Virtual Library

Background
Malignant pleural mesothelioma (MPM) is an aggressive neoplasm arising from the surface serosal cells of the pleural cavity. It is a highly lethal disease with a poor prognosis. The incidence of MPM has been predicted to increase rapidly in certain countries until approximately 2020 .Different staging systems for MPM exist . Although mainly related to surgical data, the TNM (tumour, nodes, metastasis)-based classification proposed by the International Mesothelioma Interest Group is the most widely used . MPM has long been surrounded by therapeutic nihilism, as chemotherapy, radiotherapy and surgery have not been proven to be effective as a single treatment modality. The role of surgery in providing maximal debulking is controversial and has not yet been determined. A major breakthrough was obtained with two randomised trials showing significant activity of the combination of cisplatin and a folate antagonist, pemetrexed or raltitrexed, with a significantly improved median survival time (MST) in patients with MPM. The European Organisation for Research and Treatment of Cancer (EORTC) initiated a phase II trial to evaluate the feasibility of trimodality therapy in a multicentre international setting (EORTC protocol 08031). Objective: To report on the experience with radical surgery, with emphasis on the long-term outcome, for malignant pleural mesothelioma (MPM) at a single institution.

Methods
From our database over a 20-year period, we reviewed 53 consecutive patients undergoing radical surgery for MPM in a multimodality programme. The long-term overall survival was analysed using the Kaplan–Meier method.

Results
A total of 53 patients (35 males, median age: 60 years) underwent an pleurectomy /Decorticacion 20(37%),pleural drenage and pleurodesis 30(55%) , extra-pleural pneumonectomy (EPP) 5(8%) with a palliativ/ curative intent . Epitheliod MPM was the most frequent (82%) cause. A right-sided disease was present in half of the cases 28 patients (52%). The International Mesothelioma Interest Group (IMIG) stage of the disease was stage I in 5 patients (8%) ,stage II in 19 patients (37%),stage III në 24 patient ( 47%) dhe stadi IV in 5 patients (8%). Preoperative chemotherapy consisting of a doublet cisplatin–pemetrexed (mean of three cycles) was offered to 3 patients (6%). Postoperative therapies, either chemotherapy or radiotherapy, were given in 15 patients (28%). The 30-day and 90-day mortality rates were 2 pateients (4%) and 5patients (8%), respectively. Postoperative complications occurred in 25 % and were major in 3 patients (6%). Re-operation was necessary in 3 case (6%) for one of the following reasons:pleural fistula (n = 1), bleeding (n = 1), and empyaema (n = 1). The mean hospital stay was 20 days. The median survival was 16 months, while the overall 1-, 2- and 5-year survival rates were 60%, 30% and 10%, respectively.

Conclusion
These results concur with the published data of the most experienced centre with regards to the mortality and morbidity after EPP for MPM. If a patient with epithelioid MPM is fit enough to tolerate a thoracotomy then macroscopic clearance of the tumour is the preferred option as part of a multimodality regime including chemotherapy.

Background
Prognostic models play an important role in the design and analysis of mesothelioma treatment trials. The European Organisation for Research and Treatment of Cancer (EORTC) and the Cancer and Leukemia Group B (CALGB) prognostic models are two well-known tools to predict survival in patients with malignant mesothelioma. In this retrospective validation study, we aim to assess the performance of these two mesothelioma prognostic models for overall survival (OS) with multiple clinical trials data from CALGB.

Methods
Using 204 patients with malignant pleural mesothelioma, the EORTC model (Curran et al 1998) was developed using a Cox regression with white blood cell (WBC) count, ECOG performance status (PS), diagnosis, histological type, and gender as prognostic variables. Using 337 patients with malignant mesothelioma, the CALGB model (Herndon et al 1998) was developed using a cross-validated exponential regression tree with PS, age, haemoglobin (Hgb) level, WBC count, chest pain indicator, and weight loss indicator as prognostic variables. In this validation study, 602 mesothelioma patients from fifteen completed CALGB treatment trials accrued between June 1984 and August 2009 were included. As the CALGB model was developed using the seven earlier studies, 266 patients from eight recent studies were included in the validation. For the EORTC model, we analysed all studies as well as just those eight recent studies. The concordance of predicted survival times and risk scores was estimated by c-index (Harrell et al 1996). Secondary endpoint of interest includes progression-free survival (PFS). Sensitivity analysis and multiple imputations were used to handle missing data. We also compared our results with PS alone.

Results
(1) For OS, the EORTC model produced c-indices equal to 0.592 and 0.610 for the fifteen and eight studies respectively. For the eight recent studies, the CALGB model produced c-indices equal to 0.618 and 0.593 without and with imputation respectively. PS alone produced c-indices equal to 0.591 and 0.564 for the fifteen and eight studies respectively. (2) For PFS, the EORTC model produced c-indices equal to 0.569 and 0.598 for the fifteen and eight studies respectively. For the eight recent studies, the CALGB model produced c-indices equal to 0.585 and 0.560 without and with imputation respectively. PS alone produced c-indices equal to 0.568 and 0.553 for the fifteen and eight studies respectively. See Table 1. Figure 1

Conclusion
The EORTC and CALGB models perform similarly, with little improvement in prognostic ability from either compared to using PS alone. Further improvement on these existing prognostic models is warranted.

Background
Amatuximab is a chimeric monoclonal antibody to mesothelin. Mesothelin, a membrane protein, is a potential target for molecular targeted therapy due to its high expressions in virtually all pancreatic cancers and mesotheliomas as well as several cancers, while showing little expression in normal tissues, except for normal mesothelium. Amatuximab inhibits the growth of mesothelin-expressing human tumors in vitro and in vivo xenograft model.

Methods
To investigate dose-limiting toxicities (DLTs) and estimate the maximum tolerated dose (MTD) of amatuximab in Japanese patients with advanced solid tumors. In addition, pharmacokinetics of amatuximab, human anti-chimeric antibody (HACA) and mesothelin expression by immunohistochemistry (IHC) were investigated. Patients with pancreatic cancers, mesotheliomas, or mesothelin-positive solid tumors as assessed by the IHC test, who have no other appropriate treatment were eligible in the study. Amatuximab was administered weekly until disease progression or occurrence of a DLT, and administered to 3 cohorts at 50, 100 and 200 mg/m[2] in a step-wise dose escalation manner. The pharmacokinetic parameters were calculated by model independent analysis and the dose proportionality was investigated on Cmax and AUC (0-t) values.

Results
58 patients were screened and a total of 17 patients were enrolled consisting of seven colorectal cancer, six pancreatic adenocarcinoma, two mesothelioma and two head and neck cancer (seven patients in 50 mg/m[2], three in 100 mg/m[2] and seven in 200 mg/m[2], respectively). Two DLTs were observed (grade 3 cytokine release syndrome in 50 mg/m[2] and grade 5 interstitial lung disease in 200 mg/m[2]). Treatment related adverse events were observed in 13 of 17 patients, and the most common events were grade 1 fatigue (five patients) and pyrexia (four patients). Amatuximab was eliminated from serum biphasically after reached Cmax. Estimated mean T1/2 on Cycle 1 Day 1 was 92.3 to 108 h and CL was 11.7 to 15.2 mL/h/m[2]. It was found that the Cmax and AUC (0-t) values on Cycle 1 Day 1 increased in an almost dose proportional manner and these were similar to those in US patients. HACA was detected in eight of 17 patients. Of 53 patients whose tissue samples were evaluated by IHC, 24 patients (45.3%) were mesothelin-positive (10 of 19 patients in colorectal cancer, four of eight in biliary cancer, four of five in pancreatic adenocarcinoma and six of 21 in other cancers).

Conclusion
Amatuximab was well tolerated in patients with advanced solid tumors, and MTD was not reached up to 200 mg/m[2]. Pharmacokinetic profile of amatuximab in Japanese patients was similar to that in US patients. Amatuximab is currently being investigated for its potential treatment of mesothelioma.

Background
Neutrophil-to-lymphocyte ratio (NLR), a marker of systemic inflammation, was proposed as a prognostic biomarker in a number of malignancies, including malignant pleural mesothelioma (MPM). We examined baseline variables predictive of overall survival (OS) in patients with newly diagnosed MPM, including NLR and the established EORTC and CALGB prognostic models.

Methods
Consecutive patients with newly diagnosed MPM between 1[st] January 2005 and 31[st] December 2010 at Sir Charles Gairdner Hospital, Western Australia were included in this retrospective study. Eligible patients had a confirmed diagnosis of MPM, neutrophil and lymphocyte count within 90 days of diagnosis, no concurrent haematological malignancy, and follow-up more than 90 days from diagnosis. Any subsequent treatment, including supportive care alone, was allowed. Variables to be analysed and cut-off determination was predetermined according to previous reports. Multiple imputation was performed for missing values, and univariate analyses and multivariate Cox models were calculated for OS.

Results
274 of 369 patients screened met the eligibility criteria and were included in this retrospective study. 159 received systemic chemotherapy, 10 underwent tri-modality therapy; 2 underwent surgery only, and 103 received supportive care alone. Prognostic factors predictive of shorter survival in univariate analysis were: age ≥ 65 years, non-epithelioid histology, sarcomatous histology, AJCC stage III-IV, ECOG performance status (PS) 2-3, weight loss, chest pain, low haemoglobin and high platelet count. An NLR ≥ 5 at diagnosis did not predict for shorter OS (hazard ratio (HR) 1.25; p=0.122). On multivariate analysis, age, histology, PS, weight loss, chest pain, and platelet count remained significant. The EORTC and CALGB prognostic groups were highly statistically significant as predictors for OS (HR 1.62; p<0.001 and HR 1.65; p<0.001, respectively). On preplanned subgroup analyses, baseline NLR was not prognostic in chemotherapy-treated or non-chemotherapy treated patients.

Univariate and multivariate analyses of association of prognostic factors with overall survival

	Univariate analysis		Multivariate analysis
Baseline prognostic factor	HR (95% CI)	P-value	HR (95% CI)	P-value
Baseline NLR <5* vs. ≥5	1.25 (0.94-1.66)	0.122	1.02 (0.76-1.37)	0.893
Age <65* vs. ≥65 years	1.64 (1.24-2.17)	<0.001	1.41 (1.05-1.90)	0.023
Female* vs. Male	1.23 (0.86-1.77)	0.262	1.24 (0.85-1.81)	0.269
Epithelioid* vs. non-epilthelioid	1.40 (1.08-1.80)	0.009	1.38 (1.05-1.82)	0.023
Non-sarcomatous* vs. sarc.	2.37 (1.62-3.48)	<0.001	1.86 (1.22-2.84)	0.004
AJCC Stage I-II* vs. III-IV	1.52 (1.17-1.97)	0.002	1.27 (0.97-1.66)	0.087
ECOG PS 0-1* vs. 2-3	2.35 (1.59-3.46)	<0.001	1.81 (1.21-2.70)	0.004
Weight loss absent* vs. present	2.11 (1.62-2.74)	<0.001	1.62 (1.22-2.15)	<0.001
Chest pain absent* vs. present	1.58 (1.21-2.07)	<0.001	1.34 (1.02-1.76)	0.038
Hb difference <10* vs. >10	1.87 (1.41-2.49)	<0.001	1.32 (0.96-1.80)	0.087
WCC (x 10[9]/L) ≤8.30* vs. >8.30	1.22 (0.96-1.57)	0.110	0.95 (0.73-1.25)	0.745
PLT (x 10[9]/L) ≤400* vs. >400	1.96 (1.49-2.58)	<0.001	1.71 (1.26-2.33)	<0.001
Abbreviations: *=referent; AJCC=American Joint Committee on Cancer Staging System; ECOG= Eastern Cooperative Oncology Group, WCC=White cell count; NLR=Neutrophil-to-lymphocyte ratio

Conclusion
Our findings validate established baseline prognostic variables as well as the EORTC and CALGB models, but not baseline NLR in unselected patients with newly diagnosed MPM. In guiding treatment decisions for patients at time of diagnosis, multiple variables should be considered that jointly predict survival

Background
The first all Japan multi-institutional trial was completed to evaluate the feasibility of induction chemotherapy using pemetrexed plus cisplatin, followed by extrapleural pneumonectomy (EPP) and postoperative hemithoracic radiation in patients with resectable malignant pleural mesothelioma (MPM). The main results were presented at the ASCO 2013. In this study, we especially reviewed major postoperative complications and mortality of patients who underwent EPP and determined the risk factors responsible for adverse outcomes.

Methods
From 2008 to 2010, 42 patients with MPM were enrolled in this study. Thirty-nine patients received planed chemotherapy. Thirty-three patients proceeded to EPP, which was completed in 30 patients. These patients were candidates in this study. Major complications were defined by grade 3, 4, 5 events according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Treatment-related death was defined as any death occurring within 84 days after operation. Logistic regression analysis was performed on preoperative variables for major adverse outcomes.

Results
A total of 17 institutions in Japan with certified specialists in oncology, surgery and radiation therapy participated in this trial. Thirty patients (29 male, 1 female; median age of 66 years, range 43–74) completed EPP (14 right-sided and 16 left-sided), and macroscopic complete resection was accomplished in all patients. Histology of the tumors was epithelial in 22, biphasic in 4, sarcomatous in 1, and others in 3. Median operation time and blood loss were 437 minutes (range, 335-655) and 1461 gram (range, 390-4530), respectively. Major postoperative complications developed in 73.3% of the patients, and treatment-related death occurred in 4 patients (13.3%), which causes were cardiac herniation (n = 1), ARDS (n = 2), bronchial fistula and ARDS (n = 1). There were no significant predictors for major postoperative complications and treatment related death in both univariate and multivariate analysis.

Conclusion
We cannot find the predictor of major adverse events and treatment related death in MPM patients treated with induction chemotherapy followed by EPP. Although that is why sample size is small, we also recognize that multimodality treatment including EPP for MPM has more than 10% mortality and should be included in a prospective trial at specialized centers.

Background
Malignant pleural mesothelioma remains a significant cause of morbidity and mortality in individuals exposed to asbestos. At present, around 2000 deaths per year in Britain are attributed to malignant mesothelioma, with numbers predicted to continue to increase until at least 2020. There is currently no known curative treatment. A number of management strategies have been advocated including chemotherapy, radiotherapy and surgical resection. The optimal management however remains elusive. In light of the results from the recent Mesothelioma and Radical Surgery trial there has been a move away from extra-pleural pneumonectomy (EPP) in the UK, with the majority of centres advocating a less radical approach. Pleurectomy-decortication may provide a safer alternative to EPP in patients with early stage disease as part of multi-modality treatment. Some authors, however, remain concerned about the morbidity of this operation. The aim of this study was to review patients undergoing pleurectomy-decortication for pleural mesothelioma within our institution to assess the safety and efficacy of this surgical approach.

Methods
A review of the thoracic surgical database identified eighteen patients who had undergone pleurectomy-decortication in the management malignant pleural mesothelioma between May 2009 and May 2013. Patient notes were analysed retrospectively to collect patient demographics and histological data. All surgical procedures were carried out by a single surgeon. The outcomes included were post-operative length of stay, complications and overall survival.

Results
The average age within this cohort was 68.8 years (range 54-82) and there was a higher percentage of men (M:F = 14:4). The pre-operative diagnosis of malignant mesothelioma had been confirmed in all cases, with the majority having previously undergone VATS pleural biopsy with or without talc pleurodesis. In 4 patients cytology alone was used for diagnosis and 1 patient had undergone image guided biopsy. All patients underwent surgical resection via a postero-lateral thoracotomy. The mean length of stay was 8.1 days (range 5-17). 67% of patients had an uncomplicated recovery. Of those where complications did occur, 3 patients had a persistent airleak and 3 had renal impairment requiring conservative management only. There were no in hospital deaths and the mean survival at follow-up was 17.0 months (range 2.3 – 38.7).

Conclusion
The role of surgical resection in the management of malignant pleural mesothelioma remains controversial. Although encouraging results following EPP have been reported in some large case series, these have not been replicated in randomised trials. Some researchers have suggested that the high rates of morbidity and mortality following EPP, without significant survival benefit, make this an unacceptable approach in the majority of patients. In our experience, pleurectomy-decortication can provide an alternative in patients with early stage disease and good performance status. At follow-up, 67% of patients were still alive and mean survival was 17 months. In patients with epitheliod subtype the mean survival was 21.6 months. This data supports previous studies which have identified a survival benefit with pleurectomy-decortication, although numbers are too small to draw firm conclusions. The procedure was however well tolerated in all patients with no major post-operative complications and no in hospital deaths.

Background
Malignant mesothelioma is a rare but aggressive form of cancer which has a strong causal link to asbestos exposure. While descriptive analyses have been undertaken of global patterns of mesothelioma deaths, the global pattern of malignant mesothelioma incidence is unclear. Since 1988, the International Agency for Research on Cancer (IARC) has been reporting count and incidence data for malignant mesothelioma. The aim of this study was to improve understanding of the global patterns of malignant mesothelioma.

Methods
We extracted mesothelioma incidence count data by sex recorded in Volumes VII (1988-1992, 150 registries in 50 countries), Volume VIII (1993-1997, 186 registries in 57 countries) and Volume IX (1998-2002, 225 registries in 60 countries) of the IARC Cancer Incidence in Five Continents reports. We also extracted the related age-standardised incidence rates and their standard errors. The data extraction was done for each reporting cancer registry or country in the six IARC regions (Africa, Asia, Central and South America, Europe, North America, and Oceania). The number of incident cases was summed by region and stratified by calendar period and sex. To provide accurate and conservative estimates, we removed sub-regional data from summary counts where total regional data were provided. The male to female ratio of incident count data was calculated for each combination of sex, region and calendar period. From the standard errors, we calculated lower and upper 95% confidence intervals. Inverse variance weighting was then used to provide a pooled estimate for each IARC region in each combination of calendar period by sex.

Results
We identified a total 120,544 cases of mesothelioma reported by IARC in the calendar period 1988-2002. There were 95,466 males and 25,068 females with a male to female ratio of 3.8. Of the total number of cases, 58% of these were from North American region, 33% from European region, 5% from the Oceania region, and 3% from the Asian region. The African and Central and Southern American regions made up less than 1% of cases respectively. The estimated incidence pooled across all IARC regions between 1998 and 2002 is 1.47 per 100,000 for males (95% CI 1.46, 1.48) and 0.31 per 100,000 (95% CI 0.30, 0.32) for females. There was little change in the female incidence rate from the 1988-1992 to 1998-2002 period. However, there was a non-statistically significant difference increase in the male incidence rate over the same periods.

Conclusion
We found that males made up 79% of all mesothelioma cases reported between 1988 and 2002. The majority of cases were from the European, North American and Oceania regions but this maybe an artefact of better diagnosis and reporting in those regions. Pooled across countries and calendar periods, we also found that the male incidence rate was almost 5 times higher than the female incidence rate. Continued assessment of patterns in the proportion of cases in each region and time trends in incidence by sex and region will help to evaluate trends in disease occurrence.

Background
Aquaporin 1 (AQP1) has been shown to be an independent prognostic marker for survival in malignant pleural mesothelioma (MPM). AQP1 is a trans-membrane protein normally expressed in mesothelial cells and is part of a family of proteins involved in fluid homeostasis, cell proliferation and motility. AQPs have been implicated in various aspects of tumour development. The aim of the current study was to determine the functional role of AQP1 in MPM, using in vitro and in vivo models.

Methods
Primary MPM cells obtained from patient’s pleural effusions and the MPM cell line NCI-H226 were subjected to a specific pharmacological AQP1 blocker and AQP1 siRNA knockdown and examined for proliferation and colony formation using MTS and anchorage independent assays. Levels of AQP1 expression were determined by immunohistochemistry and RT-PCR. The influence of AQP1 on tumour growth in vivo was studied using a heterotopic mouse model. Briefly, 5 x 10[6] NCI-H226 cells were injected subcutaneously in the hind flank of BALB/C nude mice and allowed to grow to 100 mm[3] before daily intra-tumour injections of AQP1 blocker. Tumour size was measured daily.

Results
AQP1 expression correlates with cell proliferation in primary MPM cells (R[2] = 0.69). Blockade of AQP1 with pharmacological blocker or siRNA knockdown in MPM cells was shown to significantly decrease cell proliferation, both in NCI-H226 (p < 0.05) and primary MPM cells expressing AQP1 (p < 0.05). Primary MPM, where more than 20% of tumour cells expressed AQP1, showed greater reduction in proliferation compared to cells having AQP1 expression <20%. Application of AQP1 blocker decreased both the number and size of colonies formed after NCI-226 cells were subjected to anchorage independent growth (p < 0.05). In a pilot study using the heterotopic mouse model the size of tumours was decreased after 5 days using 20 μM of AQP1 blocker compared to an untreated control (n=6 for each group).

Conclusion
Results indicate that AQP1 plays a functional role in MPM. Modulation of AQP1 decreases cell proliferation and colony formation as well as the growth of MPM tumours in a heterotopic mouse model. Larger scale animal studies are required to further understand the role of AQP1 in MPM and the potential clinical implications of an AQP1 blocker in the treatment of MPM

Background
Clinical TNM staging of MPM is suboptimal for predicting prognosis of individual patients. Accurate clinical assessment of T classification is limited by poor contrast resolution of the tumor from adjacent structures. Involvement of interlobar septae (ILS) is a T2 classification criterion that is amenable to quantitative measurement owing to high contrast with surrounding lung parenchyma.

Methods
All patients who underwent primary extrapleural pneumonectomy (EPP) or pleurectomy (PDC) between 2001-2012 with preoperative CT scan available for retrospective review were included. ILS were measured at their maximum thickness evident on axial CT images. ILS thickness representing the optimal threshold for predicting pathologic involvement was determined by ROC analysis among patients who underwent EPP with complete pathologic analysis including microscopic examination of the ILS. Cox regression was used to determine the threshold associated with the maximal hazard ratio for death among all patients in the study cohort.

Results
406 patients met criteria for inclusion (278 EPP, 128 PDC; 319 male; 260 epithelial histology; median age 64). Maximal ILS thickness ranged 0 - 50mm, median 5.75mm. Among 269 EPP patients with ILS pathologically evaluated (229 positive), predictive accuracy was optimized at a threshold of >2mm on CT (83% sensitivity, 57% specificity, 79% accuracy). Among 406 patients, hazard ratios for death were optimized at threshold of >5mm on CT. The table lists the numbers of patients within the entire cohort and for the subsets undergoing EPP and PDC who scored positive for at the 5mm threshold, as well as the associated hazard ratios for death and disease recurrence.

			Overall Survival		Time To Recurrence
	# Positive	#Negative	HR	95% C.I.	HR	95% C.I.
All	213	193	2.4	(1.9-3.0)	2.2	(1.7-2.7)
EPP	167	111	1.9	(1.5-2.6)	2.0	(1.5-2.5)
PDC	46	82	3.3	(2.1-5.2)	2.9	(1.9-4.4)

Conclusion
Pathologic ILS involvement is a T2 classification criterion characteristic of 85% of EPP cases. It is most accurately predicted by measured thickness >2mm on CT. However, ILS thickness of >5mm is a more discriminant and clinically useful indicator of poor outcome, particularly for patients undergoing PDC. As such, this measurement represents an available clinical prognostic marker not currently included among TNM staging criteria or standard radiology reports.

Background
For patients with malignant pleural mesothelioma (MPM), intensive local regulations are needed,whether patients will be treated with EPP or not. In order to obtain adequate control of malignant effusion and expect temporary anti-tumor effect, we have introduced intrapleural perfusion hyperthermo-chemotherapy (IPHC) with cisplatin.

Methods
Twenty-six patients with MPM underwent IPHC at the time of pleural biopsy with thoracoscope. Hyperthermo(42.5 ℃)-perfusion was performed with cisplatin (80mg/m[2]) during 60 minutes under the general anesthesia. Complications, control of pleural perfusion, treatment followed by IPHC, and survival time, were studied.

Results
Median age was 68 years (range, 56-82). Twenyy-four patients were male. Eiteen patients had epitherial, 5 had biphasic,and 3 had sarcomatoid histology. Fifteen had left-sided disease. There were no serious clinical complications associated with this procedure. The pleural effusion was well controlled in all patients. Adjuvant chemotherapies (CT) were performed immediately in 24 patients. Nine patients were treated by EPP after 2 course of CT: One/2/5 year survival rates were 87.5/50.0/37.5 %, respectively. MST was 19.5 months.Seventeen patients were treated by CT (platinum + Pem) : One/2 year survival rates were 81.9/29.8 %, respectively. MST was 14.0 months.

Conclusion
IPHC with cisplatin is easy to perform, and relatively safe. This method had brought an ideal pleural adhesion. IPHC may offer excellent local control and good survival for patients with MPM as a part of multi-modality therapy.

Background
Availability of quality assured, fully annotated mesothelioma tissue collected to rigorous standard operating procedures will facilitate better understanding of mesothelioma biology. Currently, few bioresources of mesothelioma tissue exist, the largest being the National Mesothelioma Virtual Bank hosted by the University of Pittsburgh (http://www.mesotissue.org/). A few other clinical/research groups hold fresh tissue from small numbers of mesothelioma patients but these collections are not formally linked and often do not involve collection of tissue and data to Standard Operating Procedures. The British Lung Foundation/Mick Knighton Mesothelioma Research Fund has recently funded MesobanK, a UK based bioresource of malignant mesothelioma tissue samples.

Methods
Tissue Microarray: MesobanK will construct a tissue microarray (circa 1000 cases) using historical formalin fixed paraffin embedded blocks of tissue taken at thoracoscopy/surgical resection. Inclusion criteria requires sufficient tissue to permit multiple 0.5 mm cores (to allow for tumour heterogeneity) and a clinical minimum data set. Fresh tissue: Fresh frozen mesothelioma tissue (300 cases over 3 years) will be collected prospectively from multiple centres across the UK together with parallel pleural fluid, whole blood, serum and plasma. Each case will have a detailed anonymised linked clinical data set with follow up data. Cell lines: MesobanK plans to create 20 new fully annotated mesothelioma primary cell lines. The bioresource will be supported by a web-based IT infrastructure for annotating and searching the collection. Clinical data will be collected on each case and supplemented by laboratory and pathology results, Hospital Episode Statistics data and UK Cancer Registry data in order to achieve as complete a data set as possible. MesobanK will follow the Guiding Principles laid out by the NCRI Confederation of Cancer Biobanks and the UK Medical Research Council Operational and Ethical Guidelines on Human Tissue and Biological Materials for Use in Research. It will also be managed within the scope of all relevant regulatory frameworks and quality management/quality assurance systems. In addition, we share the aim of the US National Cancer Institute (NCI) National Biospecimen Network Blueprint: to create a comprehensive framework for sharing and comparing research results through a robust, flexible, scalable and secure bioinformatics system that supports the collection, processing, storage, annotation and distribution of biospecimens and data using standard operating procedures based on best practices. A steering committee will have overall control of MesobanK. An independent scientific advisory board will review applications for samples and advise the steering committee. Prioritisation for access to samples will be based solely on scientific merit. All researchers, whether in the UK National Health Service, universities, charities, government agencies or commercial companies, and whether based in the UK or abroad will be subject to the same application process and approval criteria.

Results
Not applicable

Conclusion
It is anticipated that initial tissue (TMA and cell lines) will be available in 2014.

Background
Malignant pleural mesothelioma (MPM) remains a major challenge, with limited therapeutic options. Multifocal intrapleural disease can cause disabling symptoms of pain and breathlessness in the absence of distant metastases, so an intrapleural treatment approach is attractive. HSV1716 is a mutant herpes simplex virus type 1 deleted in the RL1 gene which encodes the protein ICP34.5, a specific determinant of virulence. Mutants lacking the RL1 gene are capable of replication in actively dividing cells but not in terminally differentiated cells – a phenotype exploited to selectively kill tumor cells. Activity against mesothelioma has been demonstrated in animal models. Studies in adult patients with high grade glioma, melanoma and squamous cell carcinoma report that HSV1716 is safe and well tolerated when administered by intra-tumoral injection. We have therefore designed a phase I study to determine the safety, tolerability and potential for efficacy of HSV1716 given intrapleurally to patients with MPM.

Methods
The study is an open label, dose escalation, phase I/IIa study in a single clinical centre. Patients with a histological diagnosis of MPM and an indwelling pleural catheter are eligible if they have performance status ≤ 2 and adequate hematologic, renal and liver function. Patients will receive 1x10[7]iu HSV1716 through their pleural catheter on one, two or four occasions a week apart, in three separate patient cohorts. The primary objectives are to determine the safety and tolerability of HSV1716 given intrapleurally in patients with inoperable MPM. Detailed safety analyses will be undertaken. The secondary objective is to obtain evidence of HSV1716 replication and lysis of mesothelioma cells through analysis of pleural fluid by determining the number of viral particles on alternate days for one week, after the last Seprehvir administration, then weekly. An exploratory objective will be to assess tumour response by CT using modified RECIST criteria.

Results
The study is open and the first two patients have been treated with a single dose of HSV1716 with no dose limiting toxicity (DLT) or serious adverse events (SAEs) reported. HSV1716 DNA has been detected in pleural fluid samples from one of the patients up to one month post treatment.Up to 12 patients will be recruited and, if successful, a randomised phase II study of intrapleural HSV1716 is planned.

Conclusion
Not applicable.

Background
Mesothelioma is increasing worldwide. However there is no approved therapy in the second-line setting. Vinorelbine exhibits promising activity, however there has been no randomised evaluation or validation of biomarkers to support patient stratification. We have recently reported that BRCA-1 is an essential regulator of mesothelioma sensitivity to vinorelbine, and its expression is lost in approximately 38%. The UK National Cancer Research Institute Lung Clinical Studies Group have therefore developed this clinical trial to investigate whether or not giving second-line vinorelbine in addition to active symptom control (ASC) will benefit patients in terms of overall survival. The study is funded by a research grant from Cancer Research UK (CRUK/12/056) and free vinorelbine, labeling and distribution from Pierre Fabre Ltd. The trial is sponsored by Leicester University, and coordinated by the Wales Cancer Trials Unit, Cardiff, UK.

Methods
A UK multicentre open-label randomised phase II trial. Eligible patients include histological diagnosis of mesothelioma, received at least one line standard platinum doublet based chemotherapy, age >=18 years, measurable lesions by modified RECIST, radiological evidence of disease progression and informed consent. Patients will be randomised to either control of active symptom control (ASC) or ASC plus vinorelbine using a 1:2 allocation ratio. ASC will be administered as per local practice, continuing follow-up until evidence of radiological progression. Vinorelbine will administered at a dose of 60mg/m[2 ]po od on day 1 (equivalent to 25mg/m[2 ]iv day 1) weekly for 3 weeks for the first cycle, incrementing to 80mg/m[2 ]weekly (equivalent to 30mg/m[2 ]iv) in the absence of haematological toxicity for subsequent cycles. Patients will continue chemotherapy until evidence of radiological progression (or unacceptable toxicity or patient withdrawal). The primary endpoint of the trial is overall survival with secondary endpoints of tolerability, response rate, change in tumour volume and progression-free survival. BRCA1 expression IHC will be evaluated as a stratification factor. The median OS for patients in the control arm is expected to be 1.5 months. With 90% power and a one-sided α of 0.2, 114 participants are required (76 in the vinorelbine arm and 38 in the control arm) to detect a hazard ratio of 0.65, based on the logrank test. The primary analysis of data will be analysed after 111 OS events.

Results
not applicable

Conclusion
not applicable

Background
Malignant pleural mesothelioma (MPM) is an aggressive tumor in the pleural lining of the lung usually caused by asbestos exposure. Median OS following frontline chemotherapy with pemetrexed/cisplatin is ~12 months. There is no established second line therapy. Approximately 50% of MPM patients exhibit homozygous disruption of the NF2 tumor suppressor gene by mutation and/or deletion resulting in lack of expression of functional merlin protein. Preclinical data have indicated that mesothelioma cell lines that lack NF2/Merlin are especially sensitive to focal adhesion kinase (FAK) inhibition in both cellular and animal models. Interestingly, pemetrexed and cisplatin increase cancer stem cells (CSCs), while FAK inhibitors have been found to decrease CSCs in mesothelioma models. Given the sensitivity of mesothelioma cells lacking NF2/Merlin and the effect on CSCs, the use of a FAK inhibitor in a maintenance setting after first line chemotherapy may be an attractive strategy to extend survival of MPM patients. VS-6063 is an orally bioavailable selective inhibitor of FAK. In a phase 1 trial VS-6063 was generally well tolerated, with grade 1/2 nausea, vomiting and fatigue as the most frequent adverse events (Jones SF J Clin Oncol 2011 29:1 suppl; abstr 3002).

Methods
A multinational, randomized, double-blind, placebo controlled, phase 2 clinical trial was designed to determine if VS-6063 provides superior clinical benefit compared with placebo as a maintenance treatment in patients with MPM following frontline therapy with pemetrexed/platinum therapy. The study aims to assess whether VS-6063 improves median OS and median PFS over placebo. Randomization will be stratified by Merlin status (high versus low) and patients will receive either VS-6063 400mg BID continuously or matched placebo (1:1). The study follows an adaptive enrichment design where, pending results from an interim analysis, sampling may be restricted to patients with low Merlin protein expression if promising results are observed among the subpopulation. Approximately 370 eligible patients with pathologically confirmed MPM, who have PR or SD following at least 4 cycles of pemetrexed with either cisplatin or carboplatin, Karnofsky PS ≥70%, will be enrolled. Patients will continue treatment until disease progression. Archival tumor tissue will be used for the analysis of Merlin status and is therefore required for participation. Secondary endpoints include patient-reported outcomes of health-related quality of life and disease- or treatment-related symptoms utilizing the LCSS-meso scale, objective response and safety and tolerability. Clinical trial information: NCT01870609.

Results
not applicable

Conclusion
not applicable

Background
Malignant mesothelioma (MM) is an uncommon cancer, caused principally by asbestos exposure. There is no approved treatment after first-line platinum-pemetrexed (Vogelzang, 2003), as no agents have shown survival benefit in this setting (Ceresoli, 2010). Novel approaches are clearly needed. Asbestos exposure induces immunosuppression and immune dysfunction in the mesothelium environment, mainly by a hyper-activation of regulatory T lymphocytes (T-reg) and an over-production of cytokines inhibiting cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells (Maeda, 2010; Kumagai-Takei, 2011; Robinson, 2011). This suggests that agents that target the immune microenvironment may be appropriate to evaluate in MM. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4, CD152) is expressed upon T-cell activation, modulating and eventually switching off T-cell activation. Tremelimumab (treme) binds to CTLA-4 antigen, preventing its negative regulatory signal to T cells. Treme has been investigated in more than 1000 patients in various tumor types. An Italian investigator-sponsored Phase 2 study of Treme in 29 MM patients who progressed on platinum-pemetrexed showed encouraging activity, including promising 1- and 2-year survival rates and a safety profile consistent with that observed across the clinical development program for treme (Calabro et al, 2012). Currently this study has been expanded and is exploring an optimized dosing schedule 10mg/kg on Day 1, every 4 weeks for 6 doses in induction phase, then every 12 weeks in maintenance phase until disease progression or severe toxicity.

Methods
Study design: This is an international, Phase 2, randomized, double-blind, placebo-controlled study. Subjects with unresectable pleural or peritoneal MM who have progressed following 1 (first line regimen containing platin plus pemetrexed) or 2 prior chemotherapy regimens will be randomized in a 2:1 ratio to receive either treme or placebo. Randomization will be stratified by EORTC status (low-risk vs high-risk), line of therapy (second vs third), and anatomical site (pleural vs peritoneal). A total of 180 subjects will be enrolled at approximately 150 study centers in multiple countries. Endpoints: Primary endpoint: Overall Survival (OS). Secondary endpoints: durable disease-control rate (DCR); progression-free survival (PFS); effect of treme on patient-reported outcomes (PROs) including disease-related symptoms, pain symptoms, and time to deterioration of disease-related symptoms; overall response rate (ORR) and duration of ORR; safety and tolerability of treme, immunogenicity and pharmacokinetics (PK) of treme in treated subjects. Exploratory objectives: DCR, PFS, ORR, and duration of response based on immune‑related response criteria (irRC); health-related QoL, disease-related symptoms, pain, and health status in subjects with durable clinical activity; biomarkers and their association with treme treatment and clinical outcome.

Results
not applicable

Conclusion
Current status: The study started recruiting in May 2013. More info is available at ClinicalTrials.gov Identifier NCT01843374.

Background
To analyse long-term survival rates, reccurence rates and prognostic factors of patients with Masaoka stage Ⅲ thymomas.

Methods
A total of 111 patients with stage Ⅲ thymoma treated in our hospital between September 1965 and December 2010 were retrospectively analysed. Sixty-eight patients(61.3%) were with complete resection, while 23 patients(20.7%)with incomplete resection and 20 patients(18%)with pure biopsy(18 patients wih thoracic exploration surgery and 2 patients with CT-guidied fine needle puncture biopsy). Fifty-six patients with complete resection(50.5%)and 10 patients with incomplete resection(9%) had postoperative radiation. Twenty patients with pure biopsy received post or preoperative radiation or chemotherapy with or without surgery.

Results
The median follow-up time was 66 months(5-540). The total overall survival (OS) rates、disease free survival(DFS)rates and disease specific survival (DSS) rates at 5 and 10 year were 75.3%、60.8%、81.9% and 54.7%、41.3%、67.1%, respectively. Postoperative radiotherapy did not improve OS、DFS、DSS compared to surgery alone (p=0.316, p=0.729 and p=0.601). The OS at 5 and 10 year among the patients with complete resection、incomplete resection and pure biopsy were 88%、59%、56.7% and 69.3%、30.6%、47.3%, repectively (p=0.002). The DFS at 5 and 10 year among the patients with complete resection、incomplete resection and pure biopsy were 73.9%、40.1%、41.2% and51.5%、26.7%、30.9%, repectively (p=0.003). The DSS at 5 and 10 year were 93.9%、69.2%、59.7% and 78.9%、46.2%、59.7%, respectively (p=0.004). The total failure rate was 36% (40/111), including 30.6% locoregional recurrence and 9% distant metastasis (including multisite failure). Local recurrent rates in patients with postoperative radiotherapy was lower than patients with surgery alone (9.4% and 19.2%), but the result was not statistically significant (p=0.173). On multivariate analysis, resection completeness (p=0.000) and lung involvement (p=0.024) were independent prognostic factors for DFS, and resection completeness (p=0.002)、age (p=0.028) and myasthenia gravis (p=0.038) were independent prognostic factors for DSS.

Conclusion
Patients with completely resected Masaoka stage III thymoma had a better survival and lower recurrence rates than patients with tumor incompletely resected. The role of postoperative radiation needs further investigation. Resection completeness and lung involvement were prognostic factors for DFS, and resection completeness、age and myasthenia gravis were prognostic factors for DSS.

Background
Even after complete resection, recurrence of thymoma is not uncommon, but the recurrent patterns remain controversial. This study sought to define the patterns and predictors of relapse after complete resection of thymoma.

Methods
A single-institution retrospective study was performed of 331 patients who underwent radical resection of thymoma from 1991 through 2012.

Results
After a median follow-up of 59 months (range, 3-256), the recurrence rates was 6.9% (23/331). Overall 5- and 10-year survival rates were 92.3% and 84.9%. Cancer specific survival rates were 95% and 89.4% at 5 and 10 years, respectively. Recurrence-free survival rates were 93.6% and 87.2% at 5 and 10 years, respectively. Among the 23 patients, relapses were found in the following sites: pleura (thirteen cases), tumor bed (six), lung (six), chest wall (four), lymph node metastasis (two) , abdominal node metastasis (one),liver (one), pleural effusion (three), and over-lapped recurrence (nine). According to the definition of the International Thymic Malignancy Interest Group, 10 (43.5%) patients had local recurrence, 15 (65.2%) had regional recurrence, 10 (43.5%) had distant recurrence (six lung, one liver, one abdominal node metastasis, and two lymph node metastasis), and 9 (39.1%) had over-lapped recurrence. The difference in survival after recurrence between lung and regional relapse was statistically significant (p=0.027), but it was insignificant between lung and distant relapse (p=0.808). Recurrence rates correlated with the initial Masaoka stage: I, 1.0% (2/196); II, 9.7% (9/93) ; III, 24.2% (8/33); IVa, 42.9% (3/7); and IVb, 100% (1/1). The difference in recurrence between Masaoka stage I and II was stastically significant (p=0.000). And they also correlated with World Health Organization tumor type: A and AB, 3.2% ( 5/154 ); B1, 6% ( 4/67 ); B2, 6% ( 3/50 ); and B3, 22.7% ( 10/44). Tumor size demonstrated a step-up of recurrence at 8 cm (<8 cm, 62.8%; ≥8 cm, 37.2%; P=0.007). In multivariate analysis, Masaoka stage (p=0.005), tumor size (p=0.033), and WHO histology (p=0.046) were predictive of recurrence.

Conclusion
Pleura are the most common recurrent sites. Recurrence in the lung had poorer survival than the regional relapse, it should be included in the distant recurrence. Regional recurrence is the most common pattern of relapse, but local and distant recurrences are not infrequently observed. Advanced Masaoka stage, larger tumor size, and Type B3 were risk factors of recurrence.

Background
Thymoma is a rare malignancy, with a paucity of data on its biology and on the role of targeted therapeutics. Wnt, notch and sonic hedgehog pathway interactions between thymocytes and thymic stroma are important to both thymus and T-cell development. AQUAnalysis[®] is a digital image analysis software that continuously measures multiplexed protein expression and has the potential to overcome limitations of small sample sizes and tissue heterogeneity in the tumor microenvironment. We analyzed a thymoma TMA for gli1, notch1 and CTNNB1 (β-Catenin) expression by AQUA[®] as surrogate markers of activity of the sonic hedgehog, notch and wnt pathways, respectively. We hypothesized this preclinical screen may provide rationale for attacking these pathways with targeted therapeutics in thymoma.

Methods
A TMA was constructed from 68 patients with thymic malignancies and 8 benign thymic controls at Stanford University School of Medicine (Stanford, CA). Gli1, notch1 and CTNNB1 expression were assayed using quantitative fluorescent immunohistochemistry at the Tom Baker Cancer Center (Alberta, Canada). The TMA was stained with anti-gli1 rabbit mAb (monoclonal antibody), clone EPR4523 (Epitomics, Burlingame, CA, USA); anti-Notch1 rabbit mAb, clone EP1238Y (Epitomics, Burlingame, CA, USA); and anti-beta-catenin mouse mAb, clone β-Catenin-1 (Dako Mississauga, ON, Canada) using a Dako autostainer. To isolate expression of these stem-cell pathway proteins separately in the tumor and the lymphocytes, the TMA was also stained with anti-pan-cytokeratin guinea pig mAb (Acris, San Diego, CA, USA); anti-vimentin rat mAb, clone 280618 (R&D Systems, Minneapolis, MN, USA); and anti-CD45 rabbit mAb, clone EP322Y (Epitomics, Burlingame, CA, USA). Automated image acquisition was performed using an Aperio Scanscope FL (Aperio Inc., Vista, CA, USA). Images were then analyzed using the AQUAnalysis® program, version 2.3.4.1. A tumor-specific mask and a tumor cytoplasmic mask were generated to distinguish thymoma cells from surrounding stromal tissue by thresholding the pan-cytokeratin images to identify pan-cytokeratin positive cells as tumor cells and define the tumor cytoplasm. Statistical analysis was performed using SAS Enterprise Guide v5.0 (Cary, NC). Two-tailed t-tests were used to compare the differences between thymic tumor and benign control tissue. ANOVA and Dunnett’s t-test was used to compare differences in gli1, notch1, and CTNNB1 expression by WHO histology.

Results
Demographics for 68 patients: M:F (53%/47%), Mean age at diagnosis: 55 years, WHO Histology: A (10%), B (57%), AB (24%), C (4%), unclassified (4%), Pathologic Masaoka Stage: I (46%), IIa (18%), IIb (4%), III (18%), IVa (9%) IVb (6%). No difference in gli1 (mean 201 vs. 211, p=0.31), CTNNB1 (mean 396 vs. 418, p=0.66) or notch1 expression (mean 317 vs. 325, p=0.82) was noted between thymic tumors and controls. In a subset analysis, we found no significant differences by WHO histology compared to controls.

Conclusion
AQUA® was used to help overcome limitations of analyzing protein expression in histologically heterogeneous thymic tumors with small sample sizes. We found no clinically or statistically significant increased expression of gli1, notch1, and CTNNB1 in thymoma compared to benign thymic tissue. Thus, this study provides no evidence for upregulation of the sonic hedgehog, notch or wnt pathways in thymic tumors.

Background
Thymic epithelial tumours are the predominant lesions that arise in the anterior mediastinum, represent 0.2—1.5% of all malignancies and overall, it is an uncommon malignancy with an incidence of 0.15 cases per 100,000 population. Recent studies have shown the usefulness of [18]F-fluorodeoxyglucose positron emission tomography (FDG-PET) in differentiating between World Health Organization (WHO) histological subgroups of thymic epithelial tumours. We present our experience in the management of patients with primary thymic tumours.

Methods
We evaluated retrospectively the medical records of 21 consecutive patients (pts) who underwent thymectomy in our department. All but one patients underwent radical thymectomy through a median sternotomy. One female patient was subjected to transcervical procedure. In all procedures, the upper and lower thymic poles were traced as far into the neck and down toward the diaphragm as necessary to ensure complete resection, and all fatty tissue between the phrenic nerves was included in the resection. Myasthenia gravis was present in 3 pts (14.28 %), while 9 pts (42.85 %) were asymptomatic.Diagnostic procedures included contrast enhanced Computed Tomography of the thorax (21 pts) and/or Magnetic Resonance Imaging (3 pts) and in the case of 7 patients, an FDG PET-CT was performed. The maximum standardized uptake value (SUV~max~) of the tumor, the mean SUV of mediastinum, and the tumor/mediastinum (T/M) ratio (ratio of peak SUV of the tumor to mean SUV of mediastinum) were compared to determine whether primary thymic tumours could be distinguished by [18]F-FDG PET/CT.

Results
There were 11 male and 10 female pts with a mean age of 46.09 years. The histopathology examination revealed 13 thymomas, 1 endocrine carcinoma and 7 hyperplasias. Type A thymomas were found in 2 pts (15.38 %), AB in 5 pts (38.46 %), B1 in 2 pts (15.38%), B2 in 1 pt (7.7 %) and B3 in 2 pts (15.38 %), while 2 thymomas were unclassified. The mean diameter of the resected masses was 7.03 cm. Three pts were classified as Masaoka IIA stage (23.07%) and two as Masaoka IIB (15.38%), who received adjuvant radiotherapy. All the others were classified as Masoka I. All tumours were totally resected. The 5 year survival was 100%. There was recurrence of the endocrine carcinoma within 5 years and the pt underwent a reoperation.The SUV~max ~values of thymomas were 2.31+/- 0.59, while the SUV~max~ values of mediastinum were 1.74 +/- 0.08.

Conclusion
Tumours of the thymus are an heterogeneous group of tumours, ranging from relatively “benign”thymomas to highly aggressive carcinomas. Surgery continues to be the mainstay of treatment and complete resection of the tumour remains the most important prognostic factor. A recurrence should be completely resected whenever possible, because this approach is associated with good long-term survival. FDG-PET can help characterize various thymic lesions, however, larger prospective studies are further required to substantiate these findings.

Background
Thymic carcinomas are rare aggressive tumors. We reviewed our experiences to evaluate the long-term prognosis regarding the multimodal treatment of thymic carcinoma.

Methods
A retrospective analysis was made of a total number of 90 patients who diagnosed with thymic carcinomas between December 1997 and July 2012. Among patients, 33 patients were treated with surgical resection followed by radiotherapy with or without chemotherapy. Of the remaining 57 patients treated initially with chemotherapy with or without radiotherapy for advanced thymic carcinoma, 24 patients could have surgical resections. The survival rate was compared between the groups. Stage was measured according to the Masaoka-Koga system.

Results
The study group was composed of 57 men and 33 women, with a mean age of 51.5 (±1.2 years). At the time of diagnosis, 10 patients (11.1%) had stage I disease, 14 (15.6%) stage II, 21 (23.3%) stage III, and 45 (50.0%) stage IV. Histologic subtypes included 50 squamous cell carcinoma (55.6%), 10 poorly-differentiated neuroendocrine carcinoma (11.1%), 5 well-differentiated neuroendocrine carcinoma (carcinoid tumors, 5.6%), and 4 other types (4.4%) among 69 patients whose histologic classification were made by pathologic study. Overall survival rates were 55.1% at 5 years and 32.3% at 10 years. Five year survival rates were 100% in stage I or II, 68.8% in stage III, and 39.8% in stage IV (p=0.012). Five year survival rates of the patients had treated with complete resection, the patients with incomplete resection, and the patients with unresectable tumors were 95.0%, 84.4%, 10.4%, respectively (p<0.001). In regard to the role of chemoradiotherapy, the survival rate of 24 patients had treated with initial chemotherapy followed by surgical resection, consisted of 13 cases of complete resection and 11 cases of incomplete resection and 4 cases of exploration, was better than those of 33 patients who were received chemotherapy with or without radiotherapy alone (5 year survival rate, 84.8% vs. 10.4%, p<0.001). On multivariate analysis, the extent of surgical resection (complete resection vs. unresectable tumors: hazard ratio [HR] =0.117; 95% CI 0.038-0.365; p<0.001, incomplete resection vs. unresectable tumors: HR=0.200; 95% CI 0.075-0.536; p=0.001) was the sole independent prognostic factor in this study.

Conclusion
The prognosis of patients with thymic carcinoma is distinct according to the extent of surgical resection. Initial chemoradiotherapy followed by surgical resection may produce long-term survival even at advanced stages of disease. Surgical resection of regressed tumors at loco-regional disease after initial chemotherapy with or without radiotherapy should have attempted.

Background
Thymic cancer is relatively rare malignant disease, and the therapeutic strategy remains to be explored. The purpose of this study is to evaluate the clinical features of thymic cancers after multidisciplinary therapy.

Methods
From January 2004 to December 2012, 13 patients were diagnosed with thymic cancer in our hospital. Clinical features of 12 cases except 1 case who was given best supportive care from the beginning were evaluated retrospectively.

Results
The mean age of patient was 62 years old, ranging 41 to 79 years old. Stages of tumors according to Masaoka staging system were as follows; the number of patients with stages 1/2/3/4A/4B was 1/2/4/0/5, respectively. The pathological subtypes of the tumor according to the WHO histological criteria included squamous cell carcinomas in 7 cases, adenocarcinomas in 3, large cell neuroendocrine carcinoma (LCNEC) in 1 and undifferentiated carcinoma in 1. Of 12 patients, 6 patients (50.0%) underwent complete resection of both tumor and thymic tissues (Surgery group, the number of patients with stage 1/2/3/4A/4B=1/2/2/0/1) and others (50.0%) received chemo-radiotherapy (Non-surgery group, the number of patients with stage 1/2/3/4A/4B = 0/0/2/0/4). In Surgery group, 5 patients (83.3%) received adjuvant radio- or chemotherapy. Despite of multidisciplinary therapy, recurrences of the tumor were observed in 2 cases (33.3%) with pathological subtypes of adenocarcinoma and LCNEC. The median disease free survival after surgery in Surgery group was not reached at the time of this analysis. Kaplan-Meier analysis revealed that the median survival times after the treatment in Surgery and Non-surgery groups were 53.0 and 18.0 months, respectively, indicating that patients in Surgery group had significant longer survival than those in Non-surgery group (P=0.049, log-lank test).

Conclusion
Multidisciplinary therapy including complete resection of tumors can achieve better therapeutic outcomes. Non-squamous cell carcinomas are likely to be subtypes with poor prognosis despite of multidisciplinary therapy.

Background
Thymic epithelial tumors are rare and morphologically heterogeneous which constitutes interpretive challenges to practicing pathologists. Advances in digital imaging provide an opportunity to disseminate knowledge of these rare tumors, and can be potentially useful as diagnostic and educational tools. However the diagnostic reproducibility utilizing digital slide imaging needs to be validated.

Methods
Twenty cases of thymomas or thymic carcinomas with characteristic morphologic features were scanned into the APERIO system. The images were sent to pathologists with expertise in thoracic pathology in 6 different centers. The pathologists were asked to classify the tumors according to the World Health Organization (WHO) 2004 classification and to evaluate invasion on the scanned material. In addition, they were asked to indicate their confidence in the diagnosis using the imaging system. Interobserver agreement was evaluated. After discussions of the first 20 cases, a second round representing 10 cases were evaluated by digital images by the participating pathologists.

Results
In the initial phase, there was agreement among pathologists for the diagnosis of thymoma and thymic carcinoma in 75 % of cases (n= 14), in the remaining 6 cases, the disagreement was between cases of B3 thymoma and thymic carcinoma in five and between Type A thymoma and thymic carcinoma in one (kappa=0.43, moderate agreement). Perfect agreement was seen in 4 thymoma cases, where all pathologists diagnosed the same WHO type. These were classical cases with pushing borders and large fibrous bands. In other cases there were disagreements among the classification of the tumor as B2, B3, and AB. The cases with most disagreement were histologically heterogeneous with combined patterns. When invasion was evaluated, the overall k coefficient is 0.49 for the presence of invasion. In the second round of cases, we observed an improvement in interobserver agreement for diagnosis thymoma vs thymic carcinoma (kappa = 0.63) and for determination of invasion (present versus absent) (k=0.57). Most pathologists found that the digital images were comparable with glass slides and the overall confidence in the diagnosis was good.

Conclusion
The diagnostic accuracy of thymic epithelial tumors by digital images is equivalent to that reported in prior studies using glass slides. Digital imaging is a good tool for remote consultation and educational purposes. In the majority of specimens, pathologists are able to make the correct diagnosis. Major challenges include distinguishing B3 tumors and carcinomas and tumors with morphologic heterogeneity. The overall agreement can be improved after training. This technology could be used to establish a digital slide bank which could provide a method for training pathologists with less experience in the pathology of thymic epithelial tumors, to foster collaborative work in the field, and diagnostic consultation.

Background
Thymoma occurs in about 10-20% of myasthenic patients and in turn, 20-25% of patients with a thymoma have myasthenia gravis. The patients with myasthenia gravis are treated by extended thymectomy. The aims of this study were to analyze the clinical outcomes of myasthenic patients after extended thymectomy by presence of thymoma.

Methods
Forty one patients with myasthenia gravis (27 patients without thymoma: Group A and 14 patients with thymoma: Group B) underwent extended thymectomy between 1995 and 2013. In patients with thymoma, the WHO histological classification was: A in 2 cases, B1 in 3, B2 in7, and B3 in 2. The Masaoka clinical staging was: I in 4 cases, II in 7, IVa in 3. A change of clinical manifestation was examined with QMG score. Reduction of anti-acetylcholine receptor antibody titer (anti-AchR) was evaluated before and at 3 months after thymectomy.

Results
Mean follow-up period was 8.7 years (range, 0.3 to 17.8). The frequency of postoperative re-aggravation was significantly high in group B (5/14) in comparison with group A (1/27). The anti-AchR were reduced from 170.9 to 76.7 (p=0.029) in Group A, and were increased from 22.4 to 35.8 (n.s.) in Group B. Re-elevation of anti-AchR after surgery was recognized to 7.4% (2/27) in Group A and 42.9% (6/14 ) in Group B, respectively.

Conclusion
These data suggest that extended thymectomy for myasthenia gravis is more effective in patients without thymoma than in those with thymoma.

Background
The differential diagnosis of solitary pulmonary nodules (SPNs) in patients with breast cancer is vital but difficult using radiological features. We assessed the nature of SPNs in these patients and the role of surgery in diagnosis and treatment.

Methods
Thirty consecutive patients who underwent surgery for an SPN between 2002 and 2011 after curative surgery for breast cancer were retrospectively evaluated.

Results
Most (93%) SPNs were malignant. Pathological diagnoses in patients with SPNs were primary lung cancer (n = 20, 67%), pulmonary metastasis from breast (n = 7, 23%) or colon (n = 1, 3%) cancer, and benign conditions (n = 2, 7%). Among the 20 patients with primary lung cancer, 15 (75%) had stage IA tumors (T1aN0M0). The average disease-free interval was significantly longer in patients with primary lung cancer than in those with pulmonary metastases from breast cancer (P = 0.031). The five-year survival rates after pulmonary resection for lung metastasis from breast cancer patients and primary lung cancer patients were 100 and 61.1%, respectively.

Conclusion
SPNs found in patients with breast cancer have a high probability of malignancy, especially primary lung adenocarcinoma. Early resection of SPNs in patients who were diagnosed with both primary and metastatic lung cancer led to a good prognosis. We suggest that early pathological diagnosis by surgical resection should be conducted for the early diagnosis and appropriate treatment of SPNs in patients with breast cancer.

Background
To evaluate the long term treatment results and the prognostic factors among patients with soft tissue sarcoma of the thoracic wall who were treated with pre-or postoperative radiotherapy

Methods
Forty two cases were referred to our clinic between December 1980- December 2007 with the diagnosis of soft tissue sarcoma of the thoracic wall, and 13 of them were excluded from further evaluation due to the absence of radiotherapy indication or the predilection of the patients to receive radiotherapy at another center. The mean age was 44 (14-85) and 15 of them were male and 11 female. Malignant fibrous histiocytoma was the most common histopathology (27.6%). 7 patients had well differentiated, 6 had moderately differentiated and 13 had poorly differentiated tumor. Tumor size varied between 1- 25 cm (mean 7.8 cm). Twenty one of the patients admitted to our clinic after primary surgery, 5 after local recurrence. Seventeen of the cases had marginal and 9 had wide local resection. The surgical margin was positive in 11 of the patients. Four cases received postoperative radiotherapy with a mean dose of 60 Gy (50-66 Gy) and 22 received preoperative radiotherapy with a mean dose of 46 Gy. adjuvant chemotherapy with Doxorubicin, Ifosfamide and Holoxan was given to 6 patients.

Results
Mean follow-up time was 97 (9-309 months) months. Nine patients (34.6%) developed local recurrence with a median time to recurrence of 20 months (2-53 months). the surgical margin was positive in 6 of them. All patients with recurrent disease had undergone surgery. And 4 of them were treated with chemotherapy, 1 of them received external radiotherapy, and 1 patient received brachytherapy afterwards. 11 (42.3%) patients developed distant metastasis after a median of 40 months (4-92 months). The most common metastases sites were the lungs (38.5%) and the bones (3.8%). Three cases developed both local and distant metastasis. Five-year local control (LC), disease-free survival (DFS), overall survival (OS), and disease-specific survival (DSS) rates were 62%, 38%, 69%, and 76% respectively. Chemotherapy was given to all cases developing distant metastasis. Seventeen cases died due to disease progression, 2 patients died due to cardiac disorders. On univariate analysis, although LC was approximately twice worse for the patients with positive surgical margin, the difference was not significant. 5-year DFS and DSS rates were significantly worse for the patients with poorly differentiated tumors than well and moderately differentiated tumors (0%, 66% and 60%, 92% respectively. DFS was significantly better for the patients who received chemotherapy (p=0.01) and there was a trend for DSS (p=0.09). On multivariate analysis, no factor affected the results significantly.

Conclusion
In our series, high grade found to be the most important factor affecting prognosis. Although we couldn’t show statistically, it seems that radiotherapy helped to achieve better LC, even in margin positive patients. In addition to this, while a definitive conclusion is not possible due to the small number of cases, chemotherapy improved the treatment results.. Thoracic wall sarcomas should be approached in a multidisciplinary manner as with sarcomas in other regions.

Background
VATS has become an increasingly popular technique for the cardiothoracic surgeon. Its use in the treatment of malignancy has been an issue of debate previously. Whilst its use has been documented for the treatment of primary lung cancers, its use in metastasectomy has been brought under question for several reasons. The low sensitivity of pre-operative CT in diagnosis of metastatic disease in the lungs, compared to palpation means that VATS may miss resection of metastatic lesions. VATS has also been associated with pleural and port site seeding. Whilst there have been several studies demonstrating roughly equivalent survival and more rapid post-operative recovery in minimally invasive approaches, there remains no randomised trials and other high level evidence regarding the oncological outcomes of VATS versus open thoracotomy for pulmonary metastases. This article attempts to provide a systematic review of studies which have directly compared open and VATS resection of pulmonary metastasis in terms of outcome.

Methods
The study followed the PRISMA protocol for systematic reviews and meta-analyses. The search strategy included an electronic literature review using the PubMed database. The MeSH terms utilised were pulmonary metastasectomy, VATS, thoracoscopic and open. The inclusion criteria for the studies are that they had to have 2 limbs for direct comparison of VATS and open thoracotomies. The studies should also provide data regarding overall survival data or recurrence free survival data separately for the 2 limbs of the study.

Results
Nine studies with 777 patients fulfilled the inclusion criteria. The VATS groups had slightly higher odds of 1, 3 and 5 year survival with OR of 1.53, 1.69 and 1.41 respectively. All these results demonstrated no heterogeneity on testing. However, only 3 year survival was statistically significant for overall effect. The VATS group also had higher odds of 1, 3 and 5 year recurrence free survival with OR of 1.29, 1.54 and 1.54 respectively for each of these outcomes. Once again the tests demonstrated no significant heterogeneity on testing. None of the outcomes demonstrated statistical significance in testing for overall effect. Overall pulmonary recurrence had lower odds in the VATS group with an odds ratio of 0.55. This data was not significantly heterogenous (p = 0.15) and did not demonstrate statistical significance in testing for overall effect also (p = 0.28).

Conclusion
Outcomes from VATS are comparable to, if not better than, open thoracotomy. VATS is a suitable choice for pulmonary metastasectomy.

Background
The optimal medical management of pulmonary carcinoid tumors, which comprise 1-2% of all lung cancers, remains to be determined.

Methods
We conducted a retrospective review of patients with typical and atypical pulmonary carcinoid tumors treated at our institution between 1990-present.

Results
We identified 34 patients treated with chemotherapy, including 26 patients with metastatic disease (22 atypical), and 8 patients treated with adjuvant platinum-etoposide chemoradiation (6 atypical, 2 typical, 6 stage IIIA, 2 stage IIB). At an average follow-up of 12 months there were 2 recurrences in the 8 patients receiving adjuvant treatment, both of whom had atypical carcinoid (1 stage IIIA, 1 stage IIB). Of patients with metastatic disease, the principal sites of metastasis were the liver (70%), bone (40%), and brain (25%); median survival after diagnosis of metastatic disease was 3.4 years with a 5 year survival of 29%. Regimens showing efficacy in metastatic disease include octreotide (77% stable disease), etoposide-cisplatin (29% disease control, 4 partial response, 1 stable disease), and temozolomide (44% disease control, 2 partial responses, 2 stable disease).

Conclusion
These results support our previous finding that pulmonary carcinoid tumors are responsive to chemotherapy and that adjuvant therapy should be offered to patients with stage II or IIIA resected disease.

Background
The concept of“Guided Bronchoscopy”has been gradually notable because of the contribution to increasing the diagnostic yields for small peripheral pulmonary lesions (PPLs). Navigation systems such as electromagnetic navigation (EMN) and virtual bronchoscopic navigation (VBN) have been fundamental equipments for that concept. We have been consistently used this navigation software LungPoint (Broncus Technologies, Inc., Mountain View, CA) since it was gone on sale in Japan. We aimed to furthermore increase of diagnostic yields for small (≦30 mm) PPLs by diversified approach case by case in the basis of the LungPoint data using thin video-bronchoscope (P260F, 4-mm outer diameter; Olympus, Tokyo, Japan)

Methods
Between October 2010 and January 2013, a new combination diagnostic technique was all performed for the first time for the consecutive 132 patients (139 lesions) at our hospital. All of the patients had small PPLs with diameters of 30 mm or less as determined by chest computed tomography which were suspected of primary lung cancers. We used all of the data obtained from LungPoint system such as VB-image, navigating pathway and virtual fluoroscopic image to determine how to approach to the target bronchus into which the bronchoscope should be advanced. The other guided devices such as 20-MHz mechanical radial-type probe EBUS (RP-EBUS) and a guide sheath (GS) kit (Olympus, Tokyo, Japan) with an external diameter of 1.95 mm including forceps and brushing were used in combination case by case. Primary endpoints were overall diagnostic yield and diagnostic yield of malignancy.

Results
The variation of a combination use of multi-guided devices was VBN/VBN-EBUS/VBN-EBUS-GS. The number of lesion using each method was 34/47/58. The overall diagnostic yield of 132 cases (139 PPLs) was 74.8%. Diagnostic yield of malignancy was 66.7%.

Conclusion
A new combination of multi-guided devises technique via thin video-bronchoscope following the obtained data from LungPoint system was useful to determine what devices we should choice for approaching to the target and contribute to increasing the diagnostic yield for small (≦30 mm) peripheral pulmonary lesions.

Background
We report North Estonia Medical Center and Tartu University Clinic 5-year experience with cryobiopsy in diagnosing endobronchial malignancies. The purpose of this study is to assess the diagnostic efficacy of the procedure, sampled tissue size and side effects of cryobiopsy in patients with central airways malignances.

Methods
The freezing system which operates according to the principle of the Joule-Thomson effect was used for cryobiopsy (CB) during fiberoptic videobronchoscopy (FVB) under local anaestesia (Erbokryo CA, ERBE Elektromedizin GmbH, Germany) with use of 2.4 mm cryoprobe.

Results
Three hundred and thirteen patients (mean age 65.5 yr, range 17- 88) with clinical and radiological suspicion of endobronchial malignancy underwent FVB with routine collection of CB samples from February 2007 to January 2013. A total of 385 cryobiopsies, ranging from 1 to 4 for a patient, with median sample size of 9.86 mm, were obtained from the trachea, main bronchi or lobar bronchi. The CB specimens were free of artefacts, contained sufficient tissue for the definite pathological diagnosis and had well-preserved surface epithelium, if visible in the biopsy, according to the pathology reports. The diagnosis of endobronchial malignancy was verified in 298 patients (95,5.%) with CB-s. In 3 cases, all CB-s taken from segmental and subsegmental airways, re-bronchoscopy with new CBs was successfully applied to verify the cancer diagnosis. In 15 cases (4, 79 %), the use of CB was unable to confirm the malignancy: the morphology was confirmed by using other minimally invasive endoscopic methods (TBNA, EBUS-TBNA or EUS-FNA). No CB associated complications requesting special intervention were observed. In 35 cases, immediate re-canalization of the bronchi obstructed by the endobronchial tumor was achieved in parallel to CBs for the diagnosis. No difference in diagnostic results was observed regardless the number of collected tissue samples for a patient.

Conclusion
CB is superior human bronchial tissue biopsying method; biopsying efficiency is very high, sampled tissue size and morphological quality cryo-bioptates is excellent, and no procedure related complications were observed. CB during FVB has also paramount value in terms of preserving high quality tissue for the genetic mutations testing in the era of rapidly evolving personalized medicine in lung cancer.

Background
The frequency of detection of peripheral pulmonary mass lesions is rising with increasing availability of radiological imaging. Their aetiology may need to be established, particularly in cases of suspected malignancy. Traditional means of obtaining tissue include CT-guided biopsy, bronchoscopic biopsy, endoscopic ultrasound with fine needle aspiration and surgery. Each modality has potential complications. Endoscopic ultrasound miniprobe (EBUS-MP) is established as a valuable tool, particularly in the staging of early GI tumours. EBUS-MP has been used for qualitative assessment of bronchial structures post lung transplant but data is sparse regarding the role of EBUS-MP sampling of peripheral pulmonary mass lesions. The paper illustrates our experience with this technique to date.

Methods
Procedures were carried out in a tertiary respiratory centre over 18 months. Patients were referred for suspected pulmonary malignancy. CT images for each case were reviewed prior to selection. All procedures were undertaken by the same consultant bronchoscopist, assisted by a respiratory trainee. Samples (biopsies / endobronchial brushings / washings) were taken from the identified subsegmental bronchus. Each case was reviewed with respect to diagnostic rate, management, complications and potential alternative non-surgical investigations.

Results
45 EBUS-MP procedures were performed on 43 patients. Age range 40 – 87 years (mean 69.2 years +/- 10.8). FEV1 ranged from 0.8L to 3.3L. Lesions from all lobes were targeted. No complications occurred in study population. Figures 1 and 2 show detailed outcomes for EBUS-MP. Figure 1 Figure 2

Conclusion
EBUS-MP is a relatively novel technique in bronchoscopy. Our early experience has demonstrated some potential usefulness of the procedure. EBUS-MP allows good visualisation of lesions, can deliver a tissue diagnosis and provide reassurance. No complications have occurred to date. We believe that EBUS-MP sampling may have a role in investigation of peripheral pulmonary mass lesions. In a well selected cohort of patients it appears to be a safe alternative to CT-guided biopsy.

Background
Endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) now offers an accurate and minimally invasive alternative to cervical mediastinoscopy for the pathological assessment of mediastinal and hilar lymphadenopathy. We aimed to establish amongst patients with mediastinal and hilar lymphadenopathy of unknown aetiology and without a radiological identified primary tumour; the yield from EBUS-TBNA for benign and malignant pathologies and the requirement for subsequent investigations in order to confirm a pathological diagnosis in non diagnostic TBNA samples.

Methods
We retrospectively reviewed 418 endobronchial ultrasound examinations performed between 03/01/2011 and 01/03/2013 at the Royal Infirmary of Edinburgh. All patients had a pre-sampling CT thorax and a maximum lymph node diameter of > 10mm. All cases without a radiological identified primary were included in the study. Final clinical diagnosis in relation to pathological diagnosis was achieved from the medical records as was the need for further investigations in order to achieve a pathological diagnosis.

Results
Of 418 EBUS procedures 340 were to stage lymph nodes with radiological primary lesion. 78 EBUS procedures were performed for the investigation of lymphadenopathy of unknown origin. Nodal sampling was achieved in 112 of 118 aspirates (95%). 32 patients (41%) had non diagnostic lymph node sampling. 72 (35.1%) had malignancy diagnosed by EBUS-TBNA (21 bronchogenic) with a further 5 suspicious of malignancy. A false negative for malignancy occurred in 1 patient who had lymphoma. Of 19 patients with a clinical suspicion of sarcoidosis 14 had non-caseating granulomatous lymphadenitis confirmed on TBNA and 3 patients had subsequent confirmation with invasive investigations. The yield then of EBUS FNA for sarcoidosis was 88% when considering those with subsequent pathological confirmation. Of 24 patients with negative sampling, 10 were considered reactive to underlying lung disease, although 11 remained without clear explanation. Follow up was variable within this group. 9 patients required further investigations to confirm disease. 3 patients required mediastinoscopy and 2 went on to have endoscopic ultrasound with core biopsy

Conclusion
EBUS-TBNA has an excellent yield for both begin and malignant pathologies causing mediastinal lymphadenopathy and should be considered as a non invasive alternative to mediastinoscopy where lymphoma is thought less likely.Where TBNA or FNA is non-diagnostic but the suspicion of malignancy is high, further investigations are indicated. Given the availability of CT scanning in today’s practice, lymphadenopathy of uncertain significance is an increasing clinical dilemma. Protocols have had to be developed for the management of incidental solitary pulmonary nodules and similar guidelines could be produced for the management of intra-thoracic lymphadenopathy incidental or otherwise to ensure a standardised investigative cycle and follow up.

Background
Ultrathin bronchoscopes can be guided under fluoroscopy to reach solitary pulmonary nodules. The aim of this study is to compare its diagnostic yield against conventional bronchoscope.

Methods
two hospitals have prospectively collected patients referred to study solitary pulmonary nodules by bronchoscopy under fluoroscopy guidance. One centre performed the procedures with a conventional bronchoscope (Olympus BF Q-180, outer diameter 5.5 mm, working channel 2.0mm) and the other an ultrathin (Olympus XP 160, outer diameter 2.8; working channel 1.2 mm). In both groups bronchial washings were routinely collected. In the conventional group, brushing was always performed and biopsies were performed only when biplane fluoroscopy confirmed that forceps were in contact with the lesion. In the ultrathin bronchoscope group, biopsies were only performed when an endoluminal lesion was seen; if there were no endobronchial lesion, then bronchial brushing was performed.

Results
both groups were similar in the main variables, except for the number of brushes performed in the conventional group (total 31 vs. 66; p <0.05)). Conventional (n=27): age 67.6; gender (M) 66.7%; diameter 20.1 (SD 5.9); SUVm (n=20) 9.1; localization 0% (inner), 50% (middle), 50% (outer); left lower lobe (11.1%), bronchus sign (45%); visualized by fluoro (88.9%); biopsy performed (40.9%); brushes (2 in 55%, 3 in 44.4%). Ultrathin (n=39): age 66.9; gender (M) 79.5%; diameter 21.5 (SD 6.0); SUVm (n=32) 7.7; localization 11.1 (inner), 55.6% (middle), 33.3% (outer); left lower lobe (12.8%), bronchus sign (68.4%); visualized by fluoro (69.2%); biopsy performed (59.1%); brushes (non2 20%, 1 in 69.2%, 2 in 7.5%%, 3 in 2.6%). The final diagnosis were achieved in 44.4% in the conventional group vs. 38.5% in the ultrathin group (p=0.6)

Conclusion
the ultrathin bronchoscope is equally effective as the conventional bronchoscopy under fluoroscopy guidance in the diagnosis of SPN.

Background
Bronchial carcinoids are considered low-grade malignancies and, traditionally, are treated surgically. Tumor biology and advances in diagnostic and therapeutic techniques, however, enable a less invasive approach such as surgical bronchoplasty can preserve normal lung parenchyma. We previously reported favourable outcome for initial bronchoscopic treatment (BT) strategy in patients with intraluminally located bronchial carcinoids. We now present our long term results.

Methods
In patients presenting with a bronchial carcinoid, an initial diagnostic therapeutic bronchoscopy is attempted for complete tumor eradication for sampling sufficient tissue for the proper differentiation between typical (TC) and atypical (AC) histologic type apart from to optimally improve pre-surgical condition. A high resolution computed tomography is performed six weeks later, to determine intra- versus extraluminal tumor growth. In case of intraluminal growth of TC bronchoscopic removal attempt can be repeated. We perform surgical resection in case of extraluminal disease, or failure to bronchoscopic radical resection (i.e. recurrence or persistent residual tumor). Complete bronchoscopic resection of AC histological type is currently not followed by surgical resection.

Results
So far, 133 patients have been treated; 76 females, 67 males, median age 46 (range 16 – 85 years). Median follow up was 87 (range 2 – 264) months. Ninety-nine patients (84%) had TC, and 34 (26%) had AC. Bronchoscopic eradication was successful in 57 (43%) patients (51 TC, 6 AC). Detailed treatment results are shown in table 1. Table 1. Initial bronchoscopic treatment strategy in patients with bronchial carcinoids

	BT	Completion Surgery	Remark
Number of patients	62	71
Histology TC AC	56 (90%) 6 (10%)	43 (61%) 28 (39%)
Follow up (median) in months	87.5 (2-223)	87 (12-264)
Completely resected	57 (92%)	64 (90%)
Residual after CT/recurrences Additional treatment bronchoscopy Additional treatment surgery	3 4	0 0	Interval in months: 10,13,63 47,104,115,192
Alive with disease	5	0	2 unfit for surgery 3 refused surgery
Alive with metastatic disease	0	1	40 months
Carcinoid related mortalities	0	2	Pulmonary metastases
Treatment related mortalities	0	1
Non-carcinoid related mortalities	8	3

Conclusion
Initial bronchoscopic treatment strategy in patients with bronchial carcinoids is justifiable with excellent long term outcome. It should be implemented in the standard algorithm for patients with bronchial carcinoids.

Background
Endobronchial ultrasound-guided transbronchial aspiration(EBUS-TBNA) is reported to show relatively high sensitivity and specificity in mediastinal node staging of non-small cell lung cancer (NSCLC). But discrepancies exist between bronchoscopic, radiologic, and surgical classification of mediastinal lymph nodes and thus can lead to misclassification. However, the impact of the misclassification on diagnostic performance of EBUS-TBNA has never been evaluated.

Methods
Medical records of NSCLC patients who underwent surgery after EBUS-TBNA for mediastinal staging from November 2010 until March 2013 in a tertiary hospital were reviewed. Of those, only lymph nodes which have been aspirated by EBUS-TBNA and removed by surgery were analyzed. Patients who received neoadjuvant chemotherapy between EBUS-TBNA and surgery were excluded. Detailed review of medical records and radiological imaging was done to infer the causes for false negative or positive results.

Results
A total of 105 lymph nodes from 96 patients were included in our analysis. Median interval between EUB-TBNA and surgery was 11 days. A total of 8 lymph nodes(7.6%) showed false negative results and only one lymph node (0.9%) showed false positive result. Sensitivity, specificity, accuracy, positive and negative predictive value (PPV and NPV) of EBUS-TBNA for malignancy were 65.2%, 97.5%, 88.5%, 88.5%, 90.6%, respectively. After detailed review of cases who had false positive or negative results, 3 false negative lymph nodes and 1 false positive lymph node (44%) were recognized to be due to misclassification. Other false negative cases were due to sampling errors.

Conclusion
Misclassification of lymph nodes can cause false positive or false negative results of EBUS-TBNA.

Background
Fine needle aspirates (FNA) are widely used in the diagnostics of non-small cell lung cancer (NSCLC). As relevant oncogenic drivers have emerged, the demand for molecular tests is increasing. To investigate mRNA expression fresh frozen tissue is required. In an everyday setting isolation of snap-frozen tissue is rarely a possibility and new procedures are needed to allow use of FNA material for mRNA expression studies.

Methods
Tumour samples from patients under suspicion of having lung cancer were isolated. Routine diagnostic procedures of FNA and/or transbronchial needle aspiration (TBNA) were performed and smears used for routine diagnostics were prepared. The remaining sample in the needle and syringe was mixed with 10 ml Cytolyt©. 9.5 ml was used for routine diagnostics, while 0.5 ml was mixed with 4.5 ml RNAprotect©. mRNA was isolated, transcribed into cDNA and quantified with quantitative reverse transcription quantitative PCR (RT-qPCR).

Results
Analysis of four reference genes in the first 50 samples consecutively collected showed that the most stable reference gene was β-actin. 211 tissue samples from 81 patients were then examined for β-actin mRNA expression. 92 % of the samples contained sufficient material for mRNA quantification containing mRNA corresponding to 100 HCC827 NSCLC cells or more. Furthermore 100 HCC827 NSCLC cells were sufficient to quantify the mRNA splice variant of BIM conferring erlotinib sensitivity.

Conclusion
We describe a novel procedure that optimizes the use of diagnostic FNA and TBNA and demonstrate that these samples contain enough material for isolation of high quality mRNA without influencing routine procedures.

Background
When a new diagnostic or staging method is implemented, the new method should at least produce results of the same level as the old method Mediastinoscopy has for decades been the golden standard in the preoperative diagnosis and staging of lung cancer. Guidelines from ESTs recommend that at mediastinoscopy biopsies from stations 2R, 2L, 4R, 4L and 7 should be the result of the procedure, but the procedure may be accepted if there is biopsies from the stations 4R, 4L and 7 Should it be decided to replace mediastinoscopy with endoskospic ultrasound this procedure should be based on the principles of mediastinoscopy. The purpose of this project is an assessment of the Endoscopic Ultrasound follow the part of the guidelines for mediastinoscopy dealing which stations recommended biopsied.

Methods
Abstracts from ERS 2012 were reviewed in order to locate projects where EBUS TBNA has been used. In Medline were the keywords EBUS TBNA, EBUS, endoscopic ultrasound endobronchial ultrasound and lung cancer sought

Results
20 relevant abstracts from ERS 2012 were found. Of these 13 abstract did not contain information that made it possible to estimate how many stations there were biopsied. The other 7 abstracts provides 526 patients (53-129) and there is biopsied 950 lymph nodes which corresponds to t mean 1.8 lymph nodes biopsied (range 1.2 to 2.5) In Medline were 18 relevant publications were located dealing with 2068 patients (22 - 190). 4188 lymph nodes were biopsied (32 - 928) mean 1.7 per patient (range 0.8 to 3.0) Unfortunately, it is only a small part of the publications which describe either the number of stations, or at least the number of nodes that were biopsied compared with the number of patients involved. Just a simple calculation of the ratio between the number of lymph nodes and patients that were included in these projects suggests that a large proportion of lung cancer patients diagnostic and staging procedure is of lower standard than if they had been offered the golden standard ( mediastinoscopy )

Conclusion
There is a big task in developing and implementing guidelines for the diagnostic and staging process of lung cancer when mediastinoscopy is not used. Since an increasing share of the staging process for the patients included in oncology projects are based on Endoscopic ultrasound can cause uncertainty about the results of these studies

Background
The anaplastic lymphoma kinase (ALK) fusion gene is a key oncogenic driver in a subset of patients with advanced non small cell lung cancer (NSCLC). ALK rearragement is detected in 2-7% of NSCLC patients. Fluorescence in situ hybridization (FISH) is the recommended method of detection. The clinical features of lung cancer that harbors ALK include light- or never-smokers, younger age, adenocarcinomas with acinar pattern or signet ring adenocarcinoma, and a lack of EGFR or KRAS mutations. Crizotinib has shown an important benefit in terms of overall response rate (ORR) and progression free survival (PFS) in the 2nd/3rd line setting. Treatment related adverse events were gastrointestinal and visual disorders.

Methods
Retrospective analysis of the clinico-pathological profile of ALK NSCLC patients between May 2011 and December 2012 in our Institution.

Results
10 cases (6,7%) were identified from 150 screened patients with adenocarcinoma histology and EGFR wild-type status. 7 (70%) patients were women. Median age at diagnosis was 62 years old (range=36-77). 90% patients were light-or-never smokers. All tumours were adenocarcinomas with EGFR wild type status: acinar growth pattern was detected in 4 cases (40%); 4 (40%) patients showed mucous cells and previous described signet-ring cells were detected in the last 2 (20%) cases. Only 5 (50%) patients received crizotinib therapy: 2 patients were treated during first line with partial response, 1 patient was treated in second line with stable disease and 2 patients received therapy in third line with partial response and no response, respectively. Only one patient required a dose reduction (200 mg bd) due to gastrointestinal toxicity.

Conclusion
Most of the patients with ALK rearregements in our serie have clinical and pathological characteristics to previously described. More women and older population were showed. In stead of the small sample size, pathological pattern based on acinar growth and mucous or signet-ring cells in adenocarcinomas with no EGFR mutation should guide the ALK screening process. ORR and toxicity profile confirmed Crizotinib benefit as soon as ALK status was detected.

Background
Molecular classification of lung cancer correlates well with histomorphologic features. However, detailed histomorphologic features which differentiate ALK rearranged tumors from ALK wild type has not been fully evaluated. To investigate histomorphologic features of tumors harboring ALK rearrangement to evaluate the predictive significance of morphologic characterization, we compared the histomorphological analysis between ALK-rearranged and ALK negative lung adenocarcinomas based on driver oncogene mutations.

Methods
Eighty resected ALK rearranged lung adenocarcinomas and two hundred thirteen resected ALK negative adenocarcinomas (91 EGFR mutated, 29 K-ras mutated and 93 triple-negative) were analyzed for several histomorphological parameters and histologic subtype based on newly proposed IASLC/ATS/ERS classification.

Results
ALK rearranged tumors were associated with a younger age at presentation, frequent nodal metastasis and higher stage at diagnosis, compared with patients with other genotypes. ALK rearranged tumors were more likely to show solid predominant pattern (43.8%, 35/80) than other genotypes (p<0.001) and a lepidic predominant histology was not observed in ALK rearranged tumors (p<0.001). In ALK rearranged tumors, considerable number of the tumors (67.5% , 54/80) contained at least 5% solid pattern but only small number of the tumors (12.5%, 12/80) contained at least 5% lepidic pattern, compared with other genotypes (p<0.001). The most significant morphological features distinguishing ALK rearranged tumors from ALK negative tumors were cribriform formation (OR: 3.253, p=0.028), presence of mucin-containing cells (OR: 4.899, p=0.008), close relation to adjacent bronchioles (OR: 5.361, p=0.001), presence of psammoma body (OR: 4.026, p=0.002) and solid predominant histological subtype (OR: 13.685, p=0.023). ALK-rearranged tumors exhibited invasive histomorphological features, aggressive behavior and frequent expression of epithelial-mesenchymal transition markers (loss of E-cadherin and expression of vimentin) compared with other genotype (p =0.015). Spatial proximity between bronchus and ALK-rearranged tumors and frequent solid histologic subtype with p63 expression may cause diagnostic difficulties to differentiate squamous cell carcinoma in the small biopsy, whereas p40 was rarely expressed in ALK-rearranged adenocarcinoma.

Conclusion
Knowledge of these features may improve the diagnostic accuracy and lead to a better understanding of the characteristic behavior of ALK-rearranged tumors.

Background
We have recently demonstrated that presence of the micropapillary pattern increases the risk of local recurrence after limited resection for ≤2 cm lung adenocarcinoma (ADC). In cases of tumors with the micropapillary pattern, a detached collection of tumor cells is frequently identified within an alveolar space separate from the main tumor, which we have named “Spread Through Alveolar Spaces” (STAS). However, the prognostic significance of this finding is not known. The purpose of this study is to investigate whether the presence of STAS correlates with an increased risk of recurrence after limited resection versus lobectomy.

Methods
All available tumor slides from patients with therapy-naive, surgically resected solitary lung ADC ≤2 cm in size (1995-2009) were reviewed (n=697; stage IA/IB, 600/97; limited resection/lobectomy, 226/471). Comprehensive histologic subtyping was performed according to the IASLC/ATS/ERS classification. STAS was defined as isolated tumor islands (morphologically solid or micropapillary pattern) or single cells within alveolar spaces separate from the main tumor. The distance between the tumor surface and the STAS was measured by a ruler (mm) and by the number of alveolar spaces. Recurrence-free probability (RFP) was estimated using the Kaplan-Meier method.

Results
STAS was identified in 224 cases (32%). The morphologic types of STAS were as follows: 119 micropapillary, 91 solid, and 14 single cell. Presence of the micropapillary or solid pattern (>5%) in the main tumor and presence of lymphatic invasion were significantly associated with presence of STAS (p<0.001 for each). Presence of STAS correlated with an increased risk of recurrence (5-year RFP, 75.6%), compared with absence of STAS (5-year RFP, 83.5%; p=0.022). In the limited resection group, tumors with STAS were associated with an increased risk of recurrence, compared with those without STAS (5-year RFP, 58.3% vs 81.9%; p=0.004); this did not follow in the lobectomy group (5-year RFP, 84.1% vs 84.2%; p=0.658) (Figure). The distance between the tumor surface and the STAS did not correlate with risk of recurrence (p=0.992). Figure 1

Conclusion
Presence of STAS correlated with an increased risk of recurrence in patients treated with limited resection for ≤2 cm lung ADC. This finding may guide surgeons to choose lobectomy over limited resection for the treatment of these patients.

Background
Immunohistochemical screening of anaplastic lymphoma kinase (ALK) rearrangement has been regarded essential and routinely carried out to select the treatment for lung adenocarcinoma. However, due to difficulty to approach a tumor by transbronchial lung biopsy (TBLB), it often fails to obtain tumor tissues whereas tumor cells are contained in cytology specimens simultaneously obtained when the bronchoscopy is done. Therefore we evaluated the expression of ALK protein by using immunohistochemistry (IHC) on TBLB specimens and immunocytochemistry (ICC) on brushing smear cytology slides in the same cases, and compared the concordance rate of IHC and ICC results. ICC was carried out on routine Papanicolaou-stained slides after cytology diagnosis and decolorization.Background: Immunohistochemical screening of anaplastic lymphoma kinase (ALK) rearrangement has been regarded essential and routinely carried out to select the treatment for lung adenocarcinoma. However, due to difficulty to approach a tumor by transbronchial lung biopsy (TBLB), it often fails to obtain tumor tissues whereas tumor cells are contained in cytology specimens simultaneously obtained when the bronchoscopy is done. Therefore we evaluated the expression of ALK protein by using immunohistochemistry (IHC) on TBLB specimens and immunocytochemistry (ICC) on brushing smear cytology slides in the same cases, and compared the concordance rate of IHC and ICC results. ICC was carried out on routine Papanicolaou-stained slides after cytology diagnosis and decolorization.

Methods
IHC was done using the commercially available antibody against ALK (dilution 1:100, clone 5A4; Novocastra, Newcastle, UK), and signals were detected using the EnVision FLEX Mini-kit (Dako, Tokyo, Japan). Papanicolaou-stained bronchoscopic brushing smear cytology slides containing cells cytologically diagnosed as adenocarcinoma were used. ICC was carried out by using the same antibody and the detection kit as used in IHC. IHC and ICC expressions were quantified by three cytopathologists. Cytoplasmic ALK expressions were quantified using a three-value intensity score (0, 1+, 2+) and the intensity scores 1+ and 2+ are defined positive.

Results
Eighteen patients with adenocarcinoma were extracted in the Hirosaki University Hospital and the Hirosaki National Hospital. IHC and ICC results showed a very high concordance rate: sensitivity of ICC in comparison with IHC was 85.7% (6/7), specificity was 100% (11/11), positive predictive value was 100% (6/6), and negative predictive value was 91.6% (11/12).

Conclusion
Detection of ALK rearrangement using ICC on routine Papanicolaou cytology slides is considered to be advantageous for lung cancer treatments.

Background
The rational use of tailored therapy for lung cancer depends crucially on high quality pathology. Not only must subtyping of the tumour be achieved consistently and with accuracy, but as much material as possible from increasingly small specimens must be preserved for the genetic analysis upon which such treatment is increasingly predicated. Although there is a general presumption that pathologists have risen to this challenge, reliable data is sparse and the nature and degree of variation in practice and quality is unknown.

Methods
We collected and scrutinised anonymised information, including pathology reports, on all consecutive, newly-diagnosed patients with lung cancer referred to 19 lung cancer units across the UK for a period of 6 months commencing late 2011, a total of 1507 cases. Centres surveyed ranged from district general hospitals to specialist regional cardiothoracic units.

Results
Achievement of a positive tissue diagnosis of malignancy ranged from 53 to 88%, figures accompanied by ‘suspicious but non-diagnostic’ rates of 10 and 2% respectively. Despite apparent adherence to the diagnostic criteria and terminology of the WHO classification of tumours of the lung, variation in proportions of tumour subtypes was wide, the prevalence of squamous carcinoma, for example, varying from less than 10 to greater than 50%. The proportion of tumours unclassified beyond ‘non-small cell lung cancer not otherwise specified’ varied from 3 to 20% despite the almost universal use of immunochemistry (most often TTF-1, class 7 cytokeratins and p63) to aid in this differential diagnosis. Testing for EGFR gene mutations was directly instigated by the pathologist at diagnosis in only 4 of the 19 centres and the proportion of tumours tested ranged from 12 to 92%.

Conclusion
Variations in practice amongst pathologists and arguably in the quality of pathology ranged widely across the centres surveyed, raising important questions about variable expertise of pathologists, adherence to guidelines, applicability and rigour of external quality assessment and, ultimately, the reliability of the pathology that crucially underpins the management of lung cancer.

Background
Treatment of non-small-cell lung cancer (NSCLC) has changed drastically in recent years with an increase in rates of detection of driver mutations in a subgroup of NSCLC patients (p); the most recent mutations described in NSCLC are HER2 and BRAF. Overexpression of HER-2 (insertion in exon 20) occurs in 2-6% of NSCLC patients and is more common in women, never-smokers, Asian and adenocarcinoma hystology (adc). BRAF is found in 1.6-4.9% of p, with a higher rate of V600E mutations in smokers, and non-V600E mutations in non-smokers.

Methods
We systematically analyzed HER2 and BRAF mutations in EGFR wild type and non-translocated ALK p and retrospectively reviewed the results. Forty six NSCLC p were included between December 2011 to June 2013. Clinical characteristics such as histological subtype, sex, age, smoking status, and mutational status were analyzed. BRAF mutation was assessed by Taqman based assay (5’ nuclease activity) in an AB 7900HT system, with specific primers and probes for V600E positions. HER2 insertion was assessed using Sanger sequencing. All samples were PCR amplified and sequenced in AB 3130, using specific primers for exon 20.

Results
All patients were Caucasian; 25 p (54.3%) were women and 21 p (45.7%) men. Fourteen p (30.4%) were never-smokers, 11 (23.9%) former smokers and 19 (41.3%) smokers. Median age was 58.74 years. Forty one p (89.1%) had adc, 2 had squamous cell histology and 3 had another histology (1carcinod tumour, 1 large cell lung cancer and 1 poorly differentiated NSCLC) . Two p (4.3%) had BRAF V600E mutation: 1 female and 1 male, with median age of 56.5, both smokers. One 65 year old, female, never-smoker p (2.2%) had HER-2 insertion. All mutations were found in adc.

Conclusion
Analysis of less common driver mutations such as BRAF and Her2 mutations is feasible for daily clinical practice and could be useful to decide treatment. In our European population, incidence of BRAF and HER-2 mutation is similar to that previously reported (4.3% and 2.2%). Both p with BRAF V600E mutation were smokers, and the p with mutation in HER-2 was a 65 year-old female never-smoker.

Background
Our understanding of the molecular landscape of lung adenocarcinoma (ADC) is evolving rapidly. Furthermore, the IASLC/ATS/ERS lung ADC classification was recently published. The histologic and molecular correlations have not yet been thoroughly explored in this rapidly changing field. We sought to investigate the molecular findings according to the IASLC/ATS/ERS classification. .

Methods
Aperio© scanned H&E stained slides were reviewed from 230 tumors according to the 2011 IASLC/ATS/ERS lung adenocarcinoma classification criteria. Molecular profiling was performed on 230 resected, untreated lung adenocarcinomas, using mRNA, miRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. Histologic molecular correlations focused on mRNA and DNA sequencing and TTF-1 proteomic findings.

Results
We found 12 lepidic predominant ADC (5%), 21 papillary predominant (9%), 77 acinar predominant (33%), 33 micropapillary predominant (14%), and 58 solid predominant (25%) as well as, 9 invasive mucinous (4%), and 20 unclassifiable ADCs (9%). EGFR mutation and KRAS mutations were found in 8% and 17% of lepidic ADC, respectively. Nine of 12 lepidic ADC (75%) were of the terminal respiratory unit (TRU) gene expression subtype (GES) and 3 (25%)were in the 19p-depleted transcriptional GES, but none were found in the solid-enriched GES (Figure; p=0.007). Most of the papillary ADC were of the TRU (10/21, 47.6%) and 19p-depleted transcriptional (9/21, 42.9%) GES (p=0.026). 46% (41/89) of acinar ADC tumors were in the TRU-GES compared to the solid enriched (18/78, 23.1%) and 19p-depleted transcriptional (18/63, 28.6%) GES (p=0.005). When the oncogene positive group was defined including KRAS, EGFR, ALK, RET, ROS1, BRAF, ERBB2, HRAS and NRAS, there was a higher percentage of solid ADC in the oncogene negative (30/93, 32.3%) compared to the oncogene positive group (28/137, 20.4%, p=0.046). The highest percentage of solid ADC was found in the solid-enriched GES (47/78, 47.4%) compared to the 19p-depleted transcriptional (17/63, 27%) and TRU GES (4/89, 4.5%) (p<0.001). Invasive mucinous ADC correlated with KRAS (but no EGFR) mutations (67%) compared to other ADC (28%, p=0.02) and also lacked elevation of TTF-1 (p=0.007). GES was associated with histologic grade: high grade with solid-enriched GES and intermediate/low grade with TRU GES (p<0.001). Figure 1

Conclusion
Our data reveal multiple correlations between molecular (mutation and GES) and histologic (subtyping and grade) features. This reveals insights into the biology of these tumors in particular genetic characteristics of the high grade tumors which may lead to better understanding of why these are more aggressive tumors.

Background
Non-small-cell lung cancers (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangement are highly sensitive to the ALK kinase inhibitor crizotinib, but drug resistance invariably emerges. Morphological transformation from adenocarcinoma to SCLC represents one acquired resistance mechanism to epidermal growth factor receptor tyrosine kinase inhibitors. We present the case of transformation to sarcomatoid carcinoma in ALK-rearranged adenocarcinoma which developed acquired resistance to crizotinib.

Methods
not applicable

Results
A 32-year-old man presented with cough and bloody sputum. Computed tomography (CT) showed a mass in the S6 segment and diffuse consolidation throughout the lower lobe of the left lung. Transbronchial lung biopsy revealed adenocarcinoma with lymphangiosis. Immunohistochemistry (IHC) showed ALK protein expression and break-apart fluorescent in-situ hybridization (FISH) showed ALK gene rearrangement. First-line chemotherapy with cisplatin and docetaxel was started. After tumor progression, the patient was enrolled in the clinical trial and was allocated to the pemetrexed arm. Subsequently, he was enrolled in other trial to receive crizotinib in July 2011. After partial response was observed, a nodule in the S9 segment developed to 2cm in February 2012, and crizotinib was discontinued. CT scans performed after 4 cycles of carboplatin and gemcitabine showed a mixed response, with improvements in lymphadenopathy and lymphangiosis but progression of the mass in S9. CT-guided core-needle biopsy revealed ALK-positive atypical cells but it was impossible to distinguish histological types because of degeneration and necrosis. Thereafter, carboplatin, paclitaxel, and bevacizumab were administered, but the same mixed response was observed. The mass in S9 increased rapidly and reached 7 cm. 　Left lower lobectomy was performed. The primary tumor in S6 was diagnosed as adenocarcinoma positive for thyroid transcription factor (TTF)-1 immunostaining, whereas the tumor in S9 was TTF-1-negative sarcomatoid carcinoma. ALK was positive with IHC in both tumors, and FISH revealed high-level gene amplification of the ALK fusion gene only in the sarcomatoid carcinoma. Reverse transcriptase polymerase chain reaction revealed the same variant of echinoderm microtubule-associated protein like 4-ALK (E13; A20) and it indicated that these tumors have the same origin. Moreover, in the sarcomatoid carcinoma, DNA sequencing revealed no additional resistance point mutations from ALK exon 20 to exon 23. Brain metastases occurred 2 months after pulmonary resection and he underwent brain surgery. The tumor was diagnosed as sarcomatoid carcinoma. Ten days later, he died due to exacerbation of lymphangiosis To discuss potential epithelial-to-mesenchymal transition (EMT), we performed E-cadherin and keratin staining as epithelial markers, and vimentin staining as a mesenchymal marker in 4 specimens. The specimens were pre-crizotinib specimen in S6, surgical specimen in S6, rebiopsied specimen in S9 after carboplatin and gemcitabine, and surgical specimen in S9. Rebiopsied specimen in S9 was unevaluable for IHC staining because of degeneration and necrosis. All of the 3 evaluable specimens showed positive expression of vimentin and only surgical specimen in S9 showed negative of epithelial markers.

Conclusion
The transformation from adenocarcinoma to sarcomatoid carcinoma could be interpreted as kind of EMT. This transformation might represent a novel acquired resistance mechanism to crizotinib, although there is another possibility that subsequent chemotherapies induced this transformation.

Background
Patients with non-small cell lung cancer (NSCLC) harboring sensitizing mutations in epidermal growth factor receptor (EGFR) benefit from treatment with EGFR tyrosine kinase inhibitors. As most patients with NSCLC present with advanced-stage disease and are not candidates for surgical resection, somatic mutation testing is often performed on small biopsy and cytology specimens. Compared to resection specimens, the suitability of these specimens is not well established. We aimed to explore the suitability of small biopsy and cytology specimens for mutation testing in NSCLC.

Methods
We undertook a retrospective review of NSCLC mutation testing cases performed at Royal Prince Alfred Hospital, Sydney, from March 2012 to May 2013. Mutation testing was requested by the treating physician. DNA was extracted from formalin-fixed, paraffin embedded tissue and a multiplex PCR assay (OncoCarta Panel v1.0) used to identify mutations in 19 oncogenes including EGFR, KRAS, and BRAF. The results were analyzed on the Sequenom MassArray platform. Fragment analysis was also undertaken to assess for exon 19 deletions.

Results
Mutation testing was undertaken on 151 NSCLC specimens, including 44 (29.1%) resection specimens (27 lung resection specimens and 17 metastatic site resections), 67 (44.4%) small biopsy specimens, and 40 (26.5%) cytology specimens. Overall, EGFR mutations were detected in 32/151 (21.2%) cases, KRAS mutations in 29/151 (19.2%) cases, and BRAF mutations in 3/151 (2%) cases. Mutations were detected in 25/44 (56.8%) resection specimens, principally lung resection specimens (19/27, 70.4%), 26/67 (38.8%) small biopsies and 13/40 (32.5%) cytology specimens. The mutation rate was significantly lower in small biopsies (p=0.006) and cytology specimens (p=0.002), compared to lung resection specimens. Specifically, EGFR mutations were identified in 13/44 (29.5%) resection specimens, again mainly in lung resection specimens (10/27, 37%), 9/67 (13.4%) small biopsies and 10/40 (25%) cytology specimens. Compared to lung resection specimens, the proportion of EGFR mutation positive cases was significantly lower in small biopsy (p=0.01), but not in cytology specimens (p=0.29). One paired cytology and lung resection specimen from a single patient was available and both specimens confirmed the presence of an L858R EGFR mutation.

Conclusion
Mutations, including EGFR mutations, were most frequently detected in lung resection specimens. Compared to lung resection specimens, the EGFR mutation rate was significantly lower in small biopsy, but not in cytology specimens. This suggests that cytology specimens are more likely to be adequate for mutation testing than small biopsies such as core and bronchial biopsies. However, we cannot exclude bias in this study from differing referral patterns which may affect these results. Careful assessment of DNA quality and quantity is important for all specimens, particularly small biopsy specimens, to reduce the risk of false positive or negative results.

Background
ALK fusion is a unique gene transversion detected among lung adenocarcinomas. It emerged as a target for cancer therapy, but little is known how this genomic abnormality is created. To unveil the underlying mechanisms leading to gene fusion, we compared the genomic structures of the two groups using SNP-array allelokaryotyping analysis.

Methods
35 ALK fusion positive and 95 ALK fusion negative cases were involved in this study. Immunohistochemical staining and multiplex RT-PCR was employed for screening and confirmation. Chromosome 2p were closely examined using SNP-array based allelokaryotyping.

Results
Copy number changes of the regions including ALK and EML4 were detected among ALK fusion positive tumors (10/35, 29%) in contrast with ALK fusion negative tumors (0/95, 0%). In other words, the genomic regions unnecessary to constitute each fusion gene variants were deleted in ALK fusion positive tumors. And some of them showed copy number gain of fusion gene. In addition, clustered genomic number changes within 2p were more frequently encountered in ALK fusion positive tumors compared with fusion negative ones.

Conclusion
Copy number changes within the genomic region including EML4 and ALK are particular findings in ALK fusion positive tumors. In addition, genomic structure of the short arm of chromosome 2 was more unstable than ALK fusion negative tumors. We speculate that clustered chromosomal rearrangements of the short arm of chromosome 2 contribute to EML4-ALK gene fusion.

Background
The distinction between typical (TC) and atypical carcinoids (AC) is currently based on histologic criteria reported by Travis and al., then accepted by WHO classification and widely used today. The crucial microscopic features that distinguish TC from AC are mitotic activity and necrosis. TC has fewer than 2 mitotic figures/2mm[2 ], whereas AC has 2 to 10 mitoses/2mm[2] and/or small foci of necrosis. The aim was to analyze the microscopic features and immunohistochemical (IHC) profile of TCs and ACs, and to identify the other pathological criteria that could be simple, and reproducible, as well as helpful in daily practice of surgical pathology and usefulness in differentiation between both of them.

Methods
We retrospectively collected 236 cases of resected BPC from 1998 to 2011 at National Tuberculosis and Lung Diseases Research Institute. All tumors were reclassified according to the 2004 WHO classification. The clinicopathological features were correlated and survival analysis were performed. We evaluated size and location of tumors (central or peripheral), depth of bronchial invasion, destruction of bronchial cartilage, tumor invasiveness, the infiltrative growth of the adjacent normal architecture, presence of pleural, perineural and vascular invasion. We also assessed cellular atypia, growth pattern, cellular morphology, especially oncocytic and clear cell, as well as spindle-cell components. The expression of a range of antigens including markers of epithelial differentiation (cytokeratins: AE1/AE3 and 19, TTF-1, napsin A), neuroendocrine markers (chromogranin A, synaptophysin, NCAM/CD56), peptide products (calcitonin, serotonin) and antigens involved in cell proliferation and death (Ki-67, p53, Bcl-2, CD117) were studied.

Results
After reclassification, 8 cases were diagnosed as LCNEC, 102 tumors (44,7%) were classified as TC and 126 (55,3%) as AC. Most tumors are localized centrally (73,7%) and occurred in females (69%). AC were larger than TC (2,54 vs 1,9 cm). Solid and insular pattern, medium and high cellular atypia, oncocytic component, centrally located tumors with cartilage destruction, invasion of peribronchial tissue and/or adjacent lung parenchyma correlated with AC. Mitotic activity was one of most accurate method of diagnosis TC and AC but more advantageous would be increasing a number of mitoses figures to 2 for TC and to ≥3/2mm[2] for AC. AC more often revealed positive reaction with CK19 and higher cellular index for p53. Routinely staining for proliferative index (PI) with Ki-67 is recommended, for TC ≤4% and for AC >4%. Immunoreactivity of broad-spectrum cytokeratin was observed in 95% cases, more then 50% showed „dot-like“ reactivity. Peripherally located tumors were distinctly different morphologically and IHC than centrally carcinoids. Peripherally tumors were smaller (1,9 vs 2,4cm), usually not-well demarcated, with solid or insular pattern and spindle-cell component as well as fibrosis. In contrast to centrally tumors, they showed expression of TTF-1, serotonin and Bcl-2 but sparsely CK19.

Conclusion
The following pathological features should be evaluated in diagnosis of AC: localization, the infiltrative growth, solid and insular pattern, high grade atypia, oncocytic and spindle-cell components, mitotic figures and IP (Ki-67). We proposed for TC 0-2 mitosis/2mm[2] and PI ≤4%, for AC ≥3 mitosis/2mm[2] and PI >4% and/or foci of necrosis.

Background
Bronchial washings/brushings (BW/B) are often used for early screening and cytological diagnosis of lung cancer. We examined the possibility of EGFR testing on cytology samples, as compared to bronchial biopsy sample.

Methods
116 BW/B samples with non-squamous histology were submitted to our department for EGFR mutation testing at Chonnam National University Hospital within 8-month period. Biopsy samples was concurrently submitted for histologic diagnosis. We used the PNA clamping method for EFGR mutation test.

Results
Histologic diagnosis were 103 cases of adenocarcinomas and 13 cases of NSCLC, not otherwise specified (NOS). Each sample was assessed by a pathologist for adequacy and DNA content. At BW/B samples, 22 cases showed exon 19 deletion, 13 exon 21 mutation, 79 were wild type and 2 failed. The EGFR mutation rate using BW/B sample was 30.2%. At bronchial biopsy samples, 23 cases showed exon 19 deletion, 13 exon 21 mutation, 72 were wild type and 12 failed. The EGFR mutation rate using bronchial biopsy sample was 31.0%. Mutation detection cases were nearly identical in both samples. But, in only one case, exon 21 mutation was detected in biopsy sample, not in BW/B sample. The median DNA content for BW/B samples compared to biopsy samples were 3.7ug and 3.2ug. The failure rate for cytology samples was lower than biopsy samples.

Conclusion
BW/B samples are superior to bronchial biopsy samples in terms of DNA quantity and rate of failure. Moreover, in case of inadequate biopsy sample, BW/B samples were a substitute material for EGFR mutation test.

Background
The incidence of EGFR mutations has been systematically analyzed in a large cohort in Germany within the REASON trial. However, systematic data on KRAS, BRAF, ALK, and p53 within the same cohort have not been published in German cohorts of patients with lung cancer. Therefore we studied the incidence of these alterations in 159 patients from a single center and correlated these with clinical characteristics and survival.

Methods
159 patients from a single center diagnosed with lung cancer were studied for the presence of EGFR mutations, ALK rearrangements, KRAS codon 12/13/61 and BRAF V600E and G469A, as well as inactivating p53 mutations. Methods for the detection of EGFR mutations included Sanger Sequencing and hybridization based COBAS testing. ALK rearrangements were either tested by RT-PCR or ALK-FISH (break apart probe, Vysis). BRAF mutations were detected by allele specific PCR, KRAS and p53 by Sanger Sequencing

Results
159 consecutive patients at the lung cancer center of the Pius-Hospital Oldenburg were studied. In all cases EGFR mutations status was successfully determined. 33/159 (21%) had EGFR mutations, of which 3 had primary resistance mutations. 5/132 successfully studied pts had ALK rearrangements (3,7%). 29/142 (20%) successfully studied for KRAS mutations had codon 12 or 13 mutations. 2/136 (1,4%) successfully studied for BRAF mutations had G469A (2) mutations, V600E mutations were not observed. p53 mutations were observed in 47% of successfully studied pts (21/45 pts). Just analyzing the 60 never or light smokers (< 100 cigarettes lifelong or < 10 packyears and ex-smoker), revealed 23/60 (38%) EGFR mutations, 4/44 (9%) ALK rearrangements, 4/49 (8%) KRAS mutations, 1/49 (2%) BRAF mutations and 7/19 (37%) p53 mutations, demonstrating that EGFR and ALK were overrepresented in never-light smokers, whereas BRAF, KRAS and p53 mutations were overrepresented in smokers. ALK, EGFR, KRAS and BRAF mutations were mutually exclusive in this patient population. However p53 mutations were observed in pts with activating EGFR mutations in 7/15 successfully studied cases. Outcome in the different subgroups will be presented at the meeting.

Conclusion
EGFR and ALK mutations were overrepresented in never-light smokers, BRAF and KRAS mutations were underrepresented. P53 mutations occurred independently of smoking status in combination with EGFR mutations, but not ALK- translocations. OS data will be presented at the meeting.

Background
The vast majority of non small cell lung cancers (NSCLC) presents as advanced disease and histological diagnosis is widely based on small biopsy or cytological samples. Recently, the adoption of new pharmaceutical agents targeting individual histotypes requires a precise subtyping of NSCLC. This task is often difficult according to morphological criteria only and the use of immunohistochemistry (IHC) is recommended for small samples or undifferentiated tumors to define the most probable histotype. However, the real impact of IHC characterization of NSCLC-Not otherwise Specified (NOS) in terms of response to therapy and outcome (compared to cases classified by morphology, only) is not well established.

Methods
A large series of 224 advanced "non-squamous" NSCLC diagnosed from year 2005 to 2010 on small biopsy or cytological samples and homogeneously treated, was retrospectively selected, all with adequate follow-up data available. All diagnoses were reviewed resulting in two groups of adenocarcinoma (ADC) and NSCLC-NOS. The latter were further characterized by IHC to identify the most probable differentiation lineage. Disease Control Rate (DCR) and Response Rate (RR) were calculated and Overall Survival (OS) curves were analyzed by Kaplan Meier.

Results
After review 120/224 (53.6%) cases were ADC based on morphological examination, only (“ADC morphology”) and 104/224 (46.4%) remained NSCLC-NOS. In terms of response to therapy no significant difference was found between the two groups (“ADC morphology” had DCR= 0.66 and RR=0.31; NSCLC-NOS had DCR=0.64 and RR=0.35; Chi-Square p=0.83). The NSCLC-NOS cases that underwent IHC profiling resulted in 66/104 (63.5%) cases that had an ADC phenotype (“NSCLC favor ADC”) and 38/104 (36.5%) cases that lack ADC features (including 5 “NSCLC favor squamous carcinoma” and 33 “NSCLC null phenotype”). The “NSCLC favor-ADC” had DCR and RR similar to “ADC morphology” group (Chi-Square p=0.23), while the “non-ADC” NSCLC group had significantly different both DCR=0.47 and RR=0.29 (Chi-Square p=0.006). Survival curves confirmed no difference in terms of survival between the “ADC morphology” and the “NSCLC favor-ADC” groups, while showed a significantly poorer survival for the “non-ADC” NSCLC group with respect the other two groups (median survival: 8.5 vs 12.3 months, respectively; HR=0.5999; p=0.018).

Conclusion
These preliminary findings indicate that the practice of minimizing the NSCLC-NOS diagnoses by means of IHC has an impact on chemotherapy response. Stratifying such tumors by IHC, cases having an ADC immunoprofile had response rates comparable to those of morphologically diagnosed ADC, thus supporting the value of IHC to maximize lung cancer histological typing in the perspective of obtaining the best response to therapy.

Background
EGFR and KRAS mutations guide treatment selection in NSCLC patients. With 75% of newly diagnosed cases at advanced stages, mutational analysis is performed in small samples: core needle biopsies (CNB) and fine needle aspiration (FNA). Both the cobas EGFR and KRAS test are CE-IVD. No validation studies of the cobas tests have been performed using cytological smears but it is important to extend the benefits of molecular targeted therapy while preserving tissue for additional marker testing.

Methods
EGFR and KRAS mutation status were studied in 140 non-selected samples from NSCLC patients: 49 CNB, 91 FNA. DNA was extracted directly from one stained smear in FNA samples and one 5-micron section in CNB using the cobas DNA Sample Preparation Kit. All samples contained ≥ 50% tumor cells. DNA concentration and ratio (A260/280) were recorded. All cases were studied using the cobas EGFR and KRAS mutation tests. Moreover, 123 and 125 cases were analyzed respectively for EGFR and KRAS mutational status using Sanger sequencing.

Results
CNB diagnosis was: 29 SqCC, 17 AC, 1 BAC, 1 adenosquamous, 1 NSCLC-NOS. FNA diagnosis was: 64 AC, 13 SqCC, 3BAC, 2 LCC, 2 adenosquamous, 7 NSCLC-NOS. DNA concentrations from CNB were higher and significantly different than DNA from FNA (p<0.001,U Mann Whitney). DNA quality was similar between sample types. Mutational analysis is shown in Table 1. Mutation rate for EGFR was 15.9% and 8.2 % and for KRAS 37% and 16.7% in FNA and CNB, respectively, but should be considered within the context of tumor type. 8.6% and 36.4% of the cases were below the manufacturer’s recommendations of 2ng/µl and 4ng/µl for EGFR and KRAS testing, respectively. Invalid rates were 2.1% (3) for EGFR and 5.5% (9) for KRAS. These results may be due to low DNA concentration (EGFR) or technical performance (KRAS) that was resolved with later samples. Sequencing invalid results were 42.3% for EGFR and 0.8% for KRAS. Table 1.

		FNA	CNB
EGFR	WT	74	45
	Exon 19 Del	8	2
	Exon 20 Ins	0	1
	L858R	5	1
	Exon 18 G719X	1	0
	Invalid	3	0
KRAS	WT	51	40
	12/13 Mutation	29	8
	61 Mutation	1	0
	Invalid*	8	1

* By sequencing 6 WT and 3 mutated

Conclusion
In addition to FFPE samples, identification of EGFR and KRAS mutations in FNA and CNB samples using cobas EGFR and KRAS Mutation Tests is faster, easier to use, and reproducible. Although DNA concentrations were lower from FNA, DNA quality was similar to CNB and provided valid results. Sequencing had lower sensitivity and was more time-consuming. Careful sample management, especially for FNA, by the pathologist is critical to ensure quality and to optimize DNA yields.

Background
The identification of EGFR mutations as a driver for oncogenic proliferation in Non-Small Cell Lung Adenocarcinoma (NSCLC), in parallel with the development of the tyrosine kinase inhibitors has opened the way to “theranostics”. However, as more targets are identified and more targeted inhibitors are marketed, the medical community now needs to interrogate multiple genes to generate an accurate molecular profile for each individual tumor and determine matching targeted therapeutics. The development of the Next Generation Sequencing (NGS) has opened a new area offering for more comprehensive screening of somatic mutations across 10s to 100s of genes. However, its application in routine clinical practice within the individual therapeutic setting remains impractical due to the large data sets produced, as well as the high potential for generating false positive mutations Therefore atargeted approach seems more appropriate when screening for actionable somatic mutations. MALDI-TOF mass spectrometry (MassARRAY® System) is a flexible high-throughput solution that can easily adapt to newly discovered mutations as well as detect minority alleles of mutated DNAof large sample sets.

Methods
We have evaluated the LungCarta™ Panel, a panel targeting 213 somatic mutations in 26 genes. The method relies on multiplex PCR followed by single base extension and analysis using MALDI-TOF Mass Spectrometry.Genes such as EGFR, KRAS, BRAF, ERBB2 or PI3KCA,MAP2K1, EPHA3, NTRKs, STK11, TP53 and DDR2are well-represented.

Results
For verification of this panel we have screened a set of 37 lung metastatic adenocarcinoma DNA isolated from formalin fixed paraffin embedded (FFPE) biopsies.These samples were previously characterized for EGFR, KRAS, ERBB2, PIK3CA and BRAF. We identified a total of 26 mutations in 23 of the 37 samples (62%) localized in 10 genes. 100% of the previously known mutations were verified and an additional 12 mutations were identified, 10 of these mutations were located in genes not previously screened. We were able to significantly reduce the DNA amount to as little as 24ng. To further validate the LungCarta panelresults we selected 15 of the samples to be analyzed using NGSand theTruSeqAmplicon - Cancer Paneland11 of the samples generated high quality libraries that could be sequenced. Using this NGS approach we validated the hits obtained by LungCarta. When comparing the two methods, NGS has a quite complicated workflow and we identified more than 50 positive hits for each sample requiring a large bioinformatics effort in order to separate true positives hits from false positive hits. This problem was not seen using the LungCarta where the standard turnaround time for each sample batch was less than 24 hours and the panel showed excellent robustness using DNA obtained from FFPE.

Conclusion
We have now applied the LungCarta™ panel to more than 400 patients with NSCLC and were able to not only treat patients promptly, but also enter some others in clinical trials We have identified targets that could be very interesting in the future. Compared to the NGS approach,LungCarta offers a relatively simple workflow with quick turnaround time and minimal sample input requirements.

Background
The advent of specific therapies for non small cell lung cancer (NSCLC) based on individual tumour genotype has impacted the development of high throughput genomic profiling strategies. A single platform designed for the synchronous screening of multiple mutations across different genes can potentially enable molecular profiling in samples of limited tumour tissue such as small biopsy samples.

Methods
Haematoxylin and eosin-stained sections and accompanying reports were reviewed from patients diagnosed with NSCLC (2008 to 2012) in Greater Manchester, U.K. Samples with less than 20% tumour cell content (TCC) were macrodissected to increase the final TCC. In each case DNA was extracted manually from 1 5µM curl/section using the cobas® DNA Sample Preparation Kit. Mutation analysis was performed with the Sequenom LungCarta™ Panel which enables screening of 214 mutations in 26 genes, and utilises multiplexed polymerase chain reactions, single base extension reactions and mass spectrometry (Sequenom MassARRAY® platform).

Results
Results Sixty cases comprising 47 lung biopsies, 1 wedge resection, 6 lymph node biopsies, 4 pleural biopsies, 1 brain biopsy and 1 pericardial effusion were classified as 21 adenocarcinomas (ACA), 17 squamous cell carcinomas (SCC), 8 NSCLC favour ACA, 10 NSCLC favour SCC, 1 adenosquamous carcinoma and 3 NSCLC not otherwise specified (NOS). Mutations were successfully detected at a mutant allele frequency of 10% and definite mutations were reported in 28 cases (47%). Possible mutations of low allele frequency or uncertain significance were detected in an additional 15 cases (25%) and also in 10 cases with a definite mutation. In total 32 definite and 39 equivocal mutations have been detected and are currently being validated by a combination of pyrosequencing, next-generation sequencing and immunohistochemistry (IHC).

Table 1. Unequivocal mutations detected according to histological subtype. ([a]Includes double mutant; TP53 and MAP2K1, [b]includes triple mutant; 2 TP53 and 1 KRAS, [c]includes double mutant; KRAS and MET)

No. of definite mutations detected	No. of mutated samples	ACA	NSCLC favour ACA	SCC	NSCLC favour SCC	NSCLC NOS	% of mutations detected in all ACA or SCC	Comment
13 TP53	12	3[a]	2[b]	5	1	1	17 % ACA 22% SCC	1 confirmed by next generation sequencing. 7 of 8 tested cases were strongly positive for P53 IHC
12 KRAS	12	8[c]	1[b]		3		31% ACA 11% SCC	7 confirmed by pyrosequencing
3 MET	3	2[c]	1				10% ACA 0% SCC	1 confirmed by next generation sequencing
2 EGFR	2	2					7% ACA 0% SCC	2 previously detected by Sanger sequencing
1 EPHA5	1			1			0% ACA 4% SCC	Moderately differentiated SCC
1 MAP2K1	1	1					3% ACA 0% SCC	Poorly differentiated ACA TTF1+

Conclusion
The MassARRAY® system of testing for multiple mutations is a sensitive method that facilitates the optimal use of tumour DNA present in small specimens, and can detect concurrent mutations with the potential to influence responses to targeted therapies. Unequivocal mutations were reported in 59% and 37% of cases diagnosed/favoured as ACA and SCC respectively. This may reflect the LungCarta™ panel design, which was based on mutations detected in ACA.

Background
Pathologically, signet ring cells (SRC) describe singly dispersed tumor cells with intracytoplasmic mucin vacuoles, which eccentrically displace and compress the nucleus. SRCs are traditionally associated with adenocarcinoma of the gastrointestinal tract and are rare in lung adenocarcinoma (LACA). Patients with primary LACA with SRC features (SRC+) have been associated with poor clinical outcome and ALK gene rearrangement (ALK+). However, the impact of SRC+ on clinical outcome is not well delineated. We systematically studied LACA survival outcomes for the impact of SRC status.

Methods
Three distinct groups of surgically treated patients with LACA (n=763) that were followed for ≥5 years were reviewed: never smokers (n=266), 2006-2007 cohort (n=222), and smokers enriched for various degrees of lepidic growth pattern (LGP, n=275). Two pulmonary pathologists reviewed all cases; SRC+ tumors were defined as having >10% SRCs, agreed by both pathologists. SRC+ tumors were TTF1+, and generally cytoplasmic mucin+ and CDX2-. ALK immunostain was performed on all SRC+ cases, and ALK status was confirmed by FISH for cases with any degree of immunoreactivity. Impact of SRC+ on patients’ survival outcomes (overall and disease-free, OS and DFS) were analyzed using Cox models (by hazard ratio, HR) separately for the three groups, with careful evaluation of known prognostic factors: age at diagnosis; gender; smoking status; lung cancer history; tumor subtype; grade and stage; and treatment (surgery, chemotherapy and/or radiation).

Results
In the total of 763 patients (61% women, mean age at diagnosis 68 years), 53 (7%) were SRC+. In never smokers (73% women), 9% were SRC+; 33% of the SRC+ were ALK+ vs. 5% among the SRC- cases (p<0.0001). In the 2006-2007 cohort (55% women), 9% were SRC+; in LGP-smokers (54% women), 3% were SRC+. Across all three groups, SRC+ tumors were more likely to occur in men and have higher stage. Univariate analysis showed SRC+ never smokers had shorter survival: median DFS was 2.4 years (vs. 5.2 in SRC- never smokers, p=0.0004), and median OS was 3.7 years (vs. 7.6, p=0.0064). However, multivariate analysis did not confirm a significant impact of SRC+ on survival. In contrast, for the other two groups, crude 5-year survival was 6%-27% decreased in SRC+ cases compared to SRC- cases (none reached statistical significance); however, multivariate analysis revealed a 2-fold higher mortality (HR=2.30, 95% CI=1.01-5.27, p=0.048) for smokers with SRC+ tumors.

Conclusion
Based on results from three patient groups, we confirmed that SRC+ is significantly associated with ALK+. Worse survival in patients with SRC+ tumors was observed in never smokers by univariate analysis. A potential negative impact of SRC+ tumors on OS in LGP-smokers was only uncovered after adjusting for known prognostic factors. These results need to be furthered confirmed.

Background
Some of molecular pathways have been shown to have prognostic impact in non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) mutations predict the effect of EGFR tyrosine kinase inhibitors. KRAS is also critical oncogene, and it has been reported that KRAS pathway might interact with EGFR. But, the role of KRAS in NSCLC is unclear. We investigated the relationship between EGFR and KRAS mutation status and clinicopathological features in NSCLC.

Methods
A total of 383 consecutive patients with NSCLC underwent complete resection from 2006 to 2008 were examined retrospectively. The expression of EGFR and KRAS were evaluated by tissue microarray.

Results
The mutations of EGFR and KRAS were detected in 181/383 (47.3%) and 32/383 (8.4%) patients, respectively. On analysis of EGFR mutations, female were 107/181 (59.1%) and 51/202 (25.2%), adenocarcinoma were 177/181 (97.8%) and 123/202 (60.9%), no vascular invasion were 147/181 (81.2%) and 110/202 (54.5%), and non-smoker were 99/181 (54.7%) and 41/202 (20.3%) patients in EGFR mutation and wild type patients, respectively. As a result, EGFR mutation was found more frequently in female, adenocarcinoma, no vascular invasion, and non-smoker. The number of patients with pathological T1a were 49/181 (27.0%) and 42/202 (20.8%), T1b were 63/181 (34.8%) and 41/202 (20.3%) in EGFR mutation and wild type patients, respectively. Moreover, average tumor diameter was smaller in patients with EGFR mutation (2.68 cm±0.92) than wild type (3.34cm±1.70) (P<0.001). There were no differences in clinicopathological characteristics between exon19 and 21 EGFR mutations. In contrast, there were no significant differences between KRAS mutation and gender, histopathological type, vascular invasion and.smoking. Although KRAS status was not correlated with pathological T factors, average tumor diameter was larger in patients with KRAS mutation (3.49 cm±2.00) than wild type (2.98 cm±1.35) (P<0.001).

Conclusion
Our results suggest that EGFR mutation may suppress vascular invasion, and tumor growth, on the other hand, KRAS mutation may correlate with activation of tumor growth.

Background
The frozen section diagnosis is often performed in the sublobar resection of lung tumor. As no standard of preparation method for the frozen section is proposed, its methodology differs depending on institutions. In this study, we examine appropriateness of our preparation method for a resected specimen with a small adenocarcinoma by comparing between radiological and pathological tumor size.

Methods
We retrospectively reviewed the records of 59 resected lung specimens for the frozen section diagnoses (54 wedges and 5 segmentectomies) of lung adenocarcninomas from January to December 2008. After the specimen was well inflated with saline using injector, the pathologist cut it into segments with a width of 3-5mm and immersed them in saline. Taking the segment with maximum diameter of tumor as a sample, the pathological tumor sizes were measured (I) macroscopically by using metal straight ruler, (II) microscopically on the frozen section, and (III) microscopically on the permanent paraffin section. For obtaining the stereoscopic tumor size (Ⅱ and Ⅲ), we used a stereoscopic image analysis software, Leica Application Suite (Leica Microsystems; Tokyo, Japan). CT tumor size was measured by using 1-2mm thin-section CT (X-Vigor/Real or Aquillion, Toshiba Medical Systems, Tokyo, Japan). We obtained the tumor shadow disappearance rate (TDR) by comparing tumor size on the lung and mediastinal window image, to classify 59 cases into two groups according to TDR; TDR≧50% defined as the air-containing type (Group A, n=44) and TDR＜50% as the solid-containing type (Group S, n=15). We also calculated the diremption rate (DR%) between the pathological and the CT tumor size (DR% = |CT tumor size － each pathological tumor size|/CT tumor size×100(%)) and compared Group A and Group S.

Results
Mean CT tumor size and its standard deviation(SD) were 18.36±5.23mm, and mean pathological tumor sizes and SD of Ⅰ, Ⅱ, and Ⅲ were 17.17±6.12, 14.29±3.66, and 14.23±4.38mm, respectively. Mean CT tumor size was statistically larger than that of Ⅱ and Ⅲ (p<0.001 using Paired t-test). All the three pathological tumor sizes were correlated to the CT tumor size by Pearson’s correlation analysis (correlation coefficient were 0.766, 0.700, and 0.682, respectively). DR% of Ⅱ and Ⅲ were significantly higher in Group A than Group S by Mann-Whitney U-test (Mean DR% of group A / S (p-values) of Ⅰ, Ⅱ, and Ⅲ were 17.0/13.8% (p=0.196), 25.8/19.3% (p=0.093), and 27.3/15.5% (p=0.032) , respectively).

Conclusion
There was a strong correlation between CT tumor size and each pathological tumor size, which shows that our preparation method of the specimen for the frozen section is appropriate to obtain sufficient information about the lung tumor. Furthermore, we found that the pathological tumor size is considerably underestimated by measuring tumor size on the frozen or permanent paraffin section, especially the tumor classified as “air-containing type” including adenocarcinoma with good prognosis. It is therefore important to inflate the lung specimen sufficiently and to transfer it to microscopical examination without tissue shrinking.

Background
Distinction between different subtypes of non–small cell lung carcinoma (NSCLC) particularly separating squamous cell carcinoma (SCC) from non-SCC is important due to the availability of specific targeted therapy based on histologic subtypes. Recent molecular testing guideline for selection of lung cancer patients for epidermal growth factor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor therapy from the College of American Pathologists (CAP), International Association for the Study of Lung Cancer (IASLC) and Association for Molecular Pathology (AMP), recommend that in the setting of fully excised lung cancer specimens, EGFR and ALK testing is not recommended in lung cancers that lack any adenocarcinoma component, such as pure SCC (Lindeman et al, J Mol Diagn 2013, 15:1-39). However, more than two-thirds of lung cancer presents as advanced stage disease and cytology specimens may only be available in most of these cases. Accurate distinction between SCC and non-SCC can be challenging in these cytology specimens due to limited cellularity. We report our institutional experience regarding the diagnostic accuracy of classifying SCC in cytology preparations compared with histopathological follow-up.

Methods
A retrospective review of the cytology specimens diagnosed as squamous cell carcinomas was carried out from January 2011 – June 2012 from our cytopathology and surgical pathology databases. All cases were correlated with subsequent histopathological diagnoses, immunohistochemical (IHC) and molecular analyses.

Results
A total of 200 histopathological specimens diagnosed as squamous cell carcinoma (SCC) were retrieved from our electronic medical records. 30 were excluded due to multiple specimens from the same patient. Corresponding cytology specimens including fine needle aspiration (FNA) specimens, bronchial brushings and bronchial washings were available in 88/170 (52%) cases. Out of these 88 cytology specimens, a diagnosis of malignancy was made in 58 (66%) specimens; these were subcategorized into (1) definite diagnosis of malignancy (32/58=55.2%), (2) favor tumor subtype (14/58=24.1%), (3) unclassified (9/58=15.5%) and (4) suspicious for malignancy (3/58=5.2%). Overall, the diagnoses of malignancy was made in 57/58 (98.3%) while the accurate diagnoses of squamous cell carcinoma was made in 52/55 (95%) cytology specimens. IHC was employed in cases 21/88 (23.9%). Molecular testing was performed on 12/170 (7%) specimens. Molecular testing was successful in these cases with mutations identified in two cases.

Conclusion
Our study demonstrates that cytology specimens are an excellent source of making a reliable, quick and accurate diagnosis of lung squamous cell carcinomas in 95% of cases and can serve as an excellent source for IHC and molecular analyses, if necessary.

Background
Adenocarcinoma (ADC) of the lungs may harbor EGFR- and KRAS-mutations, which are relevant for treatment decisions. Approximately 35% of non-small cell lung cancer (NSCLC) biopsies are diagnosed as not-otherwise-specified (NOS).To improve segregation between ADC and squamous cell carcinoma (SqCC), the classification of lung cancer was updated in 2011, adding immunohistochemistry (IHC) for p63 and TTF-1 to the diagnostic algorithm. The aim of our study was to investigate the hypothesis, that additional IHC reliably delineates lung cancer harboring EGFR- and KRAS-mutations.

Methods
From an institutional lung cancer database of specimens routinely analyzed for the presence of EGFR- or KRAS-mutations (n=816), cases harboring a mutation were selected (n=343) and corresponding original histological diagnoses and IHC for TTF-1, p63 and PAS-D were collected. Cases with a pattern compatible with SqCC were histologically reassessed.

Results
From the 343 cases 25% were resection specimen, 70% biopsy and 5% cytology specimens. 69% of cases had a KRAS-mutation and 31% an EGFR-mutation. IHC-data were conclusive in 89%. The combination of positive TTF-1 and/or mucin stain and a negative p63 stain, favoring ADC, was found in 264 cases (77%). Six (1.7%) specimens were positive for p63 only, favoring SqCC.

Conclusion
The current 2011 classification of lung tumors, based on histology and immunohistochemistry for TTF-1, p63 and mucin, segregates specimens of ADC and SqCC sufficiently well. Our study results support the use of IHC in the diagnosis of lung cancer.

Background
Since IASLC/ATS/ERS reported their new classification for lung adenocarcinoma (ADC), several groups have validated its association with prognosis in early stage. We know do not any study in advanced disease.

Methods
We included 313 patients with stage IIIB and IV histologically confirmed lung ADC from the Instituto Nacional de Cancerología (INCan). All patients received platinum-based chemotherapy (CT) and only 30% received EGFR-TKIs. ADCs were re-classified using the new IASLC/ATS/ERS criteria. Clinical characteristics, mutational profile, response and progression-free survival (PFS) to CT and overall survival (OS) were analyzed.

Results
ADCs were classified as lepidic 6.1%, acinar 36.7%, papillary 8.3%, micropapillary 2.9%, solid 28.1% and 17.9% were unclassifiable. We divided them into two groups: intermediate-grade (lepidic and acinar-predominant) and high-grade (micropapillary, papillar and solid-predominant). The response rate and PFS to CT were better in the high grade group (36.9% vs 25.4% p= 0.034; 6.4 vs 5.5 months p= 0.009, respectively). The OS was better in the high grade group (25 vs 16.8 p= 0.023). In multivariate analysis, factors associated with better OS were ECOG of 0-1, EGFR mutations and high grade group histology. We did not find association between EGFR mutations and this classification.

Conclusion
Unlike early stages, patients with advance disease and with high-grade ADC according to the new classification have longer OS compared with intermediate grade ADC, probably due to a better response to CT.

Background
Aim: We aimed to compare F-18 FDG PET-CT imaging characterictics in non-small cell lung cancer (NSCLC) with and without epidermal growth factor (EGFR) reseptor mutation.

Methods
Methods: A total of 47 NSCLC patients (38 male, 9 female, mean age : 47±10.45 )were included in this retrospective study. All patients underwent EGFR mutation resting and pretreatment F-18 FDG PET-CT scan. The maksimum standardized uptake (SUVmax) of the primary tumor and metastases was calculated for all lesions in all patients. We compared the SUVmax values for primary tumor and metastatic lesions in patients with and without EGFR receptor mutation.

Results
Results: In our study group, there were 17 adeno, 10 squamous, 2 large cell, 1 mixt-type and 17 non-small cell cancer patients. Seven patients had EGFR-mutant and 40 patients had EGFR wild-type tumors. There was a trend for higher SUVmax in primary tumors among patients with EGFR-mutant (mean SUVmax: 14.20±10.40) versus patients with wild-type EGFR (mean SUVmax:11.53±6.46). In patients with wild-type EGFR, the mean SUVmax was 7.05±3.39, 7.83±4.66, 6.10±4.44, 12.83±4.89 for hilar(17 pts), unilateral mediastinal (23 pts), contralateral mediastinal (13pts) and supraclavicular (3 pts) lymph node metastates (LNM), respectively. In 5 patients with EGFR-mutant , SUVmax was 6.48±3.39 for unilateral mediastinal LNM. There was no hilar, contralateral and supraclavicular LNM which can be demonstrated by F-18 FDG PET-CT in EGFR-mutant patients. The mean SUVmax was 7.97±6.67, 8.98±4.31 and 5.85±3.39 for lung (6 pts), bone (9 pts) and adrenal (6 pts) metastases in wild- type EGFR patient group. In EGFR-mutant group , one patient had lung, bone and adrenal metastases in which SUVmax was 4.20, 11.20 and 22.20, respectively.

Conclusion
Conclusion: Higher FDG uptake was found in primary tumors among EGFR-mutant patients than wild-type EGFR patients. In this study group, the incidence of hilar, contralateral mediastinal and supraclavicular LNM were higher in wild-type EGFR group than that in EGFR-mutant group. Bone and adrenal metastases in a patient with EGFR-mutant showed markedly increased FDG uptake. Further analyses with large number of patients are needed to describe a predictive role of FDG uptake on EGFR mutations in NSCLC patients.

Background
Acute infections can sometimes radiologically be suspected to be lung cancer. Only rarely are, however, the mediastinal lymph nodes enlarged. Tularemia is a disease in rodents caused by the bacterium Fransiscella tularensis but it can also infect humans if infective material is inhaled, and typically lung infiltrates and PET-positive nodes persist for a few months. We have not found any good description of this entity in the literature and therefore we describe three such cases.

Methods
During two years, three patients were referred for suspected lung cancer. One was a farmer and two who had cleaned out their summer house after the winter invasion of mice. PET investigation with [18]F-fluorodeoxyglycose (FDG) was strongly positive both in the "tumor" and in the enlarged mediastinal lymph nodes. Bronchoscopy showed inflammatory cells only.

Results
There was a spontaneous regression of the lesions during the investigations and serology proved the etiology.

Conclusion
Like the classical plague, there are two variants of tularemia: peripheral wounds or insect bites can cause the ulceroglandular form, with an ulceration and enlarged local lymph nodes nodes which can suppurate, and inhalation of infectious material (for example, mouse excrements) can cause a localized pulmonary infiltrate and enlarged mediastinal lymph nodes which will readily be mistaken for lung cancer. Diagnosis is by serology; treatment is mainly by tetracyclines, but by the time investigation is started the disease is usually already healing spontaneously. History is very important: has the patient has any contact with mice or other rodents or their droppings?

Background
Quantitative analysis of thoracic computed tomography (CT) scans may be used to assess response to radiation therapy (RT). The purpose was to (1) identify a set of mathematical descriptors of image texture that correlate with the severity of radiologic normal lung tissue changes following RT and (2) quantitatively measure the extent of severity-dependent change in the values of these texture features.

Methods
Twenty-four patients who underwent definitive RT (median dose: 66 Gy, 2 Gy/fraction) for lung cancer were retrospectively identified. For each patient, three CT scans were collected: pre-treatment scan, post-treatment (median: 34 days, range: 8-82 days) scan, and RT planning scan with an associated dose map. Four dose regions (0-10 Gy, 10-30 Gy, 30-50 Gy, and >50 Gy) in the RT dose map were identified and mapped to the post-treatment scan through demons deformable registration. Sixty regions of interest (ROIs) distributed evenly among the four dose regions were automatically identified in the normal lung tissue of each post-treatment scan. An experienced radiologist compared the severity of change in each ROI from pre-treatment to post-treatment and categorized each as containing: 1) no abnormality, 2) mild abnormality, 3) moderate abnormality, or 4) severe abnormality. Twenty texture features that characterized gray-level intensity, region morphology, and gray-level distribution were calculated in all post-treatment ROIs and compared with anatomically matched ROIs mapped to the pre-treatment scan using demons registration. Fitted coefficients for the percent feature value change (ΔFV) between pre-treatment and post-treatment ROIs at each category of visible radiation damage were calculated using linear regression.

Results
Most ROIs contained no abnormality (66%) or mild abnormality (30%). ROIs with moderate (3%) or severe (1%) abnormalities were observed in 9 patients. For 19 of 20 features, significant differences (p<0.05) in ΔFV existed among ROIs assigned to various severity levels. For 12 features, significant differences in ΔFV existed among all four categories of radiation damage (see figure). Compared with regions with no abnormality, ΔFV for these 12 features increased, on average, by 1.6% (95% CI: 1.3-2%), 12% (95% CI: 9-15%), and 30% (95% CI: 19-41%), respectively, for the mild, moderate, and severe abnormality ROI categories.Figure 1

Conclusion
For 12 of the 20 features, ΔFV was significantly different among all categories of visible radiation damage. As severity increased, the mean feature value change from the pre-treatment scan also increased. In future studies, this approach may be used as a quantitative indicator of the severity of acute normal lung tissue damage following RT.

Background
To evaluate the diagnostic accuracy of dynamic contrast enhanced (DCE)magnetic resonance (MR) and diffusion weighted imaging (DWI) sequences for defining benign or malignant character of solitary pulmonary lesion (SPL) in a preoperative setting.

Methods
This study was approved by the local ethics committee; all patients provided written informed consent. First, 54 consecutive patients with SPL, clinically staged (CT and PET or integrated PET-CT) as N0M0, were included in this prospective study. An additional MR examination including DCE and DWI was performed one day before the surgical procedure. Histopathology of the surgical specimen served as standard of reference. Subsequently, this functional method for SPL characterization was validated with a second cohort of 54 patients.

Results
In the feasibility group, 11 benign and 43 malignant SPL were included with a maximal diameter that varied from 3 to 71 mm (mean 23.2 mm). Using the conventional MR sequences with visual interpretation of DCE-MR curves sensitivity, specificity, accuracy were respectively 100%, 55% and 91%. By additional interpretation of quantitative apparent diffusion coefficient (ADC) values (with a cutoff value of 1.52x10-3 mm2/sec for ADC calculated from high b-values (ADChigh) these results improved to 98%, 82% and 94% respectively. In the validation group, with 14 benign and 40 malignant SPL (diameter ranged between 7 mm and 10 cm - mean 26.5 mm), these results were confirmed with a sensitivity, specificity and accuracy of 95%, 79%, and 91%, respectively.

Conclusion
Visual DCE-MR-based curve interpretation can be used for initial differentiation of benign from malignant SPL, while additional quantitative DWI-based interpretation can further improve the specificity.

Background
Pulmonary ground-glass nodules (GGNs) often grow over a long period of time. Elucidating the growth rate of GGNs is of great importance in deciding on follow-up intervals in clinical practice. The objective of this study was to clarify the natural history and tumor growth rate of GGNs after a long-term follow-up.

Methods
We retrospectively studied 121 cases of patients with GGNs, who had more than 50% of ground-glass opacity component and were monitored using high-resolution computed tomography (CT) for >2 years. Factors affecting the time to tumor progression were evaluated using the Kaplan–Meier method and Cox proportional hazard model analysis. Tumor growth rate was evaluated using specific growth rate (SGR), which was calculated using volume-doubling time (VDT) data (SGR = ln 2/VDT).

Results
During a median follow-up period of 59.7 months, GGNs showed enlargement or increase in attenuation in 66 patients and no change in 55 patients. In multivariate analysis using Cox proportional hazard model, the initial mean CT attenuation value > –670 Hounsfield unit (HU) and initial tumor size > 8 mm were independent predictive factors for time to tumor growth (p < 0.0001 and p = 0.0006, respectively). The Kaplan-Meier curves evaluating time to tumor progression, which was divided into 4 parts according to the initial mean CT attenuation value and initial tumor size, showed that the final estimated probability for patients with GGNs with a mean CT attenuation value < –670 HU and tumor size < 8 mm was 14.5%, whereas that for the other 3 groups was more than 50%, and with a significant difference (p < 0.0001). Comparing the tumor growth rates in these 4 groups, the SGR in GGNs with a mean CT attenuation value < –670 HU and tumor size < 8 mm was significantly lower than that in GGNs with a mean CT attenuation value > –670 HU and tumor size > 8 mm (p < 0.0001) and with a mean CT attenuation value > –670 HU and tumor size < 8 mm (p = 0.0005).

Conclusion
A combination of the measurement of the mean CT attenuation and the tumor size in the initial CT examination may be useful for predicting GGN growth. Lower-attenuation and smaller-size GGNs grow, but with slow growth rate, and, for patients with such GGNs, longer follow-up intervals may be useful in clinical practice.

Background
Preoperatively distinguishing non-invasive or minimally invasive lung adenocarcinomas from invasive lung adenocarcinomas on the basis of the classification proposed by the International Association for the Study of Lung Cancer, American Thoracic Society and European Respiratory Society (IASLC/ATS/ERS) is essential. However, in some cases, this distinction is potentially difficult to make by using the conventional computed tomography (CT) settings, i.e., lung and mediastinal windows. The objective of this study is to evaluate novel CT window settings for preoperative detection of pathologically invasive adenocarcinomas.

Methods
We retrospectively investigated 112 pathological T1a adenocarcinomas with a ground-glass opacity pattern ratio on preoperative CT of more than 50%. In the CT performed before an operation, the window level/window width was set as follows: -300/600, -250/500, -200/400, -150/300, and 30/400 (conventional mediastinal window). Under these viewing conditions, a maximum diameter of residual tumor was defined as the predictive invasion diameter. Receiver operating characteristic curve analyses were used to verify whether each viewing condition could be used to predict pathologically invasive adenocarcinomas that have a maximum invasion diameter of more than 5 mm.

Results
The area under the curve values for the -300/600, -250/500, -200/400, -150/300, and 30/400 settings were 0.87, 0.91, 0.86, 0.84, and 0.78, respectively. The sensitivity and specificity in the window setting of -250/500 was 98.1% and 67.8%, when the cut-off value for the predictive invasion diameter was set at 6 mm.

Conclusion
We determined novel CT window settings. The window level/window width setting of -250/500 might be useful for predicting pathological invasion of more than 5 mm in T1a lung adenocarcinomas.

Background
Junior doctors may fail to detect subtle pulmonary pathology on plain chest X-ray (CXR). Digital tomosynthesis (DT) is an emerging radiographic technique that provides multiple coronal chest images at only 2% of the radiation of a standard chest CT. Previous studies have demonstrated that pulmonary nodule detection sensitivity is three times greater with DT compared to CXR. We investigated whether DT can increase nodule detection rates by junior doctors compared to CXR.

Methods
Ten volunteer junior doctors (post-graduate years 1-3) at The Prince Charles Hospital in Brisbane, Australia, a secondary and tertiary referral hospital, were recruited to view CXR and DT images of 11 patients. All patients had CXR, DT and CT images acquired within a 30 day period for the evaluation of lung nodules. CT images (Philips Brilliance, Philips Medical Systems, Best, Netherlands), with collimation 0.625 mm and reconstructed slice width 0.9 mm, reported by experienced radiologists, served as the gold standard. DT images, consisting of 60 exposures through a 30° arc, were acquired using the GE Definium 8000 Xray Unit (GE Healthcare, Little Chalfont, United Kingdom), with simultaneous CXR as a scout image. Nine of these patients had at least one nodule >10 mm on CT, with two control patients without nodules. All participants undertook brief training to familiarise them with DT images one week prior to the study. In the study session, participants were showed anonymised CXR and DT images in random order and asked to mark “definite” or “possible” pulmonary nodules electronically. The markings were compared to CT detected “true” nodules. Markings made where there were no true nodules on CT were recorded as false positives. The time taken to view each image was measured. Participants completed a brief survey after viewing the images.

Results
Nodule detection sensitivity, represented by the proportion of true nodules marked “definitely” present, was significantly higher using DT than CXR (28/65 [43%] versus 3/70 [4%], χ[2], p<0.001), as was the proportion of nodules marked either “definitely” or “possibly” present (32/65 [49%] versus 13/70 [19%], χ[2], p<0.001). When considering instances where a nodule was marked either “definitely” or “possibly” present, where there was no true nodule on CT, significantly fewer false positives were made, on average, when viewing DT compared to CXR (0.36 versus 1.18 false positives per image, t-test, p<0.001). Although the time taken to view each DT image was statistically significantly longer than for each CXR image (86.9 seconds versus 67.9 seconds, t-test, p<0.01), the absolute difference was small. Ninety percent of participants agreed that they could identify nodules more confidently with DT than CXR.

Conclusion
In this study, junior doctors correctly identified more pulmonary nodules using DT compared to CXR and reported fewer false positive results. The time taken to view DT images was slightly longer than for CXR images, but this difference was small. Despite the small sample size, this pilot experiment has shown that DT may potentially improve identification of pulmonary nodules by junior doctors and a larger study is underway.

Background
Over the recent years, PET-CT studies have become the golden standard for the planning of high-dose definite radiotherapy of non-small-cell lung cancer (NSCLC). This is justified by their proven superiority over computer tomography in both sensitivity and specifity to determine the location of all tumor sites, helping avoid underirradiation of active malignancy as well as using unnecessarily large field sizes. Numerous reviews have pointed out that the quantifiers of tumor metabolism, primarily the maximal Standard Uptake Value (SUVmax) of [18]F-deoxyglucose as measured in PET-CT studies can as well serve as a prognostic factor in NSCLC. As we were expecting this to be particularily significant for patients with unresectable tumors yet irradiated with intention to cure, we decided to retrospectively investigate the prognostic value of tumor metabolism quantification for this group.

Methods
The material of our study consists of 53 patients, treated with definite radiotherapy (with sequential chemotherapy in 50 cases) for locally advanced, unresectable NSCLC. The doses prescribed for radiotherapy ranged from 60 to 71,2 Gy; all patients completed the intended radiation treatment. We assessed the tumor metabolism on PET-CT studies used for radiotherapy planning; in addition to measuring the SUVmax value, we quantified the tumor metabolic volume (TMV) using three different algorithms varying by the threshold above which voxels within the tumor were considered its volume. Results were co-related to various clinical parameters and the therapeutic outcome, measured as progression-free and overall survival at 36 months of follow-up.

Results
Figure 1 Of all clinical variables as well as the tumor metabolism quantifiers, the TMV was found to be the only standalone statistically significant prognostic factor for both overall (log-rank test p=0,048) and progression-free survival (p=0,014). Its value was confirmed in both Kaplan-Meier (shown) and Cox models. No co-relation was found between TMV and SUVmax, tumor type, sex or the pattern of failure. Tumor stage in PET-CT studies (after or during chemotherapy) was co-related to TMV, yet its prognostic value was not significant.

Conclusion
TMV is a simple parameter to calculate during routine analysis of PET-CT study, which provides - independently on the clinical variables and more accurately than radiological re-staging - relatively reliable prognostic information for patients who are to be treated with definite radiotherapy for NSCLC. Prospective studies on larger number of patients need to be undertaken to answer whether and how to alter the treatment regime (dose escalation, hypofractionation) in order to improve the outcome for patients with unfavorably high TMV.

Background
Most solitary pulmonary nodules(SPN) discovered by CT scan are benign. 18F-FDG PET has been reported better differentiated benign from malignant pulmonary nodules. Three previous developed clinical prediction models (Mayo model,VA model and Peking University model) are based on CT scan. We intergrating PET-CT and Clinical Data to increase accuracy in estimate the probability of malignancy of SPN.

Methods
From January 2009 to December 2012, 365 consecutive patients diagnosed SPN by PET-CT have been identified and reviewed. Clinical data were collected retrospectively. The data set was split into two groups: training set (305 patients) and testing set (60 patients). Independent factors associated with benign and malignancies were identified using training set by logistic regression analysis, and a prediction model has been established. Patients from the testing set were then used to validate the predictive value of this model, and compared accuracy with Mayo model and Peking University model.

Results
Logistic analysis showed three clinical characteristics(gender,age, smoking data) and six radiological characteristics(diameter, upper lobe,speculation, lobulation, pleural tail, FDG uptake) were independent predictors for malignancy. The area under the evaluated receiver operating characteristics curve was 0.854±0.043. Compared to Mayo model,VA model and Peking University model, this PET-CT based model showed better predictive value. Figure 1

Conclusion
Our PET-CT based clinical prediction model has better accuracy in estimate the pretest probability of malignancy in patients with SPNs.

Background
Pulmonary nodules with ground-glass opacity (GGO) are frequently encountered. We previously reported that, based on natural history of 108 pulmonary nodules that were 3 cm or less and had 50 % or more GGO component, these nodules should be followed for at least 3 years to accurately evaluate lesion growth. However, it remains unclear whether all GGOs should be followed for as long as 3 years. To establish reasonable follow-up plan, it would be useful to if we could predict which of GGO lesions tend to grow by any of clinical-radiographic characteristics. The purpose of this study was to clarify which baseline clinical and radiological characteristics were associated with growth of these nodules.

Methods
We retrospectively studied patients between 1999 and 2013 with pulmonary nodules that met the following criteria: (1) lesion diameter of ≤ 3 cm, (2) GGO proportion of ≥ 50%, and (3) observation without treatment in the prior 6 months. We evaluated the changes in lesion size on serial computed tomography. Two endpoints, “Time to 2-mm growth” and “2-mm growth incidence”, were analyzed using Cox proportional hazards and logistic regression models, respectively.Variables for univariate analysis were as follows: age; gender; smoking history; past history of lung cancer; lesion multiplicity; lesion diameter; and solid proportion. Factors for which p-value was < 0.05 in univariate analysis, as well as past history of lung cancer which was reported as a predictor in previous reports, were included in multivariate analysis. To strictly define “no growth”, we excluded lesions which had been observed for less than 3 years in logistic regression analyses.

Results
120 pulmonary lesions in 67 patients fulfilled inclusion criteria. At the median observation period of 4.2 years, 34 lesions had become larger by 2mm or more, whereas the remaining 86 had persisted without changing in size. Smoking history and initial lesion diameter were statistically significant in both regression and time-to-event analyses. In terms of time to 2mm growth, hazard ratio (HR) for smoking history was 3.67 (P < 0.01). Compared to those ≤ 1 cm, HRs for 1.1–2 cm and 21-3 cm lesions were 2.23 (P = 0.08) and 5.08 (P = 0.04), respectively. In contrast, odds ratio (OR) for the likelihood of 2mm growth for smoking history was 6.51 (P < 0.01), and OR for lesion diameter of 1.1–3 cm in comparison to ≤ 1 cm was 4.06 (P = 0.02).

Conclusion
Smoking history and initial lesion diameter are significantly associated with the growth of these nodules. These results suggested that closer follow up of larger size GGO in smoking patients be recommended.

Background
Major lung resection may induce expansion of the remaining lung, accompanied by some gain in the function of this lung. Pulmonary function studies have been performed in thoracotomy patients mainly for the purpose of predicting postoperative morbidity and mortality. Lobectomy is the standard operative procedure for lung cancer. However, the impact of this compensatory response of the residual lobes remains unclear, because spirometry cannot evaluate pulmonary function of individual lobe as single units.

Methods
Thirty-one patients who underwent lobectomy were included in this study. They were consisted of 15 males and 16 females, and 67 years old in average. Surgical procedures were 30 lobectomies and 1 bilobectomy. Chest CT scans at inspiratory and expiratory levels were performed at the same time using 40-slice MDCT (Brilliance 40, Philips, Netherlands). Scan conditions were 120 kV, ≤ 250 mAs, 0.5 sec./rotation, 32x1.25 configuration, pitch 0.906, and 5 sec. scan time. We then calculated the volume of individual lobes using graphic workstation (Virtual Place Lexus 1.0, AZE, Japan). Voxels with -215 HU or less were regarded as the air in the lung. VC of each lobe (VCL) was calculated as lobar volume at the inspiratory level subtracted by lobar volume at the expiratory level. This CT volumetry was performed before and 1 year after surgery.

Results
VCLs of the residual lobes in the operated side were 1.01±0.47L before surgery, and significantly (p=0.0094) increased to 1.22±0.74L after surgery. There was 22.3±43.6% gain in VCL of the lobes in the operated side after surgery compared with that before surgery. However, there was no significant difference (p=0.7040) in VCLs of the lobes in the unoperated side between before (1.71±0.71L) and after (1.69±0.63L) surgery. The rate of compensatory response of VCL of the residual lobes in the operated side was significantly (p=0.0002) correlated with the percentage of the VCL of the resected lobes. Statistical analysis revealed that the rate of compensatory response (%) could be calculated as the ratio of VCL in resected lung (%) before surgery multiplied by the constant of 1.556.

Conclusion
The compensatory response in pulmonary function after lobectomy appeared to occur only in the lobes in the operated side. The rate of this functional gain was significantly correlated with the ratio of the VCL in the resected lobes. These data may provide more precise prediction of postoperative lung function in patients who underwent lung resection.

Background
This study aimed to: 1) compare qualitative and semi-quantitative assessment of [18]F-fluorodeoxyglucose PET based categorical metabolic response in patients with NSCLC and determine their value for prognosis prediction; 2) investigate the relationship between semi-quantitative assessments of post-treatment change of metabolic activity and survival and explore an optimal cutoff to distinguish a subset of responders with more favorable outcome.

Methods
This is a secondary analysis of prospective studies with IRB approval. Enrolled patients with NSCLC underwent PET/CT imaging within 2 weeks prior to (pre-RT PET/CT), at 4 weeks during and after radiation treatment (post-RT PET/CT). Post-RT metabolic therapeutic response was assessed using 1) visual assessment and 2) semi-quantitative measurement based on reduction in tumor FDG uptake; SUVmax normalized to mediastinal blood pool (NSUV-A). Interpretation of PET/CT scans was performed by three nuclear medicine physicians, blinded to clinical information. The three physicians did independent reads of the patients, performing a single read for each patient’s set of PET studies. Kappa coefficient was used to evaluate the agreement between categorical variables. Survival analysis and Cox proportional hazard regression model were adopted to analyze the effect of various response criteria on overall survival (OS) and progression free survival (PFS).

Results
Forty-four patients (36 male: 8 female) were eligible for analysis. The median interval between end of RT and post-RT PET/CT scan was 93 days. A poor agreement was observed between visual and semi-quantitative responses (Kappa coefficient = 0.393). Categorical responses were significantly correlated with both OS and PFS independent of employed response assessment criteria (either visual or semi-quantitative, p < 0.001) and patients with complete metabolic response (CMR) obtained the longest survival. As a continuous variable, reduction percentage of NSUV-A showed significant correlations with OS (hazard ratio, HR = 0.980, p < 0.001) and PFS (HR=0.984, p < 0.001). Analysis of OS and PFS consistently recommended NSUV-A reduction of sixty percent (60%) as another discriminative cutoff to distinguish patients with different outcome (p < 0.01).

Conclusion
There is a great discrepancy in metabolic response rates between qualitative and semi-quantitative methods. Categorical metabolic response criteria, either from qualitative visual assessment or a semi-quantitative method, demonstrate significant association with overall survival and progression free survival. Visual method offers a simpler approach that provides good information with regard to predicting OS and PFS, while the semi-quantitative method provides ordinal value that correlates with prolonged OS. As a continuum, the numerical percentage reduction in the normalized SUV is positively correlated with longer overall survival, reinforcing the prognostic value of metabolic change on FDG PET/CT. A sixty percent reduction of SUV may be the optimal cutoff for metabolic response to identify subsets of the PMR population with distinct outcomes, pending validation by an independent population.

Background
Screening lung cancer with low dose computed tomography (CT) improved the likelihood of detection of small non-calcified nodules, and thus lung cancer might be detected earlier with more potential for a cure. The National Lung Screening Trial (NLST) showed that screening with low-dose helical computed tomography (CT) rather than with chest radiography reduced mortality from lung cancer. However, the cost-effectiveness of using low dose CT screening was still debatable in the normal population even in the smoking population. The Northern Thailand Thoracic Oncology Group (NT-TOG) would like to study focusing on the first relative of lung cancer patients which may benefit from low dose CT screening.

Methods
From January 2013 to May 2013, a prospective cohort study was performed at Chiang Mai University Hospital. We enrolled asymptomatic participants, 20 to 65 years of age who were the first relative of lung cancer patients and received a structural interview and informed consent. Low-dose CT scan and chest radiography were performed on the same day for each participant. Nodules or other suspicious findings were classified as positive results. Nodules or suspicious findings from either low-dose CT or chest radiography which have a high risk of malignancy will be worked up rapidly for tissue pathology whereas low risk nodules will be followed up with low-dose CT and chest radiography every six months, for two years. This study reports findings from the initial screening examination.

Results
There were 14 (45.2%) cases of positive nodule from low- dose CT screening out of a total of 31 cases, whereas, there were no positive nodules from the chest radiography. The average number of nodules was 2.1 nodules and the average size of nodule was 0.4 cm in diameter. There was ground-glass opacity (GGO) in seven cases (22.6 %), subsegmental atelectasis in 14 cases (45.2 %), traction bronchiectasis in four cases (12.9 %), and a lung cyst in one case with subcentimeter lymphadenopathy in 26 cases (83.9 %). The average size of the mediastinal lymph node was 0.7 cm in diameter (range 0.2-0.9 cm).

Conclusion
This study reported initial findings from low-dose CT and chest radiography. These results demonstrated that low-dose CT screen may be a valuable method for screening in the first relative of lung cancer patients compared with chest radiography. However, all of the positive cases need to be worked up for a definite tissue diagnosis in order to have an earlier diagnosis of lung cancer and potentially more curative treatment or at least to be closely monitored. This study will be continued and more participants will be recruited and evaluated.

Background
Therapeutic decision and prognosis in non-small cell lung cancer (NSCLC) relies on accurate staging. Currently, Positron Emission Tomography/Computed Tomography (PET/CT) appears to have better efficacy, and is considered the gold standard method for staging lung cancer. Diffusion-weighted Magnetic Resonance Imaging (DWI) for the whole body has become feasible and provides images with good resolution. Some investigators have suggested that DWI could be used for assessment of primary tumor, lymph nodes and distant metastases in lung cancer. To date there are few data assessing DWI for staging of NSCLC. The purpose of this study is to compare the role of DWI and PET/CT for staging NSCLC patients.

Methods
This is a prospective study. Institutional review board approval and written informed consent was provided by all patients. From May 2011 to April 2012, thirty-two patients were included. Twenty (62.5%) were men, and the mean age was 62.4 years old. Non-small cell lung cancer (NSCLC) was proved at pathological examination. PET/CT and brain MRI was performed as a routine staging work up. DWI was studied as an alternative method for staging. Final stage in each patient was defined by pathological examination when available or through radiologic and clinical examinations/follow-up. Sensitivity, specificity, and accuracy were evaluated and were compared between both groups.

Results
Preliminary results demonstrate that WB MRI and PET/CT have satisfactory levels of sensitivity, specificity and accuracy, with no significant difference (p>0.05), as disclose in Table 1. Table 1 – Sensibility, specificity and accuracy of WB MRI and PET/CT.

	WB MRI	PET/CT
Sensibility	72.3%	73.5%
Specificity	91.6%	94.5%
Accuracy	86.8%	88.2%

Conclusion
PET/CT has shown to be an excellent tool for the clinical staging of lung cancer. DWI has been considered an alternative method for staging these patients. Advantages of whole-body DWI include absence of ionizing radiation exposure, excellent contrast resolution and information from different sequences allowing a better characterization of lesions, mainly brain and liver metastasis. Our preliminary results demonstrate no significant difference in accuracy between both methods for staging patients with NSCLC.

Background
Sputum cytology is a widely accepted non-invasive diagnostic method for lung cancer. However, the efficacy to reduce lung cancer mortality has not been clearly proven in mass screening setting. To understand the potential value of sputum cytology to detect squamous cell carcinoma (SCC) of the lung, we evaluated its sensitivity and specificity. We simultaneously attempted to clarify the effect of repeated screening on the incidence of SCC.

Methods
In total, 104,872 sputum cytology tests combined with miniature chest X-ray were performed on 44,809 people belonging to the high-risk population of Miyagi Prefecture in Japan from 1990 to 1996. The sensitivity and specificity were calculated based on the information from the Cancer Registry. The incidence of SCC in the year after sequential annual repeat or sequential annual absences was analyzed.

Results
In total, 183 SCC-positive cases were diagnosed. The sensitivity and specificity of sputum cytology for SCC were 66.7% and 99.9%, respectively. Among cases with known localization, sensitivity for the central type was 90.7%, while that for peripheral type was 64.2%. Similarly, significantly decreased screen-detected SCC was observed in the third repeated test . A significant increase in screen-detected SCC cases was observed in the third year of sequential absence from screening.

Conclusion
Annual screening by sputum cytology for the high-risk group showed high sensitivity for SCC of the lung, particularly for central type SCC. Significantly reduced incidence of central type SCC was observed by repeating annual sputum cytology screening.

Background
Doctors´ delays can sometimes be very large in investigations of suspected lung cancer. The main problem seems to be the many steps involved, with delays at all levels. In order to speed up the process within the available limited resources we have in Stockholm constructed a “fast track”.

Methods
The majority of suspected lung cancers in the Northern Stockholm area are referred to the Lung Clinic in Solna from GP:s and other clinics. Patients who from this information were judged to suffer from potentially curable lung cancer were admitted to the fast track, where the first visit should occur within a week and the investigations (broncoscopy, PET-CT, spirometry etc) was planned by a special nurse within the next week.

Results
From December, 2009, to march, 2013, 219 patients, 109 women and 110 men, have been investigated. The mean age was 67 years (55-82). The mean time from referral to first visit was 6,1 days and 77% were seen within one week. From referral to treatment decision, the mean was 17.8 days. There were 149 primary lung cancers, thereof 105 adenocarcinomas, 18 squamous, and 13 small cell cancers. Stage I-II were 74, III 35, and IV 41. Surgery was performed on 65 patients, 17 of whom the diagnosis was made at surgery. Potentially curative radiotherapy or chemoradiotherapy was given in 44 patients. Three lymphomas, one sarcoma, and 6 metastases from earlier unknown cancers were also seen. Thus, 109 (73%) received a potentially curative therapy. Benign lesions were seen in 56 persons (26%), mostly hamartomas or infections but only one active TB. Two granulomas were operated. PET-CT also disclosed 6 concurrent and earlier unknown cancers in other organs among the cancer patients and in two with a benign diagnosis. During the period, approximately 900 primary lung cancers were diagnosed at the clinic, so about 17% went in the fast track, which was limited by available resources.

Conclusion
A fast track is feasible and possible even without added resources. PET-CT gives very valuable information on spread of disease but also other cancers.

Background
Low-dose computed tomography (LDCT) screening improves lung cancer prognosis, but also results in diagnostic work-up and surgical treatment in many individuals without cancer. We therefore analyzed procedures that screening participants underwent to better understand the extent of overdiagnosis.

Methods
Between 2009 and 2011, 8649 healthy volunteers in the age 50-75 with 20 pack-years smoking history underwent LDCT screening with two years control in individuals with lung nodules. Participants with nodules diameter >10 mm or with suspected tumor morphology underwent diagnostic work-up. It was performed in 283(6%) of 4694(54%) screening participants with detected lung nodules. One hundred four individuals were operated, 27 were underwent oncological treatment and in 154 patients without cancer diagnosis further follow up with LDCT was applied.

Results
Our results showed that in 75% of the participants accepted for diagnostic work-up those procedures were futile. The same holds for 25% receiving surgery. Only in 70(24,7%) participants a specific diagnosis was obtained. That was mainly due to low efficacy of Fine Needle Aspiration Biopsy (Sensitivity 65,2%, NPV 95,9%) and bronchofiberoscopy (sensitivity 71,4%, NPV 50%) caused by overinterpretation of LDCT (PPV 2%). Of 104(36.7%) participants that were accepted for surgery, forty-three patients (41,4%) had preoperative cancer diagnosis and 61(58,6%) underwent operations without obtained pathology. In the latter group intervention was justified in 35(57,3%) patients. Complications occurred in 49 (17.3%) participants subjected to diagnostic work-up. In patients accepted for surgery 67 (64.4%) malignant and 37 (35.6%) benign lesions were resected. In the latter group intervention was justified in only 11 (29,7%) patients. No patient died as a result of diagnostic or treatment procedures during the study. The complication rate was 14,5% in the malignant and 10,8% in the benign groups. Finally in 94 screening participants a neoplasm was found. Of those, 67(71.3%) patients underwent operation; the remaining 27(28.7%) patients were not candidates for surgery. Adenocarcinoma accounted for 49/67(73%) operated NSCLC patients; 56/67(84%) patients had stage I non-small cell lung cancer, and 26/67(38%) underwent video-assisted thoracoscopic surgery lobectomy.

Conclusion
Futile diagnostic work-ups and operations must be reduced before LDCT screening can be broadly used. Stage I adenocarcinoma dominated in the operated NSCLC patients.

Background
Individuals who present with squamous metaplastic and dysplastic lesions are considered at high risk of lung cancer. However, these lesions behave erratically and only a minority progresses towards lung cancer. Therefore, biomarkers need to be discovered that can aid in assessing an individual’s risk for subsequent cancer. We recently identified a DNA copy number aberration (CNA)-classifier, including changes at 3p26.3-p11.1, 3q26.2-29, and 6p25.3-24.3, as a risk predictor for cancer in individuals presenting with endobronchial squamous metaplasia (van Boerdonk et al, AJRCCM, 2011). The current study was set out to validate this classifier in an independent series of endobronchial squamous metaplastic and dysplastic lesions.

Methods
DNA copy number profiles (i.e., chromosomal gains and losses) were determined in a set of endobronchial lesions (8 squamous metaplasia (SqM), and 28 dysplasias (Dys) of various grades), identified and biopsied during autofluorescence bronchoscopy, of 36 high-risk subjects using a nested case-control design. Of the 36 patients, 12 cases had a carcinoma in situ or invasive carcinoma at the same site at follow-up (median 11 months, range 4-24), while 24 controls remained cancer-free (median 78 months, range 21-142). DNA copy number profiles were related to lesion outcome. The prediction accuracy of the predefined CNA-based classifier to predict endobronchial carcinoma (in situ) in this series was determined.

Results
All SqM and Dys lesions of controls showed no or a relatively low number of CNAs (i.e., quiescent profile with on average 0.2% altered probe features, range 0.0 – 2.4%), while the majority of lesions of cases showed multiple CNAs (i.e. highly aberrant profile with on average 38.8% altered probe features, range 0.0 – 76.7%). The previously defined CNA-classifier demonstrated 92% accuracy for cancer (in situ) prediction in the current series. All nine subjects with CNA-classifier-positive endobronchial lesions at baseline had cancer as final outcome (i.e., a positive predictive value of 100%). The negative predictive value of the classifier was 89%, i.e., all 24 controls and 3 cases were classified as being low-risk.

Conclusion
CNAs are a highly accurate biomarker for assessing the progression risk of endobronchial squamous metaplastic and dysplastic lesions. This classifier could assist in selecting subjects with endobronchial lesions who might benefit from more aggressive therapeutic interventions.

Background
To evaluate the volume doubling times (VDTs) of subsolid nodules (SNs) detected using low-dose CT lung cancer screening.

Methods
Patients with SNs detected between February 2004 and January 2005 were enrolled. Among the SNs that were detected after February 2005, increasing SNs and resected SNs after follow-up were also included in this study. After confirming the persistency of the SNs at 3 months after screening, a follow-up thin-section CT examination was performed every year, in principle. Dedicated software was developed to analyze the SNs. The volumes of the subsolid nodules were calculated based on the summation of the area of each CT slice multiplied by the CT slice thickness (i.e., 1 mm). The area of a SN on each CT slice was determined semiautomatically. The measurement of each area was performed twice, and the average of the first and second measurements was used for the volume calculation. VDTs were calculated using the following formula; (T1-T0)*log2/log(V1/V0).

Results
As of June 14, 2013, the measurements of 81 SNs in 72 cases had been completed. The interim results were as follows. VDTs were classified into positive values (n = 56) and negative values (n = 25). VDTs with positive values ranged from 333 to 83384 days (median, 1981 days; VDT >4500 days, n = 13), while the VDTs with negative values ranged from -110007 to -1014 days (median, -13317 days; VDT <-4500 days, n = 20). The initial volumes for the positive VDTs ranged from 45 to 3486 mm[3 ](median, 199 mm[3]), while the initial volumes for the negative VDTs ranged from 45 to 1037 mm[3 ](median, 189 mm[3]); the difference in initial volume between the positive VDTs and the negative VDTs was not statistically significant (P = 0.468)[. ]Among the 72 cases, 9 SNs in 9 cases (12.5%) were resected and diagnosed as adenocarcinomas (adenocarcinoma in situ [AIS], n = 4; minimally invasive adenocarcinoma [MIA], n = 3; and invasive adenocarcinoma [IA], n = 2). The VDTs for AIS ranged between 726 and 1723 days (median, 1154 days), the VDTs for MIA ranged between 333 and 806 days (median, 536 days), and the VDTs for IA ranged between 348 and 448 days (median, 398 days). The measurements of other SNs are ongoing.

Conclusion
The interim results showed that adenocarcinomas with a higher degree of invasiveness had a shorter VDT. Tentatively assuming that absolute values of VDTs >4500 days indicate clinical stability in volume despite the inherent variability of semiautomatic volumetry, 40% of the SNs were stable after an eight-year observation period.

Background
EarlyCDT®-Lung, a clinical blood test that detects autoantibodies to lung cancer-associated antigens, has shown high specificity in case-control validation studies[(1)].The performance of this test in routine clinical use was audited in an initial series of 1612 patients tested by EarlyCDT-Lung who signed HIPAA authorization permitting disclosure of their health information to Oncimmune®; the reported specificity and sensitivity (91%/41%) of the test was as predicted by case-control studies[(2)].

Methods
A prospective audit was conducted of 423 individuals known to have a lung nodule for whom lung cancer-associated autoantibodies were measured by EarlyCDT-Lung. Physicians were contacted following patient testing by EarlyCDT-Lung to determine whether a cancer diagnosis had been made or a pulmonary nodule identified by imaging. Imaging and pathology reports were reviewed. This report focuses on patient outcomes at 6 months following EarlyCDT-Lung, and specifically on the 318/423 individuals for whom a lung nodule was detected prior to EarlyCDT-Lung testing. The EarlyCDT-Lung panel was modified in November 2010 from a 6 autoantibody (AAB) panel to 7AAB to improve specificity of the test[(3)] ; there were 152/318 individuals with nodules who had the 6AAB test and 166/318 who had the 7AAB test. Analyses comparing EarlyCDT-Lung results by malignant and non-malignant nodules were made using chi-squared tests.

Results
Of the 423 individuals with nodules, there were 77 patients diagnosed with a lung cancer, and 346 were deemed to have a non-malignant nodule; 32/77 and 76/346 were positive for EarlyCDT-Lung, respectively (p=0.0004). Overall, this represented a 2-fold increased incidence of lung cancer with a positive result. Of the 318 individuals with lung nodules known prior to testing by EarlyCDT-Lung, the number of positive tests were 27/62 lung cancers and 43/256 non-malignant nodules (p= 0.000005); therefore, a positive result reflected a 2.7-fold increased incidence in this group. Considering nodule size, there was no difference for nodules <8mm, but the number of lung cancers in this group was small at only n=3. For nodules between 8-20mm and ≥20mm, a positive EarlyCDT-Lung test was statistically more likely to signify a lung cancer (p=0.06 & p=0.002, respectively; p=0.00008 combined). When only the 7AAB test was assessed, which has greater specificity, for 8-20mm and ≥20mm nodules a positive EarlyCDT-Lung test remained significantly more likely to indicate a lung cancer even though the numbers in each group were relatively small, n=58 & n=52, respectively (p=0.01 & p=0.004, respectively; p=0.0001 combined). For the 7AAB test overall and also for indeterminate nodules (8-20mm), a positive result represented a 3.5-fold increased incidence of lung cancer.

Conclusion
EarlyCDT-Lung positivity reflects a statistically significant increased risk of malignancy for lung nodules ≥8mm. This varies from 2-fold to 3.5-fold depending on nodule size. These data confirm that EarlyCDT-Lung adds to the armamentarium of the pulmonologist in assessing the risk of malignancy in nodules ≥8mm. More data are required for lung nodules <8mm size. References: (1) Boyle P, et al. Ann Oncol. 2011;22:383-389. (2) Jett JR, et al. J Thoracic Oncology 2012;7:S222. (3) Chapman CJ, et al. Tumor Biol. 201;33(5):1319-1326.

Background
NLST generated excitement reporting that CT-screening reduces lung cancer mortality in comparison to CXR-screening. In randomized population trials (RPTs) on cancer screening, disease-specific mortality is assumed to provide an unbiased measure of screening effectiveness. This is based upon the assumption that randomization produces comparison groups with equal probability of death from the target cancer, unless the intervention reduces risk. However, these assumptions have often been violated in the RPT setting, leading to uncertainty about the effectiveness of several screening interventions. Objectives of this analysis are to assess whether the mortality endpoint provides an unbiased measure of screening efficacy in NLST.

Methods
In NLST, 53,454 current/former smokers, age 55-74 years, were randomized to CT or CXR-screening. Participants were offered a prevalence screen followed by two annual incidence screens.

Results
There was a highly significant 20% lung cancer mortality reduction in the CT-group (TABLE). There was also a significant 12% increase in lung cancer incidence in CT-group. Because CT is more sensitive than CXR, higher lung cancer incidence is predictable based upon lead-time and length-biases, and possibly overdiagnosis. The significant three-fold excess of BAC in the CT-group may reflect some overdiagnosis. Moreover, the highly significant two-fold excess of stage I cancers may reflect conventional biases. However, incidence of the most virulent lung cancers, including small-cell lung cancer and NSCLC-not-otherwise-specified was 16% lower in experimental-group. There exists no plausible hypothesis to explain lower incidence of highly biologically aggressive lung cancers in the CT-group. These differences strongly suggest imbalances in randomization. This is not to suggest that CT is not superior to CXR. While survival has not been reported, there is a significant 29% reduction in case-fatality in CT-group. Moreover, despite higher incidence, there was a highly significant one-third reduction in the absolute number of stage IV cancers in CT-group.

	CT Group	CXR Group	p value	Relative Risk (95% Confidence Interval)
Population	26,722	26,732
LUNG CANCER DEATHS
mortality	356 (1.33%)	443 (1.66%)	0.0022	0.80 (0.70-0.92)
fatality	356/1060 (33.6%)	443/941 (47.1%)	<0.0001	0.71 (0.64-0.80)
LUNG CANCER INCIDENCE AND STAGE
incidence	1,060 (3.97%)	941 (3.52%)	0.0067	1.12 (1.03-1.23)
stage I lung cancer	416 (1.56%)	196 (0.73%)	<0.0001	2.12 (1.79-2.51)
stage IV lung cancer	226 (0.85%)	335 (1.25%)	<0.0001	0.67 (0.57-0.80)
LUNG CANCER HISTOLOGIC SUBTYPES
bronchioalveolar carcinoma (BAC) incidence	110 (0.41%)	35 (0.13%)	<0.0001	3.14 (2.15-4.60)
adenocarcinoma, squamous cell carcinoma, or large cell carcinoma incidence	664 (2.48%)	527 (1.97%)	<0.0001	1.26 (1.12-1.41)
small cell carcinoma or nonsmall cell carcinoma-not otherwise specified (NSCLC-NOS) incidence	268 (1.00%)	317 (1.18%)	0.046	0.84 (0.72-0.99)
carcinoid incidence	6 (0.022%)	2 (0.007%)	0.18	3.00 (0.61-14.87)

Conclusion
In NLST, lower incidence of lethal lung cancer subtypes in CT-group predicts for lower lung cancer mortality, independent of CT-screening efficacy. Accordingly, lower lung cancer mortality does not provide an unbiased measure of CT-screening efficacy in NLST. While stage distribution and case-fatality advantages strongly support that CT is superior to CXR, further analysis, which must include survival, is required to judge the true effect of CT-screening. While a simple survival comparison of CT versus CXR would also be biased, an analysis comparing survival stratified by histologic subtype or other outcome predictors, would be useful in judging the effectiveness of CT-screening in NLST.

Background
Early diagnosis and referral to specialist treatment are critical factors in the management of lung cancer. Survival is improved when lung cancer is diagnosed at an early stage and the patient is referred to a multidisciplinary specialist lung cancer team for diagnosis, staging and treatment planning. However, as symptoms can be non-specific and often present similarly to other chronic health issues, an early diagnosis of lung cancer may be missed. Patients with symptoms of lung cancer are likely to present to their general practitioner (GP). Therefore, it is important to enhance awareness of the risk factors, signs and symptoms of lung cancer, and provide GPs with the most recent evidence to facilitate timely and effective assessment and appropriate referrals. Cancer Australia commissioned Monash University (MU) to develop an evidence-based guide for GPs (the Guide), and to develop strategies for promoting uptake of the Guide.

Methods
An Expert Advisory Panel (EAP) was established to oversee development of the Guide, using the ADAPTE framework for guideline adaptation. Following a search of the literature to identify potentially relevant guidelines and shortlisting using the Appraisal of Guidelines for Research and Evaluation instrument (AGREE), three international guidelines (UK, NZGG, USA) were selected to inform development of the GP Guide. MU conducted interviews with GPs to assess the feasibility of incorporating the Guide into a computerised decision support tool for the GP setting. An evidence-based, multifaceted approach to promoting the Guide and supporting uptake of best practice cancer care within the general practice setting is ongoing, in consultation with a Project Working Group. The approach includes development and implementation of an Active Learning Module (ALM) and workshops for primary care providers and organisations.

Results
The Guide includes 24 recommendations focusing on key topics including: risk factors and symptoms of lung cancer; appropriate investigations in primary care; and effective referral to a specialist linked to a lung cancer multidisciplinary team and services. The Guide was published on the Cancer Australia website and disseminated to GPs throughout Australia. The feasibility assessment found that GPs’ consultation styles did not support additional online ‘pop-up’ reminders, preferring to access the Guide external to patient consultations. Incorporation of the Guide into an appropriate format is ongoing. The ALM provides a structured learning activity in an online, interactive format, providing further detail and context to using the Guide in the primary care setting. The ALM includes case-based learning, literature for further reading, and reflection and reinforcing activities. Workshops for GPs have been held to promote and support implementation of the Guide, including strategies to adopt the Guide’s recommendations in practice. Train-the-Trainer workshops have commenced with primary care providers. Evaluation of the uptake of the Guide into clinical practice is currently unavailable.

Conclusion
A new evidence-based guide is available to support GPs to assess symptoms that may be lung cancer, to undertake appropriate investigations, and to support rapid referral into the cancer care pathway. The evidence-based, multifaceted implementation strategy supports the translation of the evidence into best practice cancer care.

Background
BACKGROUND: Chest radiographic screening is a commonly used conventional method for the detection of lung and mediastinal tumors. However, more than half of the tumors detected by chest radiography are those that have already progressed to the advanced stage. Recent studies have shown that low-dose spiral computed tomography (CT) is effective for the early stage detection of lung cancer, and this facilitates better resectability and long-term survival. The present study was performed to evaluate the usefulness of chest radiography and spiral CT in the diagnosis of mediastinal tumors.

Methods
METHOD: More than 50000 consecutive asymptomatic individuals had undergone a health check-up at our institution during a 1-year period (from December 2011 to November 2012). Of these individuals, approximately 45000 had undergone chest radiography or low-dose spiral CT. The presence of mediastinal tumors was investigated in these individuals.

Results
RESULTS: Five mediastinal tumors were detected (2 thymoma, 1 teratoma, 1 liposarcoma, and 1 neurofibroma with Recklinghausen’s disease). Two cases were detected using both chest radiography and CT, whereas the other 3 were detected using chest CT only. In these 3 cases, no abnormal opacity was observed on chest radiographs. The tumors in all 5 cases were successfully resected, and to date, no tumor recurrence has been observed.

Conclusion
CONCLUSION: These results suggest that screening using low-dose spiral CT is more useful than chest radiography and might contribute to the early detection and treatment of mediastinal tumors, although further studies to confirm of these findings will be needed.

Background
Lung cancer is the top cancer killer in North America and worldwide. Current lung cancer detection tools involving X-ray, CT and bronchoscopy are relatively time-consuming and costly. Breath analyses done by mass spectrometry have shown that certain endogenous volatile organic compounds (VOCs) are related to lung cancer and revealed the potential of breath analysis for lung cancer detection. But mass spectrometry is costly and has slow turnaround times. In another interesting development, electronic noses were made for breath analysis, however the signals generated from semiconductor array cannot accurately quantify nor correlate with VOCs. Raman spectroscopy is a promising candidate for breath analysis because it can offer unique fingerprint-type signals for molecular identification. Our objective is to develop a simple, cost-effective and non-invasive tool based on Raman spectroscopy for breath analysis and potentially for lung cancer screening.

Methods
A Raman-gas analyzer was designed and built, based on photonic technologies. We employed a hollow core-photonic crystal fibre (HC-PCF), a novel light guide that allows light to be guided in a small hollow core and it can be filled with a gaseous sample (i.e., human breath) for spectral analysis. A gas supply system was built to provide a sealed environment for the loading and unloading of gaseous samples. A 785 nm diode laser was used for Raman excitation. Stokes Raman signals generated in the hollow core of the HC-PCF were guided to the collection optics and were analyzed by a Raman spectrometer for molecular identification.

Results
Raman spectra have been obtained successfully from air, reference gases (hydrogen gas, oxygen gas, carbon dioxide gas), and human breath. The limit of detection of the system was found to be approximately 15 parts per million by CO~2~ concentration in the ambient air, characterized by the Raman peaks at 1286 cm[-1] and 1388 cm[-1]. This is a more than 100-fold improvement over the recently reported detection limit with a reflective capillary fibre-based Raman cell. The detection limit can be further improved by changes to the optical configurations, optimizing the interaction length of the HC-PCF and the use of sample pre-concentration method to enhance signal-to-noise ratio.

Conclusion
This work demonstrated a working prototype of a simple, compact, and cost-effective breath analyzer based on hollow core photonic crystal fibre and Raman spectroscopy. With further improvement in the detection sensitivity, this method can potentially be used for lung cancer screening.

Background
Lung Cancer accounts for the greatest cancer related mortality worldwide. To date, no effective screening tool for Non-Small Cell Lung Cancer (NSCLC) exists. For patients with operable stage IA NSCLC, the 5-year survival can be as high as 80%. Early detection is crucial in improving long-term survival. MicroRNAs (miRNAs), a class of short noncoding RNA molecules. miRNA expression in biological fluid samples such as sputum has shown promise as a potential means of detecting NSCLC. Our objective was to utilize an efficient, cost-effective panel consisting of 3 miRNAs (miR-21, miR-210 and miR-372) for prospective validation as a potential means of accurately detecting NSCLC. This panel was selected based on retrospective analysis of 11 miRNAs our group had previously undertaken using separate NSCLC and control cohorts.

Methods
21 early NSCLC (≤ Stage II) patients, 22 advanced NSCLC (≥ Stage III) patients and 10 control subjects were prospectively accrued. A single sputum sample was obtained through spontaneous expectoration from each study participant. Detailed study participant and tumor characteristics were obtained. miR-21, miR-210 and miR-372 expression was conducted on each sputum sample and normalized to an endongenous control (U6) relative to a MRC-5 reference sample, using RNA reverse transcription and Quantitative real-time Polymerase Chain Reaction (RT-qPCR). Statistical evaluation consisted of unsupervised hierarchical cluster analysis of the experimental-normalized miRNA expression profiles using within-group linkage.

Results
The median ages of the early NSCLC cases, advanced NSCLC cases and controls were 68, 68 and 58.5 respectively. The majority of the early and advanced NSCLC patients had smoking histories (>90%). 60% of the controls had smoking histories. Mean tumor size (± standard deviation) for early and advanced NSCLC cases were 3.4 cm (± 2.1 cm) and 4.8 cm (± 1.7 cm) respectively. Adenocarcinoma and squamous cell carcinoma comprised 62% and 23.8% of early NSCLC cases. Adenocarcinoma and squamous cell carcinoma comprised 45.5% and 22.7% of advanced NSCLC cases. Comparing early NSCLC to controls, the use of miR-21, miR-210 and miR372 expression yielded a diagnostic sensitivity of 66.7% and a specificity of 90.0%. Advanced NSCLC patients had an improved sensitivity of 81.8% with the same specificity of 90.0%.

Conclusion
The utilization of miR-21, miR-210 and miR372 sputum expression might provide a sensitive and specific means of detecting NSCLC. The potential linkage between their expression and NSCLC stage may account for the higher sensitivity observed in the advanced NSCLC group. Future use of this promising panel on a larger population will be required to establish its potential application as a screening tool.

Background
Primary and metastatic squamous cell carcinomas (SCC) in the lung are often histologically indistinguishable, and the differential diagnosis between them is primarily dependent on clinical information such as the location of the lung lesion, the tumour stage, and the disease-free interval, particularly when the pulmonary nodule is solitary. The management of solitary pulmonary SCC in patients with a history of SCC may pose diagnostic and therapeutic challenges.

Methods
A retrospective chart review analysis was conducted. The study included 244 consecutive patients with antecedent cancer histories who subsequently underwent pulmonary resections for newly discovered solitary pulmonary nodules (new SPNs) from January 1998 to December 2007 at our institute.

Results
Of the 244 patients, 36 had a history of SCC (neck: 14, oesophagus: 9, neck and oesophagus: 3, lung: 5, anal canal: 1, unknown: 1, uterine cervix: 3), and 208 had no history of SCC. A history of SCC was significantly associated with the squamous pathology of new SPNs (22 of 36, p < 0.0001). Of the 22 new SPNs with a squamous pathology, 14 of them were diagnosed as metastatic (mSCC), and 8 were diagnosed as primary carcinomas (pSCC). The mSCC showed a more advanced initial disease (p = 0.0109) and a marginally shorter disease-free interval (p= 0.0818) than the pSCC. The overall survival (OS) and recurrence-free survival (RFS) of patients with pSCC were superior to those of patients with mSCC (OS: p = 0.0413, RFS: p = 0.0282) (Figure 1). Notably, 6 intra-thoracic recurrences were observed in the mSCC group.Figure 1

Conclusion
The current policy for differentiation between mSCC and pSCC, which is based on clinical information, appears to be acceptable. In cases in which the origin of the pulmonary lesion is unclear, it might be better to treat solitary lung SCC as a primary lung cancer because it might offer the best chance for a cure.

Background
Malignant pleural effusions (MPEs) are a common and important cause of cancer-related mortality and morbidity. Prompt diagnosis using minimally invasive procedures is a key point in the evolution of disease since the overall median survival after diagnosis is only 4-9 months. Tumour markers analysis has been proposed as a less invasive alternative for categorizing malignant and non-malignant pleural effusions. This multi-centre study aimed at establishing diagnostic cut-offs for a panel of markers in pleural fluid and plasma to identify patients with lung cancer.

Methods
Pleural fluid specimens and plasma samples from 112 patients (46 malignant, 66 non-malignant) consecutively admitted over one year in three Italian university hospitals were analyzed for Ca 125, Cyfra 21.1, NSE, CEA, M2PK. The diagnosis of malignant or non-malignant effusion was based on cytology, pleural biopsy, thoracoscopy, video-assisted thoracic surgery (VATS). Statistical evaluation included Kolmogorov-Smirnov, Mann-Whitney, Chi-square and Fisher’s exact tests. Non parametric (Spearman) correlations were determined. ROC curve analysis was performed to determine analyte cut-offs, sensitivity, specificity and AUC values of each marker. A p-value <0,05 was considered statistically significant.

Results
Cytological negative samples were analyzed to ensure that they truly represented non-malignant effusions related to other diseases such as congestive heart failure (CHF), renal imbalance, pneumonia, tuberculosis or post-traumatic. Patients with a history of malignancy or subsequent diagnosis of malignancy with a cytological negative pleural sample were excluded from the study. All examined concentrations were significantly higher in malignant effusions compared to non-malignant effusions. The value of AUC of pleural samples was always higher than in plasma for all malignant cases. The best AUC value in both pleural samples and plasma was detected for Cyfra 21.1 (0,91 vs 0,695) and CEA (0,836 vs 0,681).

Conclusion
Tumour markers assay in pleural fluid complements cytology and other classifying tests. A few tumour markers over-expressed in pleural fluid of patients with known malignancy have been identified. Therefore the use of a panel including the best performing markers may prevent patients with suspected malignancy from undergoing invasive procedures such as thoracoscopy or VATS. Our study shows a significant performance of pleural fluid vs plasma samples when comparing AUC values. Tailoring a specific marker assay in pleural fluid for a specific malignancy is highly advisable especially in patients with relevant comorbidity. Moreover, the evaluation of tumor markers in pleural fluid may well be considered as a prognostic factor in those patients with known malignancy undergone surgery and/or chemoradiotherapy during follow up.

Background
The bone is the most common distant site of metastasis in non-small cell lung cancer (NSCLC), and patients with bone metastasis have a markedly poor prognosis. There are three types of bone metastasis; such as osteolytic type, osteoblastic type, and mixed type. Assessment of bone metastatic type may be important as a part of therapeutic strategy because it has been noted that osteoblastic tumors would have lead to both a better prognosis and activating epidermal growth factor receptor (EGFR) mutation presence. The aim of this study was to examine the relationship between the type of bone metastasis and clinical characteristics including EGFR gene mutation status in NSCLC patients.

Methods
We reviewed the records of 85 unresectable or postoperative recurrent NSCLC patients with at least one site of bone metastasis. The type of bone metastasis was classified by two radiologists reviewing the radiological examination as osteolytic type (OL), osteoblastic type (OB), and mixed-type from the CT findings.

Results
Median follow-up time for survivors was 25.4 months. There were 53 (62%) patients with unresectable NSCLC and 32 (38%) patients with postoperative recurrent disease. The number of patients with adenocarcinoma is 75 (87%). The bone metastasis type was OL group in 39 (46%) patients, OB group in 37 (43%) patients, and mixed type in 9 (11%) patients. Survival analysis incorporating mixed type bone metastasis into OB group revealed median survival time of 20.3 months and 30.9 months for OL and OB group, respectively. The difference was not significant (p=0.314), but OB group seems to have better prognosis than OL group. The prevalence of activating EGFR gene mutation was marginally significance in OB group (58%) than in OL group (36%) (p = 0.052). There are no significant relationship between the type of bone metastasis, and sex and smoking history.

Conclusion
This study shows that evaluating the type of bone metastasis by CT image enable prediction of EGFR gene mutation status and prognosis in NSCLC patients with bone metastases separately from sex, smoking habit, and race. The presence of osteoblastic metastases or the evolution to metastases should always be noted since it might represent an important predictive factor of response to EGFR-TKI treatment.

Background
Background: Vibrational infrared (IR) spectroscopy is a powerful chemical analytical tool that can be used to detect and analyse many types of chemicals and materials including complex mixtures. Absorptions in this region arise from molecular vibrational properties and most molecules have characteristic IR spectra. There is a growing literature on its possible medical diagnostic use to distinguish cell types and states by characterising their IR ‘molecular fingerprints’ in the 1800 -900 cm[-1 ]range. Such spectra are complex since they represent an overlapping mixture of proteins, lipids, carbohydrates, DNA and cellular metabolites. Hypothesis: IR spectroscopy will differentiate histological grade of bronchial biopsies by identifying spectral changes corresponding to the stepwise progression from dysplasia to invasive cancer.

Methods
Methods: 52 biopsy specimens were obtained bronchoscopically from 38 patients representing 21 normal, 9 low grade dysplasia, 18 high grade dysplasia and 7 invasive squamous cell carcinomas. Matched histopathological samples were examined by H&E staining and microscopy for pathological classification. In all cases, IR data were collected in the 4000 – 900cm[-1] region using a Bruker IFS66s FTIR spectrometer, both absolute absorbance spectra and their second derivatives were calculated. Biopsies are analysed fresh; time taken to capture each reading is approximately 1 minute.

Results
Results: There were minimal changes to differentiate low grade changes from normal epithelial cells however there were significant and reproducible changes corresponding to high grade dysplasia and cancer (Fig 1). We have developed an algorithm analysing the relative size of IR peaks in the 1290-1270cm[-1 ]range that differentiates with 100% accuracy between normal/ low grade and high grade/ cancer in this small pilot study. We have observed differences in regions suggesting changes in intracellular glycoproteins and lipids and work continues to define the exact cause of the observed differences. More subtle spectral changes also discriminate between high grade dysplasia and cancer and are the subject of further algorithm development and validation.Figure 1

Conclusion
Conclusions: High quality mid-IR spectra of ex-vivo biopsies do reveal differences between normal and dysplastic/ cancerous cells in bronchial tissues. This technology has the potential to provide real-time near patient cytopathological diagnosis for the bronchoscopist or thoracic surgeon for instance to confirm clear resection margins at surgery. Identification of the chemical changes occurring at a cellular level may lead to reverse translation and better understanding of the processes driving progression to malignant transformation. Future work will refine and validate the observed changes.

Background
Lung cancer is the leading cause of cancer-related death in the United States, with non-small cell lung cancer (NSCLC) accounting for 87% of cases. Roughly half of all patients present with advanced disease and the majority with earlier stage disease eventually develop disease recurrence. The objectives of this study were to characterize patients diagnosed with NSCLC and assess overall survival in the United States Military who receive equal and open access to healthcare in the Department of Defense (DoD) medical system.

Methods
We identified patients (military service members and their dependents) ≥18 years old, with an initial diagnosis of NSCLC from January 2003- March 2013 in the DoD Cancer Registry (N=4,751). Descriptive statistics were generated for demographic and clinical characteristics. Kaplan Meier (KM) curves and Cox proportional hazards regression assessed overall survival (OS).

Results
Military service members comprised 63% of the cohort. The mean age at diagnosis was 66, 64% were male and 72% were Caucasian. Adenocarcinoma (AC) histology was the majority (45%), followed by 31% NSCLC not otherwise specified (NOS), 21% squamous cell (SC), and 2% Large Cell (LC). A majority (57%) were diagnosed at advanced stage and tended to be younger (mean age 65 vs. 67; p<.0001) and more likely male (66% vs. 61%; p<.0001) compared to patients diagnosed with earlier stage disease. In the early stage cohort 78% had stage I disease. Patients with advanced stage disease presented predominately with either AC (41%) or NOS (38%) compared to SC (20%) or LC (2%). Most of the cohort were either currently using or had a history of tobacco use (82%). The unadjusted OS for the cohort was 14.97 months (95% confidence interval (CI): 13.9-15.7) with significantly decreasing survival as stage increased (Table). In the multivariate survival analysis, older age, male gender, increasing stage (Table), squamous cell histology, higher number of comorbidities, and tobacco history were associated with a higher risk of death.

Conclusion
In this DoD cohort, NSCLC patients were diagnosed at a younger age and had a higher proportion of Stage I disease than often seen in the general US civilian population, perhaps due to more open access to health care. Stage at diagnosis was a significant predictor of mortality and further research comparing factors influencing survival relative to the general population is warranted including the role of open access to care.

Table: Unadjusted and Adjusted Survival by Stage

		Unadjusted		Adjusted
Stage	N	Median Survival (Months)	95% CI	HR	95% CI
I	1141	64.2	58.4-70.1	ref
II	324	29.5	26.2-34.1	1.78	1.49-2.12
III	1049	13.5	12.5-15.2	3.31	2.94-3.73
IV	1678	6.5	6.0-7.0	7.15	6.38-8.02

Background
In advanced lung cancer, for the treatment based on one specific driver mutation, it is important to make diagnosis by the use of small biopsy or cytological samples obtained from bronchoscopy examination. With the development of multiple molecular target agents, we need to simultaneously examine several kinds of genetic alterations in small samples.

Methods
Patients who were considered necessary to examine bronchoscopy for diagnosis of lung cancer were prospectively enrolled. Between November 2012 to March 2013, 123 patients were enrolled, and molecular analysis were performed in 115 patients. Liquid based cytological samples (LBC) by bronchoscopy were divided equally into routine pathological examination and molecular examination. After extraction of DNA and RNA from LBC, we evaluated EGFR, KRAS and BRAF mutations and ALK fusions.

Results
Patients characteristics were as follows: the median age 69 (range: 42-83); female 43 (37%); never smoker 40 (22%). Finally, 80 patients were pathologically diagnosed as lung cancer (Ad/Sq/NSCLC/Sm/Unclassified; 50/14/8/6/2). Fifty-nine patients showed class V of LBC, and 16 patients had molecular change (11 EGFR mutation and 5 KRAS mutation). Moreover, 1 patient of class III had an EGFR mutation. In a procedure of bronchoscopy (EBUS-TBNA, bronchoscopy for peripheral lesions and bronchoscopy for central lesions), median quantities of DNA in class V patients of LBC were 1.19, 0.67 and 0.16μg, respectively (Fig1 shown). Median quantities of RNA were 1.24, 0.37 and 0.49μg respectively (Fig2 shown). The quantity of DNA and RNA extracted from EBUS-TBNA were more than that of other bronchoscopy procedures. Figure 1Figure 2

Conclusion
Small samples such as LBC by bronchoscopy may be used to molecular analysis. Especially, our results suggest that LBC from EBUS-TBNA is very usefulness.

Background
Computed tomography (CT)-guided fine needle aspiration (FNA) and biopsy is a well-established diagnostic method for pulmonary lesion.The aim of our study was to update the diagnostic outcomes and the safety profile of CT-guided lung biopsies.

Methods
We retrospectively analyzed the results of the CT -guided FNA and biopsies for 750 pulmonary lesions in 696 patients, and investigated the diagnostic yield, and complication rates.The independent risk factors for the diagnostic failure (ie, nondiagnostic, false-positive, and false-negative results) and the complications (severe pneumothorax) were determined using multivariate logistic regression analysis.

Results
The study included 417 male patients and 279 female patients, with a mean age of 71 years.The mean lesion size was 2.0 cm in maximal diameter.The biopsy results were nondiagnostic in 1.4% of the lesions (11 of 750 cases).The diagnostic accuracy was 92.6% (685/739cases).The sensitivity and specificity for the diagnosis of malignancy was 91.7% (534 of 582 cases) and 99.3% (156 of 157 cases), respectively.The significant independent risk factor for diagnostic failure was Lesions measuring < 2.0 cm (OR, 3.94; p <0.0001).Pneumothorax was the most common complication, and occurred in 36% (272 cases), pneumothorax requiring temporal drainage or chest tube insertion in 7.3% (55 cases), and tension pneumothorax, in 0.2% (2 cases).There were 27 cases (3.6%) with pulmonary hemorrhage, 63 cases (8.4%) with hemoptysis, 2 cases (0.2%) with air embolism , 5 cases (0.6%) with hypertension requiring antihypertensive treatment , 1 case (0.1%) with posterior reversible encephalopathy syndrome（PRES）, and 8 cases (1.0%) with others, including pain, shock, subcutaneous emphysema, subcutaneous hematoma, epilepsy, and bradycardia or tachycardia spell.From a total of 13 patients with severe complications, 12 patients recovered without sequela, however 1 patient recovered but developed paraplegia due to spinal cord infarction; there were no fatalities.The significant independent risk factors for pneumothorax requiring drainage were the depth from pleura < 3.0 cm (OR, 3.60; p <0.001), lesions in the middle lobe (OR, 2.25; p 0.0284),　and COPD patients(OR, 4.38; p <0.001).

Conclusion
CT-guided lung FNA and biopsy have a high diagnostic yield, but factors such as the acquisition of lesions measuring <2.0 cm significantly increased the rate of diagnostic failure.The complication rates were acceptable and comparable to previously published figures.The rate of pneumothorax requiring drainage was correlated with the depth from pleura < 3.0 cm, lesions in the middle lobe, and COPD patients.

Background
Anaplastic Lymphoma kinase (ALK) alterations play a significant role in the pathogenesis of non-small-cell lung cancer (NSCLC), and the ALK pathway has become an important target for novel NSCLC treatment. Despite strong participation in industry-sponsored and recently investigator-initiated multicenter clinical trials, little is known about the prevalence, clinic-pathological parameters and clinical outcomes related to ALK fusion in Latin American (LATAM) NSCLC patients. Preliminary data from previous small studies suggest that the prevalence of other NSCLC driver genes such as EGFR and BRAF may be more frequent in LATAM than in other non-Asian populations. This highlights a clear need for a comprehensive molecular epidemiology investigation in this genetically heterogeneous region.

Methods
Collaboration with the Brazilian National Cancer Institute (INCA) and Latin America Oncology Group (LACOG), through a research agreement with Pfizer Inc., was established and 11 sites from 5 different LATAM countries were contacted for participation (Brazil, Mexico, Argentina, Peru and Bolivia). Countries and site selection was based on ethnic, social and cultural characteristics in order to (appropriately) represent the continent’s population. A total of 1,154 patients will be retrospectively enrolled for molecular analysis. Considering that the expected prevalence is no greater than 10%, this sample permits this estimation with a half-width of the 95% confidence interval < 1.7%. Tissue samples will be shipped to INCA (the coordinator center) for central analysis. Clinical data will be collected by local investigators and retrieved by the coordinator center. The primary goal of the study is to estimate the prevalence of ALK fusion gene in LATAM nonsquamous NSCLC patients and build a stable LATAM network for future molecular epidemiology studies. The secondary objective is to perform a comparison of FISH, PCR and IHC methods for ALK fusion gene detection. FISH will be considered the standard method for comparison and performed using the ALK Dual Color Break-Apart probe (Abbott Molecular Inc.). Real time PCR will be performed in collaboration with Fundación Santa Fé, Colombia (probes and primers synthesized at TIB MOLBIO, LLC and designed with Primer 3 software) and IHC performed with Ventana[TM] reagents.

Results
The protocol was planned in 2011. Since then, the first LATAM molecular epidemiology network was established with LACOG collaboration, and molecular analysis methodology standardization completed.

Conclusion
This trial represents the first cooperative effort for genotype patients in LATAM using sample shipment for central analysis. Enrollment of patients is still pending, waiting for final approval from country regulatory agencies which have different requirements and timeframes for review. Moreover, additional data on tumor specific biomarkers and diagnostic testing across the region may provide a basis to guide future decisions by regulators and treating physicians.

Background
Patients with advanced lung cancer and EGFR mutations can derive significantly benefit by receiving first line EGFR tyrosine kinase inhibitor (TKI) therapy. Multiple trials have showed that clinical selection is not sufficient and that EGFR mutations test should be requested for all non-squamous patients. Moreover there is a suggestion that a lag time between diagnosis and molecular test could harm patients. In this retrospective trial we describe EGFR mutation analysis after the implementation of reflex testing in a cohort of Brazilian patients.

Methods
After May 2011 EGFR reflex testing was recommended for all stage IVA and IVB non-squamous lung cancer patients treated at INCA. EGFR exons 18, 19, 20 and 21 were examined using a commercially available Polymerase chain reaction and Sanger sequencing assay. We retrospectively reviewed clinical and EGFR tests characteristics from medical charts of all patients with available results.

Results
From May 2011 to May 2013 samples from 189 patients (56.2%) out of 336 were screened for EGFR mutations. Main reason for non-testing was insufficient material. Turn around time for EGFR mutation processing substantially improved over this period, from over three weeks to less than 5 working days. Of those patients tested 58.8% were women and 22% were non-smokers or light smokers. Results were obtained from cytological specimen in 33 cases (17.4%). Most patients had adenocarcinoma (95.2%) with only 6 cases (3.2%) of unspecified carcinoma. EGFR mutations were detected in 52 patients (27.5%). The incidence of mutations was higher in females (58.8%) and non-or light smokers (56%). Of the mutations identified 18 (34.6%) were in frame deletions in exon 19, and 8 (15.3%) were exon 21 L858R. Exon 18 G719A and exon 20 insertions were detected in only 1 (1.9%) and 2 (3.9%) cases respectively. We found a high incidence of atypical mutations (44.3%). All of them were single aminoacidic substitutions in exon 18 (7 cases; 30.5%), exon 19 (5 cases; 21.7%), exon 20 (5 cases; 21.7%), exon 21 (5 cases; 21.7%), and a single case of double mutation (exons 19 and 20). We did not detect any de novo T790M exon 20 mutation.

Conclusion
The results of the first 2 years of reflex molecular testing at a single Brazilian institution reported demonstrate the feasibility and potential for a non-clinical selective approach. This high frequency of atypical mutations must be further investigated since to date there are no published data regarding EGFR mutations in the Brazilian population.

Background
Histological differentiation in NSCLC has been addressed recently due to the importance regarding prognosis and treatment options. Adenocarcinoma is considered the most frequent histology and recent guidelines recommend the EGFR mutation testing. Epidemiological characteristics of EGFR mutation positive patients have been widely described in Caucasian and Asian population. Given the differences between these populations, it is important to evaluate the epidemiology in other populations. More than 90% of Costa Rica’s population is treated in a government-based hospital. Hospital San Juan de Dios (HSJD) attends approximately a 40% of Costa Rica’s population. Starting at the end of 2011, all patients with lung adenocarcinoma are evaluated for EGFR mutations.

Methods
We conducted a retrospective analysis of all patients diagnosed with NSCLC in HSJD between January and December 2012. A total of 42 patients were diagnosed with a NSCLC but 2 patients were excluded from the study due to insufficient clinical information. Epidemiologic data was obtained and EGFR mutation status was analyzed.

Results
The NSCLC population analyzed had a median age of 68 y (41-87 y). The most frequent histology reported was adenocarcinoma. All adenocarcinomas were analyzed for EGFR mutations (exon 18, 19, 20, and 21). 33.3% of adenocarcinoma patients had an EGFR mutation. Smoking history was statistically associated with the occurrence of an EGFR mutation. Patient characteristics are summarized in Table 1.

Table 1: Characteristics of patients diagnosed with NSCLC in HSJD-Costa Rica during 2012 Total NSCLC population n=40 Adenocarcinoma population n=27 EGFR mut positive population n=9 Median age 68 y (41-87 y) Sex p=0.504 M (%) 24 (60) 15 (55.6) 4 (44.4) F (%) 16 (40) 12 (44.4) 5 (55.6) Smoking history (PY) p=0.022 Non smoker (%) 14 (35) 12 (44.4) 7 (77.8) 5-20 (%) 3 (7.5) 3 (11.1) 0 21-40 (%) 4 (10) 1 (3.7) 0 41-60 (%) 9 (22.5) 4 (14.8) 1 (11.1) >60 (%) 10 (25) 7 (26) 1 (11.1) Adenocarcinoma histology (%) 27 (67.5) Stage of diagnosis I-II 3 (7.5) 2 (7.4) 0 IIIA 9 (22.5) 4 (14.8) 0 IIIB 5 (12.5) 2 (7.4) 0 IV 23 (57.5) 19 (70.4) 9 (100) % EGFR mutation positive 22.5 33.3 % of type of EGFR mutation Exon 18 0 0 0 Exon 19 17.5 25.9 77.8 Exon 20 2.5 3.7 11.1 Exon 21 2.5 3.7 11.1

Conclusion
In Costa Rica, the incidence of EGFR mutations in adenocarcinoma patients tends to be higher to that of the Caucasian population and lower than the Asian population. This incidence might be similar in other Latin American countries. Epidemiological characteristics of EGFR mutation positive patients are similar to that reported in the literature.

Background
Differentiation of atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma(IA) on computed tomography (CT) is useful for determining ‘‘follow-up or resection’’ strategies for lesions displaying ground-glass opacity nodules(GGN). The purpose of this study is to compare the morphologic features of persistent GGNs of <20 mm in diameter at thin-section CT (TSCT) with histopathology.

Methods
Jan 2010 and Dec 2012, a total of 200 nodules in 191 resected GGNs that were evaluated with TSCT were included in this study. Correlations between histopathology and CT characteristics were examined.

Results
The nodules included 45 AAH (22.5%), 99AISs (49.5%), 11 MIAs (5.5%), and 45 invasive adenocarcinomas (22.5%). The mean CT value (P < .0001), size of nodule (P < .0001) were significant factors that differentiated AAH lesions from invasive adenocarcinoma or AIS or MIA. While the size of nodule (P < .0001) and mass of nodule (P < .0.001) were significant factors that differentiated invasive adenocarcinoma from AIS or MIA.

Conclusion
Size of nodule less than 10 mm and mean CT value less than -510Hu are determinants of AAH, while size and mass of the nodule are determinants of invasive adenocarcinoma in Chinese population.

Background
The Japanese Joint Committee of Lung Cancer Registry (JJCLCR) is jointly established by the Japan Lung Cancer Society, the Japanese Respiratory Society, the Japanese Association for Chest Surgery and the Japan Society for Respiratory Endoscopy, conducting Japanese nation-wide registries of lung cancer patients

Methods
In 1999, 2004 and 2009, registries were conducted for surgical patients in 1994, 1999 and 2004, respectively. In 2002, both surgical and non-surgical (non-biased) patients in 2002 were registered with a follow up period of 3 years or more. In 2012, a registry has been conducted for non-surgical patients in 2012 with a follow up period of 3 years. In 2016, surgical patients in 2010 will be registered. These registries were observationally assessed.

Results
Registries for surgical cases in 1994, 1999 and 2004 which were conducted in 1999, 2004 and 2009 revealed the trend of increase in mean age, rates of female, the aged, small sized lesion, adenocarcinoma and stage I, and that of decrease in the rate of perioperative death. Furthermore proposals for TNM classification were stated as peer reviewed papers- invasion to visceral pleura, chest wall and fat tissue in the mediastinum for T factor. In addition, status of N2 disease were assessed resulting in that highly selected cases (3.8%) were subjected to surgery or surgery-included multimodal therapy with a 5-year survival rate of 30.1% in cN2/pN2-Stage IIIA and it was better than previous registries. Registry for surgical and non-surgical patients in 2002 revealed that stage-specific prognosis was within a range similar to other reports and stage, gender, surgery and performance status were independent prognostic indicator of both non-small and small cell lung cancer. Registry of non-surgical cases in 2012 was conducted and greater than 8,000 cases were registered. In this study, status of usage of FDG-PET scan for staging, EGFR gene mutation and individual therapy were, and prognosis of patients will be registered. In up-coming registry for surgical cases in 2010 which will be performed in 2016, new parameters- the size of tumor regarding non-invasive regions in adenocarcinoma (ground grass opacity in computed tomography), quantitative assessment of lymph node metastasis (the number of metastasized lymph node) as a prognostic indicator, which may be assessed as factors of TNM classification in the future. Besides, the TNM classification will be revised in 2016 according to the proposal from IASLC staging project, to which the JJCLCR offered data of 47,306 cases (approximately 25% of whole world wide cases) from the recent 4 registries.

Conclusion
The JJCLCR conducted nation-wide lung cancer registry in Japan, revealing the condition of the treatment of lung cancer and contributing to the TNM staging program.

Background
Malignant Pleural Mesothelioma (MPM) is a rare disease and often associated with a history of long-term exposure to asbestos. Recently, It’s related to Simian virus 40 (SV-40). The determination is related to exposure to asbestos based on clinical history and possible asbestos in tissue pathology specimens. Diagnosis related to SV-40 based on immunohistochemical staining The Simian Virus 40 Large T Antigen.

Methods
: Retrospective descriptive statistics. Survey by interviewing patients and pathological examine specimens can find asbestos and immunohistochemistry with The Simian Virus 40 Large T Antigen.

Results
From Jan, 2008 to Dec, 2012 at the Pham Ngoc Thach Hospital, we have take diagnosis of 60 cases of malignant pleural mesothelioma, including 29 men and 31 women, with histopathological classification: 28 cases of epitheliod MPM (46.7%), 11 cases with biphasic MPM (18.3%), 09 cases with sarcomatoid MPM (15%), 06 cases with Desmoplastic MPM (10%), 04 cases with Well-Differentiated Papillary Mesothelioma (6.7%) and 02 cases with Anaplastic MPM (3.3%).  Elements related to contact asbestos: 22cases (44.4%).  Confirm the diagnosis of asbestos in tissue specimens:12cases(20%).  Presence of The Simian Virus 40 Large T Antigen: 11 cases (18,3%).  Only one case (1,7%) with both two factors positive asbestos and SV-40.  And having 16 cases (26,7%) did not identify epidemiological factors.

Conclusion
Through the the study series cases of Malignant Pleural Mesothelioma, initially issued a warning about the causative factors in those tumors, including long-term exposure to asbestos and can be caused by infections with Simian virus 40.

Background
BIM (BCL2L11), which encodes a BH3-only protein, is one of major pro-apoptotic factors that facilitate cell death. A 2,903-bp genomic deletion polymorphism in intron 2 of BIM showed 12.3% carrier frequency in East Asian population. This polymorphism results in expression of BIM isoforms lacking the pro-apoptotic BH3. We evaluated whether the presence of the BIM deletion polymorphism is a major risk factors of lung cancer in Korean population.

Methods
We designed 1:1 matched case-control study between lung cancer and control subjects. Lung cancer patients and age, gender and smoking status matched control subjects without other types of malignancies were prospectively enrolled from Feb. 2013 to now. Subjects under 18 years old and who denied to present informed consent were excluded. The presence of 2,903-bp genomic DNA deletion polymorphism in intron 2 of BIM were analyzed by PCR and validated by sequencing. BIM deletion polymorphism status and relationship with clinical and pathological parameters were analyzed using chi-square test, t-test, Kaplan-Meyer estimator, and Log-Rank test.

Results
There were no statistically significant differences in age, gender and smoking status between lung cancer and control subjects. Twenty-three out of 102 (22.5%) lung cancer patients revealed a BIM deletion polymorphism whereas 9 out of 75 (12%) control subjects showed polymorphism. The odd ratio for the association of BIM deletion polymorphism and lung cancer was 2.139 (p=0.076). Sixty-nine out of 102 (67.6%) lung cancer patients were male and 52 (51%) were smoker. Among them 97 (95%) were non-small cell lung cancer (NSCLC) and 5 (5%) were small cell lung cancer. Adenocarcinoma was the most common histological subtype accounting for 69 out of 97 (71%) in NSCLC. When lung cancer patients were categorized according to the presence of polymorphism status, there was no difference in the age between subjects with and without polymorphism (mean age; 63.3 vs. 63.4 year). Among the lung cancer patients harboring BIM deletion polymorphism, there were more female (9 out of 23, 39%) and non-smokers (15 out of 23, 65%) when compared to those without polymorphism showing 24 out of 79 (30%) female and 35 out of 79 (44%) non-smokers. The histological subtypes between the two groups were not significantly different. A total of 64 out of 102 lung cancer patients had been tested EGFR mutation status. The odd ratio for the association of BIM deletion polymorphism and EGFR activating mutation was 0.87. In lung cancer patients, the BIM deletion polymorphism did not have a statistically significant impact on the clinical outcome of the patients.

Conclusion
Our results indicate that BIM deletion polymorphism may be one of major lung cancer risk factors in Korean population. To strengthen our results, we are extending the sample size and are going to perform hierarchical analysis prospectively. To validate our results, we are performing a validation analysis with an external validation dataset from the national cohort.

Background
Due to its high incidence and bad prognosis, lung cancer is a major health problem. In the 2000s, several social and scientific changes (such as decreased smoking, improved diagnosis methods, or the development of new drugs and therapeutic strategies) may have changed the epidemiology and prognosis of this cancer. The objective of the present study was to compare 1-year mortality in adult patients with primary lung cancer at a 10-year interval.

Methods
In 2000 and 2010, the French College of General Hospital Respiratory Physicians (CPHG) performed 2 prospective multicenter cohort studies collecting information on all new cases of lung cancer diagnosed histologically or cytologically from 01 January 2000 to 31 December 2000, and from 01 January 2010 to 31 December 2010, and managed in the respiratory department of one of the participating general hospitals. A standardized form was completed for each patient. A steering committee checked recruitment exhaustiveness.

Results
137 hospitals in 2000 and 104 hospitals in 2010 included respectively 5667 and 7051 patients. The 2 cohorts represented about 1 in 5 lung cancers diagnosed in France in 2000 and 2010. The characteristics of patients and lung cancer changed during the 10-year period in France. In 2010, compared to 2000, patients were older (mean (SD): 65.5 (11.3) years vs. 64.3 (11.5) years; p<0.0001), more frequently women (24.3% vs. 16.0%; p<0.0001) and more frequently never-smokers (10.9% vs. 7.2%; p<0.0001); they had a lower performance status score (PS) at diagnosis (PS 3 or 4: 12.7% vs. 17.7%; p<0.0001); their tumor was more frequently an adenocarcinoma (45.4% vs. 29.0%; p<0.0001). One-year mortality also changed, decreasing from 61.8% in 2000 to 56.4% in 2010. Multivariate analysis showed that the year of diagnosis was an independent risk-factor for death. Other independent risk-factors were older age, male sex, higher PS, active smoking, and small cell lung cancer (please see the table hereafter).

	Odds ratio	95% CI	p-value
Year of diagnosis
2000	1 (Ref)
2010	0.84	0.77-0.91	<0.0001
Age (years)
<60	1 (Ref)
60-75	1.03	0.94-1.13	0.55
>75	1.53	1.35-1.42	<0.0001
Sex
Female	1 (Ref)
Male	1.28	1.15-1.42	<0.0001
Smoking status
Never-smoker	1 (Ref)
Former-smoker	1.02	0.87-1.19	0.84
Active-smoker	1.23	1.05-1.44	0.01
Performance status
0- Asymptomatic	1 (Ref)
1- Symptomatic but completely ambulatory	2.45	2.23-2.69	<0.0001
2- Symptomatic, < 50% in bed	6.49	5.73-7.36	<0.0001
3- Symptomatic, > 50% in bed	15.2	12.6-18.3	<0.0001
4- Bedbound	39.0	23.5-64.8	<0.0001
Small cell lung cancer
Yes	1 (Ref)
No	0.83	0.74-0.93	0.002

Conclusion
In 10 years, 1-year mortality decreased in patients with primary lung cancer. The improvement in survival was not solely due to epidemiological changes in patient characteristics (age, sex, smoking habits, or PS) and tumor characteristics (histological type) over the 10-year period. This supports the hypothesis of improved management of lung cancer in patients followed up in French general hospitals.

Background
In Japan, crocidolite had been used for asbestos cement pipe and spraying and amosite had been used for building board and spraying. These two types of asbestos had stopped to use in Japan in the late 1970s. Asbestos exposure will increase the risk of lung cancer, mesothelioma and nonmalignant lung parenchymal and pleural disorders, including asbestosis, pleural plaques, pleural thickening, and pleural effusions. Asbestosis is a form of diffuse interstitial pulmonary fibrosis and pneumoconiosis caused by the inhalation of excessive amounts of asbestos fibers. By contrast, pleural plaques are the most frequent response to asbestos exposure, appearing even with low-dose, often intermittent, exposures. Plaques occupy irregular, discrete areas on the parietal pleura and are often found as incidental chest radiographic findings. Therefore, radiographic evidence of pleural plaques in lung cancer patients indicates the history of asbestos exposure.

Methods
Between 2003 and 2011 in our hospital, there were 979 patients in whom pleural plaque was confirmed by computed tomography (CT) scanning of the chest. Among those patients, 62 were histologically diagnosed as primary lung cancer.

Results
Grouped according to sex, there were 61 men and an woman. The frequent histologic types of the cancers were adenocarcinoma ( 21 patients ) and squamous cell carcinoma ( 22 patients ), followed by small cell carcinoma (8 paients). 16 patients had Stage1A disease, 8 patients had stage 1B disease, 3 patients had stage 2B disease, 8 patients had stage 3A disease, 6 patients had stage 3B disease and 21 patients had stage 4 disease. The median overall survival was 23.0 months and 1 year, 2 year and 5 year survival rate of all the patients were 56.0 %, 49.0 % and 23.7 %, respectively. Based on the primary treatment, 28 patients received surgery, 4 patients received radiation therapy, 5 patients received chemoradiotherapy, 19 patients received chemotherapy and 6 patients received best supportive care. The median overall survival of the patients treated by surgery, radiation therapy, chemoradiotherapy, chemotherapy, and best supportive care, were 96.0 months, 40.9 months, 6.3 months, 8.4 months and 3.0 months, respectively. Six patients showed radiographic findings of asbestosis accompanied with pleural plaques. Five patients received surgery and a patients received chemotherapy as a primary treatment, but the median overall survival of these 6 patients was as short as 6.5 months.

Conclusion
Among the lung cancer patients associated with pleural plaques alone, early stage patients showed favorable prognosis. But the lung cancer patients in whom pleural plaque and asbestosis were detectable in chest CT showed poor prognosis even after diagnosis at early stage. Therefore, the early detection of lung cancer may contribute to a better outcome in the population which has pleural plaque alone, not accompanied with asbestosis.

Background
Lung cancer is the leading cause of death from cancer in the world and 70 to 85% of these tumors are non-small cell (NSCLC) type. Up to 50% of patients have metastatic disease at the diagnosis, and the brain is one of the most common sites of metastasis. Prognosis of patients with central nervous system (CNS) involvement is usually dismal and is determined by performance status (PS), systemic disease status and age. Recently there is a growing amount of evidence suggesting that aggressive treatment for patients with brain oligometastasis may improve prognosis.

Methods
In this retrospective cohort, forty-nine charts of patients with non-small cell lung cancer (NSCLC) metastatic to the brain and treated with neurosurgery (NS) or radiosurgery, between 1996 and 2008, were reviewed at the Brazilian National Cancer Institute. The primary outcome was overall survival (OS), defined as the interval from the diagnosis to death or last follow-up.

Results
Median age was 54 years (range 32-82), 61% were male and more than 95% had PS 0-1. Most patients were smokers (95.7%) and had adenocarcinoma (77.6%). Twenty-three patients (47.9%) presented with metastatic disease at diagnosis, and 13 (38.8%) with BM upfront. Imaging for the diagnosis of BM varied between computed tomography (CT) (n=19;38.8%), magnetic resonance (MRI) (n=12;24.5%), both CT and MRI (N=15;30.6%) and positron emission tomography (n=1;2%). Forty-three patients (87.8%) were submitted to NS and only one was treated with radiosurgery. Patients had more often single metastasis (84.8%), and none had more than three lesions. Most patients (80%) still received adjuvant whole brain radiotherapy (WBT) after NS. The median OS was 15.8 months (95% CI 9.4-22.2).

Conclusion
Our data confirmed that compared to historical control patients with good PS and brain oligometastasis could derive a better survival when submitted to aggressive local therapy. In our center, until 2008 NS was the most common procedure used and adjuvant WBT was still frequently indicated.

Background
New drug developments in the past decades have improved the prognosis of patients with advanced non-small cell lung cancer (NSCLC). This study aimed to quantify the change in 5-year overall survival of patients ≥65years diagnosed with advanced NSCLC from 1991 to 2009 in United States (US).

Methods
Patients aged ≥65years that were first diagnosed with NSCLC stage IIIB/ IV between 1991 and 2009 (n= 83,930) were identified in the Surveillance, Epidemiology and End Results database that collects data from several US cancer registries. Four cohorts were defined based on patients’ diagnosis year: 1991-1995, 1996-2000, 2001-2005 and 2006-2009. For each cohort, median survival time from diagnosis and 6-month, 1-year, and 5-year survival rates were reported. The 5-year hazard of death was compared between cohorts using Cox multivariable regression adjusted for age, sex, tumor ‘s differentiation level, cancer stage and patient’s socio-economic status.

Results
The main study results are summarized in the table and figure. Patient characteristics changed over time, with patients in the 2006-2009 vs. 1991-1995 cohorts being older (26.1 vs. 17.5% aged ≥80 years), more patients being females (47.6 vs. 42%) and having stage IV cancer (74.1 vs. 64.7 %) at their first diagnosis. Median survival was 4.03 months for the 1991-1995 cohort and increased to 4.30, 4.62 and 4.98 months for the 1996-2000, 2001-2005 and 2006-2009 cohorts. From the earliest (1991-1995) to the latest (2006-2009) cohort the 6-month and 1-year survival rates have increased by 23% (from 37.4 to 46.0%) and 63% (from 16.6 to 27.0%) respectively. After adjustment for potential confounding factors, the 5-year hazard of death decreased by 11%, 21% and 30% respectively for the patients diagnosed in 1996-2000, 2001-2005 and 2006-2009 vs. those diagnosed in 1991-1995.Figure 1Figure 2

Conclusion
The last 20 years witnessed a steady improvement in extending the survival of the patients ≥65years diagnosed with advanced NSCLC.

Background
Gender differences in lung cancer (LC) have been reported, but with many unresolved issues . Family history of cancer might play an important role in lung cancer, especially in never-smoker patients. The aim of this study was to analyze potential clinical, molecular and epidemiological differences between WLC with or without family history of cancer.

Methods
WORLD07 is a Spanish prospective, multicenter, epidemiologic female-specific LC database sponsored by ICAPEM, a professional association committed with WLC research. Clinicopathologic data, tumor genotype, family and personal history of cancer were collected and analyzed in order to detect differences between both groups.

Results
From October/2007 to November/2012, 2081 WLC were included in an e-database from 32 centers. Family history of cancer was common (49.4%, in first-degree was 77%), family history of lung cancer was present in 33%, of breast cancer in 25% and of colorectal cancer in 17%. No differences in median age of diagnosis of LC, previous hormonal therapy, number of children, menstrual status, tumor histology or stage at diagnosis were observed between WLC with or without family history of cancer. WLC with family history of cancer were ever smokers in a higher percentage (63% vs 56%, p=0.006), with no differences in passive smokers. The presence of EGFR mutations was similar in WLC with family history of cancer versus WLC without family history (38% vs 37%), although WLC patients with family history of cancer had a higher rate of exon 21 mutation (36% vs 28%), both in smokers WLC (32% vs 16%, p=0.220) and in never smokers WLC (43% vs 32%, p=0.094). The median overall survival was 25 months (CI95% 21.0-29.0) for WLC with family history of cancer and 22.0 months (CI95% 19.4-24.5) for patients without family history of cancer (p=0.027). Of note, the median overall survival was 34.8 months (CI95% 22.9-46.6) for WLC with family history of LC and 22.5 months (CI95% 20.5-24.5) for patients without family history of LC (p< 0.001).

Conclusion
The presence of familiar history of cancer in WLC patients included in the WORLD07 database was high (49.4%), being lung cancer the most common, followed by breast cancer. No clinical or pathologic characteristic differences were observed between patients with or without family history of cancer. The presence of EGFR mutations was similar, although WLC patients with family history of cancer had a higher rate of exon 21 mutation. The median overall survival was significantly higher in WLC patients with family history of cancer and LC. Family history of cancer, especially of LC, might have a role in LC development and deserves further studies focused in inherited genetic alterations related with an increased susceptibility to LC.

Background
Lung cancer is the fourth most common cancer in Victoria and the leading cause of cancer mortality. Little local knowledge exists of the factors which influence outcome in lung cancer. A pressing need exists to describe regional structure, process and outcome in lung cancer care to improve quality of care and to inform translational research and health care planning. We aim to develop and pilot a population-based lung cancer clinical quality registry to describe clinical assessment, diagnosis, staging, management and outcomes in lung cancer in Victoria.

Methods
The establishment of the Victorian Lung Cancer Registry Pilot Project commenced with the appointment of a Steering Committee to provide project governance. Review of current literature and evidence-based national and international clinical practice guidelines was undertaken by an expert working group. Included data items were epidemiologically sound, reproducible and valid. The data set enables the capture of identified quality indicators designed to describe the structural quality, process quality and indicators of outcome in lung cancer management. Case ascertainment is derived from institutional ICD-10 coding of small and non-small cell lung cancer. Consent to recruitment to the registry occurs via an “opt-off” system. Follow up and outcome measures are collected 6 and 12 months after initial diagnosis capturing survival, treatment and quality of life assessments. Survival will be reconfirmed at 2 and 5 years post diagnosis. Institutional recruitment was designed to sample from metropolitan public, metropolitan private and regional hospitals. A quantitative, case finding audit was employed to evaluate the case ascertainment methodology at a major metropolitan hospital.

Results
Ethics approval was received for 8 pilot sites and a mechanism for rapid case ascertainment and secure data transfer has been established. A web enabled data collection tool has been developed and data has been collected on 576 eligible and consenting patients. Evidence of distress screening was available for 13.02% of subjects. Diagnosis was confirmed < 28 days from referral in 56-86% of cases across institutions. A statement of ECOG status was available in 52.51% of cases and clinical T staging in 48.43% prior to treatment. A record of multidisciplinary team meeting presentation was available in 48.43% of cases. Curative surgery was provided for 27.78% of subjects, curative chemotherapy <5% and curative radiotherapy < 5%. Curative surgery was provided < 14 days from diagnosis in 82-100% of cases. 30 day post curative surgery mortality was 3.12% following 160 curative surgical procedures.

Conclusion
Cancer registries have proven capacity for improving process in the delivery of cancer care and the ensuing outcomes. The development of rapid case ascertainment and “opt off” recruitment strategies appear viable and should ensure broad recruitment from eligible patients diagnosed with lung cancer in Victoria. For registries to inform quality of care and benchmark performance, high quality data is needed on all eligible cases. Our study has identified significant gaps in the documentation of this information in the patient’s medical record. Efforts to improve documentation are required to ensure that registries can perform their important function.

Background
According to a Lung cancer report by The Australian Institute of Health and Welfare, between 2003 and 2007 the highest number of lung cancer diagnosed in New South Wales. The incidence of in lung Cancer in NSW was 59 per 100 000 population, the second highest in Australia. This report also found that the incidence of lung cancer was higher in those living in outer regional, remote and very remote area compared to males living in major cities and inner regional areasAccording to a Lung cancer report by The Australian Institute of Health and Welfare, between 2003 and 2007 the highest number of lung cancer diagnosed in New South Wales. The incidence of in lung Cancer in NSW was 59 per 100 000 population, the second highest in Australia. This report also found that the incidence of lung cancer was higher in those living in outer regional, remote and very remote area compared to males living in major cities and inner regional areas

Methods
Retrospective and descriptive study.

Results
In this study a total of 1245 new cases were included. Mean age at diagnosis was 70 years and 67% were men. 63 % of the cases were from the Illawarra region. The age adjusted incidence of lung cancer in Illawarra region was 70.7/100,000 and 42.5/100,000 for males and females respectively, which was not statistically different compared to the rest of Australia and the world. However, the age adjusted incidence for Shoalhaven region was 103/100,000 and 76.5/100, 000 for male and female respectively which was higher and statistically significant compared to Australian data (P = 0.0239 for NSW and 0.0369 for Australia). Non-Small Cell Lung Carcinoma comprise 73% and 70 % of cases in the Illawarra and Shoalhaven region respectively. The incidence of pleural Mesothelioma was similar to rest of the Australia. The proportion of sub types of lung cancers was not statistically different compared to national and world data. Only 11.2% of cases were diagnosed at early stage of the disease but surgical resection rate for early stage lung cancer was similar to international data. More than 50% of the patients with NSCLC and more than 80% of patients with SCLC received some form of Chemotherapy. More than 80% of patients received radiotherapy at some point of their treatment cycle. 10% with stage IV disease did not receive treatment and 85% of patients of patients with late stage disease were referred to palliative care. Average mortality from lung cancer in Illawarra and Shoalhaven region was not statistically different to national data and international data. Only 42 % of cases were discussed in the Multi Disciplinary Team (MDT) Meeting.

Conclusion
This study confirms a higher incidence of thoracic malignancy in regional and rural Australia compared to metropolitan areas. A significantly higher percentage of lung cancer was diagnosed in late stage of disease compared to national and international data but outcomes were not statistically different. We also found that a significant proportion of the cases were not discussed in MDT meeting

Background
Non-small cell lung cancer (NSCLC) comprises 87% of all lung cancer in the United States with the vast majority diagnosed in advanced stage. Military personnel have higher smoking rates compared to the general population and consequently an increased incidence of lung cancer. We set out to examine whether there were variations in smoking rates and outcomes among patients diagnosed with NSCLC, based on self described ethnicity, in the United States Military and their dependents who receive equal and open access to healthcare in the Department of Defense (DOD) medical system.

Methods
We identified 4,547 patients ≥18 years, with an initial diagnosis of NSCLC from January 2003- March 2013 in the DOD Cancer Registry and categorized into the following self described ethnic groups: Caucasian, African American, Hispanic and Asian/Pacific Islander (PI). Differences in patient characteristics by race were compared using Chi-square and t-test. Kaplan Meier curves and Cox proportional hazards regression assessed overall survival.

Results
There were 3434 (76%) Caucasian, 533 (12%) African Americans, 468 (10%) Asian/PI, and 112 (2%) Hispanics who met the study inclusion criteria. Mean age at diagnosis was highest among Caucasians (67 yrs) followed by Asian/PI (64 yrs), Hispanics (63 yrs) and African Americans (62 yrs). A large majority of Caucasians (87%) and African Americans (86%) had a history of tobacco use, followed by Hispanics (74%) and Asian/PI (65%). Asian/PIs were also more likely to be female, married, have adenocarcinoma histology and were more likely to be sporadic cases (no family history) compared to the other self described ethnic groups. Asian/PIs had significantly higher unadjusted overall survival (Log rank p = 0.0012) and in the multivariate survival analysis, adjusting for age, sex, race, stage, histology, comorbidity, tobacco history, alcohol history, family history, and marital status, Asian/PI patients demonstrated a 20% lower risk of death (Table 1) compared to Caucasian patients. There was no difference in mortality risk between Caucasian and African Americans, and Caucasian and Hispanics.

Conclusion
In this military cohort, equal open access to care in NSCLC patients resulted in similar overall survival among Caucasian, African Americans and Hispanics with significantly higher OS among Asian/PIs. Racial disparities in survival often seen in US civilian populations were not seen in this study of patients treated in the military health system, perhaps due to more equal access to health care. Continued research evaluating treatment patterns and outcomes in the military relative to the general population is warranted.

Table: Cox Proportional Hazards Regression of Overall Survival

RACE	N	HR	95% CI
Caucasian	3434	ref
African American	533	1.001	0.89-1.12
Asian/Pacific Islander	468	0.803	0.71-0.91
Hispanic	112	0.984	0.77-1.26

Background
Lung cancer survival remains poor with only modest progress in absolute terms in recent years. Survival has been lower in the UK than many comparable European countries. There is some evidence that this survival deficit is particularly apparent early during follow-up. Within the UK, survival has been lower among deprived patients. Recent evidence suggests that this 'derivation gap' in survival also predominates early during follow-up. Although early deaths could reflect advanced disease, previous research in both Scotland and England does not support the hypothesis that deprived patients with lung cancer present with more advanced disease.

Methods
Using Scottish lung cancer audit records linked to cancer registrations, hospital discharge records and mortality records, the aims of this project were 1) to describe patterns of survival from lung cancer by socio-economic position 2) to explore the influence of the 'deprivation gap' in survival factors such as age, sex, tumour stage, tumour morphology, emergency presentation, performance staus and co-morbidity by modelling deprivation category-specific relative survival.

Results
Preliminary results confirm that survival remains lower in patients with lung cancer from deprived areas of residence. In multivariate modelling, this finding does not seem to be explained by competing causes of death or stage of disease at diagnosis. The main explanatory variables seem to be performance status and treatment.

Conclusion
Preliminary analysis suggests that performance status and treatment are the most important explanations for the 'deprivation gap' in survival from lung cancer in Scotland.

Background
At diagnosis approximately 25-40% of patients with non-small-cell lung cancer (NSCLC) are older 70 years. There is a scarcity of data on this elderly subpopulation. The aim of this study was to report clinical characteristics of this subpopulation, highlighting some challenges in their clinical management.

Methods
In this retrospective cohort, data from 631 patients with lung cancer diagnosed from 1995 to 2011 at a private Cancer Center in Brazil were analyzed.

Results
At diagnosis, 33% patients (n=214) were older than 70 years. Within this elderly group most patients (n=193; 90%) were classified as NSCLC and became the focus of our analysis. As expected, performance status (PS), staging and smoking were associated with survival (table1). Metastatic disease was present in 60% of this subpopulation, and most patients had good PS (PS0-1: 83%) and 84% were smokers. Additionally, 70% of this group with NSCLC had at least one comorbidity. The median overall survival time was 15 compared to 22 months for patients aged <70 years (p<0.001). In the metastatic group the majority of patients (62%) received only one cycle of chemotherapy (CT) and only 10% received more than 3 cycles. Of note, in patients with stage II and III adjuvant CT was correlated with survival (14 months vs 69 months in no adjuvant CT and adjuvant CT group respectively; p=0,02), although this therapy was administered in only 30% of patients with stage II and 20% of those with stage III. Figure 1

Conclusion
These data show that in this cohort elderly patients with NSCLC do constitute a special subpopulation with associated comorbidities. However, despite most of them had good PS at diagnosis, limited oncology treatment options were offered leading to suboptimal treatment. The fact that oncologists do not feel confortable to offer standard oncology treatment for this population may be due to the fact most of clinical trials exclude elderly patients. Although these data were generated in a private Cancer Center in Brazil we believe it mirrors the stiatuation across the country. These results highlight the urgent need for clinical trials focused on elderly patients, in order to provide a better care for those patients.

Background
Smoking appears to start at ever earlier ages, occurring in the great majority of adolescents between 13 and 15 years old. It is often associated with body image dissatisfaction and eating behaviors disorders. Objective: Assess tobacco consumption and its influence on body image dissatisfaction among high school Portuguese students, aged 15 and 19 years old.

Methods
Based on all students attending 3 high schools from the northern Portugal, the sample was randomly selected and 100 students were recruited from each high school. The adolescents smoking behavior was evaluated according to a protocol adapted from the Global Youth Tobacco Survey (Centers for Disease Control and Prevention, 2001) and body image dissatisfaction was also assessed.

Results
The mean age of the total sample (n=285) was 16.6 ± 1.2 years (min = 15, max = 19) and 46% were male. More than half (55.8%) were dissatisfied with their body image and had already started smoking (59.6%), with greater incidence among girls (54%). More than a half of these students who have tried smoking referred that it had happened between 12 and 15 years old. In all the three schools, 41.1% of adolescents think that smoking leads to weight loss (EA = 40.4%; EB = 41.7%, EC = 41.2%). There was not found any association between body image dissatisfaction and onset of tobacco use (p=0.388), although a stronger association was seen between the wish to be thinner and the fact that they had tried smoking.

Conclusion
Tobacco consumption is increasingly associated with diet behaviors and body image dissatisfaction among adolescents, particularly in girls. Such behavior points to the need for an early, clarifying and effective educational intervention.

Background
Lung cancer caused 1.37 million deaths in 2008 worldwide, 71% of which are caused due to tobacco smoking. Secondhand smoke (SHS) exposure can lead to lung cancer. 60% of the global lung cancer deaths occur in low and middle income countries (WHO). Despite the existing prohibition on smoking in public places in India (Section 4, COTPA), the prevalence of SHS exposure is 40% in homes, 30% in workplaces and 17-48% in other public places. The objective of this study was to describe air quality through PM~2.5~ and air nicotine levels, as well as smoking behavior, in public places and hospitality venues in two Indian states, Gujarat and Andhra Pradesh (AP).

Methods
A random sample of 400 public places was recruited; stratified into hospitality venues (N=200) and other public places (N=200). The air nicotine study was conducted in a subsample of 38 venues out of those recruited. Air nicotine monitors were put in place for 1 week according to standard protocol. PM 2.5 side packs, indicative of ambient SHS, were used with 30 minutes spent each in several rooms including restrooms and offices at each venue. Median and range were reported as the data was skewed.

Results
Air Nicotine monitoring - Detectable levels of air nicotine were found in all building types. In Gujarat, the highest recorded air nicotine concentrations were found in Hospitals (3.319 ug/m[3]), however the highest median air nicotine concentration was recorded in Tea Shops (0.214 ug/m[3]), followed by Railway Station, Waiting Rooms and Restaurants. In AP, air nicotine was highest in Bars/Pubs (median value: 4.445 ug/m[3]), followed by the Tea Shop and Hospitals. 90% of the hospitals monitored in Gujarat and 80% in AP registered smoking on the premises. PM~2.5~ monitoring – Overall, across the states, the highest median PM~2.5~ concentrations were found in recreational venues (44 μg/m[3]), followed by auditoriums (25 μg/m[3]) and offices (20 μg/m[3]). Transportation (19 μg/m[3]), hospitals (15 μg/m[3]) and educational venues (14 μg/m[3]) also recorded PM~2.5~ concentrations. PM~2.5~ levels were significantly higher in places where smoking was observed. PM2.5 levels were significantly higher in hospitality venues as against other public places.

Conclusion
Concentration of tobacco smoke and nicotine was found in most public places including hospitals and government offices. Apart from violation of Section 4 of COTPA these results also suggest that the smoke-free policy as currently implemented is not effectively protecting the masses from SHS and the resulting adverse effects including lung cancer. There is an urgent need to strengthen compliance with smokefree laws at all levels, while provision of designated smoking areas should be removed from the law to ensure 100% protection from SHS.