing (56%), appetite/weight changes (46%), and pain (40%). The most common psychosocial concerns were; Fear/anxieties (48%), and sadness (48%). With increasing national focus on cancer survivorship and rehabilitation initiatives for cancer patients there is growing evidence that support programmes can increase quality of life and psychological functioning. A multi-disciplinary team (MDT) was established to develop a health and wellbeing programme for thoracic cancer patients treated at Guy's and St Thomas' NHS Foundation Trust (GSTT).

Methods:
Working as a MDT, consisting of Cancer Nurse Specialists, Physiotherapists, Occupational Therapists and Dietetics, a programme of physical, psychosocial and educational components was devised to address the key symptoms, including the following; 1. Managing your energy 2. Keeping active 3. Eating Well 4. Managing breathlessness 5. Keeping on top of things 6. Time to relax - Qigong Inclusion criteria; Medically stable thoracic cancer patients under GSTT, at any point along their pathway plus carer/family member Exclusion criteria; Anaemia, Hb <80g/L, untreated brain mets/cognitive issues restricting ability to participate in group sessions. Each session was paced to optimise patient care allowing interventions to be tailored to individual's situations, stage of disease, and their wishes. Patient experience questionnaires, which were standardised across all sessions, are handed out and following the end of the programme the CSQ-8 is completed by the patients, allowing for continuous quality control of our service from the patient's perspective.

Results:
Data to February 2015 showed the following; -94% of patients reported an improvement in their ability to self-manage their symptoms -100% of patients reported increased confidence in managing their symptoms -100% of patients reported that anxiety was reduced -Mean CSQ-8 evaluation score = 9.6/10 Patient attendance; -6 week programme format: 9 patients started the programme, 3 completed. -3 week programme format: 21 patients started the programme, 12 completed. -1 week programme format (only 1 programme completed at time of abstract submission): 9 attended and completed entire day

Conclusion:
A programme of this nature represents a valuable intervention output following HNA across the cancer pathway. It supports local and national cancer strategies around survivourship and rehabilitation. With progression free survival in thoracic cancer improving the self-management of physical and psychosocial symptoms, longer term, becomes increasingly relevant. The numbers have been limited, indicative of the symptom and treatment burden for this patient group, however overall results are impressive. This indicates the requirement of a flexible approach. In adapting the format over time patient reported experience remained very positive, moreover attendance improved. Thus making it more accessible for our patient group, as well as enabling, equiping and empowering them to self-manage symptoms and live well with cancer. This model can be adapted and translated into other health care settings and tumor types, both nationally and internationally.

Background:
Although surgery for lung cancer is often a successful treatment, very little is known about how patients cope and live with the possibility of recurrence of cancer in the future. Two published literature reviews on prognosis disclosure in cancer care have identified no papers focused specifically on risk of recurrence in post-surgical lung cancer patients. Aims were to develop a synthesis of the current literature around prognostic disclosure in cancer care in order to: · Identify a thematic framework that can be used to provide a model for the factors present in prognostic disclosure in cancer care. · Identify research questions that will inform future study into disclosure of recurrence risk in lung cancer patients following potentially curative surgery.

Methods:
A review of published studies on prognostic disclosure in cancer care up until the end of 2003 was used as a starting point. An updated review was undertaken and a systematic approach was taken to searching the literature from 2004 – June 2014. Data were extracted from the identified papers using a comprehensive data extraction form. Codes were assigned to key elements of data within the results and conclusion sections of the papers. Critical interpretive synthesis was used to explore themes by constructing an integrative grid to examine findings between studies and to identify similarities and contradictions. Themes from the original review were identified and compared to the updated findings. A further framework grid was constructed to investigate between-theme relationships and to help identify “synthetic constructs” and a thematic framework.

Results:
Twenty papers were identified in the updated review and were diverse in their objectives and patient groups. Themes were identified in these studies and in the original review covering the nature of prognostic information, patient need for prognostic information, patient need to maintain hope, balancing hope and realism, patient factors, disease factors and clinician factors. A thematic framework was developed. Future research questions were framed around disclosure of risk of recurrence following lung cancer surgery.

Conclusion:
There are no studies looking at prognostic information-giving in post-surgical lung cancer patients. Patients generally want prognostic information, but also want information that supports hope. Patients appear to struggle to fully understand complex prognostic information and value help making sense of information. Working with patients to understand and manage the uncertainty of their situation may be particularly valuable. Future research questions include: · How do patients and their clinical teams manage information disclosure about possible cancer recurrence following lung cancer surgery? · What is the emotional impact on patients of the uncertainty of potential recurrence following lung cancer surgery? · What information do patients want regarding recurrence risk? · What strategies do patients and professionals currently use to help manage the uncertainty of potential recurrence after lung cancer surgery? · Are there strategies or interventions aimed at managing uncertainty in this group that could have wider application for patients?

Background:
The Lung Cancer Nurse Specialists (LCNS) at Papworth Hospital provide support and information throughout the surgical patient’s pathway. The Thoracic Enhanced Recovery Program has shortened post-operative length-of-stay from 9 days (2010) to 5 days (2013). The aim of this audit was to evaluate the role of a follow up telephone link line call 30 days post-surgery. There is evidence in the literature that telephone contact is beneficial for patients. Patients receive a telephone call from a LCNS within the first week of their discharge and this is considered to be a good means of providing health education and advice, managing symptoms, recognizing complications early and giving reassurance to patients after discharge. However, in order to gain a more detailed account of a patient’s recovery / rehabilitation (particularly visits to A&E, readmissions and complications) it was proposed that a second phone call be made by the LCNS at 30 days post discharge.

Methods:
A data collection spreadsheet was designed. From 01/01/2013 to 31/08/2013 patients following a lung cancer resection received a telephone call from a LCNS, 30 days post-surgical discharge. A holistic assessment of the patient’s needs, and their progress was explored and actioned. Information regarding advice sought, recovery perception and readmission rates were gained.

Results:
101 patients underwent surgery, 93 received a 30 day call (61M/32F). 91 (98%) were aware of whom to contact following discharge and were able to name their LCNS. 73 felt ready for discharge, 11 unsure, 9 not ready (8 unanswered). 37 recovered better than expected, 35 as expected, 15 slower and 6 worse than expected. Post-operative pain was more persistent / severe in thoracotomy patients 48/57 (84%) compared to a video assisted thoracoscopy approach 24/36 (66%). 26 patients required advice for constipation, 7 diarrhoea. 60 breathlessness on exertion, 1 discharged home on oxygen. 10 felt low in mood since discharge. 7 were readmitted within 30days.

Conclusion:
The 30 day post discharge link line call has revealed some areas of self-care needs which appear not to have been fully understood or addressed. Patients were perhaps not able to retain the information. The introduction of a structured pre-operative education program may assist with addressing these issues. Also, active telephone follow ups, initiated by the LCNS, appeared relevant to the problems patients face after discharge. With telephone follow-up information can be reinforced, thereby increasing compliance, and ensuring the physical and emotional comfort of the patient. Limitations to this audit include the use of no nationally recognised quality of life tools / scales. A review of the timing and number of calls to a patient with focus given to pain, constipation and psychological support will help deliver a more comprehensive service.

Background:
Support groups can help to improve patients' coping and mental adjustment to a cancer diagnosis and treatment. They have also been shown to have a positive impact on psychological wellbeing and reduce anxiety and depression. However, at Papworth Hospital (a regional cardio-thoracic centre), it became increasingly difficult to recruit patients to the lung cancer support group. Consequently, before starting any new initiative, the decision was made to disband the group in December 2013 and to identify alternative and beneficial ways of supporting patients.

Methods:
With patient user involvement, a questionnaire was designed Living with lung cancer - how can we help you? From 12/05/2014 to 30/05/2014, 100 questionnaires were distributed to all patients with a confirmed diagnosis of lung cancer who attended a thoracic oncology outpatient clinic. Responses were anonymous and returned to a secure box for review in the audit department.

Results:
81% of the questionnaires were returned. Patients were referred to Papworth from 8 different hospitals in the region. 79% were over 60 years old at diagnosis. 84% recorded a diagnosis within the last 4 years, the remaining recording diagnosis back to 2001. Since diagnosis, the most useful sources of information are listed below as recorded by the patients (please note more than one answer could be selected):

Family/ friends	38
Hospital doctor	62
LCNS / key worker	60
GP	32
District nurses	9
Macmillan nurses	9
Hospice	3
Cancer Centre	3

Of those diagnosed within the last 12 months the Lung Cancer Nurse Specialist (LCNS) was the most useful source of information. The questionnaire proposed a number of topics that might be included in some form of additional support of which 34% were interested. The most common request was for information on symptom control (breathlessness and fatigue), relaxation techniques and treatment options. The questionnaire suggested a number of different formats for providing additional support. Of the 27 respondents, 15 (55%) preferred telephone support from a LCNS.

Conclusion:
The LCNS plays a pivotal role in providing relevant information and support. The challenge is to find new and innovative ways that will help to optimize patients’ psychosocial as well as physical wellbeing. Consideration will be given to increasing telephone support to signpost patients to appropriate information on treatment options and symptom control. We plan to audit the effectiveness of LCNS telephone consultations to ascertain the impact on patient wellbeing. Different types of relaxaion techniques such as yoga classes will be explored. Co-ordination of information management within a large geographical area, incorporating many hospitals and local community facilities, is essential.

Background:
Breathlessness is common amongst lung cancer patients. It leads to inactivity, helplessness and loss of self esteem. As the experience of breathlessness has physical and non-physical aspects, management of the symptom of breathlessness is challenging. It is recognised that non pharmacological intervention for breathlessness is beneficial. In 2012 lung cancer patients expressed the need for an easy to use breathlessness aid. A breathlessness booklet was subsequently developed. Patients were asked to assess the usefulness, understanding and easiness of each entry. The booklet evaluated well with patients and users. The appointment of a Macmillan specialist occupational therapist to the palliative care team was an ideal opportunity to re-examine the breathlessness aid and introduce a multi disciplinary approach.

Methods:
The booklet was reviewed with the layout redesigned and an additional section added on activities of daily living. Information includes anatomy and physiology, breathing control, anxiety management including relaxation techniques, activity pacing and positional aids.

Results:
The revised A5 booklet has since been used by patients and a number of the multi-disciplinary team have had sight of it. Information remains, as intended simplistic but is comprehensive. The booklet is being distributed by the Macmillan lung cancer CNS and palliative care team which includes consultant, CNS’s Macmillan OT and healthcare support workers. Patient feedback remains very positive. It suggests patients feel more equipped to cope with their breathlessness. They report it has helped them cope with pacing themselves and controlling breathing when using the stairs. Others enjoy the choice of breathing techniques and tips for managing activities of daily living in and out of the home.

Conclusion:
Interest in this breathlessness aid has been expressed from a variety of specialities and hospitals within Aneurin Bevan Health Board. Requests have been made for the breathlessness leaflet to be available on intranet so that all personnel within ABHB can access information. An additional booklet has been produced on Fatigue. Both booklets have subsequently been presented at The All Wales Lung Cancer Forum 2014 Annual Conference. Delegate feedback was very positive.

Background:
A large majority of patients who receive chemotherapy suffer from fatigue, which lowers their QOL and activities and also has a negative influence on therapeutic efficacy. Although supportive care for those undergoing chemotherapy has steadily progressed, the pathogenesis and treatment of fatigue during chemotherapy is still unknown. Carnitine is an amino acid with a molecular weight of 161, and it plays a critical role in energy production. A decreased level of plasma carnitine has been reported in the case of cancer patients who developed cachexia. It has been reported that carnitine is excreted in the urine after the administration of platinum-type anticancer drugs. We examined the relationship between carnitine pharmacokinetics in patients who received chemotherapy including cisplatin (CDDP) and fatigue.

Methods:
Ten patients (7 male/3 female, median age 66.5 yrs (46-73), 3 SCLC/4 NSCLC/3 malignant mesothelioma, 6 PS0/4 PS1) who received standard chemotherapy including CDDP were examined. We performed 24-hour urine collection and took blood samples on day 1 (before the administration of chemotherapy), day 2, 3, 4, and 8 to measure free carnitine concentration, total carnitine concentration, and acylcarnitine concentration in the plasma and urine. We simultaneously evaluated fatigue levels using the CTCAE, STAT Japanese version, and “Functional Assessment of Chronic Illness Therapy-Fatigue” (FACIT-F).

Results:
The total carnitine concentration in the plasma samples was the highest after 48 hours (day3) of administration and showed significant increase compared to before the administration of CDDP (day1)(65.3±17.6 µmol/L vs. 95.2±28.9 µmol/L, p=0.001). Total urine carnitine concentration was the highest after 24 hours (day2) of administration and showed significant increase compared to day1 (122.3±108.7 µmol/L vs. 632.9±376.6 µmol/L, p=0.003). Fatigue levels were the most severe on day 4 and did not improve thereafter.

Conclusion:
The study suggests an increase of the amount of carnitine excretion within urine is a possible predictive factor for the appearance of fatigue related to chemotherapy. Future studies will be planned to investigate the protective effects of carnitine administration for fatigue in patients treated with CDDP-containing chemotherapy.

Background:
Prognostic factors in nonsmall cell lung carsinoma (NSCLC) has been described in many studies in medical literature. It is unclear the relationship between overall survival and symptom burden. The aim of our study is defining the prognostic factors in advanced NSCLC and to describe relationship between symptoms and overall survival.

Methods:
In this study, the patients newly diagnosed stage 3b and 4 with NSCLC and Eastern Cooperative Oncology Group Performans Status (ECOG PS) of 0 to 2, from August 2011 to May 2013 in Ataturk Chest Diseases and Chest Surgery Education and Training Hospital were included. We obtained the demographic, diseases related and laboratory data for all patients. Symptoms were analyzed with The Edmonton Symptom Assessment Scale (ESAS) before and after chemotherapy. The study was designed prospectively and the patients were followed up to 826 days. Cox model proportional risk analysis was performed at the end of the the followed-up period to assess the beginning symptoms, symptoms differences after chemotheraphy and the relationship between the general characteristics and the survival.

Results:
We conducted a multivariate analysis and it is found that as one of the general characteristics; the stage of the diseases (p= 0,004 HR: 2,373 95% CI: 1,317-4,274) and the histopathologic subtypes (p=0,006 HR: 2,311 95% CI:1,271-4,202) were prognostically significant. The patients with fatigue as the beginning symptoms (p=0,001 HR:2,389 %95 % CI: 1,460-3,908) and the sadness score 4 and over (p= 0,032 HR:2,311 95% CI: 1,271-4,202) had lower survival, it is also found that patients with cough intensity increasing after chemotheraphy (p=0,006 HR: 1,933 95% CI: 1,128-3,314) had lower survival and high mortality risk as well in multivariate analysis.

Conclusion:
During the treatment process, together with performance scores of patients with symptom score monitoring will be meaningful. Further prospective studies including a larger group of patients are required in order to describe better the relationship between the symptoms and the prognosis.

Background:
The change in quality of life (QOL) through the early intervention by a palliative care team was analyzed in patients with advanced lung cancer. The contrast between patients’　own evaluation on their QOL and their QOL estimated by their attending physicians was examined as well.

Methods:
The eligibility criteria were newly-diagnosed Japanese patients with stage IV lung cancer, whose ages were over 20- years old, whose Eastern Cooperative Oncology Group Performance Status were from 0 to 3, and those who had written informed consent. For the patients and attending physicians, QOL questionnaires, which were in line European Organization for Research and treatment of Cancer Quality of Life Questionnaire-Core15 （EORTC QLQ c-15）, were conducted at the time of the enrollment and twelve weeks later. The primary endpoint was a change in global QOL score, which ranged from 0 (worst) to 100 (best), after the twelve-week intervention.

Results:
58 patients out of 96 who were newly diagnosed as stage IV lung cancer were enrolled in this study. 43 patients had the QOL evaluation after twelve weeks. One patient withdrew consent, one patient moved to another hospital and other thirteen patients died during the intervention period. The primary endpoint improved by more than 25% that was originally anticipated (50 points at the enrollment, 64.7 points after the intervention.). All of the following factors including emotional state, nausea, vomiting, pain, constipation improved by more than 25% similarly to the primary endpoints, although other QOL factors showed a slight improvement or no change. While the difference between the QOL score by the patients and the physicians was apparent at the beginning the intervention, it became smaller by every measurement after twelve weeks. In Japan, Palliative care units (PCUs) have a role of hospices as well, and there are not enough number of them, to meet the entire needs for the end-of-life care. Some patients end up dying while on the waiting lists of PCU. Less percentage of patients who had early palliative care (EPC) died while waiting PCU admission, as compared with other cancer patients who applied for PCU during the same period as the present study. (12.5 % vs 30.4 %) In addition, duration of best supportive care in patients were extended approximately one month, as compared with past patients with stage IV　lung cancer in undergoing EPC.(108.7day vs 78day)

Conclusion:
QOL improved in studied Japanese patients after the early interventions by the palliative care team. This result may indicate that discrepancy of QOL evaluation between the patients and physicians was lessened due to the early intervention by the palliative care team, which is considered to have fostered the improvement of the overall QOL. It was suggested that such intervention might support the patients in decision making for end-of-life-care.

Background:
Pain is one of the most frequent and burdensome symptoms in cancer patients. In addition, inadequate pain management may limit anti-cancer active treatment in these patients and impair their quality of life. Chemotherapy in the outpatient settings has become common in Japan in the last decade. However, the adequacy of pain management in patients who receive outpatient chemotherapy is not yet well-known. The primary objective of this study was to assess pain prevalence and intensity in these patients. The secondary objective was to assess the pain management status using the pain management index (PMI).

Methods:
Cancer patients with solid tumors or hematologic malignancies who received chemotherapy in the outpatient setting were enrolled. The PMI scores were calculated using the patient-rated pain score and the analgesic score. The PMI was evaluated twice in each patient on the first day and 3 to 5 weeks later when patients received chemotherapy at Outpatient Chemotherapy Administration Unit, Kyushu University Hospital, Japan. Patients were required to complete questionnaires including Japanese Brief Pain Inventory and the Distress Thermometer and Impact Thermometer.

Results:
Of 740 patients enrolled, 524 patients (71%) who completed the questionnaires at both baseline and follow-up were applied to the statistical analysis. 54% patients experienced any pain and 14% patients had moderate or severe pain. 286 patients (55%) received adequate pain management at both baseline and follow-up, while 238 patients (45%) received inadequate pain management at baseline and/or follow-up. Multivariable analysis revealed that major depression had the most impact on adequacy of pain management.

Conclusion:
Patients who receive outpatient chemotherapy have a high prevalence of pain. The PMI is available to evaluate the pain management status of cancer patients in outpatient setting. Pain management for cancer patients needs to be assessed regularly even though their initial pain management is adequate.

Background:
Approximately 50% to 70% of patients with cancer who receive neurotoxic chemotherapy with taxanes and platinums will develop painful chemotherapy-induced peripheral neuropathy. Duloxetine is a balanced serotonin and noradrenaline reuptake inhibitor licensed for the treatment of major depressive disorders and the management of neuropathic pain associated with peripheral neuropathy. Our objective is to assess the efficacy, compliance and toxicity of duloxetine for treating painful neuropathy.

Methods:
We analyzed data from 79 patients of the Instituto Oncológico de Córdoba (IONC) with breast, lung, colorectal, cervix and endometrium cancer. Eligibility required that patients have grade 2 (G2) or higher sensory neuropathy according to the NCI Common Terminology Criteria for Adverse Events, after paclitaxel, other taxane, or platinum treatment. The initial treatment consisted of taking 1 capsule daily of 30 mg of duloxetine for the first week and 2 capsules of 30 mg of duloxetine daily for 4 additional weeks.

Results:
We enrolled 79 patients with a median age of 63.25 years. Of these, 67% were female and 33% male; 40.5% received adjuvant treatment, 55.6% advanced treatment and 3.7% neoadjuvant treatment. Chemotherapies used were Oxaliplatin (35.4%), paclitaxel (36.5%) carboplatin + paclitaxel (25.3%), and cisplatin (2.5%). At the time of starting treatment with duloxetine, 78.5% of patients had neuropathy G3 and 21.5% G4. 91.5% of them have at least one decrease of neuropathy grade after 30 days of treatment (p = 0.001). 12.6% of patients discontinued treatment due to somnolence (10.8%), vomiting or abdominal pain. 6.3% refused to receive treatment for being a psychotropic drug.

Conclusion:
In our study, treatment with duloxetine showed a response rate, statistically significant, of 91.5% (p: 0,001). Adherence to treatment was 81.1%, with somnolence and vomiting as the primary adverse events.

Background:
The most common comorbid conditions related to Lung Cancer are age- and tobacco-related illnesses, such us cardiovascular disease, chronic obstructive pulmonary disease(COPD) and other malignancies. Different studies have demonstrated and impact in clinical outcome. We retrospectively review the clinical and molecular characteristics, and the outcome related to comorbidities of an homogeneus cohort of advanced NSCLC.

Methods:
The study included data from all consecutive p who were diagnosed as having advanced NSCLC at our hospital between January 2008 and December 2013. Overall survival (OS) and progression free survival (PFS) were evaluated with Kaplan-Meier curves and groups are compared using the Log-rank test. Variables analyzed included patient characteristics (age, gender, smoking history, Performance Status by ECOG), tumor characteristics (histology, stage, molecular profile, site of metastasis), treatment characteristics (chemotherapy regimen, total cicles per line, total chemotherapy lines, objective response(ORR) according to the RECIST criteria). Comorbidities analyzed were: COPD, Cardiovascular diseases, Other Cancers and Others.

Results:
A total of 580 p were included, 163 p no had comorbidities and 417(71.8%) had at least one. Table 1 summarized patient’s characteristics. Any comorbidity were more frequent in female sex (79.6% vs 64.4%; p0.0002), older patients(mean age 64.3 vs 56.7 yo; p<0.0001), less never-smokers(16.1% vs 25.2; p0.033), less molecular alterations (14.2% vs 22.1%; p0.025) and more squamous histology (25.7% vs 12.9; p0.0043). No differences is ORR, PFS and OS were seen globally. For each comorbidity, COPD was associated to worse ORR (65.9% vs 75.6%; p0.023) and OS (8.1 months vs 14 months; p0.018), and cardiovascular diseases were associated to worse OS (9.1 monthsvs 15.5 months; p<0.0015). In univariate and multivariate analysis COPD, Cardiovascular comorbidity, male sex, age more than 65 yo, and non molecular alteration were related to worse OS. Table 1. Baseline characteristics (N of patients treated with at least one line: 486).

	No comorbidities (N=163)	Any comorbididy (N=417)	p-value
Median age Gender (Female) Smoking history (%) -never -former -current -not reported EGFR mut/ ALK translocation Histology -NOS -Adenocarcinoma -Squamous -Adenosquamous -LCC -LCC-NE Site of metastasis -Lung -Brain -Bone -Liver -Adrenal gland	56.7(11.0) 105(64.4) 41(25.2) 63(38.7) 58(35.6) 1(0.6) 36(22.1) 22(13.5) 109(66.9) 21(12.9) 1(0.6) 9(5.5) 1(0.6) 59(36.2) 35 (21.5) 59(36.2) 23(14.1) 25(15.3)	64.3(9.8) 332(79.6) 67(16.1) 209(50.1) 138(33.1) 3(0.7) 59(14.2) 60(14.4) 228(54.7) 107 (25.7) 7(1.7) 8(1.9) 6(1.4) 159(38.1) 96(23.0) 131(31.4) 50(12.0) 53(12.7)	<0.0001 <0.0001 0.033 0.025 0.0043 0.70 0.74 0.28 0.49 0.99

Conclusion:
Comorbidities are frequent in patients with advanced NSCLC p, and are age and tobacco related. Patients with COPD have a worse ORR and OS, and patients with Cardiovascular comorbidities have worse OS. In our knowledge, is the first study that relates comorbidities in NSCLC to molecular alterations.

Background:
Interdisciplinary oncology approach for geriatric patients (pts) is essential to improve health care, in the global era of populational aging. A possible way to implement that is to use CGA and interventions directed by its findings. Lung cancer (LC) treatment is a good scenario to present the importance of CGA, since its pts are usually old and with multiple comorbidities.

Methods:
LC pts with 70+ years old were found in our cohort of more than 600 pts, evaluated from Jan/12-Dez/12, the period of implementation of CGA in the Geriatric Oncology Unit of A. C. Camargo Cancer Center, a tertiary cancer care institution in Sao Paulo-SP, Brazil. Important geriatric data were extracted to evaluate those pts, to exemplify the importance of a coordinated interdisciplinary treatment plan with better chances of improving favorable clinical end-points. CGA assessments included scales of: activities of daily living/ADL (basic: Katz; instrumental: Lawton), mini-nutritional assessment, depression (geriatric depression scale/GDS), comorbidities and polypharmacy. Fit pts received mainly full treatment; frail/borderline pts, mainly modified tx and/or specific supportive care.

Results:
Eighty pts with LC were part of a subgroup of the major cohort. Most relevant data at first visit are show in the table below. All pts were assessed with CGA by at least one nurse, before medical oncology evaluation - sometimes, by a psychologist as well. Table 1. Relevant CGA data and elderly with lung cancer (n=80).

Variable	Categories or values
Age	Median (range)	75 (70-88)
		n (%)*
Sex	Male/Female	44/36	55/45
ECOG/PS	0-1/2-3	53/23	63/29
Histology	Adeno/SCC/Small cel	42/17/8	53/21/10
BADL	KATZ = A	60	75
	Altered KATZ	20	25
IADL	Lawton = 27	27	34
	Altered Lawton	53	60
GDS	Normal (0-4)	43	54
	Altered (≥4)	17	21
	Not available (na)	20	25
Nutrition	Undernourished ( < 8)	15	19
	Under risk (8-11)	24	30
	Normal (12-14)	24	30
	na	17	21

* Some subjects may have variable not available. In addition, selected comorbidity count ranged 0-5 (median 2); polipharmacy 0-6 (median 5). Seventeen pts were in follow-up only (21%); 48 (60%) pts were under chemotherapy (isolated or combined with other therapies). Even though CGA domains were altered in around 60% of them, the planned treatment could be offered to 57 (71%) pts. Longer survival probability, in the series, was predicted by performance status (ECOG), BADL (Katz) and mini-nutritional assessment.

Conclusion:
CGA is gaining increasing importance in geriatric oncology. In the present LC subgroup cohort, even though in a small case series, it shows that many pts are vulnerable or even frail; however, interdisciplinary evaluation and multimodal treatment could be offered, without major complications. Limitations include missing data in any domain of CGA, for example. All efforts to better study and define CGA and help to implement interdisciplinary interventions may be utile to improve elderly quality of life and survival in LC care.

Background:
Thoracic radiotherapy can negatively affect cardiopulmonary function. We herein report on a prospective assessment of the association between heart/lung dosimetric parameters and subsequent changes in the quality of life (QOL) in patients receiving thoracic radiotherapy.

Methods:
Patients about to initiate a course of 3D-planned external beam RT for tumors in/around the thorax were prospectively studied as part of an IRB-approved clinical study. Written informed consent was obtained. Patients had assessments of cardiopulmonary QOL pre-RT and serially post-RT (e.g. 1.5, 3, 6, 12... months post-RT) using the Functional Assessment of cancer Therapy-Lung (FACT-L) questionnaire. An association between a variety of dosimetric parameters for the heart and lungs (e.g. mean dose, Vx) and changes in pulmonary QOL (e.g. declines in QOL; pre-RT minus post-RT values) were assessed using univariate and multivariate techniques.

Results:
The data from 24 patients treated between 2009-2013 and with evaluable QOL were studied. Their demographics are as follows: median age 68 (range 48-87), 46% male, 92% white, 98% primary tumor from lung, 70% stage III or IV, 50% current or former smokers, 67% having no coexisting lung or heart disease before, 42% also receiving chemotherapy. For the overall group, there were no statistically significant differences between the pre-RT value (QOL score 80.6) and any of the post-RT time points (QOL scores 79.9, 79.9 and 76.3 at 1.5, 3 and 6 months post-RT, respectively). On a per-patient basis, there were no significant associations between any of the lung or heart dosimetric parameters and subsequent declines in QOL, though there was a non-significant trend towards greater declines in QOL with larger lung doses (e.g. mean, V20 and 30). There were no similar trends seen with the heart-based dosimetric parameters. When limiting the analysis to patients whose QOL score declined post-RT, there was a positive correlation between the degree of decline and the V30 and V40 of heart (p＜0.05). Among patients with lung cancer, the degree of decline in QOL was associated with the heart V20, V30, V40 (p＜0.05).

Conclusion:
There are no significant associations seen between lung and heart dosimetric parameters and subsequent declines in QOL. Additional analyses involving a larger number of patients are needed to better define predictors of RT-associated declines in QOL. (Supported in part by National Institutes of Health Grant CA69579 , a grant from the Lance Armstrong Foundation)

Background:
Introduction: Research evidences show that depression and disability are important comorbid conditions in patients with Malignancies. However, little is known regarding the relationship between depression, disability and lung cancer in Nigeria. Objectives: The objectives of this study were to determine the prevalence of depression and disability in patients with lung cancer in a teaching hospital.

Methods:
Eighty patients diagnosed with lung cancer aged 35 to 80 years, were matched by age and gender with 80 patients without lung cancer from the Out-Patient Department of the study centre. Depression was assessed using the Mini International Neuropsychiatry Interview (MINI) while the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0), was used to assess disability. All analyses were carried out using SPSS version 16.0.

Results:
Fifty one percent of patients with lung cancer had depression compared to 6.4% in the matched control. Among patients with lung cancer, disability was significantly associated with depression after controlling for smoking OR = 9.1, 95% CI (2.5-28.5), and stage of lung cancer OR = 2.1, 95% CI (1-13-9.42).

Conclusion:
There is a critical need to screen and manage depression in lung cancer patients in other to reduce disability and improve quality of life.

Background:
Patients with lung cancer experience elevated risk of venous thromboembolism Prothrombotic factors in lung cancer include the ability of tumour cells to produce and secrete procoagulant substances and inflammatory cytokines, and the physical interaction between tumour cell and blood. Other mechanisms of thrombus promotion in malignancy include surgery, metastatic disease and use of chemotherapeutic drugs in combination with novel targeted drugs, such as antiangiogenic agents. Cancer patients with thrombosis have a shorter life expectancy than cancer patients without this complication. The occurrence of VTE worsens the quality of life and may delay, interrupt, or completely halt the cancer therapy.

Methods:
Patients diagnosed with primary lung cancer were followed up between 2006-2010. We recorded demographic data, histology and clinical stage, basic laboratory values of blood and coagulation, frequent and significant comorbidities, and details of initial cancer treatment. In patients with advanced, unresectable or metastatic lung cancer, these parameters were evaluated before the first cycle of chemotherapy or targeted therapy. Thromboembolic events were being detected by standard diagnostic procedure; if detected, the risk of VTE was automatically considered to be high. Statistical analysis included standard descriptive statistics; absolute and relative frequency of each category for categorical variables, median and 5% -95% percentile in the case of continuous variables. Analysis of categorical variables was supplemented with an analysis of frequency tables.

Results:
A total of 950 patients were enrolled, of whom 600 were men and 350 women. The median age of all patients was 64 years. Squamous cell carcinoma was the most frequent histological subtype (27.3%), followed by adenocarcinoma (23.8%), small cell carcinoma (18.4%) and non-small cell NOS. Hypertension was the most frequent comorbidity (39.6%),followed by COPD (38.2%), diabetes mellitus (19.4%), cerebrovascular disease 9.6%, and heart failure (7.7%). Ninety-one thromboembolic events were registered in the entire group (9.6%), of which 80 (87.9%) were severe and 11(12.1%) less severe. In the group of patients with thromboembolic disease, platelet counts were significantly increased at the time of diagnosis of lung cancer – 368 x10[9] (191.0 to 540.0). Among comorbidites, heart failure was associated with an increased risk of VTE – OR 13.48 (7.80 to 23.28), followed by cerebrovascular disease – OR 3.17 (1.78 to 5.64), atrial fibrillation – OR 2.96 (1.50 to 5.83), and obesity – OR 2.40 (1.26 to 4.58). Among laboratory parameters, platelet counts above 330,5x109 were associated with the occurrence of severe VTE – OR 3.66 (2.25 to 5.96).

Conclusion:
The incidence of serious thromboembolic events (8.4%) in our group of lung cancer patients was high, especially in patients with adenocarcinoma, advanced-stage disease, and in patiens on cancer treatment. In patients with thromboembolic disease, significantly higher median platelet counts were observed at the time of cancer diagnosis. In patients treated with chemotherapy, most thromboembolic events were observed shortly after the treatment starts and the majority of thromboembolic events occurred within 6 months after the initiation of chemotherapy. These results justify prophylactic treatment in most patients with advanced or metastatic disease, adenocarcinoma, patients receiving radiotherapy or chemotherapy, and in presence of some associated disorders.

Background:
Hyponatraemia due to the syndrome of inappropriate anti-diuretic hormone (SIADH) occurs in 10-25% of small cell lung cancer (SCLC) patients. Management of SIADH includes review of medications, fluid restriction and increased solute intake in addition to commencing chemotherapy. The risk/benefit of the tetracycline derivative demeclocycline and the vasopressin receptor antagonist tolvaptan were recently questioned in a clinical practice guideline for hyponatraemia management (Spasovski, 2014). We sought to evaluate how demeclocycline and tolvaptan were used in addition to chemotherapy in the management of hyponatraemia in patients with SCLC and their effect on serum sodium prior to the publication of this guideline.

Methods:
A retrospective case-note review of 132 patients with SCLC treated at The Christie NHS Foundation Trust between 2009 and 2013 was undertaken to identify patients with serum sodium ≤132 mmol/L at diagnosis. Clinical and laboratory data were collected and change in sodium from nadir to peak values at day 7-14 and day 20-40 was calculated. Patients were divided in three groups: treated with chemotherapy alone, and chemotherapy plus demeclocycline or tolvaptan. Patients with complete data were included in the statistical analysis. Mean values were compared using an unpaired Students t-test.

Results:
Twenty seven patients (20%) had sodium ≤132mmol/L at diagnosis (mean 128 mmol/L, SD 3.9). Measurement of urine and plasma osmolality and urine sodium were performed in 6/27 (22%); thyroid function was measured in 6/27 patients and adrenal function in 4/27. Remaining patients were treated empirically. Patients receiving platinum based chemotherapy alone (12/27 patients receiving 1 to 6 cycles) had the highest mean sodium nadir of 128 mmol/L. Those receiving demeclocycline (13/27 patients) had a mean sodium nadir of 126 mmol/L. Patients receiving tolvaptan (6/27, 4 after prior demeclocycline) had the lowest mean sodium nadir of 121 mmol/L (p=0.0132 comparing with chemotherapy only group). Chemotherapy alone increased mean sodium from 128 mmol/L to 134 mmol/L by day 7-14 (p=0.0062) and 135 mmol/L by day 20-40 (p=0.0007). The addition of demeclocycline increased mean sodium from 126 mmol/L to 130 mmol/L (p=0.0527) and 132 mmol/L (p=0.0102) at the same time-points. The addition of tolvaptan increased mean sodium from a nadir of 121 mmol/L to 135 mmol/L at 7-14 days (p=0.0126) and 133 mmol/L at 20-40 days (p=0.0080). No significant toxicity of demeclocycline or tolvaptan were reported.

Conclusion:
Most cases of hyponatraemia were treated empirically as SIADH using demeclocycline and/or tolvaptan in over half of patients in addition to chemotherapy. Tolvaptan was used to treat patients with the lowest mean sodium most often following failure of demeclocycline. Despite this, these patients had peak sodium levels post treatment equivalent to those in other patients in this study. Clinician choice to treat patients with tolvaptan and/or demeclocycline in adition to chemotherapy was associated with a statistically and clinically meaningful improvement in serum sodium levels in all groups studied. Although this study is limited by the retrospective nature of the analysis, our group is using these data to produce guidelines on the management of hyponatraemia in SCLC to standardise patient management which will be prospectively evaluated.

Background:
According to 2015 data of WHO, lung cancer is still the most common causes of cancer death (1.59 million deaths in 2012) which is more than the combination of next three most common cancers (colon, breast and pancreatic). The number of deaths due to lung cancer has increased approximately 3.5 percent between 1999 and 2012. The number of deaths among men has reached a plateau but the number is still rising among women perhaps related with changesinsmoking habits. The age-adjusted death rate for lung cancer is higher for men than for women.

Methods:
In this study, firstly we retrospectively reviewed the data of 123 patients who died in respiratory intensive care unit of our hospital within last two years. We determined that 63 of them died because of lung malignancies and associated pathologies. Ages, genders, smoking habits, survival times, diagnosis methods, histopathological types of lung cancer, stages, metastatic states of the patients were compiled. In addition; clinical findings just before the death, indications of intensive care unit intake, underlying and immediate death causes were detected. The underlying death cause defines the disorder which initiated the events leading to death.The immediate death cause defines the final disorder or condition resulting in death.Some definitions were used in classifying the cause of death. When the amount of tumor in the lungs was the most important factor in fatal respiratory failure, this death cause was defined as tumor burden. Malfunction of the organs due to widespread metastases was defined as metastatic organ failure.

Results:
56 cases were primary lung cancer patients. 11 cases were female and 45 cases were male. Mean age of the cases was 71.81 (46-88) in females and 68.91(50-84) in males. 5 of female cases were adenocancer, 4 were squamous cell lung cancer and 2 were small cell lung cancer. 20 of male cases were squamous cell lung cancer, 14 were adenocancer, 11 were small cell lung cancer. Diagnostic methods were bronchoscopy in 33 patients, transthoracic lung biopsy in 12 patients, thoracentesis in 7 patients, metastatic organ biopsy in 4 patients. Mean survival periods were 3.1 months for small cell lung cancer, 6.7 months for squamous cell lung cancer and 8.2 months for adenocancer. All of the small cell lung cancer cases had metastasis at diagnosis time. Pneumonia and MODS-sepsis were the most common death causes in all cases.

Conclusion:
We think that our results would be helpful clinicians about lung cancer and follow up these patients.

Background:
In Croatian population Lung cancer (LC) is the most common cancer in male and third most common in women. The age-adjusted incidence rates are 63.5 per 100,000 populations per year. The aim of this study was to investigate the prognostic factors associated with overall survival in patients with cytological and/or histological confirmed advanced (IIIA-IV stage) LC.

Methods:
In this single institution prospective study, 164 consecutive patients were included between September 2008 and January 2013 from Istrian County, Croatia.The prognostic factors evaluated for 2-year overall survival including gender, age, performance status, histology, blood group type, location od tumor, metastatic sites, anemia, elevated WBC, platelets, and diabetes mellitus. All factors with a P value < 0.05 at univariate analysis were entered into a multivariate analysis using Cox proportional-hazards models.

Results:
The median age of patients was 64.0 years (range 36 – 85 years) with males predominance (115 males vs. 49 females). The histological types included: adenocarcinoma 56 (34%), squamous cell carcinoma 50 (30%), small cell carcinoma 33 (20%) other or not-otherwise specified 25 (16%). The median follow-up time was 14.1 months. The 2-year overall survival rate of 164 patients was 27.0%. Female gender and non liver metastatic disease are significantly associated with better overall survival. Data were shown in Table 1. Cox Regression analysis adjusted to tumor stage and age demonstrated that patients with 0 type blood group in adenocarcinoma subpopulation present a worst overall survival when compared to other blood type groups. Not elevated serum platelets in squamous NSCLC and elevated WBC, and female gender are independent prognostic factors in SCLC. Table 1 Significant prognostic factors for overall survival in NSCLC

Baseline prognostic factor	Univariate analysis	Multivariate analysis		2-year survival rate %
	P-value	HR (95% CI)	P-value
Female* vs Male	0.020	0.62 (0,41-0.93)	0.022	38.0
Non-liver metastasis	0.024	0.60 (0.39-0.95)	0.028	28.8
0 blood group in adenocarcinoma NSCLC	0.008	6.64 (1.38-32.14)	0.019	18.7
Normal serum platelets level	0.013	1.27 (0,45-3.59)	0.654	23
Female* vs Male gender in SCLC	0.01	0.30 (0.11-0.82)	0.019	44
Non-liver metastasis in SCLC	0.027	0.43 (0.18-1.01)	0.055	20
Elevated serum WBC	0.015	0.39 (0.17-0.90)	0.026	19

Abbrevations: *referent, NSCL=Non Small Cell Lung Cancer, SCLC= Small Cell Lung Cancer, WBC= White Blood Cells

Conclusion:
Our results indicated that female gender is powerfull favorable prognostic factor in NSCLC and SCLC. 0-type blood group is significant prognostic factor for short term survival following diagnosis of advanced lung adenocarcinoma and elevated WBC is associated with longer survival in SCLC subpopulation of advanced disease.

Background:
The reported rate of tunneled pleural catheter (TPC)-related infections in patients on chemotherapy ranges from 4-20%. Thus, infection is often cited as a contraindication to placement of a TPC in patients with recurrent symptomatic malignant/para-malignant pleural effusions (MPE/PMPE) receiving chemotherapy. Delay in the definitive management of such pleural effusions can result in an increased number of procedures, progressive symptoms and decreased independence in patients with advanced disease. Current data does not directly associate TPC-related infections to a patient’s immune status on chemotherapy. We aim to correlate catheter-related infections to immune system competency around the time of chemotherapy.

Methods:
A review of patients with MPE/PMPEs managed with a TPC from 2009-2014 was conducted. We identified 182 patients, of which 109 had chemotherapy within 1 month of TPC insertion or at any time during TPC drainage. An immunocompromised state was defined as the presence of leukopenia [white blood cells (WBC) <4 th/mm[3]] when a differential count was unavailable; or lymphopenia [lymphocytes <1 th/mm[3]], and/or neutropenia [absolute neutrophil count (ANC) <1.5 th/mm[3]]. A pleural infection was defined as the presence of a positive gram stain/culture of pleural fluid.

Results:
Seventy-three (67%) of the 109 patients were identified to be immunocompromised. Only 5 (7%) of the 73 developed a pleural infection. All 5 (100%) received antibiotic treatment. Two of the 5 (40%) pleurodesed and underwent catheter removal, 2 (40%) maintained effective catheter drainage, while 1 (20%) underwent TPC removal and replacement with a pigtail catheter. Of the 5 patients, 4 (80%) demised at a median of 5 months (IQR, 3-8) following the pleural infection. All deaths were considered related to progression of malignant disease and not a consequence of infection. One patient is alive and still undergoing drainage.

Conclusion:
These preliminary results suggest that chemotherapy and immune suppression do not significantly increase the risk of TPC-related infections as the rate is low and comparable to immunocompetent patients. Chemotherapy should not delay the decision to definitely palliate patients with TPCs in the setting MPE/PMPEs.

Background:
Lung cancer is one of increasing cancer in incidence with longer survival of life in Korea. Some patients do not have a condition to receive cancer therapy by the decision of patients themselves and/or family as well as doctors. Refusal or avoidance of active treatment is prone to suffer from cancer symptoms and causes to shorten life survival. The purpose of this study is to define factors related to avoid or refuse active therapy in lung cancer.

Methods:
The population was retrospectively collected from patients’ record in one tertiary university hospital from 2010 to 2012. Total 306 subjects were enrolled as lung cancer and 18 subjects were excluded due to incomplete data or follow-up loss. Among 288 subjects, 66 subjects, avoiding cancer treatment were allocated to nontreatment group (NTG), whereas remaining 222 subjects to treatment group (TG).

Results:
Mean age of NTG was older than TG. Previous operation history, low BMI, high ECOG score and Charlson comorbidity index (CCI) score were significant in NTG. Factors of sex, smoking behavior, drinking, offspring number, degree of scholarship, familial history of cancer, pathologic type, TNM stage, presence of chest symptoms or systemic symptoms, and absence of occupation, religion and partner were insignificant. In univariate and multivariate analysis, high ECOG (2-3 vs 0-1; odds ratio [OR]: 6.0; 95% confidence interval [CI]:1.5-23.4) and high CCI score (OR: 1.3; 95% CI; 1.02-1.7) were the significant determinants to the avoidance of treatment.

Conclusion:
Nontreatment decision in lung cancer was associated with performance status and comorbidities, which are considered prior to the guidance of cancer treatment. Patient's personal factors give little influence to the decision of cancer treatment.

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Background:
ROS1 fusion variants represent an important subset of oncogenic driver mutations in approximately 0.7 – 3.4% of non-small cell lung cancers. Since the frequency of ROS1 positive lung cancer patients is relatively low, it is unclear whether there are significant clinicopathologic associations for positive cases. Thus far, ROS1 positive patients tend to be younger and never-smokers with tumors displaying adenocarcinoma histology. This study describes a further cohort of ROS1 positive lung cancer patients in an effort to identify clinicopathologic associations.

Methods:
The data represent a retrospective analysis of the clinicopathological profiles of primary and metastatic lung cancer patients tested for ROS1 gene rearrangements by break-apart (BA) FISH at the University of Colorado School of Medicine.

Results:
The cohort consisted of 452 patients enriched for triple-negative (EGFR-, KRAS- and ALK-) non-squamous cell carcinomas screened for ROS1 rearrangements using the BA FISH assay. Nineteen cases (4.2%) were identified as positive for rearrangement, the majority (68%) of which were female, with a mean cohort age of 54.9 years (range 30-79); as compared to negative cases which included 56% female patients (P= 0.1083), and had a mean cohort age of 62.9 (range 21-90) (P= 0.0058). Seventeen out of the 19 ROS1 positive tumors were classified as adenocarcinomas, one was diagnosed as adenosquamous carcinoma, and the histology on one specimen was not otherwise specified (NOS). Among 12 individuals with information on pathologic stage at diagnosis, the majority (75%) were stage IV. The prevalent FISH pattern for rearrangement was a split 5’ and 3’ signal (68%) with the remaining specimens showing primarily single 3’ signals (21%) or a mix of split and single 3’ signals (11%).

Conclusion:
The ROS1 positive tumors in this cohort were primarily classified as adenocarcinomas, diagnosed at an advanced stage, in patients significantly younger and more likely to be women, although the sample set was biased for non-squamous lesions thereby limiting the application of this information to squamous cell lung carcinoma. The higher prevalence of ROS1 positive cases in this cohort compared to unselected cohorts is best explained by the inclusion of specimens with known negative status for EGFR and KRAS mutations and ALK fusions. As such, these data are in agreement with previous descriptions of ROS1 positive cohorts. Screening for ROS1 rearrangements in lung cancer patients displaying adenocarcinoma histology and negative for EGFR, KRAS and ALK activating events should identify a higher frequency of ROS1 rearranged tumors compared to unselected approaches and facilitate this subset of patients to be treated with targeted ROS1 inhibitors.

Background:
Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare histological type of large cell NSCLC. Histopathologically it is similar to nasopharyngeal carcinoma which is most commonly occurred in Southern China. It had close relationship with Epstein-Barr virus (EBV) infection. Over the past 28 years since it was first reported, less than 300 Primary pulmonary LELC cases have been reported in the literature. Due to its rarity, the treatment of advanced LELC is not only empirical, but controversial. Testing for EGFR mutation and ALK rearrangement are routine for NSCLC patients in clinical practice now. However, only few genotype studies have been done in pulmonary LELC, and till now no targeted therapy has been shown effective in the treatment of these patients.

Methods:
We investigated a cohort of 42 patients with primary pulmonary LELC and genotyped for ALK rearrangement and EGFR mutation. ALK rearrangement was detected by Fluorescence in situ Hybridization (FISH). EGFR mutational analysis of exons 18 through 21 was analyzed by TaqMan real-time polymerase chain reaction (PCR).

Results:
The clinicopathologic characteristics of 42 patients with pulmonary LELC are presented in Table 1. Twenty-seven of 42 patients were in stage I-IIIA (64.3%), and only 15/42 patients (35.7%) were in stage IIIB or IV. The female to male ratio was about 22:20, and the median age at diagnosis was 51 years (range, 29-67 years). Only 13 (31.0%) patients were smokers. In situ hybridization for Epstein-Barr virus-encoded RNA (EBERs) showed positive signals in all 42 patients. By immunohistiochemistry staining, all patients demonstrated positive expression of CK5/6 and P63, but almost all patients were negative for TTF-1(34/34, 100%) or CK7 (34/35, 97.1%). None of the 42 patients had ALK rearrangement. Of 42 patients tested EGFR mutation, only one patient (2.4%) harbored L858R mutation and gefitinib was applied to this case, however no objective response was observed and the progression free survival PFS time was only 1 month.Figure 1



Conclusion:
Primary pulmonary LELC is a unique histological subtype of non-small cell lung cancer. ALK rearrangement and EGFR mutation are lack and they may not be the oncogenic driver gene in pulmonary LELC. Conventional cytoxic chemotherapy is by far still a backbone treatment in advanced stage primary pulmonary LELC. Future efforts should be made to explore other oncogenic driver gene to guide targeted therapy in this rare disease to determine the optimal treatment.

Background:
Activation of the MET signaling pathway can propel the growth of cancer cells in non-small cell lung cancer (NSCLC). Increased MET gene by amplification and/or polysomy can cause MET protein overexpression; less common causes include mutations, translocations, and alternative RNA splicing. Clinical trials using MET as a biomarker for selection of lung cancer patients who might most benefit from targeted therapy have experienced variable outcomes. We aimed to characterize the relationship between MET protein overexpression and MET amplification or mean copy number alterations in patients with NSCLC.

Methods:
The Lung Cancer Mutation Consortium (LCMC) is performing an ongoing study of biomarkers with patients with NSCLC from 16 cancer center sites across the United States. For this analysis, 403 cases had complete data for MET protein expression by immunohistochemistry (IHC, monoclonal antibody SP44, Ventana) and MET gene amplification by fluorescence in-situ hybridization (FISH, MET/CEP7 ratio). Pathologists evaluated MET expression using the H-score, a semi-quantitative assessment of the percentage of tumor cells with no, faint, moderate, and/or strong staining, ranging from 0-300. Spearman's correlation was used to analyze the correlation between MET protein expression (H-scores) and FISH results (MET/CEP7 ratio (N=403) and MET copy number (N=341). Protein overexpression using 5 different cut-offs was compared with amplification defined as MET/CEP7 ≥ 2.2 and high mean copy number defined as ≥ 5 MET gene copies per cell using the Fisher’s exact test. Cox Proportional Hazards models were built to examine the associations of these different definitions of positivity with prognosis, adjusting for stage of disease.

Results:
MET protein expression was significantly correlated with MET copy numbers (r=0.17, p=0.0025), but not MET/CEP7 ratio (r=-0.013, p=0.80). No significant association was observed between protein overexpression using a commonly used definition for MET positivity (“at least moderate staining in ≥ 50% tumor cells”) and MET amplification (p=0.47) or high mean copy number (p=0.09). A definition for MET protein overexpression as “≥ 30% tumor cells with strong staining” was significantly associated with both MET amplification (p=0.03) and high mean copy number (p=0.007), but a definition of “≥ 10% tumor cells with strong staining” was not significantly associated with either. Definitions of protein overexpression based on high H-scores (≥200 or ≥250) were associated with high MET mean copy numbers (p=0.03 and 0.0008, respectively), but not amplification (p=0.46 and 0.12, respectively). All 5 definitions of MET protein overexpression demonstrated a significant association with worse prognosis by survival analyses (p-values ranged from 0.001 to 0.03). High MET copy number (p=0.045) was associated with worse prognosis, but MET amplification was not (p=0.07).

Conclusion:
Evaluation of NSCLC specimens from LCMC sites confirms that MET protein expression is correlated with high MET copy number and protein overexpression is associated with worse prognosis. Definitions of MET protein overexpression as “an H-score ≥250” and “≥30% tumor cells with strong staining” were significantly associated with high mean MET copy number. It may be worth reevaluating the performance of MET as a biomarker by different definitions of positivity to predict response to MET-targeted therapies.

Background:
Identification of driver mutations has led to the dramatic improvement in personalized therapy for lung adenocarcinoma. However, few targeted therapeutics are approved for treatment of squamous cell lung carcinoma. The identification of druggable molecular targets in SqCLC has been becoming a top research priority. Therefore, the aim of this study was to analyze the driver mutation profiles in a large cohort of Chinese squamous cell lung carcinomas to identify potential therapeutic targets.

Methods:
Approximately 2,800 COSMIC mutations from 50 oncogenes and tumor suppressor genes were analyzed on 159 samples by using Ion Torrent semiconductor-based next-generation sequencing. The gene copy numbers of FGFR1, EGFR, HER2, PDGFRA, CCND1, SOX2, CDKN2A, and PTEN were assessed by FISH on 250 samples. In addition, the status of PTEN expression was examined by immunohistochemistry on 250 samples.

Results:
Somatic mutations were detected in 73.6% (117/159) of patients. The most commonly mutated gene detected in this study was TP53 (56.0%, 89/159), followed by CDKN2A (8.8%, 14/159), PI3KCA (8.8%, 14/159), KRAS (4.4%, 7/159), EGFR (3.1%, 5/159), FBXW7 (2.5%, 4/159), PTEN (2.5%, 4/159), FGFR3 (1.3%, 2/159), AKT1 (1.3%, 2/159) and KIT (0.6%, 1/159). Copy number alterations were present in 77.6% (191/246) of patients, including FGFR1 amplification (13.7%, 34/248), EGFR amplification (11.4%, 28/246), HER2 amplification (8.9%, 22/246), PDGFRA amplification (7.7%, 19/246), CCND1 amplification (11.0%, 27/246), SOX2 amplification (35.0%, 86/246), CDKN2A deletion (18.7%, 46/246), and PTEN deletion (29.3%, 72/246). The loss of PTEN expression was observed in 43.5% (108/248) of patients. TP53 mutations were significantly more common in men and smokers, while the frequency of EGFR mutation was significantly higher in women and never smokers. Amplification of FGFR1, CCND1 and SOX2 genes were significantly associated with smoking. The incidence of FGFR1 amplification in patients without lymph node metastasis was significantly higher than that in patients with lymph node metastasis (19.4% vs. 10.2%，P=0.043). The frequency of SOX2 amplification in tumors with moderate and poor differentiation was significantly higher than that in tumors with well differentiation (39.6% vs. 33.6% vs. 0%，P=0.036). The incidence of loss of PTEN protein expression in patients with pleural invasion was 51.2%, which was significantly higher than that in patients without pleural invasion (P=0.017). The loss of PTEN expression was significantly associated with PTEN gene deletion (P=0.001). No significant association was observed between the molecular abnormalities and disease-free survival and overall survival.

Conclusion:
Genetic alterations are common in squamous cell lung cancers. The findings of this study may facilitate the identification of molecular target candidates for precision medicine in patients with squamous cell lung cancers.

Abstract not provided

Background:
Identification of mutations which drive pulmonary adenocarcinomas (ADC) has rapidly moved from the research arena to clinical practice. The prevalence of these mutations has been suggested by a multitude of studies but here we describe the prevalence of mutations from a large study of patients with advanced ADC treated in the international phase III study INSPIRE (Lancet Oncology 2015) with all testing performed in one CLIA-certified laboratory under standardized conditions.

Methods:
Mutation testing was performed on 412 adenocarcinoma specimens using SNaPshot® methodology. Mutations were examined in the AKT, EGFR, KRAS, BRAF, NRAS, PIK3CA, TP53, PTEN, CTNNB1, and MEK1 genes. The relative frequencies of genetic alterations were calculated based on the total number of adequate specimens and specific consent for testing.

Results:
Of the 412 adenocarcinoma specimens tested, 372 (90.3%) had evaluable results from mutation testing. A single mutation was detected in 157 (42.2%) specimens, whereas mutations in two genes were detected in an additional 20 (5.4%). The overall prevalence of mutations for each specific gene was as follows: KRAS (34.2%), EGFR (12.2%), TP53 (4.9%), PTEN (2.8%), PIK3CA (2.2%), CTNNB1 (2.2%), NRAS (1.8%), BRAF (1.2%), MEK1 (0.3%), and AKT (0%). Figure 1 Evaluation of smoking status identified a substantially higher percentage of KRAS mutations in ex-light smokers and current smokers (38.2% and 40.5%) combined compared to never smokers (7.6%, p<0.0001) , and a lower proportion of EGFR mutations in ex-light and current smokers (10.9% and 4.9%) combined compared to never smokers (39.7%, p<0.0001). Patients ≥70 years old had a higher proportion of both NRAS (7.1% vs. 0.7%, p=0.009) and TP53 mutations (12.5% vs. 3.3%, p=0.010). In addition, males had a lower incidence of EGFR mutation (8.6% vs. 19.0%, p=0.007) as compared to females. Patients from North America, Europe, and Australia/New Zealand demonstrated lower rates of mutation in CTNNB1 (1.4% vs. 8.6%, p=0.030) and PIK3CA (1.4% vs. 8.3%, p=0.032) compared to patients from Central/South America, South Africa and India. Finally, among specimens with two mutations, combinations involving KRAS were the most prevalent (70%, 14/20) followed by TP53 (50%, 10/20).



Conclusion:
These results demonstrate the wide spectrum of mutations that can be detected in adenocarcinoma specimens, with high prevalence rates in the EGFR and KRAS genes. Most patients had only one identified driver mutation. The study revealed age and geographical associations in some mutations. The clinical relevance of the studied mutations in relation to chemotherapy and the human EGFR antibody, Necitumumab, will be studied.

Background:
Various protein kinases have been discovered as drivers in cancer and subsequently used as therapeutic targets.

Methods:
To discover potential target driver genes, we investigated characteristics of genome wide scans of genetic lesions in kinases from 103 Korean lung adenocarcinoma patients, whose driver mutations were unknown or negative after conventional screening of EGFR and KRAS mutations as well as EML4-ALK fusion. We employed targeted, pair-end deep sequencing and screened the coding sequences of 518 protein kinase and genes that are known to be mutated with considerable frequencies in lung adenocarcinoma such as TP53 and EGFR.

Results:
Pathway analysis revealed that recurrent alterations were enriched in p53 signaling (TP53, ATM, CHEK2, CDKN2A) and ErbB signaling (EGFR, BRAF, KRAS, ERBB4) pathways. Mutations in TP53 and an EGFR exon 21 hotspot regions were found in 28% (29/103) and 13% (13/103) of cases (Fig 1). TP53 mutation was significantly more common in older group (97%) than in younger group (3%). We identified novel somatic mutations of genes, including CHEK2, NEK2 (mitotic progression) and SMG1 (nonsense-mediated mRNA decay), that have not been highlighted in lung cancer previously. Figure 1 Fig 1. Discovery of recurrent mutations with identical substitutions at the same site



Conclusion:
As the inhibitors of these protein kinases can be therapeutic candidates to eradicate cancer cells, our results provide useful information for the development of effective therapeutic target agents, by which the activity of various kinases can be modulated, in adenocarcinoma of the lung.

Background:
The prognosis of lung SCC continues to be poor with no molecularly targeted agents specifically developed for its treatment. LCGI aims to identify potential targetable oncogenes in lung SCC.

Methods:
The LCGI study is being carried out in 500 patients with surgically resected lung SCC, treated at St James’s University Hospital and Beaumont University Hospital, Dublin. We used the platform of Sequenom’s MassArray to perform genotyping for accustomed panel of 258 somatic hotspot mutations in 49 genes including genes in the MAPK and PI3K pathways. We also evaluated FGFR1 amplification by fluorescence in situ hybridization (FISH) and MET protein expression by immunohistochemistry (IHC).

Results:
Lung SCCs from 258 patients have been tested by Sequenom MassArray to date. Lung SCCs from 150 patients have been evaluated for MET protein expression and 89 for FGFR1 amplification. 163 (63.2%) patients were male. The median age of the cohort was 68. The majority of patients were either current (39.5%) or former (58.1%) smokers at the time of diagnosis. 138 (53.5%) were stage I, 87 (33.7%) were stage II, and 33 (12.8%) were stage III SCCs. At least one aberrant, potentially targetable oncogene was identified in the SCC of 101 (39.1%) patients (see Table). The presence of PIK3CA or KRAS mutations, or FGFR1 amplification did not have a statistically significant impact on median overall survival or recurrence-free survival. However, the presence of two or more aberrations in driver oncogenes in a tumor (patients, n=19) was associated with a worse median overall survival compared to patients with either a single driver aberration (p=0.04) or no aberrations (p<.01). Table: Frequency of driver mutations in LCGI compared to The Cancer Genome Atlas (TCGA) study

Mutation	LCGI (n=258)	TCGA (n=178)
FGFR1 amp (n=89)	13 %	16.8 %
PIK3CA	15.1 %	10.1 %
KRAS	6.5 %	0.6 %
PTPN11	3.5 %	1.7 %
STK11	3.1 %	1.7 %
MYC	1.9 %	0.0 %
NRAS	1.6 %	0.0 %
BRAF	1.2 %	3.9 %
HRAS	1.6 %	1.7 %
CTNNB1	1.5 %	1.7 %
FBXW7	1.5 %	3.4 %
MET Overexpression (n=150)	1.3 %	NA
EGFR	0.9 %	2.8 %
AKT1	0.4 %	0.6 %
CDK4	0.4 %	0.0 %
GNA11	0.4 %	0.6 %
MAP2K1	0.4 %	0.6 %
DDR2	0 %	1.1 %

Conclusion:
39.1% of lung SCC patients have an aberrant, potentially targetable driver oncogene in their tumor. The presence of two or more aberrant oncogenes is a poor prognostic factor in lung SCC. These findings can be used to guide clinical trials in lung SCC.

Background:
Research into druggable driver gene mutations in non-small cell lung cancer has identified several molecule-targeting agents that are clinically prescribed to inhibit tumor growth in adenocarcinoma. However, lung cancers without targeted driver gene mutations show poorly differentiated histologies and unfavorable prognoses without medication. Pleomorphic carcinoma, a lung cancer that includes a mixed conventional histology and sarcomatoid components, is an extremely aggressive tumor and rarely responds well to anticancer treatments. However, it has recently been reported that lung cancer with a sarcomatoid component contains the ALK gene rearrangement. Therefore, we used a next-generation sequencing (NGS) analysis of the driver gene mutations in pleomorphic carcinoma (PC) of the lung to identify druggable target molecules.

Methods:
We selected PCs from primary lung carcinomas by reviewing the records of 944 patients who had undergone surgical resection between 2007 and 2014. The Ion PGM™ NGS sequencer (Life Technology Inc., US) was used to identify known gene rearrangements in lung cancers by analyzing RNA with IonAmpliSeq™ RNA Lung FusionPanel® (Life Technology). With our original panel for targeted gene amplifications, the Ion PGM was also used to analyze nucleotide sequence of whole exons of 41 driver genes reported to be involved in lung cancers. The cases examined were also analyzed with ALK immunohistochemistry (ALK-IHC) using the N-Histofine® ALK Detection Kit (Nichirei Bioscience Inc., Tokyo, Japan) on sliced paraffin-embedded tumor specimens.

Results:
Twenty-one lung cancer specimens diagnosed as PC and frozen material from nine patients were available for NGS. The EML4ex6/ALKex20 fusion gene was detected in one case, which was also positive on ALK–IHC. No other fusion genes were detected. Another case, which was negative for the fusion gene, was weakly positivity on ALK–IHC, so an unbalanced 5¢/3¢-end ALK expression test is planned. Six of nine cases but not the ALK-fusion-positive cases showed driver gene mutations in TP53. We also found several somatic mutations in druggable genes in this study, which should be considered carefully to determine whether they are driver or passenger genes.

Conclusion:
Although a small number of PCs were examined in this study, the ALK fusion gene was detected, which indicates the frequency of ALK fusion might be high in PC. Other possible druggable gene mutations were also identified in PCs. Further cases must be investigated to understand the mutation status of driver genes in PC.

Abstract not provided

Background:
Genotyping of non-small cell lung cancers (NSCLC) is important for directing patient care, particularly in adenocarcinomas (ADC) where targeted therapeutics are available. There is emerging evidence of efficacy of targeted therapy in the treatment and prevention of brain metastases. With recent adoption of next-generation sequencing technologies it is possible to test individual tumors simultaneously for somatic mutations in multiple genes. Here, we present the mutational spectrum of NSCLC brain metastases in our institution over a three year period.

Methods:
The department of pathology archives was searched to identify cases of NSCLC metastatic to brain that underwent surgical resections during 2012-2014. Clinicopathologic information was recorded from the pathology reports and the medical records. Molecular genotyping analysis was performed for EGFR/KRAS mutations using single gene analysis (prior to 2013) or by next generation sequencing (NGS) using the AmpliSeq Cancer Hotspot Panel v2. FISH was used to test for ALK rearrangements.

Results:
During 2012-2014, 31 NSCLC patients underwent surgical resection for brain metastases. Eighteen patients were female (58%) and 13 were male. The median age was 70 years (range 51-89). Tumor histology included 24 ADC and 7 squamous cell carcinomas (SCC). Twenty-three cases had molecular genotyping studies performed on the metastatic disease or the primary lung cancer. These included 3 SCC and 20 ADC. Of the ADC, 12 were tested with the NGS panel; 8 had been tested prior to 2013. The most frequently mutated genes were KRAS (8/20; 40%) and TP53 (7/12; 58%). Of the patients with KRAS mutations 7/8 were female (p = 0.085). The NGS assay detected clinically actionable mutations that would have not been detected with prior single gene assays including an EGFR exon 20 insertion, an ERBB2 exon 20 insertion, and two PIK3CA mutations. Additional mutations were detected in JAK3, FLT3, FBXW7, ATM, STK11, VHL and RB1.

Conclusion:
We found that 40% of the genotyped ADC metastases harbored KRAS mutations more frequently in females (although not significant), similar to prior reports. In addition, with NGS we were able to detect additional clinically significant targetable mutations. In summary, NSCLC genotyping can potentially help guide treatment and prevention of brain metastases.

Background:
Incresing data show advanced non-small cell lung cancer (NSCLC) patients with EGFR activating mutant have discrepant response to EGFR-TKI. The abundance of EGFR mutations may be a powerful explanation for the uneven clinical benefit. This study was designed to investigate the influence of EGFR mutant abundance on efficacy of EGFR-TKI by a quantitative method.

Methods:
201 NSCLC patients treated with EGFR-TKI with available tissue samples for EGFR mutation test were enrolled into the study. EGFR common mutations were detected by amplification refractory mutation system (ARMS) and percentage of mutant EGFR was tested with the method of an Allele Specific Quantitative PCR with Competitive Blocker (ASB-qPCR). In this assay, the copies of all mutations and EGFR locus were calculated by standard curve respectively. The cutoff values were obtained by the receiver operating characteristics (ROC) curve in training set. Further, the cutoff values were confirmed in validation set and the whole population. The relationship between the abundance of EGFR mutations and efficacy of EGFR-TKI was statistically analyzed.

Results:
Of the 201 samples, 72 harbored 19DEL mutation, 63 carried L858R mutant, and 66 with wild-type. The cohort was randomly divided into training and validation sets. The cutoff values of 19DEL and L858R mutation abundance were 4.84% and 9.47% determined by ROC curve in training set. 9.7% of patients with 19DEL positive were low abundance (<4.84%, LA group), while 33.3% of L858R-positive patients were LA (<9.47%).High abundance (HA) group, regardless of 19DEL or L858R positive had more longer median progression free survival (PFS) compared with LA and wild-type groups in either validation set or the whole population (15.0 vs 2.0 vs 1.9, 8.0 vs 1.9 vs 1.9; 15.0 vs 4.0 vs 2.0, 12.0 vs 2.0 vs 2.0; p<0.001). COX regression analysis showed that EGFR mutation abundance, together with smoking status, were independent factors of response to EGFR-TKI.

Conclusion:
The abundance of EGFR mutation could more precisely predict EGFR-TKI efficacy. NSCLC patients with LA mutation had inferior clinical benefit with EGFR-TKI. The heterogeneity in EGFR mutant abundance partly explain the efficacy discrepancy in patients with 19DEL or L858R positive.

Background:
EGFR-m in NSCLC and its responsiveness to TKI has proved beneficial in a subset of NSCLC patients (p) Breast cancer (BC) represents the most incident neoplasm among women. The co-existence of both EGFR-m-NSCLC and BC has been reported in p with Li-Fraumeni Syndrome. However, no systematic evaluation of the presence of both types of cancers has been performed in the general population.

Methods:
We sought to evaluate if EGFR-m-NSCLC associates higher rates of 2[nd] BC than the EGFR-wild type (WT)p. Clinical and molecular characteristics, as well as clinical outcomes of female p visited at our Institution from 2008 to 2014 and harboring both types of tumors were registered.

Results:
69/578 female p with EGFR-m were identified. Data on treatment and follow-up of 62p were available. 11/ 62p (17.7%) were diagnosed with both EGFR-m-NSCLC and BC. For EGFR-m-W-p, BC was diagnosed in 3 cases (0.52%) Regarding EGFR-m-NSCLC, age of diagnosis was 65y; 100% of p were Caucasian and never smokers. Del19, L858 and L861Q represented the 72.7%, 27.3% and 9% of EGFR-m. 36.3% had stage IV, 27.2% recurred after surgery and 36.3% initial stages never recurred. 63.6% received a TKI (42.8% erlotinib). 85.7% received TKI as 1[st] line. The overall response rate was 85.7%. 42.8% received subsequent therapies. The cause of death was related to lung cancer in all cases of death (54.5%). mOS was 29 months from the time of LC diagnosis. Regarding BC, the median age of diagnosis was 52y, BC was a prior diagnosis in 90.9%; the stage was 0, I, IIA and IIIA in 18.18%, 27.27%, 45.45% and 9.09%, respectively. After surgery (100%), 36.36% received ET, 36.36% both chemotherapy and ET and 54.54% radiotherapy (RT). 83.33% of p treated with RT developed the LC in the RT field. 90.90% of p never recurred.

Conclusion:
Diagnosis of BC appears to be higher in EGFR-m-NSCLC-p than in the general population. Evaluation of the molecular mechanism potentially related to this association is warranted.