Virtual Library

Background
Chemoradiation is the standard of care for the treatment of unresectable LA-NSCLC. Cisplatin plus either etoposide or vinorelbine are two of the chemotherapy (CT) regimens widely used for the disease concurrently with radiotherapy. Oral vinorelbine is a formulation which has achieved comparable results to the IV vinorelbine. The purpose of the study is to evaluate the efficacy and safety of cisplatin when combined with etoposide or oral vinorelbine with radical radiation for the management of stage III NSCLC.

Methods
Patients (pts) between 18 and 75 years, with histologically proven untreated and unresectable LA stage IIIA/IIIB NSCLC, adequate bone marrow, hepatic and renal function, ECOG PS 0-1, were randomized to: Arm OV-P: OV 60 mg/m[2] D1, D8 cycle 1 and 80 mg/m[2] cycle 2 (if no grade 3-4 toxicity) plus P 80 mg/m[2] D1 every 3 weeks for 2 cycles as induction; patients without progression received OV 40 mg/m[2] D1, D8, and P 80 mg/m[2] D1 every 3 weeks for 2 more cycles (4 cycles in total). Arm E-P: E 50 mg/m[2] intravenously D1 to D5 plus P 50 mg/m[2] D1, D8 every 4 weeks for 2 cycles. Both regimens administered with concurrent RT 66 Gy in 6.5 weeks. The primary endpoint was progression free survival using RECIST 1.1, and secondary endpoints were overall response rate, overall survival, and safety profile. To guarantee an overall type-1 α error (one side) no greater than 0.05 and a type II (β) error 0.1 for the primary endpoint of PFS, a sample size of 134 pts allocated in a 1:1 ratio is planned.

Results
Since August 2011 77 pts have been recruited. 46 pts have been included in the interim analysis, 23 pts have been randomly allocated to each treatment arm. Patient’s characteristics were: Male 91.3%; median age 64 (range 44-75); PS1 56.5%; smokers 46.8%; adenocarcinoma 40.4% / squamous 55.3%; stage IIIA 46.8% / IIIB 53.2%. Median of months between initial diagnosis and study start was 1 (range 0.3-15.7). Safety: 118 cycles (cy) were analysed, 79 in arm OV-P and 39 in arm E-P. Hematological toxicities arms OV-P/E-P (% cy): grade (g) 3/4 neutropenia 8.9%/13.1%; g3 thrombocytopenia 0%/5.3%; g3 anemia 0%/2.6%; febrile neutropenia 3 cases on OV-P arm (all during induction CT on cy 1) and 1 case on E-P arm (during concurrent chemoradiation). Non-hematological toxicities arms OV-P/E-P (% cy): g3 esophagitis/mucositis 1.3%/15.5%; g3 infection without neutropenia 1.3%/5.1%. No treatment-related deaths were reported. There was no remarkable difference in other toxicities between both arms. 39 pts completed the treatment as per protocol, 19 in arm OV-P and 20 in arm E-P. Overall response rates were 73.7% and 50% for the OV-P and the E-P arm, respectively.

Conclusion
This interim analysis shows that OV-P and E-P when administered concurrently with RT have a manageable safety profile with efficacy. Safety data is consistent with other studies reported for both chemoradiation regimens. Based on these positive results for safety, accrual is ongoing. Clinical trial information EudraCT 2010-022927-31.

Background
The Japan Clinical Oncology Group (JCOG) undertook 2 randomized phase III trials (JCOG9812 and JCOG0301) to assess whether daily low-dose carboplatin plus radiotherapy could improve survival in elderly patients with stage III non-small cell lung cancer (NSCLC) when compared to radiotherapy alone. Although JCOG9812 was prematurely terminated because of a high incidence of treatment-related deaths (TRDs) and instances of protocol violation, especially with regard to radiotherapy planning, the trial regimen was assumed promising. Therefore, JCOG0301 was conducted for the same subjects using the same protocol regimen with modified inclusion criteria regarding pulmonary function and radiotherapy quality control (RTQC) measures. We then carried out a preplanned pooled analysis of these 2 studies.

Methods
The eligibility criteria for both trials were age of ≥71 years and unresectable stage III NSCLC. Patients were randomized to receive radiotherapy alone (60 Gy, RT arm) or chemoradiotherapy (radiotherapy, 60 Gy plus concurrent carboplatin, 30 mg/m[2] per fraction up to the first 20 fractions, CRT arm). The primary endpoint for both studies was overall survival (OS). The pooled analysis included OS, progression-free survival (PFS), response rate, and toxicities.

Results
In JCOG9812, 46 patients (RT arm, n=23; CRT arm, n=23) were enrolled from November 1999 to August 2001. In JCOG0301, 200 patients (RT arm, n=100; CRT arm, n=100) were enrolled from September 2003 to May 2010, and in total, 246 patients were included in the pooled analysis. Patient characteristics for the RT (n=123) and CRT (n=123) arms were as follows: median age, 77 years (range, 71–93) and 77 years (range, 71–89); stage IIIA/IIIB, 65/58 patients and 63/60 patients; performance status (PS) 0/1/2, 44/74/5 patients and 50/69/4 patients; men/women, 103/20 patients and 96/27 patients, respectively. The median OS for the RT (n=121) and CRT (n=122) arms were 16.3 months (95% CI, 13.4–18.6) and 20.7 months (95% CI, 16.3–26.9), respectively (HR, 0.672; 95%CI, 0.502–0.898, stratified log-rank test one-sided p=0.0034). The pooled HR for PFS was 0.671 (95%CI, 0.514–0.875, stratified log-rank test one-sided p=0.0015). Response rates for the RT and CRT arms were 46.3% and 53.3%, respectively. The number of patients with grade 3/4 hematological toxicities was higher in the CRT arm than in the RT arm: leucopenia (62.2% vs 1.7%), neutropenia (54.6% vs none), and thrombocytopenia (30.3% vs 3.3%). The incidence of grade 3/4 pneumonitis decreased from 4.4% (JCOG9812; RT, 4.5% and CRT, 4.3%) to 2.1% (JCOG0301; RT, 3.1% and CRT, 1.0%), and that of late lung toxicity, from 14.0% (JCOG9812; RT, 10.0% and CRT, 17.4%) to 5.9% (JCOG0301; RT, 5.3% and CRT, 6.5%). The incidence of TRD also decreased from 8.9% (JCOG9812; RT, 1 patient and CRT, 3 patients) to 3.6% (JCOG0301; RT, 4 patients and CRT, 3 patients). As per subgroup analyses, ≤75 years, stage IIIA, male, PS 0, and smoking history were associated with statistically significant improvement in OS in the CRT arm.

Conclusion
This combination chemoradiotherapy for elderly patients with locally advanced NSCLC provides clinically significant benefits and RTQC measures are imperative to improve treatment outcome.

Background
This single-arm multicenter Phase II study investigated the efficacy and safety of PEM+CIS induction chemotherapy (CT) followed by full-dose PEM+CIS with concurrent radiotherapy (RT) in patients with LA NS-NSCLC. The 1-year progression-free survival (PFS) rate (primary endpoint) was 51.3% (ESMO 2013). Here, we report the safety data for induction CT and concurrent CT+RT.

Methods
Patients with unresectable Stage IIIA/IIIB NS-NSCLC (AJCC Version 6), ECOG-PS 0-1 and forced expiratory volume (FEV) >50% of predicted normal FEV received 2 cycles of PEM 500mg/m[2] + CIS 75mg/m[2] on Day 1, every 21 days. Patients who did not progress, with no residual neurological toxicity >Grade (G)2, ECOG-PS 0-1 and lung V20<35% were candidates to receive 2 cycles of the same full-dose PEM+CIS regimen with concurrent thoracic RT of 2Gy/fraction, 5d/week for 7wks (66Gy total). All patients received vitamin supplementation/dexamethasone prophylaxis as per PEM-label.

Results
90 patients were enrolled in 4 European countries, 75 (83.3%) completed induction CT and started concurrent CT+RT. Characteristics of 90/75 patients starting induction/concurrent therapy: median age 61/62yrs, male 57%/53%, ECOG-PS 0 66%/65%, mean(SD) FEV 2.3(0.62)/2.3(0.59)L, adenocarcinoma 90%/92%, Stage IIIA 36%/37%. 63 of 75 patients starting concurrent CT+RT (84.0%) received all 4 CT cycles and full dose RT. Median PEM+CIS dose intensities were 90-92% during induction and >97% during concurrent CT+RT, median RT dose was 66Gy (only 6 patients <60Gy). One patient died from study-drug-related toxicity (enteritis) during Cycle 4. Four patients discontinued due to non-fatal drug- or radiation-related adverse events (AEs), 1 on induction CT (renal failure), 3 on concurrent CT+RT (hypoacusis, 2 patients with radiation esophagitis). During induction/concurrent therapy, 8 of 90 patients (8.9%)/12 of 75 patients (16.0%) had ≥1 CT dose delay due to AEs, mainly neutropenia (n=5/6). 2/6 patients (2.2%/8.0%) required CT dose reductions. 13 of 75 patients (17.3%) experienced AEs requiring interruption of radiation, mainly radiation esophagitis (9.3%). Common G1-4 toxicities are presented in the table. 41.3% of patients reported ≥1 G3/4 toxicity during concurrent CT+RT, mainly esophagitis (12.0%), neutropenia (10.7%) and leukopenia (9.3%). G3 mucositis, G3 dysphagia and G3 acute pneumonitis were each reported by 1 patient (1.3%); 6 patients (8.0%) required blood-cell transfusions. Figure 1

Conclusion
PEM+CIS induction CT followed by full-dose PEM+CIS with concurrent thoracic RT was well tolerated in this study. Incidences of both G3/4 and low-grade toxicities were low, not only during PEM+CIS induction CT, but also during the subsequent 2 cycles of full-dose PEM+CIS CT with concurrent thoracic RT.

Background
To evaluate the effect and safety of concurrent thoracic radiotherapy (TRT) with Cisplatin/Etoposide (PE) compared with weekly Paclitaxol/Carboplatin (PC) regimens in patients with stage III non-small cell lung cancer (NSCLC).

Methods
Patients with stage III NSCLC were randomly assigned to receive PE regimen (PE arm) cisplatin 50mg/m[2] d1, 8, 29 and 36, etoposide 50mg/m[2] d1-5 and 29-33 concurrent with TRT 60Gy, or PC regimen (PC arm) carboplatin (AUC=2) and paclitaxol 45mg/m[2] concurrent with TRT 60Gy.

Results
156 patients were registered. Eventually, 149 were assigned to PE arm (73) and PC (76). The median follow-up time was 38 months. The median survival time (MST) was 20 months. The 2-year overall survival (OS) and 3-year OS were 39.8% and 32.9%. The 2-year progress free survival (PFS) and 3-year PFS were 24.8% and 22.4%. The MST of PE arm and PC arm were 22 months and 20 months, and the median progress free time were 13 months and 11months, respectively. The 2-year OS of PE arm and PC arm were 44.9% and 35%, the 3-year OS were 40% and 26.2% (p=0.323), respectively. The 2-year PFS of PE arm and PC arm were 27.7% and 22.1%, 3-year PFS were 24.5% and 20.5% (p=0.449), respectively. The incidence of Great 3/4 bone marrow depression of PE arm and PC arm were 34.2% and 23.7% (p=0.29). The incidence of Great 2 or greater radiation pneumonitis of PE arm and PC arm were 19.2% and 26.3% (p=0.059).

Conclusion
For stage III NSCLC, concurrent TRT with PE regimen has improved PFS and OS comparing with PC regimen without significant difference. Concurrent PE regimen has a lower incidence of Great 2 or greater radiation pneumonitis.

Abstract not provided

Background
Endostatin has been proved to be a potent endogenous angiogenic inhibitor. Recombinant human endostatin (Endostar) was reported to be efficient in blocking angiogenesis and suppressing tumor growth. Preclinical studies demonstrated that Endostar could normalize tumor vasculature, alleviate hypoxia and sensitize the function of radiation. This study was conducted to evaluate the efficacy and safety of Endostar combined with concurrent chemo-radiotherapy (CCRT) in patients with stage IIInon-small-cell lung cancer (NSCLC).

Methods
Patients with unresectable stage IIINSCLC were eligible. Patients received Endostar (7.5 mg/m[2]/d) through 7 days at weeks 1, 3, 5, and 7, and two cycles of docetaxel (65 mg/m[2]) and cisplatin (65 mg/m[2]) on days 8 and 36, with concurrent thoracic radiation at 60~66 Gy. Primary end points included the short-term efficacy and treatment-related toxicity of Endostar combined with CCRT.

Results
In all, 50 patients were enrolled onto the study, and 48 were assessable. Median follow-up was 32.1 months. Response rate was 77%. The estimated median progression-free survival (PFS) was 10.2 months and the estimated median overall survival (OS) was 22.6 months. The 1-year and 2-year PFS rates were 48% and 25%, respectively. The 1-year and 2-year OS rates were 81% and 47%, respectively (Figure 1).Nine patients (19%) experienced grade 3 or higher treatment-related nonhematologic adverse events (AEs). Predominant nonhematologic toxicities were grade 3 esophagitis (n = 4; 8%), and grade 3 to 5 pneumonitis (n = 6; 13%). The rates of observed grade 3 and 4 hematologic AEs were 77% (n = 37). The predominant hematologic toxicity was grade 3 to 4 lymphopenia (n = 32; 67%) and neutropenia (n = 23; 48%). Overall, the entire treatment regimen was well tolerated. Figure 1 Figure 1

Conclusion
The combination of Endostar with CCRT is feasible and shows promising activity. This regimen should be studied further in patients with locally advanced NSCLC.

Background
Increased treatment-associated esophagitis could be responsible for concurrent chemo-radiotherapy (CT-RT)-induced weight loss in patients with non-small cell lung cancer (NSCLC). However, based on clinical observations, we hypothesized that weight loss already starts early after initiation of concurrent CT-RT and might therefore be not solely dependent on decreased intake due to esophagitis symptoms.

Methods
In a retrospective cohort, the onset and frequency of weight changes and their association with esophagitis grade ≥2 were assessed in patients with NSCLC treated with concurrent (n=102) or sequential (n=92) CT-RT. The findings in the retrospective cohort were validated in a prospective study in which weight loss and esophagitis grade ≥2 was assessed over a longer time period and additional data on nutritional intake, muscle strength and quality of life was obtained of patients treated with concurrent CT-RT (n=9).

Results
In the retrospective cohort, both the number of patients with weight loss and the magnitude of weight loss was significantly higher in concurrent than sequential treated patients in week 2, 3 and 4 of (CT-)RT (p<0.05). Longitudinal data analysis showed no significant associations between weight loss and grade esophagitis ≥2 in patients treated with concurrent CT-RT (p=0.10). In the prospective cohort, a similar pattern of ‘early’ weight loss was observed in the first weeks of concurrent CT-RT (p<0.05). This early weight loss was not accompanied by significant decreases in nutritional intake but muscle strength did already decline in this early stage (p<0.05). In the following weeks of concurrent CT-RT, the weight further decreased and reached its minimum at the end of treatment (p<0.05), while the number of patients with grade esophagitis ≥2 increased during this time period. During the later part of concurrent CT-RT, dietary intake was significantly lower and patients became more reliant on supplemental nutrition (p<0.05). Although the weight increased again in the weeks after concurrent CT-RT, it had still not reached the baseline level after 4 weeks post treatment (p<0.05).

Conclusion
Weight loss is a common complication of concurrent CT-RT for locally advanced NSCLC, starts early after initiation of CT-RT and is not dependent of esophagitis. It is presumably caused by active catabolism as this ‘early’ weight loss is accompanied by decreased muscle strength, despite stable dietary intake. In the later weeks of treatment, concurrent CT-RT is characterized by a further decline in body weight, decreased dietary intake and higher reliance on nutritional support. In this phase the occurrence of radiation-induced esophagitis grade ≥2 increases. In the weeks following concurrent CT-RT, partial recovery of body weight takes place but this is still not complete after 4 weeks post CT-RT. The sustained weight loss during and following concurrent CT-RT might have major negative consequences as weight loss in patients with underlying malignant disease might has been associated with higher mortality, lower treatment responses and decreases in quality of life. Though the origin of weight loss during concurrent CT-RT seems to be different in the subsequent phases, more aggressive supportive nutritional support throughout the treatment course seems conceivable to prevent negative energy balances and optimize concurrent CT-RT management.

Background
In this study, impact of high pretreatment white blood cell count (WBCC) on survival outcomes in locally advanced non-small cell lung cancer (LA-NSCLC) patients treated with concurrent chemoradiotherapy (CRT) was investigated.

Methods
Medical records of LA-NSCLC patients treated with definitive CRT at our department between dates January 2007 and December 2011 were retrospectively evaluated. All patients received 60-66 Gy thoracic radiotherapy concurrently with 1-3 cycle cisplatin-vinorelbine/taxane (q21) regimen chemotherapy. Patients were divided into two groups according to pretreatment basal WBCC: Group1: normal (4.000-11.000) and Group 2: high (>11.000). These two groups are compared in terms of overall survival (OS), and progression-free survival (PFS).

Results
Pretreatment characteristics of 718 patients were given in Table 1. At a median follow-up of 23.2 months (range 8.8-44.6), median OS and PFS for whole group were 20.6 (%95 CI: 19.3-21.9) and 9.9 months (%95 CI: 9.4-10.1), respectively. On comparative survival analyses, patients with high pretreatment WBCC had inferior OS (22.8 vs.14.7 months; p<0.001) and PFS (10.4 vs. 7.0 months; p<0.001) than those with normal WBCC. On univariate analyses, T-stage (T1-2 vs. 3-4; p=0.035), N-stage (N2 vs. N3; p=0.002), and pretreatment WBCC (4.000-11.000 vs >11.000; p<0.001) were the significant prognostic factors. These factors also retained their significance on multivariate analyses as well (p<0.05 for each). Table. Pretreatment patients characteristics

Conclusion
Worse survival outcomes observed in patients with pretreatment WBCC above the reference limits suggest that pretreatment WBCC may be a potentially cheap and relevant independent prognostic factor that can be used besides other well-known factors to predict treatment outcomes in LA-NSCLC patients treated with definitive CRT.

Background
Perioperative chemotherapy improves overall survival in patients with resectable non-small cell lung cancers. In contrast to adjuvant chemotherapy, neoadjuvant chemotherapy enables radiographic assessment of chemotherapy effect and hence, the option to switch non-responding patients to a potentially more effective regimen. Responses to neoadjuvant chemotherapy assessed by PET imaging correlate better with clinical outcomes than does CT imaging. We have initiated a Phase II trial of PET response guided chemotherapy, where chemotherapy administration decisions are based on comparisons of baseline PET imaging, imaging after 2 cycles of platinum-based chemotherapy, and imaging after ‘switch’ chemotherapy in patients with an initial suboptimal response.

Methods
This Phase II trial (NCT01443078) is enrolling patients with clinical Stage IB-IIIA non-small cell lung cancers deemed operable by a thoracic surgeon. To be eligible, the primary lung mass must be >2 cm with a SUV ≥4.5. Patients with diabetes requiring insulin are excluded. Patients are initially treated with cisplatin (or carboplatin if cisplatin ineligible) + gemcitabine (squamous cell) or pemetrexed (non-squamous). After 2 cycles, if repeat PET imaging shows less than a 35% decrease in SUV of the primary tumor, patients are switched to vinorelbine + docetaxel every 2 weeks with pegylated filgrastim support (2 doses = 1 cycle). The primary endpoint of this study is partial metabolic response after 2 cycles of switch vinorelbine + docetaxel as assessed by PERCIST (SUV decrease of ≥30% using the pre-switch scan as the new baseline). We considered a >20% partial metabolic response rate in those who received vinorelbine + docetaxel worthy of further study. Therefore this study was powered to see at least 6 of 25 partial metabolic responses to vinorelbine + docetaxel, estimating a total patient accrual of 100 patients.

Results
27 patients have been enrolled. 5 are undergoing platinum-based chemotherapy and have not yet been reassessed. 22 patients have been reimaged after 2 cycles of platinum-based chemotherapy, 13 (59%) have had a > 35% decrease in SUV and continued on platinum-based chemotherapy. 9 (41%) patients have had a <35% decrease in SUV after platinum-based therapy and were assigned to switch chemotherapy. 7 received vinorelbine + docetaxel, and 5 (71%, 95% CI 29-96%) have had a PERCIST partial metabolic response after 2 cycles, 1 progressive disease and 1 is pending reassessment. 17 patients have been surgically explored with 13 (76%) R~0~ resections.

Conclusion
Preliminary results from this ongoing trial suggest that patients with resectable non-small cell lung cancers who have a suboptimal PET-assessed response to standard histology-selected, platinum-doublet neoadjuvant chemotherapy can be effectively treated with vinorelbine and docetaxel followed by surgery. This study is on-going. Assessment of pathologic response in resected patients and clinical follow-up in all patients will be available by the time of presentation.

Background
We hypothesized that individualized radiation treatment targeting to the FDG-avid tumor identified mid-treatment would improve local tumor control.

Methods
This is a phase II trial for patients with inoperable/unresectable NSCLC. Conformal radiotherapy (RT) was given in 30 daily fractions. RT dose was individualized to a fixed rate of grade >2 lung toxicity and adaptively escalated to the residual tumor on mid-tx FDG-PET upto a total dose of 86 Gy. Patients were given concurrent weekly followed by consolidation carboplatin/paclitaxel. The primary endpoint was local-regional tumor control (LRTC) and local-regional progression free survival (LRPFS) at 2 years.

Results
42 patients were enrolled: median age 63 years (range 45-83); 28 (67%) male; 39 (93%) smokers; 38 (92%) stage III; and 45% squamous cell. Median physical dose reached was 83 Gy (range 63-86 Gy), equivalent to 90 Gy in 2 Gy fractions (biological effective dose 107 Gy). Minimum and median follow-up were 9 and 27 months, respectively. The 2-year rates of in-field LRTC, overall LRTC, and LR-PFS were 84% (62-94%), 61% (39-77%), and 37% (22-52%), respectively. 15 patients progressed: 2 (13%) at primary tumor alone; 4 (27%) first at distant sites alone; 2 (13%) at nodal regions alone; 5 (33%) at both distant sites and nodal regions; 1 (7%) at both distant site and primary tumor; 1 (7%) at both nodal region and primary tumor. Median overall survival was 22 months (10-33 months) and 2-year overall survival rate was 49% (32-63%). These results compared favorably to stage-matched patients treated with standard-dose RT in our center 2-year overall survival 23% (8-41%) during the same time period.

Conclusion
Adapting RT by targeting high dose radiation to the FDG avid region detected mid-treatment provides outstanding 2-year local-regional tumor control. RTOG 1106 is currently testing this regimen in a randomized fashion.

Abstract not provided

Background
Integration of the proposed IASLC classification of adenocarcinomas (ACA) into TNM staging has been challenging for pathologists. Until recently, at Swedish, we staged patients per the AJCC staging and separately described lesions with a BAC component placing them into 3 groups based on the percent of ACA invasion. But, we found this was not a good predictor of survival. We aimed to more clearly define this population by comparing patients reclassified according to the proposed IASLC classification and the AJCC 7[th] edition staging to determine if they could be integrated as a single staging system.

Methods
We retrospectively reviewed patients with BAC from 2000-2012 and classified them according to the IASLC classification as ACA in situ (AIS), minimally invasive ACA (MIA) or lepidic predominant ACA (LPA) and according to the AJCC 7[th] edition staging (stage I, II or III). We then reclassified these patients separating AIS and MIA as stage 0 in the AJCC 7[th] edition staging.

Results
We evaluated 145 consecutive patients with a median follow-up of 30 months. Using IASLC [AIS (N=23), MIA (N=18), LPA (N=104)]; local recurrence rates were: AIS (4%), MIA (11%) and LPA (2%). Regional (8%) and distant (10%) recurrences were only with LPA. Disease-free survival in patients with AIS (96%) and MIA (89%) was higher versus patients with LPA (80%). Five year cancer-specific survival was 100% for patients with AIS and MIA while it was 84% for LPA patients. Using AJCC 7[th] edition [I (N=125), II (N=12), III (N=8)]; recurrence rates were local: stage I (3%), stage III (13%). Regional: stage I (5%), stage II (8%), stage III (13%); and distant: stage I (6%), stage II (17%), stage III (13%). Stage I disease-free survival was 86%, stage II 75% and stage III 61%. Five year cancer-specific survival was stage I 90%, stage II 81% and stage III 60%. Separating AIS and MIA as stage 0 [0 (N=42), I (N=84), II (N=11), III (N=8)]; local recurrence rates were: stage 0 (7%), stage I (1%), stage III (13%). Regional: stage I (7%), stage II (9%), stage III (13%); and distant: stage I (10%), stage II (18%), stage III (13%). Disease-free survival was higher in stage 0 (93%) compared to stage I (82%), stage II (73%) and stage III (61%). Five year cancer-specific survival was 100% for stage 0, while it was lower for stage I 84%, stage II 80%, and stage III 60%, p<0.05.

Conclusion
The IASLC/ATS/ESR classification system appears to better discriminate patients with BAC compared to current AJCC staging. The results also suggest that patients with AIS and MIA may be classified as stage 0 in the AJCC staging system based on favorable outcomes and survival.

Background
The purpose of this study is to validate the prognostic impact and the frequency of EGFR mutation in lung adenocarcinoma of Japanese patients based on new lung adenocarcinoma classification proposed by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS).

Methods
We reclassified 486 adenocarcinomas according to the new classification. The percentage of each histopathological subtype and the predominant pattern were determined. EGFR mutation also was investigated 241 of 486 adenocarcinomas. The relationship between these results and clinicopathological backgrounds was investigated statistically.

Results
The histopathological assessment according to the IASLC/ATS/ERS classification showed that 8.4% (n = 41) of the cases were adenocarcinoma in situ (AIS) ; 9.2% (n = 45) were minimally invasive adenocarcinoma (MIA) ; 18.3% (n = 89) were lepidic predominant ; 20.4% (n = 99) were acinar predominant ; 28.0% (n = 136) were papillary predominant ; 10.5% (n = 51) were solid predominant ; 2.3% (n=11) were micropapillary (MP) predominant, and 2.9% (n=14) were invasive mucinous adenocarcinoma (IMA). In univariate analysis, the patients with AIS and MIA subtypes had neither recurrence nor death within the follow-up periods. This was followed by the patients with lepidic predominant. The patients with papillary predominant, those with acinar predominant and those with IMA showed almost similar disease-free survival. The patients with solid predominant and MP predominant showed worse disease-free survival (Figure). Multivariate analysis showed that the new classification was an independent predictor of disease-free survival (Hazards ratio: 2.59; 95% confidence interval: 1.69-3.96; p<0.001). EGFR mutation was detected in 131 of 241 adenocarcinomas (54.4%). The each prevalence of EGFR mutation of AIS/MIA/Lepidic/Papillary/Acinar/Solid/MP/IMA was 62.1%/60%/77.1%/50%/49%/27.8%/42.9%/0%.Figure 1

Conclusion
The new IASLC/ATS/ERS adenocarcinoma classification is very useful predictive marker to plan and determine a therapeutic strategy for lung adenocarcinoma.

Background
In 2011, the IASLC/ATS/ERS proposed a new classification for lung adenocarcinoma (ADC) that has powerful prognostic value. However, tumors in each subtype may still include heterogeneous prognostic subgroups - especially in the acinar, papillary, and solid subtypes, in which the majority of tumors are classified. Recently, immune markers such as CD markers and cytokines have been identified as prognostic factors in lung cancer. In this study, we investigate whether tumor budding further stratifies prognosis for stage I lung ADC, independent of the IASLC/ATS/ERS classification, and whether it correlates with prognostic immune markers.

Methods
All available tumor slides from patients with therapy-naive, surgically resected solitary stage I lung ADC (1995-2009) were reviewed (n=1038). Tumors were classified according to the IASLC/ATS/ERS classification. Mitoses were counted at 10 high-power fields (HPFs) (x400 magnification). Tumor budding (tumor nest composed of <5 cells) was assessed, at 10 HPFs (x200 magnification), in areas with the smallest tumor nests and was graded by the maximum number of budding : 0, 0/HPF; 1, 1-4/HPF; 2, 5-9/HPF, and 3, ≥10/HPF. Tissue microarrays were constructed from tumoral and stromal cores, and immunostaining for CD3, FoxP3, IL-7R, and IL-12Rβ2 was performed. Lymphocytes positive for CD3 and FoxP3 were scored in tumor and stroma, and tumors were classified using our recently reported FoxP3/CD3 risk index (JCO 2013). Tumoral expression of IL-7R and IL-12Rβ2 was dichotomized by the sum of intensity (0-3) and distribution (1, 1%-50%; 2, >50%) scores: negative (total score <1) and positive (≥1). Recurrence-free probability (RFP) was estimated using the Kaplan-Meier method; multivariate analyses were performed using the Cox proportional hazards model.

Results
RFP was lowest for patients with budding grade 3 (n=180; 5-year RFP, 69%; p<0.001), followed by grade 2 (n=139; 75%), 1 (n=189; 81%), and 0 (n=530; 89%). Budding grade was dichotomized into negative (grades 0-1) or positive (grades 2-3) using colorectal cancer criteria. The RFP for patients with positive budding (n=319; 5-year RFP, 72%) was significantly lower than that for patients with negative budding (n=719; 87%; p<0.001), which was confirmed in a subgroup analysis limited to stage IA (p=0.004) and IB (p<0.001) patients. Tumor budding further stratified RFP in patients with acinar (p<0.001), papillary (p=0.027), and solid (p=0.015) tumors. Budding was more frequently observed in tumors with high-grade histology (solid and micropapillary; p<0.001), lymphovascular invasion (p<0.001), and high mitotic count (p<0.001). Tumor budding was positively correlated with stromal CD3+ lymphocytes (p<0.001), stromal FoxP3+ (p<0.001), FoxP3/CD3 risk index (high FoxP3, low CD3) in stroma (p<0.001), and tumoral IL-7R expression (p<0.001). In multivariate analysis, tumor budding was an independent prognostic factor for recurrence (HR=1.13; p=0.002).

Conclusion
Tumor budding was a significant prognostic factor in stage I lung ADC, independent of IASLC/ATS/ERS classification, and it correlated with a protumor immune microenvironment (high FoxP3+ lymphocyte infiltration and high IL-7R expression). These findings may inform therapeutic decisions and stratify patients for additional therapy, including immunotherapy.

Background
Currently, non-small cell lung carcinomas (NSCLCs) are mainly classified by histologic analysis and mucin staining: (1) squamous cell carcinoma (SCC) shows keratinization and intercellular bridges; (2) adenocarcinoma shows lepidic, acinar, papillary, micropapillary, or solid pattern, with mucin production; and (3) large cell carcinoma lacks these findings. However, recent studies have shown promising improvements in the classification of NSCLC with immunostain-based markers, including p40 and thyroid transcription factor–1 (TTF-1). In this study, we investigate the use of immunohistochemical analysis in reclassifying NSCLCs originally diagnosed as SCCs.

Methods
All available tumor slides from patients with therapy-naive, surgically resected solitary NSCLCs originally diagnosed as SCC (1999-2009) were reviewed. Tissue microarrays were constructed with 3 cores (n=480), and immunostaining for p40, p63, TTF-1 (clone 8G7G3/1), TTF-1 (SPT24), napsin A, chromogranin A, synaptophysin, and CD56 was performed. Immunoreactivity was scored semiquantitatively by staining intensity (weak, moderate, or strong) and percentage of positive tumor cells (diffuse, ≥50%; focal, <50%). Tumors were first grouped by p40 and TTF-1 (8G7G3/1) status: (1) group A (favor SCC): p40 (+) and TTF-1 (8G7G3/1) (-); (2) group B (favor adenocarcinoma): p40 (- or +) and TTF-1 (8G7G3/1) (+); and (3) group C (favor large cell carcinoma): p40 (-) and TTF-1 (8G7G3/1) (-). Immunostain-based tumor classification was then confirmed with histologic findings and other markers.

Results
In group A (n=448), 1 tumor was reclassified as adenosquamous carcinoma by histologic findings and focal immunoreactivity for p40, p63, and TTF-1 (SPT24). In group B (n=15), 2 tumors were reclassified as large cell neuroendocrine carcinoma (LCNEC) by neuroendocrine morphologic findings and differentiation (1 as pure LCNEC and the other as combined LCNEC with SCC). In group C (n=17), 6 tumors were confirmed as large cell carcinoma because they lacked adenocarcinoma morphology and TTF-1 [SPT24] expression (2 of these showed focal p63 reactivity without keratinization); 4 were reclassified as large cell carcinoma (favor adenocarcinoma) because they were focally positive for TTF-1 (SPT24) but negative for TTF-1 (8G7G3/1) and napsin A; 2 were reclassified as adenocarcinoma because they were diffusely and strongly positive for TTF-1 (SPT24) but focally (<10%) positive for p63, without keratinization; 3 were reclassified as LCNEC by neuroendocrine morphologic findings and differentiation; and 2 were reclassified as small cell carcinoma by morphologic findings. All tumors finally diagnosed as SCC (n=447) using histologic findings and immunohistochemical analysis were positive for p40 and p63. Among them, 27 tumors were positive for TTF-1 (SPT24) (19 focally and 8 diffusely) but negative for TTF-1 (8G7G3/1), with all showing clear squamous morphologic pattern, thus verifying the greater specificity of the TTF-1 8G7G3/1 clone in SCC.

Conclusion
After immunohistochemical reevaluation of 480 NSCLCs originally diagnosed as SCC by classical morphologic analysis, 33 (7%) were reclassified as other histologic types. Immunohistochemical analysis may provide additional valuable information to achieve an accurate diagnosis, particularly in poorly differentiated NSCLCs and in tumors for which the diagnosis of nonkeratinizing SCC is considered.

Abstract not provided

Background
Rapid on site examination (ROSE) is encouraged at EBUS-TBNA to improve the yield of this procedure. However, many centres do not have the resources to meet this demand. Due to new therapeutic options in lung cancer, it is not sufficient to merely distinguish between non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC). Immunohistochemistry (IHC) distinction where possible is now standard practice, as well additional molecular testing where clinically indicated. We investigated the diagnostic yield of smears vs. cell block and the provision of cellular material for ancillary testing.

Methods
A retrospective audit of all EBUS-TBNA procedures performed until the end of July 2012 was undertaken. Diagnostic yield on smears versus cell block was recorded. Cell blocks were reviewed by an experienced pathologist to determine diagnostic accuracy and whether IHC and molecular testing were possible.

Results
208 procedures were recorded with 101(48.5%) malignant cases, 81(38.9%) benign cases and 26(12.5%) with insufficient sampling. The average number of passes was 4.5. For malignancies, smear diagnosis was possible in 95% of cases and cell block diagnosis in 93.5% (87/93) of cases. There was sufficient material for IHC in 97.7% (85/87) of malignant cases where required. In 79.3% (69/87) of NSCLCs molecular testing was theoretically possible based on the tumour load of samples obtained.

Conclusion
Cell blocks are not inferior to smears for diagnostic accuracy and provide sufficient samples for ancillary testing. However, ROSE assists the physician on how best to manage samples for ancillary testing.

Background
ALK gene rearrangement defines a new molecular subtype of NSCLC with response to Crizotinib, (Xalkori®) a dual MET and ALK inhibitor. To date, determination of ALK gene rearrangements has been performed in biopsies and/or surgical specimens. However, advanced lung cancer is often diagnosed by FNA cytology obtained through minimally invasive procedures, and frequently cytological specimens are the only samples available. We assessed the feasibility of determining ALK gene rearrangements in cytological samples.

Methods
We studied prospectively 53 cytological samples from 53 NSCLC patients (30 M/23 F) for ALK gene rearrangements by FISH (Abbot dual colour break apart probe). Tumour samples were obtained by bronchoscopy -FNA in 26 cases (49.1%), EBUS-FNA in 7 (13.2%), EUS-FNA in 3 cases (5.7%), CT-FNA in 3 (5.7%), and direct FNA in 6 cases (11.3%). Two cavity fluids (3.8%), 4 imprints from surgical specimens (7.5%), and 2 cellblocks received for consultation (3.8%) were also studied. FISH was performed on Papanicolau stained smears in 15 cases (28.3%), non-stained ThinPrep in 28 cases (52.8%), cell block in 9 cases (17%), and 1 stained ThinPrep. All cases were tested for EGFR and KRAS mutations.

Results
Thirty-seven samples (69.8%) were adequate for FISH analysis. Three cases (8.1%) had ALK gene rearrangements: positive cases were non-smoker women with adenocarcinoma, two of them with signet ring cells. One case had a concurrent EGFR mutation in exon 21. FISH study was unsuccessful in 16 cases (30.2%): 10 from Papanicolau stained smears (62.5%), 5 from unstained ThinPrep (31.3%), and 1 from a cell block. Nineteen ThinPrep slides were adequate for FISH analysis (86.4%) as well as 8 out of 9 cell blocks. Correlation cytological / paraffin embedded samples was performed in 4 cases with a concordance rate of 100%.

Conclusion
Determination of ALK gene rearrangements in cytological specimens is feasible. It is mandatory an exquisite management and care of the samples to preserve quality. ThinPrep and cell blocks are the most suitable samples for FISH analysis, while Papanicolau stained smears provide poor results. Coexistence of ALK gene rearrangements and EGFR mutations was observed in one case, indicating that such alterations are not necessarily mutually exclusive.

Background
Activating mutations in the epidermal growth factor receptor (EGFR) confer sensitivity to gefitinib and erlotinib in patients with NSCLC. However, response is often short-lived, and patients ultimately relapse, indicating that other concomitant actionable mutations could influence outcome in these patients. The EML4-ALK fusion gene has recently been identified in a subset of NSCLCs, but its specific role remains unclear. We have evaluated the frequency and impact of the concomitant presence of EML4-ALK in patients included in the randomized phase III EURTAC trial.

Methods
The EURTAC study enrolled 173 EGFR-mutant NSCLC patients who were randomized to receive erlotinib or standard chemotherapy with cisplatin or carboplatin plus docetaxel or gemcitabine. Tumor specimens were available from 95 of these patients for the analysis of EML4-ALK. EML4-ALK variants 1 and 3 (v1, v3) were analyzed by an independent single round of PCR followed by sequencing, using cDNA as a sample.

Results
EML4-ALK was detected in 15 samples (15.79%). Nine tumors contained v1 (E13;A20) and six v3 (E6;A20). No significant differences were found in baseline characteristics between patients with and without EML4-ALK. Progression-free survival was 10.4 months (m) for patients harboring the EML4-ALK fusion gene compared to 7.1 m for those without EML4-ALK. Overall survival (OS) was not reached in patients with EML4-ALK, compared to 22.9 m in those without. Complete data on outcome according to treatment arm will be presented.

Conclusion
Our findings indicate that the EML4-ALK rearrangement is concomitant with EGFR mutations in a considerable number of NSCLC patients and may affect outcome.

Background
Stromal cells, including macrophages, lymphocytes and fibroblasts, are known to interact with cancer cells and to produce a specific microenvironment capable of influencing tumor progression. Tumor-associated macrophages (TAMs) are recruited into cancer-induced stroma and produce a specific microenvironment for cancer progression. CD204 positive TAMs are reportedly related to tumor progression and clinical outcome in some tumors. The aim of this study was to clarify the correlation between CD204 positive TAMs and the clinicopathological features of lung squamous cell carcinoma.

Methods
We investigated the relationships between the numbers of CD204 positive TAMs and clinicopathological factors, microvessel density (MVD), and the numbers of Foxp3 positive lymphocytes in 208 consecutively resected cases. We also examined the relationships between the numbers of CD204 positive TAMs and the expression levels of cytokines involved in the migration and differentiation of CD204 positive TAMs.

Results
A high number of CD204 positive TAMs in the stroma was significantly correlated with an advanced p-stage, T factor, N factor, and the presence of vascular and pleural invasion. A high number of CD204 positive TAMs in the stroma was also a significant prognostic factor for all p-stages and p-stage I. Moreover, the numbers of CD204 positive TAMs were correlated with the MVD and the numbers of Foxp3 positive lymphocytes. A high number of CD204 positive TAMs was strongly correlated with the tissue expression level of MCP-1. CD204 positive TAMs were shown to be significant independent prognostic factors in a multivariate analysis.

Conclusion
CD204 positive TAMs were an independent prognostic factor in lung squamous cell carcinoma. CD204 positive TAMs, along with other tumor-promoting stromal cells such as regulatory T cells and endothelial cells, may create tumor-promoting microenvironments.

Abstract not provided

Background
We investigated blood vessel invasion (BVI) as a possible negative prognostic factor in patients with stage I non-small cell lung cancer (NSCLC) according to the 7[th] Edition of the TNM classification.

Methods
Between 1999 and 2007, a total of 694 consecutive patients with pathological stage I NSCLC underwent complete resection with systematic lymph node dissection at Tokyo Medical University Hospital. All sections of the specimens were stained by Elastica van Gieson to visualize elastic fibers and were examined to determine the prognostic symptoms of BVI. We statistically analyzed the association between BVI and clinicopathologic factors, as well as clinical outcomes.

Results
BVI was detected in 201 patients with stage I NSCLC (29.0%). The 5-year overall survival (OS) rates of the non-BVI and BVI patients were 90.5% and 66.0%, respectively (p < 0.0001). BVI was found to be a significant independent prognostic factor by multivariate survival analysis in stage IA and stage IB NSCLC (HR 2.591, p < 0.001; HR 2.347, p = 0.009, respectively). The 5-year OS rate of patients with BVI was significantly worse than that of patients without BVI in the T1a (94.5% vs 87.5%, p < 0.0001), T1b (82.7% vs 65.9%, p = 0.034), and T2a (90.9% vs 61.8%, p < 0.0001) subgroups.

Conclusion
We identified the presence of BVI as an independent poor prognostic factor in patients with stage I NSCLC. In the future revision of the TNM staging system, the routine use of elastic fiber stains in pathological evaluations of lung cancer for BVI determination might be recommended, and tumors with BVI should be upstaged to the higher current T staging.

Background
In non-small cell lung cancer (NSCLC), visceral pleural invasion (VPI) is incorporated as a staging factor in the current TNM classification. Microscopic vessel invasion (MVI: defined collectively as histological blood vessel invasion and lymphatic permeation) has been reported to be a strong independent predictor of poor prognosis, but it has not been incorporated in the TNM classification. We assessed the prognostic significance of MVI as well as VPI.

Methods
Between August 1992 to December 2009, 2657 consecutive patients with pathological T1-4N0-2M0 NSCLC underwent complete resection at our institution. We analyzed the prognostic significance of MVI for recurrence in addition to the conventional prognostic factors. The recurrence-free proportion was estimated using the Kaplan-Meier method and differences were analyzed by the log-rank test. Cox regression analyses were used to identify independent risk factors for recurrence.

Results
The 5-year recurrence-free proportion for patients with or without MVI was 52.6% and 87.5%, respectively (p < 0.001). On multivariate analysis, MVI, similarly to VPI, was found to be an independently significant predictor of recurrence (HR 2.78). In 1601 patients with pathological stage I disease without adjuvant chemotherapy, MVI and VPI were the two strongest independent predictors of recurrence on multivariate analysis (HR 2.74 and 1.84, respectively). Evident and significant separation of the recurrence-free proportion curves among the following 3 groups according to the number of the two risk factors (VPI and MVI) was observed; both VPI and MVI absent (0), either VPI or MVI present (1), and both VPI and MVI present (2). We compared the recurrence-free proportion of patients stratified by tumor size and the number of the risk factors (0/1/2) (Table 1). The groups of small tumor size without PL and MVI showed the best recurrence-free proportions (T1a_0, T1b_0, and T2a_0). The T1a_1, T1b_1, and T2a_1 subgroups showed poorer outcomes which were comparable with the T2b_0 subgroup. The groups with both PL and MVI, even in small tumor size groups, resulted in poor outcomes equivalent to that of T3_0/1 groups. The T3_2 group showed the poorest outcome equivalent to the T4 group.

Conclusion
This study demonstrated that MVI was a significantly independent risk factor for recurrence in resected T1-4N0-2M0 NSCLC patients. We propose the T-classification of tumors with either MVI or VPI (1) should be upgraded to the next T level and that with both MVI and VPI (2) to the second T level (Table 1).

Background
The distinction of intrapulmonary metastases from multiple primary tumors is of great clinical importance as it influences staging, prognosis and therapeutic strategy. Although Comprehensive Histologic Assessment (CHA) was recommended by International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) to differentiate multiple lung primary non-small cell carcinomas from metastases, the limitations of CHA have been addressed. Lung adenocarcinoma in situ is characterized by noninvasive lepidic growth. Whether this histological characteristic could be served for assessing primary lung cancer has not been well determined. In this study we evaluated the application value of CHA and lepidic growth component (LGC) in distinguishing multiple primary lung cancers from intrapulmonary metastases.

Methods
We retrospectively analyzed a cohort of 23 patients with 50 multiple lung tumors. All of the patients have follow up data. The histological evaluation was performed according to 2011 IASLC/ATS/ERS Classification of Lung Adenocarcinoma. The percentage of each tumor subtype in each case was recorded. The intrapulmonary metastases and multiple primary tumors were differentiated based on CHA and LGC (if applicable).

Results
According to CHA alone, there were 11 and 12 cases diagnosed as multiple primary tumors and intrapulmonary metastases, respectively. Disease-free interval (DFI) of the 11 patients with multiple primary tumors was ranged from 11 to 110 months and DFI of the 12 patients with intrapulmonary metastases was ranged from 1 to 93 months. There was no statistically significant difference between these two types of patients (P=0.362). According to CHA with inclusion of LGC, 15 and 8 cases were diagnosed as multiple primary tumors and intrapulmonary metastases, respectively. DFI of the 15 and 8 cases were ranged from 11 to 110 months and from 1 to 34 months, respectively. Statistical significance was detected (P=0.034). These results suggested that CHA combining with LGC might have assessment advantage to distinguish multiple primary tumors from intrapulmonary metastases compared to use CHA alone. Figure 1

Conclusion
The appearance of adenocarcinoma with LGC might indicate lung primaries. Combining with CHA, LGC could potentially improve diagnosis to differentiate multiple primary tumors and intrapulmonary metastases.

Background
The current IASLC/ERS/ATS classification of pulmonary adenocarcinoma indicates that different patterns of growth in adenocarcinoma are associated with prognostic value. There is however, very little information concerning histological prognostic markers in squamous cell carcinomas of the lung. In contrast to adenocarcinoma, squamous cell carcinoma is more homogeneous histologically. However, the World Health Organization classification of lung tumors recognizes different patterns of growth in squamous cell carcinomas. In this study we evaluated several histological parameters including growth patterns and nuclear features and their association with prognosis in a population of stage 1 squamous cell carcinomas.

Methods
A cohort of 165 stage I squamous cell carcinomas of the lung were evaluated. The presence of different histological growth patterns such as papillary, infiltrative, pushing borders, intraalveolar, pseudo-glandular, basaloid, small nest and presence of infiltrating single cells, as well as the cell type (clear cell, transitional, syncytial, and glassy) were evaluated in a semi- quantitative manner by recording the percent of each histological pattern or cell type with 10% increments totaling 100% for tumor. In addition, the presence of peripheral palisading, nuclear features (nuclei size, chromatin patterns, nuclear contour, presence of nucleoli, and mitotic figures), and keratinization were also evaluated. The association of predominant pattern of growth, cell type, and nuclear features with recurrence free survival (RFS), characterized by time to recurrence or death of disease and overall survival (OS) were evaluated.

Results
There were 66 women and 97 men in this population with a mean age of 75±9 year old. All patients were smokers. The mean follow-up was of 47.8 months (4 years). Among histological growth patterns, tumors with predominant papillary and pushing borders appear to have a slightly better outcome compared to other predominant patterns of growth (RFS p=0.05 and OS 0.025). It is interesting to note that squamous cell carcinomas with a predominant basaloid growth pattern, which is considered to be a pattern of poor differentiation, did not have worse prognosis copared to other features. There was no association of cell type, nuclear features, presence of palisading or keratinization with prognosis. There was no difference of nuclear features among tumors with different growth patterns and cell types.

Conclusion
Squamous cell carcinomas appear to be more homogeneous than adenocarcinomas of the lung despite some histological variances. Evaluation of several histological parameters like growth pattern, cell type, and nuclear features failed to indicate a strong association of any of these parameters with prognosis, with exception of papillary and pushing border growth patterns that when present as predominant patterns of growth were associated with a better prognosis. This suggests that contrary to adenocarcinoma, a histological based grading system may not be easily established for squamous cell carcinomas of the lung.

Abstract not provided

Background
Lung cancer patients have complex problems and are considered as disadvantaged when compared with other cancer patients. The needs of lung cancer patients during the treatment trajectory still remain to be identified systematically. The present study is part of a Ph.D. study investigating ’Four critical moments’ in daily life during disease and treatment trajectory in operable lung cancer patients. The Ph.D. study is part of the Centre for Integrated Rehabilitation of Cancer Patients – CIRE. The present study aims to explore lived experiences at diagnosis of operable lung cancer patients in order to identify needs of supportive and rehabilitative care.

Methods
A sample of nineteen patients is included in the study. Inclusion criteria are a diagnosis of non small cell lung cancer referred for surgery at department of Thoracic surgery, Rigshospitalet and age above 18. Individual in-depths interviews with a phenomenological approach were conducted approximately seven days following diagnosis. The phenomenological approach is based on the French philosopher Paul Ricoeur. Focus in the interviews is the present and deals with themes of patients’ experiences with the diagnosis and daily life, bodily experiences, smoking and physical activity. Follow-up interviews are performed 14 weeks post surgery focusing on the patients return to daily life.

Results
Through the analysis of the narrative interviews, patients' lived experiences are described in themes such as onset of illness with no symptoms; resilience expressed as managing on their own, used to be strong and not complaining; psychological response expressed as feelings of unreality, trying to push it away and experiences of lack of concentration, lack of energy and excessive thoughts; existential thoughts, expressed as a confrontation with death, anxiety, loneliness, afraid of the unknown and an emotional rollercoaster ride; the continued daily life focusing on continuing with usual activities and patterns; disruptions in the social relations expressed as withdrawal from social situations or experiences of family and friends’ withdrawal from the ill person. Will not be a burden or receive compassion from family and friends and will not express their vulnerability to family and friends; physical activity as a daily activity but not used to exercise; smoking as stress reduction; supportive needs from a patient perspective such as conversations with healthcare professionals about the whole situation, early information about surgery and no need of further written information; confidence in the meeting with the health care system; uncertain but hopeful about the future.

Conclusion
It is important that health care professionals provide patients with opportunities to talk about their fears, concerns and experiences. Through listening to and understanding operable lung cancer patients, nurses can identify appropriate resources and help patients to access them. Results are expected to contribute to the development and initiation of further interventions for lung cancer patients early in the treatment trajectory.

Background
Malignant pleural effusion (MPE) is common in individuals with advanced cancers and has an adverse impact on respiratory function and quality of life (QOL). Research evaluating treatment methods for MPE have focused on medical endpoints such as chest x-ray and there are no studies that have evaluated patient centered outcomes. Taking into consideration the short life expectancy in this patient population at the time of diagnosis, this study aims to determine the effect of any of the currently accepted treatment methods on QOL and hospital length of stay (LOS).

Methods
A prospective study of patients with a radiologically confirmed pleural effusion and an underlying malignancy evaluated patient centered outcomes using the London Chest Activity of Daily Living Scale (LCADL), Functional Assessment of Chronic Illness Therapy –Palliative (FACIT-PAL) and Functional Assessment of Chronic Illness Therapy Treatment Satisfaction (FACIT-TS-G). Cytological confirmation of MPE was obtained in the majority of patients. Treatment of MPE was determined by the attending physician. The study was approved by the institutional REB. Patients who were unable to read or speak English were excluded from the study. After providing informed consent, patients completed the questionnaires (LCADL, FACIT-PAL and FACIT-TS-G) prior to treatment, immediately post treatment and 2 and 6 weeks post treatment. Spearman correlation coefficients were calculated with 95% confidence intervals and p-values were utilized to assess linear relationships between QOL measurements. Mixed model regression analysis was used to estimate linear trends in LCADLS, FACIT-PAL, FACIT-TS Recommendation and FACIT-TS Satisfaction scores in the entire cohort and between treatment groups. Mean QOL scores at measurement time points were plotted in order to assess trends over time for both the entire cohort and for treatment groups.

Results
There were 105 study participants from 4 hospitals with a median age of 61 years (range 26-89 years). Lung cancer was the most common underlying malignancy, followed by breast and gastrointestinal cancers. MPE was treated by chest tube + pleurodesis (n=39), Tenckhoff catheter alone (n=27), VATS + Tenchkoff (n=20) and VATS + pleurodesis (n=17). In analyzing the entire cohort, there was an overall improvement in shortness of breath (p<0.0001), ability to perform activities of daily living (p=0.03) and quality of life (p<0.0001) for all treatments. There was no statistically significant difference between treatment groups. However, individuals treated with chest tube + pleurodesis had a decrease in treatment satisfaction, while individuals who were treated with VATS + Tenckhoff (p=0.03) or Tenckhoff alone (p=0.04) reported improvement in their treatment satisfaction. LOS was longer for individuals treated with chest tube + pleurodesis (median 10 days) and VATS pleuroscopy (median 6 days) when compared to VATS + Tenckhoff (median 3 days) & Tenckhoff catheter alone (median 2 days).

Conclusion
In the management of MPE, patient centered outcomes are most important. All treatment strategies evaluated in this study provided similar improvements in dyspnea, ability to perform activities of daily living and QOL. However, Tenchkoff catheter treatment strategies offer shorter LOS as well as improved treatment satisfaction which is important given the limited life expectancy of patients with MPE.

Background
Cancer patients' satisfaction with their treatment decision has been proven to be associated with improved health outcome, but few studies have been conducted in Japan. Doctor-centered medicine has been prevailing in the area of cancer treatment in Japan. It has been common among Japanese physicians to withhold "bad news" from patients. Several studies have reported that cancer patients were dissatisfied with this situation and desired to participate in the decision -making on their cancer treatments. Such trends led to the enactment of Cancer Control Act in 2006.The purpose of this law was to establish an environment in which cancer patients were informed about their diagnosis ,and allowed to participate in making decision on their treatment. In this study we hypothesized that cancer patients' satisfaction with their treatment can enhance their psychological outcomes. Furthermore, we hypothesized that cancer patients' satisfaction with their treatment was associated with a rapport established by patient-centered communication with their caregivers. We conducted a cross-sectional survey among 576 Japanese cancer patients.

Methods
We conducted cross-sectional questionnaire surveys among patients who had received cancer treatment. One source was inpatients of a Cancer Center Hospital, and the other a website of Japan's biggest newspaper. The questionnaire included demographics, and general self-rated life status such as peace of mind, quality of life, daily activities, family relationships, rapport with attending physician, assessment of physician's explanations and feeling of happiness during the previous week.

Results
Of 576 participants who responded, 383 subjects were satisfied and 193 dissatisfied. The dissatisfied group included more females and fewer mandatory retired subjects than did the satisfied group. The patients in the more satisfied group had a more favorable subjective opinion on their recent life. Assessment of physician's role showed significant differences between the two groups; the patients in the satisfied group felt more than those in the dissatisfied group that the doctor's explanations of treatment were sufficient and were satisfied with the rapport with their doctors. Multiple logistic regression analysis revealed that rapport with their doctors showed a significant odds ratio (3.79, 95% CI, 2.25-6.39).

Conclusion
Cancer patients' well-being is associated with treatment satisfaction. Rapport between physicians and patients is the most important key factor for patients' satisfaction with their treatment decision.

Background
Supportive care needs (SCNs) of people with lung cancer (LC) are highly prevalent; yet, are often unrecognised and unmet. Patient Reported Outcome Measures (PROMs) are a way of identifying the SCNs of people with lung cancer in clinical practice. Objectives: To explore the use of PROM's by lung cancer nurse specialists (LCNS) in the delivery of supportive care to people with LC.

Methods
A mixed-methods study design was used. Patients (N=20) were recruited from 3 sites in Scotland and took part in the study over 3 time-points: baseline (T1), one month (T2), two months (T3). At each time point, patients completed the Sheffield Profile for Assessment and Referral to Care (SPARC) and used the PROM to direct consultations with their LCNS (N=3). End of study interviews explored patients’/clinicians’ experiences of using the SPARC in the delivery of supportive care.

Results
SCNs were highly prevalent at baseline. A significant reduction in overall psychological and spiritual needs from T1-T2, and family/social and treatment concerns from T1- T3 was recorded. The use of the SPARC resulted in patients disclosing needs that they would not have previously raised and promoted them to ask questions about their condition/care. LCNSs perceived that using the SPARC to guide consultations resulted in patients discussing a wider array of SCNs particularly sensitive issues such as death/dying, concerns regarding family/carers, and sexuality.

Conclusion
Our findings demonstrate the feasibility and acceptability of the use of PROMs in the delivery of supportive care to people with LC in clinical practice.

Abstract not provided

Background
The pattern in which functional decline in people living with advanced cancer occurs has been described as an initial period of reasonably stable function, followed by more rapid functional deterioration with a defined terminal phase. However little is known about the more subtle changes in function in the more advanced stages of cancer, and the role that breathlessness plays in functional changes. The aim of this pilot study is to compare the feasibility of conducting a range of standardised assessments at different levels of performance status in people with advanced cancer.

Methods
A consecutive cohort was recruited to a cross sectional study from three large palliative care units in metropolitan Sydney. Participants completed four breathlessness-inducing assessments: Six-minute Walk Test, Two-minute Walk Test, Isometric Upper limb Exercises and Reading Numbers Aloud. Performance status was assessed using the Australian Modified Karnofsky Performance Scale, Eastern Cooperative Oncology Group Performance Scale and Life-Space Assessment. Comorbidity was identified using the Charlson Comorbidity Index. Four scales were used to assess breathlessness in each participant: Medical Research Council Dyspnoea Scale, Intensity and Unpleasantness of Breathlessness Visual Analogue Scales and Numerical Rating Scale for Breathlessness.

Results
The results of the pilot study have allowed a comparison of the four methods of breathlessness-inducing assessments by functional status in 37 people with advanced cancer. Median scores for performing breathlessness-inducing assessments by level of function where ≥80% of people could complete the assessments will also be presented.

Conclusion
This oral presentation will highlight the pilot study results and the feasibility of using these assessments in research and clinical practice, to improve the assessment of functional capacity and breathlessness in people living with advanced cancer. There is currently limited evidence into how function can be assessed in advanced cancer when breathlessness is present. This study adds to the evidence and knowledge base around the assessment of function in people living with advanced cancer.

Background
All cancer survivors should have a personalised assessment and care plan, and support to self manage their condition (UK DoH 2010) The SPARC (Sheffield Profile for Assessment and Referral to Care) is a tool designed to be completed by the patient, with support from carers if needed, and forms the starting point for the holistic needs assessment process. SPARC is a screening questionnaire that explores a variety of issues and may help the patient/carers to reflect on their needs. The SPARC assessment tool was evaluated for its application utilising lung cancer patients who attended the Lung Cancer Clinic in Rotherham from 2011-2012.

Methods
100 patients responses utilising the SPARC assessment tool were analysed at various time points of their pathway including diagnosis, post treatment, disease recurrence and 5 years post discharge.

Results
The results analysed were in the domains of physical symptoms, communication and information issues, treatment issues, psychological symptoms and distress thermometer outcomes. Key results showed that: - all patients suffered with common symptoms from lung cancer; - were mostly concerned about the effect that their illnes was having on their family or other people; - many required input to help with their personal affairs; - psychological symptoms were evident in a significant proportion of patients; - the distress thermometer was an appropriate tool in this clinic. The results will be shown in detail in the poster.

Conclusion
The SPARC assessment tool is an efficient and validated audit tool for assessing patient concerns and to provide feedback to the patients healthcare team. In Rotherhamm the tool will continue to be utilised and evaluated and is offered to all patients at the first post treatment phase and when no further active treatment is planned. The tool is an appropriate audit tool for assessing patient concerns and to provide feedback to clinicians and community health care teams.

Background
Lung cancer patients continue to experience higher symptom distress than others with different cancer types. We assessed changes in the needs and symptoms of advanced lung cancer patients over a 10 year period.

Methods
Consecutive outpatients with advanced lung cancer attending thoracic oncology clinics at a major Canadian cancer centre were invited to complete a 25-item self-administered questionnaire assessing physical and psychosocial symptoms, functional impairment, cancer knowledge and information preferences. Patients were surveyed over 6 months in 2002, and a second cohort surveyed over 3 months in 2012. Summary data and relevant changes over time are presented here.

Results
108 advanced lung cancer patients were surveyed in 2002, and 100 in 2012. Fatigue, cough, and shortness of breath are the most common physical symptoms, affecting over one-third of patients on a frequent or constant basis. Significant anxiety was reported by 27% in 2002, 20% in 2012, and 15% reported depression, unchanged over time. Lung cancer or treatment-related symptoms impair daily activities in approximately two-thirds of patients. More than a third experience significant financial hardship, and 62% believe their lung cancer imposed significant hardship on their family. More patients in 2012 reported receiving advice on symptom management, information on the goals and benefits of cancer therapy, and an understanding of clinical trials. However a quarter of patients still perceived that they received little to no advice on symptom management, and 19% felt uninformed about treatment goals for their advanced lung cancer. Despite advances in palliative care, less than 20% discussed their end-of-life care wishes with their healthcare team, even though ~40% had specific wishes or plans, with no change over 10 years. In 2002, most advanced lung cancer patients preferred to receive information in print media. In 2012, while most would still be interested in print media, significantly more were interested in a telephone helpline (~60%). Half of patients indicated they would not use internet-based resources even if readily available in 2002, but this number did not change over time (46% in 2012).

Conclusion
Advanced lung cancer patients continue to experience a significant burden of physical and psychosocial symptoms, with no decrease in this burden over time despite perceived advances in treatment and support. Patients are more informed about symptom management and treatment goals than a decade ago, although a significant number still require more information. Patients with advanced lung cancer also need greater empowerment and support from their oncology team in advanced care planning. Printed information continues to be preferable to internet-based resources for the majority of advanced lung cancer patients, and a growing number are interested in telephone help-line support.

Background
Lung cancer affects nearly 41, 500 people per year in the United Kingdom (UK) of which 5000 (12%) will undergo major lung resection for primary lung cancer with approximately 15% of all patients having complications post operatively. Once the patient develops a post surgical pulmonary complication mortality increases from 0.5% to 12%, ITU admission rate increases from 1.5% to 26% and the length of stay increases from 5 to 14 days. The UK National Lung Cancer Forum for Nurses have produced a Guideline for Telephone Follow Up for Patients Undergoing Thoracic Surgery . The aim of the Guideline is to help to provide a telephone follow up service to patients to reduce rates of re-admission and to improve patients satisfaction of their care. The guideline was produced following an audit of patients who had undergone thoracic surgery and a consensus of expert opinion within the thoracic surgical speciality.

Methods
In 2012 a retrospective audit of patients who had lung surgery was undertaken by UK National Lung Cancer Forum for Nurses Thoracic Surgical Group (TSG) in 2012 to assess the timing of intervention after discharge and what assessments would be important to patients. Following a literature review, opinions gathered from Thoracic Surgeons (who worked with the TSG members) and other Lung Cancer Nurse Specialists an assessment was made on how best to support patients after lung surgery. The guideline was developed through regular meetings of the TSG and was developed following the audit, literature review and consideration of the expert views provided.

Results
The audit data was collected from 147 patients from across four Thoracic Surgical Centres in the UK and received 439 comments and focused specifically on post-operative care. The data showed that the consensus opinion from patients was that a preferred interval for post-operative assessment by telephone was between two and seven days after discharge and provided information on the aspects of care that were important to them. The aspects of care that were important to patients included wound management, pain, breathlessness, activity, anxiety, constipation, fatigue and sleep. Following the literature review and expert opinion gathered from Thoracic Surgeons and Clinical Nurse Specialists the decision was made to produce the Guideline for Telephone Follow Up for Patients Undergoing Thoracic Surgery for which can be used by any health professional. The guideline includes assessment tools and interventions utilising best available evidence to assist in the identification of concerns or problems that a patient may face after thoracic surgery. The full guideline can be found at www.nlcfn.org.uk

Conclusion
This guideline aims to help support health professionals in the provision of a follow up service to patients after thoracic surgery. The audit of patients who had undergone lung surgery helped to focus on the problems that patients had identified as being important to them and, together, with best available evidence and expert consensus opinion allowed the development of this guideline. The guideline is being utilised in thoracic centres in the UK and could be adapted for use in other countries.

Abstract not provided

Abstract
Thymomas are epithelial neoplasms arising in the thymus with a spectrum of morphology, genetic characteristics and clinical behavior. Thymomas are composed of a mixture of neoplastic epithelial cells and non-neoplastic T lymphocytes, admixed in varying proportions. Much of the controversy about classification of thymic epithelial tumors can be attributed to confusion about differences in histologic classification versus grading. While genetic studies have provided some insights into the biology of these tumors and classification, a major hurdle is how to identify molecular abnormalities specific to the epithelial cells of B1 and B2 tumors because the genetic findings are dominated by the numerous lymphocytes in the tumor stroma. Thymic epithelial tumors are classified into thymomas and thymic carcinomas according to the 2004 World Health Organization (WHO). Thymomas are classified into Type A and Type B tumors with the latter being divided into B1, B2 and B3 with an increasing percentage and degree of atypia of epithelial cells and decreasing numbers of lymphocytes. THYMOMA Type A thymoma, is composed of bland spindle or oval shaped and few lymphocytes. Type AB thymoma, , is composed of two components, one resembling the type A thymoma and one with plump cells and predominant lymphocytic infiltrate. Type B1 thymoma, is composed of a prominent lymphocyte population with a minor component of epithelial tumor cells with vesicular nuclei and small nucleoli. Type B2 thymoma, is a thymoma with relatively even mixtures of lymphocytes and plump epithelial cells with vesicular nuclei. Type B3, is predominantly composed of polygonal or round epithelial cells with mild atypia. This category shows variable degree of cytologic atypia. THYMIC CARCINOMA Thymic carcinoma was previously classified as Type C thymoma, but in the 2004 classification this term was dropped. These tumors show much greater degree of cytologic atypia than thymoma. CLASSIFICATION ISSUES Histologic heterogeneity is common, with more than one histologic subtype frequently present in a given tumor, making histologic subclassification difficult. The clinical relevance of the WHO classification system has been validated by many studies. In general the classification from type A to AB, B1, B2 and B3, then thymic carcinoma represent an increasing histologic grade that corresponds to increasing aggressiveness of clinical behavior. Increasing molecular alterations are also found along this spectrum from A to B3 thymoma and thymic carcinoma. Thymic epithelial cells stain for epithelial markers such as keratin and squamous markers such as p63 or p40 while thymic lymphocytes stain for T-cell markers such as TdT and CD3. Type A thymomas tend to have fewer immature (CD1a+) lymphocytes and more mature (CD1a-) lymphocytes, while the type B thymomas have many CD1a+ lymphocytes. PAX8 has been reported to be positive in tumor cells of thymomas. Confusion between histologic classification and grading has led to proposals to collapse the classification into a smaller number of entities. One meta-analysis suggested that the current WHO classification scheme of thymomas could be simplified into three types with significant prognostic value: A/AB/B1, B2, and B3. However, what these authors propose is more of a grading system based on clinical behavior rather than histologic typing. The proposal suggests combining two tumors that are completely different morphologically and genetically (type A and B1) both of which are low grade tumors with indolent clinical behavior. Genetic studies have shown distinct gene expression profiles that support the WHO subclassification of thymomas, as far as the subdivision in type A and B thymomas is concerned. Type AB thymomas are genetically heterogeneous, being more closely related to type B thymomas. Expression of the autoimmune regulator AIRE is lost in approximately 95% of thymomas. Genetic alterations in thymomas are most frequent on chromosome 6p23.3 (major histocompatibility complex locus) and 6q25.2 to 25.3. Thymic carcinoma has a distinctive morphology and biology. It is composed of highly atypical cells with cytoarchitectural features of carcinoma similar to those seen in other organs. Although many lymphocytes can be seen in its stroma, they are of B cell type and mature T cell type. Thymic carcinoma lacks the immature T cell lymphocytes that are present in thymoma. Thymic carcinomas are cytologically malignant.{Travis, 2004 #21463} While a certain amount of necrosis, atypia, and mitoses can be encountered in occasional epithelial thymomas, these findings are common in thymic carcinomas. An infiltrative growth pattern associated with desmoplastic stroma is often seen, without evidence of immature T lymphocytes. Thymic carcinomas display a variety of histologic subtypes, emphasizing the ability of thymic epithelium to differentiate toward different cells: squamous cell carcinoma, basaloid carcinoma, mucoepidermoid carcinoma, lymphoepithelial-like carcinoma, sarcomatoid carcinoma, clear cell carcinoma, adenocarcinoma, and NUT carcinoma with t(15:19) translocation. Several immunohistochemical studies have been employed in an attempt to confirm the diagnosis of thymic carcinoma. Several studies have found that CD5 will stain the epithelial cells of some thymic carcinomas. C-kit (CD117) also frequently stains thymic carcinomas. However, neither of these markers are found in all thymic carcinomas and uncommonly they can be positive in B3 thymomas or carcinomas from other sites such as the lung. Comprehensive genomic analysis using comparative genomic hybridization has shown thymic carcinomas are molecularly distinct from thymomas and squamous cell carcinomas of the lung. While c-Kit expression is common in thymic carcinomas mutations are rare. Despite multiple trials of molecular targeted therapies for the EGFR pathway, angiogenesis inhibition, c-kit pathway, histone deacetylase inhibition, octreotide, an IGF-1 receptor pathway, there are no validated targeted therapies that can be recommended at this time. With some of these approaches in early therapeutic trials, and active molecular investigation of these rare tumors, hopefully, in the near future, new treatment options for patients with advanced disease will become available. So far, molecular studies have provided useful insights into the histologic subtypes of thymic epithelial tumors and provide genetic validation of the existing classification, but they have not demonstrated superiority over morphology in classifying these tumors. Hopefully molecular markers can be identified that will aid in refining the existing classification or in separating the existing subtypes.

Abstract
There are many impediments to achieving scientific progress in thymic malignancies, starting with the fact that these are relatively rare tumors. Another problem is the fact that there is no official stage classification system. At least 15 different systems have been proposed, all of which have been based on a limited number of patients, and none of which has been universally adopted with clear definitions that are consistently interpreted. This lack of a common basic language is a crucial fundamental building block for scientific advancement. The International Thymic Malignancies Interest Group (ITMIG) is an academic organization devoted to promoting the scientific advancement in thymic and other mediastinal malignancies. ITMIG has partnered with IASLC to develop proposals to the AJCC/UICC for the 8[th] edition of the stage classification system. This process began in 2010 and is now in full swing. ITMIG has pulled together an international database of approximately 9,000 patients. This involves 77 centers and 16 countries, with a notable major contribution from the Japanese Association for Research in the Thymus (JART). This data, together with an additional approximately 1,800 patients provided by the ESTS have been made available to CRAB, the statistical center for IASLC stage classification analyses. The Thymic Domain of the Staging and Prognostic Factors Committee (SPFC) is currently analyzing this data. The committee is considering multiple factors, starting with an analysis of the prognostic value of the Masaoka and Masaoka-Koga stage classification systems. Subcommittees of the thymic domain are also looking specifically at T, N, M factors, the impact of tumor size, invasion into particular structures and clinical stage. Internal validation will be performed, considering treatment factors, clinical stage, histologic subtypes, geographic regions and taking into account both survival and recurrence. Potentially useful factors will be compared to assess the relative impact, and to select the best factors to propose for use in the 8[th] edition stage classification system.

Abstract
Introduction: Thymic tumors are rare malignancies and most of the current literature is composed of single-institutional series collecting small number of patients spanned over short time periods. The European Society of Thoracic Surgeons (ESTS) thymic working group developed a retrospective database among its members collecting patients with thymic tumors submitted to surgical resection between 1990 and 2010. Methods: A total of 2151 patients were collected from 35 Institutions, including 1798 thymomas, 191 thymic carcinomas (TC), and 41 Neuroendocrine Thymic Tumors (NETT)). 1709 patients (89%) received a complete resection. Myasthenia Gravis (MG) was present in 629 patients (35%). Different clinical-pathologic characteristics were analyzed for their impact on survival and recurrence. Primary outcome was overall survival (OS); secondary outcomes were the proportion of incomplete resections, disease-free survival (DFS) and the cumulative incidence of recurrence (CIR). Results: Ten-year OS and DFS rates were 73% and 70%. The risk of mortality increased with age and with the stage. It also increased in the presence of TC, NETT and incomplete resection. Ten-year CIR was 12%. Predictors of incomplete resection included male gender, tumor size, the absence of MG, non-thymoma categories (TC and NETT) and high-risk thymomas (B2-B3). The risk of recurrence increased with tumor size, increased stage and NETT. Finally, our analysis indicates that the overall effect of adjuvant therapy after complete resection on OS was significantly beneficial (p=0.05) using a propensity score. Conclusions: Masaoka stages III-IV, incomplete resection and non-thymoma histology showed a significant impact in increasing recurrence and in worsening survival. The administration of adjuvant therapy after complete resection is associated with improved survival.

Abstract
Thymic epithelial tumors represent a wide range of anatomical, clinical, histological, and molecular malignant entities, which may be aggressive and difficult to treat. The histopathological classification distinguishes thymomas from thymic carcinomas. Chemotherapy may be used in two clinical scenarios in thymic epithelial tumors: 1) chemotherapy may constitute primary part of the multimodal curative-intent treatment of locally-advanced tumors, and is subsequently combined with surgery or radiotherapy; the main objective is to achieve long-term survival with no evidence of tumor recurrence; 2) chemotherapy may be delivered as the sole treatment modality in unresectable, advanced, metastatic, or recurrent tumors; then a palliative-intent treatment, the aim is to improve tumor-related symptoms through achievement of tumor response, while no prolonged survival is expected. Several chemotherapy regimens have been used in the curative-intent setting, mostly consisting of adriamycin- and/or platin-based multi-agent combinations. Usually 2-4 cycles of chemotherapy are administered before imaging reassessment. Aiming at increasing the response rate to primary treatment, and thus complete resection rate, chemotherapy may be combined with radiotherapy; however, retrospective data available do not provide with interpretable figures to compare chemotherapy to chemo-radiotherapy in the pre-operative setting. Response rates to curative-intent chemotherapy ranged from 70% to 80% in the largest studies. Patients for whom R0 resection was thought to be feasible undergo surgery, and complete resection is achieved in about 50% of cases. Postoperative radiotherapy is then frequently delivered. When the patient is not deemed to be a surgical candidate - either because R0 resection is not thought to be achievable or because of poor performance status or co-existent medical condition, definite radiotherapy, as reported above, is delivered. If radiotherapy is not feasible, either because of a large tumor burden that precludes safe delivery of appropriate doses or because of co-morbidities increasing the risks of radiation-induced toxicity, treatment is chemotherapy alone, in a strategy that may ultimately be considered palliative. In the reported literature, 10-21% of patients with locally-advanced thymic tumors receiving upfront chemotherapy did not receive either surgery or radiation therapy or other local treatment. Survival of these patients is frequently limited. Overall, the major challenge in interpreting data about pre-operative chemotherapy in thymic malignancies is the wide variation in the number of patients subsequently treated with surgery, radiotherapy, or chemotherapy alone, which suggests significant heterogeneity in the inclusion criteria among series. Response has been evaluated based on elusive criteria in some studies published before CT scan was largely available. In most studies, thymomas and thymic carcinomas, as well as newly diagnosed and recurrent tumors, were not analyzed separately. Ultimately, the majority of studies are retrospective, with uncontrolled design. Finally, one should consider the potential effect of corticosteroids, that have been known for a long time to have a “lympholytic” effect. Palliative chemotherapy is given as the sole treatment modality for thymic tumors, usually in the setting of stage IV, unresectable, recurrent disease. Prolonged disease control is possible, but tumor eradication is not expected. Several studies - both prospective and retrospective - described several regimens for definite chemotherapy, but because there are no randomized studies, it is unclear which are best; multi-agent combination regimens and anthracycline-based regimens appear to have improved response rates compared to others, especially the etoposide, ifosfamide and cisplatin combination. In general, combination regimen is recommended, for at least 3 and no more than 6 cycles. Overall, response rates are 20-40%, lower than that observed in the preoperative setting. Progression-free and overall survival of patients ranges from 12 to 66 months, and 37 to 72 months, respectively; such variability may be related to the various settings in which chemotherapy was delivered in those studies. In the palliative-intent setting, several consecutive lines of chemotherapy may be administered when the patient presents with tumor progression. It is estimated that 50-70% of patients with thymoma recurrence are eligible to chemotherapy. Strategy may consist of the re-administration of a previously effective regimen, especially in case of previous response, late occurring recurrence, and for anthracyclins, a patient in a good medical condition and not having received cumulative doses precluding the safe delivery of at least 3 additional cycles. In case of recurrence, the strategy may actually primarily consist of a similar multimodal management to that conducted at time of first diagnosis, with surgery and radiotherapy in eligible cases. Complete re-resection remains a major prognostic factor in this setting. In patients not eligible to receive additional chemotherapy, octreotide may represent a valuable option; as a single agent, octreotide produced objective tumor responses rates, and of more relevance in this setting, disease control rates. Novel treatment strategies are needed, especially for refractory, recurrent tumors, and thymic carcinomas, which carry a poor prognosis despite multimodal treatment. Potentially druggable targets are emerging, laying the foundations to implement personalized medicine for patients. Given the currently available targeted agents outside of a clinical trial, the signaling pathways that are relevant in the clinical care of patients, are the KIT and the Vascular Endothelial Growth Factor (VEGF)-R (Receptor) pathways. Promising new targets in thymoma and thymic carcinoma include IGF-1R and histone-deacetylase. Cixutumumab, an IGF1-R directed monoclonal antibody was recently reported to produce a promising 90%-disease control rate in refractory thymomas. Belinostat, a histone deacetylase inhibitor was evaluated in thymic malignancies in a recently completed phase II trial enrolling 41 patients (25 thymomas and 16 thymic carcinomas). Response and 2-year survival rates were 8% and 77% in thymomas. mTOR inhibitors, in the setting of phase I trials, have been reported to produce significant control rates in thymoma and thymic carcinoma. Along with the large variety of questions relative to the treatment strategy, thymic epithelial tumors represent a model of therapeutic implementation and achievement in orphan thoracic oncology, showing how the advent of new results induces new questions, as well as diversifies further clinical research directions; in this setting, regional and international collaborative initiatives are mandatory to progress both in the understanding of the biological mechanisms underlying the development of thymic malignancies, and in the identification and validation of new targets with prognostic and predictive value.

Abstract
Although the predominant approach in the treatment of thymoma and thymic carcinoma is surgery, radiation therapy also has an important role, either as postoperative therapy to reduce the risk of mediastinal recurrence or as part of definitive treatment for patients that who cannot undergo surgery. We present here a review of radiation therapy for thymic malignancies and briefly discuss the potential benefits from novel technologies for such treatment. Thymic carcinoma is a rare but more aggressive tumor which has a tendency to fail locally and distantly. Thymic carcinoma has more frequent EGFR and/or HER2 abnormalities compared to thymoma., and the outcome of thymic carcinoma is usually worse than invasive thymoma. Postoperative Radiation Therapy: Indications R0 (Completely Resected) Thymic Malignancies In general, radiation should be considered more strongly as the risk of recurrence increases. Therefore, for patients with the lowest likelihood of recurrence (i.e. completely resected Masaoka stage I thymoma), radiation can be safely omitted. For those at intermediate risk of local recurrence after complete resection, i.e. those with aggressive tumor histologies (such as thymic carcinoma) or Masaoka stage II and stage III disease, retrospective evidence exists both to support and contradict claims of benefit from adjuvant radiotherapy after complete resection. In general, our institutional practice includes postoperative radiation for completely resected Masaoka-Koga stage III thymoma and stage II or III thymic carcinoma. Risk assessment and stratification is usually done in a multidisciplinary setting and drives the choice of adjuvant treatment. The International Thymic Malignancy Interest Group (ITMIG) published a set of definitions and reporting guidelines for the use of radiation therapy for thymic malignancies in 2011. Pertinent recommendations for postoperative therapy are as follows. First, the term “postoperative” should be used for situations in which the tumor is resected and no residual disease is evident on imaging. If gross disease is present on postoperative imaging, then the disease should be defined as “recurrent” and the intent as “radiation for postoperative disease.” Second, the minimum acceptable dose for postoperative R0 disease is 50 Gy in 5 weeks. Finally, radiation to elective nodal regions not recommended, and the extent of malignancy before surgery should be used as a guide for designing the treatment fields. Microscopic Positive Margins (R1) and Gross Disease (R2) Radiation for R1 or R2 thymic malignancies should be started within 3 months of surgical resection. Doses between 40 Gy and 64 Gy are most appropriate for microscopically positive margins, whereas doses of 54 Gy or higher should be used for gross disease; both given in standard fractions of 1.8- to 2.0-Gy. Patients with positive margins should be considered for concurrent chemotherapy and radiotherapy, especially among patients with thymic carcinoma. Definitive Radiation Therapy Definitive radiation therapy is generally used for patients who are not candidates for surgery because of either the extent of disease at diagnosis or medical comorbidities. Because chemotherapy is a known radiation sensitizer, the combination of chemotherapy and radiation is considered most likely to control disease in these circumstances. In this setting, which is analogous to recurrent disease after surgical resection, we recommend radiation doses of 60 Gy -66 Gy to encompass gross disease plus a margin for microscopic regions at risk. Thymic carcinoma behaves more like non-small cell lung cancer arising from the thymus. Therefore, unresectable thymic carcinoma needs to be treated based on the histology or molecular biomarkers of expression e.g. EGFR, HER2 c-KIT and BCL-2. Approximately 50% of thymic carcinoma has squamous histology which can be treated with cisplatin based chemotherapy and radiotherapy. If unresectable thymic carcinoma has atypical carcinoid histology, etoposide and cisplatin plus radiotherapy might be the best option. For recurrent thymic carcinoma, molecular targeted agents e.g EGFR-TKI, c-KIT inhibitors and VEGFR inhibitors can be delivered in the protocol setting with or without radiotherapy. Techniques Because of the central location of thymic malignancies and the relatively high doses used in radiation therapy, we strongly recommend the use of conformal techniques, such as three-dimensional conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), or, if available, proton beam therapy owing to the physical properties of the particles (i.e., the Bragg peak) which produce lower doses both proximal and distal to the target volume. In addition, because tumors can show substantial changes in shape or size over the course of several weeks of radiation therapy, we recommend that when radiation is to be used as definitive therapy, adaptive planning should be considered. Long-Term Consequences of Radiation on the Heart and Vasculature An abundance of evidence exists to show that long-term survivors of mediastinal radiation therapy can develop both acute and chronic cardiac sequelae. With regard to acute effects, the dose and fractionation of the radiation and the volume of heart irradiated all affect the risk of pericarditis and pericardial effusion. Given the close physiologic association between perfusion and ventilation, one might expect that radiation to the heart could affect lung function and vice versa. In a clinical study, investigators found that several heart dose-volume variables predicted radiation pneumonitis and that the fit of a model predicting pneumonitis was improved by the incorporation of heart variables. In conclusion, considerable evidence has shown that irradiation of the heart and vasculature can lead to increased acute and long-term toxicity and that these side effects are related to the dose, volume, and exact location of the irradiated field. Short-term surrogates of long-term toxicity such as findings on cardiovascular imaging or biomarker correlates would be helpful for identifying which patients at greatest risk for cardiac events. In the meantime, we recommend the continued use of advanced radiation therapy technologies such as IMRT, proton beam therapy, 4D imaging and treatment planning, and adaptive planning whenever possible to minimize the dose to mediastinal structures for patients with thymic disease, many of whom will survive for several decades and thus will live to see the long-term consequences of irradiation of these vital organs.

Abstract
Dramatic response has been achieved by EGFR inhibitors in lung cancer expressing EGFR activating mutations. However, cancer cells show either intrinsic or acquire resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI), gefitinib and erlotinib, and cause disease progression. Known major mechanisms for acquired resistance to EGFR-TKI include T790M gatekeeper mutation in the EGFR gene and activation of bypass survival signal via receptors other than EGFR. The latter mechanism can involve Met gene amplification and ligand-triggered receptor activation as well. For example, HGF, the ligand of a tyrosine kinase receptor Met, activates Met and the downstream PI3K/Akt pathway and triggers resistance to EGFR inhibitors in EGFR mutant cancer cells. Moreover, common polymorphism in BIM gene was recently reported to be found specifically in East Asian and confer intrinsic resistance to EGFR-TKI. These accumulating evidences suggest that mechanisms of EGFR-TKI resistance are complicated and heterogenous even in one individual. In this session, the resistance mechanisms will be introduced and therapeutic strategies will be discussed.

Abstract
ALK gene rearrangements occur in approximately 5% of lung adenocarcinomas and less frequently in other histologic subtypes. Crizotinib is currently the standard of care for ALK+ NSCLC (1). Treatment with crizotinib leads to remarkable objective response rates, durable progression free-survival and superiority over standard second line chemotherapy. Unfortunately, patients eventually experience disease progression on crizotinib. Disease progression may occur primarily in the central nervous system (CNS) alone, likely because of poor penetration of crizotinib into this space, or simultaneously with systemic progression outside of the CNS (2). Systemic disease progression likely occurs via cellular resistance that occurs by multiple mechanisms, which have been observed in vitro or in patient tumor samples derived following progression on crizotinib. Mutations in the kinase domain of ALK currently account for approximately 25% of observed drug resistance (3-5). Resistance mutations occur at the ‘gatekeeper’ position, L1196M, but multiple other ALK kinase domain mutations have been observed in patient samples or in cell lines with induced drug resistance. Indeed, in the first case of published crizotinib resistance, the tumor harbored two separate ALK mutations (6). This pattern stands in contrast to EGFR mutant lung cancer, where the observed rate of resistance mutations is 50-60% and the majority of resistance mutations occur at the gatekeeper position, T790M (7). Also in contrast to EGFR mutant lung cancer, resistance mutations in ALK do not appear to confer a fitness disadvantage to the tumor cell (3). Mutations induce resistance by allowing persistent ALK signaling despite the presence of crizotinib. Copy number gain of the ALK fusion has also been observed in both cell line models and in patient tumor samples following crizotinib resistance (3, 4). It is hypothesized that that a fraction of ALK fusion proteins are not inhibited by clinically achievable doses of crizotinib and that increased expression may allow sufficient downstream signaling for tumor cell survival. Collectively, we have termed resistance mutations and copy number gain as ‘ALK-dominant’ mechanisms of resistance, because the tumor cells are still predicted to be ‘addicted’ to ALK signaling. Multiple mechanisms of ‘bypass’ signaling have been observed in both cell line models and post-progression tumor biopsies. These include activating mutations in EGFR and KRAS, and ligand dependent activation of EGFR or KIT (3, 4). In some cases the ALK gene rearrangement is no longer observed in post-crizotinib biopsy, also suggestive of an alternate or bypass signaling pathway. We have termed these bypass signaling mechanisms as ‘ALK non-dominant’ resistance as the tumor cells may no longer be dependent on ALK signaling. Approximately 50% of patients have been shown to harbor each class (dominant vs. non-dominant) resistance and this may have implications for post-progression therapy in these patients (1). Next generation ALK inhibitors such as LDK378, AP26113, and CH/RO5424802 which potently inhibit the ALK kinase and have activity against many of the resistance mutations in vitro, may be the favored post-progression therapy for patients with ALK dominant resistance. All of these drugs have also demonstrated anecdotal evidence of activity in the CNS. Although not ALK-specific, HSP90 inhibitors, such as ganetespib, IPI-504, and AUY-922, can inhibit ALK signaling by decreasing proper folding of the chimeric ALK fusion proteins and may also overcome ALK dominant resistance (8). ALK non-dominant resistance may require dual inhibition of ALK and a bypass signaling pathway to overcome resistance and the selection of drugs would be dependent on the alternate signaling pathway. Currently, no post-crizotinib therapies are approved in ALK+ lung cancer, but systemic chemotherapy remains as useful treatment strategy and some evidence suggests that pemetrexed-based regimens may be an optimal initial choice in the absence of a clinical trial (9). References 1. Camidge DR, Doebele RC. Treating ALK-positive lung cancer--early successes and future challenges. Nat Rev Clin Oncol. 2012;9:268-77. 2. Costa DB, Kobayashi S, Pandya SS, Yeo WL, Shen Z, Tan W, et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol. 2011;29:e443-5. 3. Doebele RC, Pilling AB, Aisner DL, Kutateladze TG, Le AT, Weickhardt AJ, et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res. 2012;18:1472-82. 4. Katayama R, Shaw AT, Khan TM, Mino-Kenudson M, Solomon BJ, Halmos B, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med. 2012;4:120ra17. 5. Huang D, Kim DW, Kotsakis A, Deng S, Lira P, Ho SN, et al. Multiplexed deep sequencing analysis of ALK kinase domain identifies resistance mutations in relapsed patients following crizotinib treatment. Genomics. 2013. 6. Choi YL, Soda M, Yamashita Y, Ueno T, Takashima J, Nakajima T, et al. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med. 2010;363:1734-9. 7. Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240-7. 8. Normant E, Paez G, West KA, Lim AR, Slocum KL, Tunkey C, et al. The Hsp90 inhibitor IPI-504 rapidly lowers EML4-ALK levels and induces tumor regression in ALK-driven NSCLC models. Oncogene. 2011;30:2581-6. 9. Camidge DR, Kono SA, Lu X, Okuyama S, Baron AE, Oton AB, et al. Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed. J Thorac Oncol. 2011;6:774-80.

Abstract not provided

Abstract
Lung cancer therapy in the metastatic setting is invariably characterized by the emergence of resistance. This applies both to conventional chemotherapy and molecular targeted agents. This presentation will focus on the biological background and subsequent trial designs as it applies to resistance regarding molecular targeted agents (MTA). In the clinical setting when a patient develops progressive disease while exposed to a MTA some key basic considerations should be taken into account before considering acquired biological resistance. Compliance of the patient to the prescribed therapy is an obvious one. Indeed chronic exposure to tyrosine kinase inhibitors (TKI) exposes the patient to chronic toxicities. Some of these toxicities can become intolerable for the patient, thus leading to patient-driven therapeutic breaks that are frequently not specified to the clinician. This is notably true for week-end breaks as well holiday breaks. Honest dialogue with the patient is necessary to identify compliance issues and pharmacological (PK) dosage in the blood of the relevant TKI is an approach to be discussed. Further pharmacokinetic interactions represent a real issue with TKI: many TKI are metabolized by the liver and can have CYP liabilities (ie erlotinib, gefitinib are susbtrated of CYP3A4). Inter-individual PK variability due to genotypic background (polymorphisms in genes encoding drug metabolizing enzymes), inflammatory and nutritional status, may result in suboptimal drug concentrations and decreased efficacy. Significant decrease in drug exposure over time have also been described for and may result in secondary progression despite preserved sensitivity to these agents, with a potential role for subsequent dose escalation. From a biological perspective, 3 main mechanisms have been described to explain resistance to TKI: a) mutation/amplification in the target (ie T790M for EGFR or ALK L1196M), bypass mechanism (ie Met amplification, PI3K mutation, HER 3 activation,) and growth survival/apoptosis resistance (ie loss of BIM, SCLC, EMT). Stronger kinase inhibitors and use of combinations appear as potential solutions to deal with these resistance mechanisms. Some of the potential designs to address acquired resistance include: a) upfront combinations, b) use of third generation inhibitors or mutant-specific inhibitors, c) rolling trials (ie the use of sequential TKI therapies), c) alternating therapeutic approaches (TKI followed by chemotherapy or TKI followed by immunotherapy).

Background
The impact of primary procedure and procedure sequence has not been studied in combined application of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) in lung cancer staging.

Methods
In a randomized controlled trial, 160 patients with histologically confirmed or strongly suspected potentially operable non-small cell lung cancer were enrolled (Group A, n=80, EBUS-centered; Group B, n=80, EUS-centered). In Groups A and B, EBUS-TBNA and EUS-FNA with ultrasound bronchoscope were used as the first procedure, respectively, and secondary procedures were added.

Results
Diagnostic values were evaluated in 148 patients (74 in each group). In Groups A and B, the diagnostic accuracy (93.2% vs. 97.3%, respectively, p=0.2454) and sensitivity (85.3% vs.92.0%, respectively, p=0.4312) in detecting mediastinal metastasis were not statistically different. In Group A, adding EUS-FNA to EBUS-TBNA did not significantly increase the accuracy (91.9% to 93.2%; p=0.7540) and sensitivity (82.4% to 85.3%; p=0.7419). In group B, adding EBUS-TBNA to EUS-FNA increased the accuracy (86.5% to 97.3%; p=0.0160) and sensitivity (60.0% to 92.0%; p=0.0081). There were no inter-group differences in procedure time, cardio-respiratory parameters during procedures, complications, or patient satisfaction.

Conclusion
In combination of EBUS-TBNA and EUS-FNA in mediastinal staging, diagnostic values and patient satisfaction were not different between EBUS-centered and EUS-centered group. However, the necessity of EBUS-TBNA following EUS suggests EBUS-TBNA is a better primary procedure in endoscopic mediastinal staging.

Background
Expert analysis of endobronchial ultrasound (EBUS) images obtained with the mini probe (MP) has established certain subjective criteria for predicting benign or malignant disease. Minimal data is available for objective analysis of these images. The aim of this study was to determine if greyscale texture analysis of EBUS-MP images could differentiate between benign and malignant peripheral lung lesions.

Methods
Digital EBUS-MP images with contrast set at 4 and gain set at 10 were included in this study. A region of interest (ROI) was mapped for each image and analysed in a prediction set. The ROIs were analysed for the following greyscale texture features in MATLAB (v7.8.0.347 (R2009a)); mean pixel value, difference between maximum and minimum pixel value, standard deviation of the mean pixel value, entropy, correlation, energy and homogeneity. Significant greyscale texture features were used to assess a validation set. Figure 1

Results
Eighty-five peripheral lung lesions were in the prediction set (47 malignant and 38 benign). Benign lesions had larger differences between maximum and minimum pixel values, larger standard deviations of the mean pixel values and a higher entropy than malignant lesions (p<0.0001 for all values). Eighty two peripheral lesions were in the validation set; 63/82 (76.8%) were correctly classified. Of these 45/49(91.8%) malignant lesions and 18/33 (54.5%) benign lesions were correctly classified. The negative predictive value for malignancy was 82% and the positive predictive value was 75%. Figure 1

Conclusion
Greyscale texture analysis of EBUS-MP images could assist in differentiating between benign and malignant peripheral lung lesions but tissue diagnosis is still important.

Background
Due to a widespread use of a CT there is recently increased incidence of smaller peripheral lung lesions. Because of an obvious need for a morphological verification new bronchoscopy methods for biopsy of such small peripheral lesions are needed. We have utilized two methods of spectroscopic detection in peripheral lung cancer. In vivo method- NIR spectroscopy of penetrating light and ex vivo method-Raman spectroscopy of biopsy specimens. Correlation of these two methods gives us the insight into molecular biology of in vivo spectroscopic measurement. In vivo NIR spectroscopy together with transbronchial biopsy under fluoroscopic guidance appears to be useful and reliable method for peripheral lung cancer diagnosis.

Methods
We have designed a simple instrument for measurement of a penetrated NIR light through the lung tissue. It consists of two fibres of 1 mm in diameter contained in one bundle covered with insulation sleeving. One of the fibres is a detector; the other is a source fibre. The indicator fibre is 1,5 cm longer than the source fibre and it is separately covered with insulation till its ending. The ending is cut in the angle of 60 degrees and titan coated in order to facilitate NIR light transmission toward detector fibre. The detector fibre is connected to NIR spectroscope and the source fibre to NIR source. The instrument for ex vivo Raman spectroscopy measurement has been derived from above described system. The endings of fibres have been grinded down perpendicularly in order to allow systematic Raman measurement.

Results
In vivo measurement: Measurements of a normal lung tissue at various areas of a lung tissue show characteristic peak at 735 nm which is not present during cancer tissue spectroscopy. In cancer tissue in addition all detected spectra have got fixed ratio (with minimal dispersion) of two standardized transmittance values at two chosen wavelengths (773 and 823 nm)- mirroring the source values with its mild modification by tissue auto fluorescence. By help of those findings we utilized endobronchial measurement of NIR transmittance spectra in attempt to improve sensitivity of trans bronchial biopsy under fluoroscopic guidance. Ex vivo measurement: Biopsy specimens has been immediately transferred to Raman spectroscope laboratory (within 10 minutes) on temperature 8-10°C. For tissue Raman studies we used excitation at 785 nm. Raman spectra in the 700-1,800 cm(-1) range from lung tissue biopsies were obtained within 10 sec. Raman Spectroscopy results from biopsy specimens taken from the in vivo spectroscopy pathological areas showed higher signals for nucleic acid, tryptophan and lower signals for phospholipids and proline, compared to normal tissue.

Conclusion
In vivo NIR spectroscopy together with transbronchial biopsy under fluoroscopic guidance appears to be useful and reliable method for peripheral lung cancer diagnosis. Ex vivo Raman spectroscopy confirmed diagnostics value of in vivo measurements. Such device or its modifications could be easily included for example into the examination by electromagnetic navigation.

Abstract not provided

Background
Adequate tumour samplings for biological analyses are currently of major importance in treating oncological patients. Obtaining histological samplings from the primary lung cancer can be a challenge due to tumour accessibility, small biopsies or tolerance to bronchoscopy such as bleeding or dyspnoea in case of limited airflow capacity. The ELCWP developed a multicentre prospective study searching for predictive factors for response to chemotherapy based on genomic analyses. We aim to analyse the capability in obtaining adequate tumour samplings from the primary non small cell lung cancer (NSCLC) for studying the transcriptome (miRNA and mRNAs) with high throughput techniques.

Methods
All patients presenting with a suspected lung cancer were proposed participating to the study. To be evaluable for the primary endpoint of the study, patients needed to have a confirmed diagnosis of NSCLC treated with chemotherapy and assessable for response. During the diagnostic bronchoscopy, 3 biopsies were collected from the primary tumour, with a control sample from normally appearing bronchial mucosa. One was formalin fixed and paraffin embedded for pathological diagnosis. A second was used for transcriptome analysis and the third one was frozen and stored in a tissue bank. We are presenting the flow chart of the patients screened for entry in the ELCWP study and the limitations for obtaining tumour samplings in assessable patients.

Results
From 1/04/2009 to 12/06/2013, 307 patients suspected to have NSCLC were prospectively registered. Eleven are under evaluation for pending histological confirmation leaving 296 patients evaluable for the present analysis. In 25 cases, no lung cancer confirmation was obtained (other tumour n = 12, no pathological confirmation at all n = 6, benign lesion n = 6, other reason n = 1) and 6 further patients withdrew their initial consent. Among 265 pathologically confirmed lung cancer (samples obtained during bronchoscopy or by another technique), 38 small cell lung cancers (SCLC) and 227 NSCLC were diagnosed. In addition to the diagnostic biopsy, further samplings for genomic analyses could be obtained during the same bronchoscopy in 30/38 SCLC (79%) and 116/227 NSCLC (51%). Among 227 NSCLC, 107 were presenting with an advanced disease treated with a cisplatin-based chemotherapy and were assessable for response to chemotherapy (primary study endpoint). Among these 107 patients, 59 adequate tumour samplings could be obtained for transcriptome analysis (20% from the initial cohort and 55% among assessable patients).

Conclusion
This analysis of a prospective multicentre study is showing the difficulties and limitations in obtaining adequate tumour samplings for biological analyses when conducting translational cooperative research in non-small cell lung cancer.

Background
Tumor localization and the precise evaluation of tumor invasion are most important for the management of central type early stage lung cancer (CELC) and Photodynamic therapy (PDT) has come to be considered as the first choice of treatment for CELC. The present guidelines of PDT for CELC were established based mainly on the data obtained from studies since 1980’s. CELCs less than 1 cm in diameter showed a favorable cure rate by PDT, thus this was a good standard to decide the indications of PDT. To obtain complete response (CR) by PDT, evaluation of each lesion is extremely important, including the extent of the tumor on the bronchial surface and the depth of invasion in the bronchial wall. We postulate that the combination of comprehensive diagnosis and the new generation of photosensitizers may increase the CR rate and expand the indications of PDT for larger tumors.

Methods
Autofluorescence bronchoscopy (AFB) has been used in the objective evaluation of the margin of the tumor before endoscopic treatment and Endobronchial ultrasonography (EBUS) has been employed to determine the depth of tumor invasion. Ooptical coherence tomography (OCT) has been investigated for clinical use as well. Also, the relatively newer photosensitizer NPe6, which has a stronger antitumor effect than Photofrin has been extensively used for PDT. We routinely used these diagnostic methodologies and NPe6 since 2004.

Results
A total of 122 consecutive CELCs were treated by PDT using NPe6 in Tokyo Medical University and CR was obtained in 115 lesions (CR rate 94.3%). Of the 122 lesions examined in this study, 78 had a diameter of ≦1.0 cm and the rest of the 44 cancer lesions were >1.0 cm in size. The CR rate of CELC ≦1.0 cm in diameter was 93.6% (73/78) and for those >1.0 cm in diameter, 95.5% (42/44), respectively. There was no significant difference between tumor size and clinical response. The CR rate to NPe6-PDT is higher than that of Photofrin-PDT in our previous studies. This early result suggests that PDT with NPe6 has a stronger antitumor effect than Photofrin therefore similar treatment outcome even for larger tumors >1.0 cm in diameter should be possible.

Conclusion
Objective evaluation by a comprehensive approach using AFB and EBUS enables to select the optimal therapeutic strategy for CELC. These results suggest that PDT with NPe6 may have a similar treatment outcome regardless of tumor size, as long sufficient laser illumination of the entire tumor is possible.

Background
The intra-operative diagnosis of pleural malignancy may facilitate surgical decision-making including the need for pleurodesis. A scanning laser confocal endomicroscopy device has been developed which allows histological-detail optical imaging of subsurface tissues in vivo. Confocal laser microscopy illuminates and detects light from a fixed point of a specimen which is scanned across a tissue plane and adjustable depths, providing a 3D structural view in a living body. Applied to screening of mucosal lesions in patients undergoing GI endoscopy, endomicroscopy obviates the need for many tissue biopsies and operators can rapidly learn to identify malignant tissues.

Methods
We performed the first intra-operative examination of pleural tissues using this equipment which is a thoracoscope-mounted endomicroscope device in patients administered iv fluorescein prior to imaging. Intra-operative endomicroscopic images were correlated with biopsies of pleural tissues.

Results
Sixteen patients were imaged: including mesothelioma 5 (2 biphasic) and pleural metastases from malignancies of lung 2, ovary 2 and one case each of breast, adenoidcystic (see figure), thyroid, colorectal, carcinoid and non-Hodgkin’s lymphoma, and also one benign case. We were able to image and identify normal mesothelium, sub-mesothelium, connective tissues and blood vessels (including RBC). Malignant cells and clusters of cells had a characteristic appearance including poor uptake of fluorescein and cellular pleomorphism. Appearances of mesothelioma correlated closely with histology. Glandular and papillary structures were identified in metastatic pleural tumour. In ovarian cancer calcification was readily identified as were psammoma bodies, while the typical cystic spaces surrounded by small dark cells mirrored closely the histological appearances of adenoidcystic carcinoma.

Conclusion
Images obtained on scanning confocal endomicroscopy of pleural malignancy generally correlated well with the histological appearance on biopsies. We plan now to extend our experience of malignancy and also the ability to discriminate between benign disease and malignancy of the pleura. Supported by a Tumour Stream Grant from the Victorian Cancer Agency. Figure: Endomicroscopy image of pleural metastases from adenoidcystic carcinoma of the parotid. Figure 1

Abstract not provided

Background
The risk of developing lung cancer increases with age and is highly associated with exposure to tobacco smoking. This study aimed to understand public awareness about the risk of developing lung cancer in New South Wales (NSW), Australia and to investigate attitudes and beliefs about lung cancer which could potentially impact health seeking behaviours regarding symptoms of lung cancer. The risk of developing lung cancer increases with age and is highly associated with exposure to tobacco smoking. This study aimed to understand public awareness about the risk of developing lung cancer in New South Wales (NSW), Australia and to investigate attitudes and beliefs about lung cancer which could potentially impact health seeking behaviours regarding symptoms of lung cancer.

Methods
A mixed methods triangulation approach was used, with a sequential-parallel design which incorporated 16 qualitative focus groups (n=125) to explore themes. Participants were aged 45+ from metropolitan and regional centres and grouped according to smoking status (current, former and never smokers). Data were analysed by content and thematically. A cross sectional quantitative telephone survey (n=1,000) followed to determine overall awareness and generalisability of findings amongst adults >45 years across NSW.

Results
The qualitative research highlighted that symptoms of haemoptysis, dyspnoea and an unusual or persistent cough were well recognised symptoms of lung cancer however participants were more likely to assume these symptoms were related to other health problems. Haemoptysis was the only symptom which created a sense of urgency to seek immediate medical attention. A ‘wait and see’ attitude towards any concerning symptom was prevalent across groups, only severe/ long term persistent symptoms would induce action. Smokers and former heavy smokers were more likely to say they would delay seeing their doctor because of perceived stigma associated with smoking. Older participants were more likely to rely on previous experiences of symptoms to govern their health seeking behaviour. Perceived susceptibility and understanding of causes of lung cancer differed by smoking status; smokers more likely to down-play the risk of smoking or attempt to offset their risk through lifestyle choices. Former smokers were more likely to perceive their risk comparative with a never smoker. The quantitative research findings suggested that unprompted awareness of lung cancer related symptoms was high with 88.5% able to correctly identify ≥1 symptoms however symptoms were more typical of late stage cancer. Age(<65 years), sex(female) and high socio-economic status were associated with higher recognition of symptoms (p<0.05). The majority of the survey respondents identified smoking as a cause of lung cancer (90.6%, 95%Confidence Interval (CI) 88.4-92.8) however fewer recognised the risk from second-hand smoke (25.6%,95%CI22.3-28.9). Ever-smokers were less likely to recognise the risk of smoking (odds ratio 0.7 95%CI0.5-0.9).

Conclusion
These findings provide evidence that while awareness of lung cancer symptoms and causative factors is reasonably understood in the community, perceived susceptibility is low (particularly among current and former smokers). A lack of urgency in seeking medical attention for symptoms considered not severe, together with other smoking-related barriers, may lead to further delays in diagnosis and missed opportunity for surgical treatment.

Background
In May 2012 the United Kingdom Department of Health initiated a centrally funded National Lung Cancer Awareness Campaign. This campaign was influenced by encouraging results from local pilot studies, and featured news items and public health awareness adverts in national and local media, including nationwide television and radio exposure, accompanied by celebrity involvement and endorsements. The cost of this initiative has not been disclosed. Liverpool has the highest lung cancer incidence and mortality in England, and our Lung Cancer Unit, providing a service for patients in South Liverpool, is the largest in the Cancer Network and the largest in the country

Methods
To assess the impact of the national campaign we have reviewed referrals to our Rapid Access Lung Cancer Service from General Practice via the two week suspected cancer pathway, during the months of April to December 2012; we have also reviewed referrals during the same months in 2011 and 2010. For these time periods we have compared the total number of referrals, the number and proportion of referrals judged as unsuitable for immediate investigation with CT scan and bronchoscopy, the number and stage distribution of cancers diagnosed and the proportion of patients undergoing potentially curative surgery.

Results
In the period May to December 2012 a total of 323 patients were referred to our Rapid Access Service; of these, 140 (43%) did not have any features suggestive of a possible lung cancer - these patients were reviewed in a routine chest clinic. A total of 103 patients (32% of referrals in this time period) were diagnosed as having lung cancer. Of these 34 (33%) had stage I or II disease on CT staging and 30 patients (29%) underwent potentially curative surgery. The corresponding figures for 2011 are: total referrals 283, 93 (33%) sent to routine chest clinic, 88 (31%) diagnosed lung cancers, 17 (20%) stage I and II and 16 (18%) potentially curative operations. In May to December 2010 we received 274 referrals. 75 (27%) were referred on to routine chest review. 106 patients (39%) were diagnosed as having lung cancer. 23 (21%) were stage I or II and 24 (23%) underwent potentially curative surgery.

Conclusion
In the 8 months following the initiation of a National Lung Cancer Awareness Campaign, the largest lung cancer unit in England recorded a 14% increase in patients referred from General Practice with suspected lung cancer. There was a 17% increase in diagnosed lung cancers, and the percentage of patients undergoing potentially curative surgery for stage I and II disease increased from 18% to 29%. Compared to the same time period in 2010, an additional 6 patients underwent surgery for stage I and II disease in 2012, an increase of 6% in the surgical resection rate. We have observed a beneficial effect from the National Lung Cancer Awareness Campaign, with significant increases in our lung cancer diagnosis rates and the number of patients undergoing curative surgery.

Abstract not provided

Background
Circulating tumor cells (CTCs) in the bloodstream of lung cancer patients provide a source for early detection, prognosis, and therapy monitoring. CTCs are currently mostly isolated in vitro from small volumes of patient blood samples. In order to increase the sensitivity of the CTC detection in the peripheral blood GILUPI has developed a novel in vivo method, the CellCollector, which enables the capture of CTCs from the patient´s blood stream with a higher sensitivity and efficacy than existing methods. Enumeration and characterization of those CTCs will serve to improve and monitor clinical cancer early detection and treatment. The aim of this study was to assess the Detektor CANCER01 (DC01) for in vivo isolation of CTCs directly from the blood of NSCLC patients, and to compare it to the CellSearch® method.

Methods
The device was inserted in a cubital vein through a standard cannula for thirty minutes. The interaction of target CTCs with the DC01 was mediated by an antibody directed against the epithelial cell adhesion molecule (EpCAM). To confirm the CTCs binding to the wire, the immunohistochemical staining against EpCAM and/ or Cytokeratins as well as CD45 for negative cell selection and nuclei counterstaining was performed. There were enumeration data available for 34 stage I-IIIB NSCLC patients and 8 non cancer patients. For 34 patients, samples were also tested with the CellSearch® method.

Results
In this study, we successfully isolated EpCAM-positive tumor cells in the peripheral blood originating from NSCLC patients. We obtained in vivo CTC detection rate of 94% in 32 of 34 NSCLC patients with a median (range) of 13 (0-300) CTCs. In 2 of 34 samples (5.8 %), CTCs were detected by the CellSearch® method. In all matched pairs, the DC01detected the same number or more CTCs compared to the CellSearch® method. The sensitivity was similar for early and late stage NSCLC patients. In the non-cancer patients, no CTCs were detected (100 % specificity). ALK gene rearrangements in NSCLC patients are an indication for targeted therapy with crizotinib. Therefore the staining for CTCs on the CellCollector was enhanced to identify the anaplastic lymphoma kinase (ALK). It could be identified by capturing cells and immunohistochemical staining.

Conclusion
Due to a detection rate of over 90% this new device might overcome present limitations in the enrichment of CTCs. This proof of concept study may have important clinical implications, as the implementation of the device into clinical practice may improve early detection, prognosis and therapy monitoring of NSCLC patients. The performed IHC for ALK expression on samples using a novel combination of a new ALK antibody with the high detection rate of the CellCollector offers an alternative to FISH or IHC on tumor tissue. This new technology also allows, as the captured tumor cells are ready using immunofluorescence approaches or qPCR, the possibility of establishing more personalized treatment regiments.

Background
The presence of ground glass opacity (GGO) on high-resolution computed tomography (HRCT) is well known to be pathologically closely associated with adenocarcinoma in situ. Recently, measuring the tumor diameter including areas of GGO on HRCT has been reported to possibly overestimate the T status. The purpose of this study was to evaluate the significance of the tumor size measured eliminating the area of GGO on HRCT as a prognostic factor and to propose a refined TNM classification based on modified T descriptors.

Methods
Four hundred and seventy-five patients with clinical T1a-T2bN0M0 non-small cell lung cancer underwent surgical resection. All tumors were reclassified based on the diameter measured eliminating the GGO area on HRCT according to the 7th TNM classification of lung cancer. We defined this new classification as modified T descriptors categorized into four groups: mTis+T1a, mT1b, mT2a and mT2b. The overall survival rates of the patients in the current and modified staging groups were evaluated.

Results
The 5-year survival rates were 88% and 82% in the patients with T1a and T1b tumors and 90% and 75% in the patients with mTis+T1a and mT1b tumors, respectively. The differences in the survival of the patients classified using mTis+T1a and the other modified T descriptors were more clearly separated statistically than those of the patients classified using the current T1a and other T descriptors.

Conclusion
The use of clinically modified T descriptors of the tumor size measured eliminating the GGO component on HRCT may more clearly classify the prognoses of patients with early lung cancer.

Background
Whole-body metabolic tumor volume (MTV~WB~) is a prognostic index independent of TNM staging, age, gender, performance status and treatment in non-small cell lung cancer (NSCLC). The current TNM staging system is also a prognostic index. However, it lacks advanced quantitative volumetric measurement in the 7[th] edition NSCLC TNM staging system. Integrating quantitative MTV~WB~ measurement into the current NSCLC staging system may make the staging system more quantitative and probably more prognostic. This study’s aim was to determine the utility of a FDG-PET volumetric prognostic (PVP) staging system based on univariate Cox regression models as a new prognostic index in NSCLC.

Methods
328 consecutive patients (156 males,172 females) with histologically proven NSCLC and median age of 68.3 years were identified for this retrospective analysis. The PET metabolic tumor volume in the whole body (MTV~WB~) was measured using a semi-automated 3D contouring program on baseline FDG PET/CT scans. The prognostic power for survival status of the PVP staging system was evaluated using the Kaplan–Meier method, Cox regression models, and compared with those of TNM staging system and ln(MTV~WB~) using C-statistic index (Gönen and Heller’s K concordance statistic).

Results
There were 46 cases with stage IA, 43 stage IB, 19 stage IIA, 18 stage IIB, 52 stage IIIA, 39 stage IIIB and 111 stage IV NSCLC. At the end of this investigation, 249 patients had died (88.4%). Median follow-up of 79 lost follow-up and known surviving patients was 58 months. On univariate survival analysis the HR of ln(MTV~WB~) was 1.56, and the HRs of TNM stages 2.25, 1.96, 2.89, 4.24, 4.93 and 7.63 for TNM stages IB, IIA, IIB, IIIA, IIIB and IV in reference to stage IA, respectively. These HRs were used for computing the PVP stage of each patient using following equation; PVP stage = [Hazard ratio of ln(MTV~WB~) × ln(MTV~WB~)] × [Hazard ratios of TNM stage]. There was a statistically significant association of better overall survival with lower PVP stage on both univariate [HR of 1.033 (95%CI =1.027 to1.039)] and multivariate [HR of 1.03 (95%CI =1.02 to1.04)] survival analyses. The range of the PVP stage were 0.06 to 87.57. For comparison with 7[th] edition of TNM stage and ln(MTV~WB~), the PVP stage and ln(MTV~WB~) were divided into 7 groups with similar numbers of patients. The C-statistic value of PVP staging system (mean±SE = 0.70±0.014) was statistically significantly higher than those of TNM stage (0.67 ±0.015, p=0.002) and ln(MTV~WB~) (0.67±0.015, p=0.02) on univariate survival analysis. In multivariate Cox regression models adjusted by patient’s age, gender, treatment types, tumor histology and tumor SUV~max~, the C-statistic value of PVP staging system (mean±SE=0.73±0.013) was also statistically significantly higher than that of TNM stage (0.71 ±0.015, p=0.036).

Conclusion
The PVP staging system from FDG-PET/CT has better prognostic ability and may prove to be a useful prognostic index in NSCLC. It can be treated as a complement to the TNM staging system.

Background
In the 7th TNM classification, non-small cell lung cancer (NSCLC) with adjacent lobe invasion (ALI) is classified as T2a regardless of whether across the complete or incomplete fissure. However, no validation analysis has been conducted on this classification. The aim of this study was to analyze the survival of NSCLC patients with ALI with emphasis on the interlobar fissure status at invasion point.

Methods
We retrospectively evaluated 2097 consecutive patients with surgically resected NSCLC from 1993 through 2006. Of these, 90 (4.3%) patients had tumors with ALI. Interlobar fissure status of tumors with ALI was examined by using elastic stain. We classified ALI into 2 types: direct ALI beyond incomplete interlobar fissure (no visceral pleurae separating two lobes; ALI-D) and ALI across complete fissure (two lobes separated by 2 visceral pleurae; ALI-A), and compared the clinicopathological features and survival between the groups.

Results
The patients with ALI without any other criteria higher than T2b category (n = 60) demonstrated intermediate survival between T2a and T2b tumors (5-year overall survival [OS]: T2a, 61.0%; ALI, 59.6%; T2b, 49.2%). Distinct survival difference was observed between the patients with ALI-A (n = 46) and ALI-D (n = 14) (5-year OS: ALI-D, 85.7%; ALI-A, 52.0%; p = 0.01). The survival of patients with ALI-A was not statistically different from that of patients with T2b tumors, regardless of tumor size (p = 0.85). Conversely, the survival of the patients with ALI-D did not statistically differ from those with T1a or T1b tumors (p = 0.77 and 0.42, respectively).Figure 1Figure 2

Conclusion
Interlobar fissure status clearly affected survival of the patients with ALI. ALI should be examined by elastic stains and only ALI-A should be classified as true ALI. We propose that ALI-A tumors ≤ 5 cm should be assigned to T2b but ALI-D tumors do not require adjustment of T descriptor.

Abstract not provided

Abstract
Biological function of RAS An activity that transforms mouse NH 3T3 cells in DNA from human cancers turned out to be present in human homologues of retroviral oncogenes found earlier. These genes were named as HRAS or KRAS according to the names of corresponding viruses; Harvey- or Kirsten- ratsarcoma viruses. The difference between RAS gene present in normal tissue and that in cancer tissue was a single missense point mutation either at codon 12 , and less frequently at codons 13 or 61. The third member of the RAS family gene, NRAS was identified one year later from a human neuroblastoma cell line, although its viral homologue was not identified. There is a tendency that a certain type of cancer uses a particular type of RAS gene; e.g. most RAS mutations in lung or pancreas cancer occur in KRAS gene, whereas most RAS mutations in bladder cancer occur in HRAS gene . RAS gene encodes for a 21kDa protein that toggles guanosine diphosphate (GDP)-bound inactive form to and from guanosine triphosphate (GTP)-bound active form because RAS has a GTPase activity. Guanine nucleotide-exchange factors (GNEFs) and RAS GTPase activating proteins (RAS-GAPs) positively and negatively regulate the amount of GTP bound RAS, respectively. Oncogenic point mutations either at codon 12,or less frequently at codons 13 or 61 make RAS impair its intrinsic GTPase activity and confer resistance to GAPs, thereby causing RAS to accumulate in its active GTP-bound state and sustained activation of RAS signaling. It is known that GTP-bound, active RAS interacts with more than 20 effector proteins and stimulates downstream signaling cascades. These effectors and corresponding functional outcomes include RAF (proliferation), RIN1 (endocytosis), PI3K (survival), PLCe (second messenger signaling), RalGEF (endocytosis). Rather paradoxically, oncogenic RAS has been shown to cause senescence in primary cell culture through the activation of the WAFp21-p53 or p16-Rb pathways. It is also known that, to acquire its biological and transforming activities, RAS proteins should be bound to inner surface of the plasma membranes by appropriate post-translational modification. This process includes farnesyltation, proteolytic cleavage of AAX motif, carboxymethylation of the terminal Cys and palmitoylation. This process was initially thought to be a target of therapeutic intervention. However, inhibition of farnesyl transferase results in alternative geranylgeranylation of RAS which supports membrane binding. RAS gene activation in lung cancer Frequent somatic mutation of the RAS gene in lung cancer was first identified in 1987. RAS mutation in lung cancer usually occurs in KRAS, although rare instances of HRAS or NRAS mutations are reported. Mutation of the KRAS gene usually occurs in adenocarcinoma, rarely in squamous cell carcinoma and almost never occurs in small cell lung cancer. KRAS mutations predominantly occur in Caucasian patients (~30%) rather than East Asians (~10%). Association between KRAS mutation and smoking exposure has been reported back in 1991. KRAS mutation at codon 12 in lung cancer is characterized by the frequent a G to a T transversion in contrast to the frequent a G to a A transitions found in colorectal cancer. Even within lung cancer, more than half of KRAS mutations in smokers are either G12C (GGT-TGT) or G12V (GGT-GTT), while those in never smokers are G12D (GGT-GAT). It is thought that not all the KRAS mutations are created equal. There is a report that G12V has a weaker GTPase activity than G12D, suggesting stronger oncogenic activity of G12D. It is also generally believed that KRAS codon 13 mutation is weaker oncogene than codon 12 mutation. In terms of effect of cetuximab in colon cancer, tumors with G13D behaves like those with WT KRAS. Prognostic impact of KRAS mutations in lung cancer are variably reported, but in general it is thought to be a weak negative prognostic factor. Whether there is a difference in prognostic impact among different KRAS mutations remains to be elucidated. In terms of histologic types, KRAS mutations are associated with lung adenocarcinoma with mucus production / goblet cell morphology. Lung cancer with KRAS mutations often accompanies with CK20 and CDX2. These phenotypes are commonly observed in colorectal, pancreato-biliary, and ovarian mucinous carcinomas. How to cope with KRAS mutated lung cancer Although KRAS mutations occur in mutually exclusionary fashion with activation of other driver oncogenes such as EGFR, ALK, ROS1, RET, etc, it appears that not all cancers with KRAS mutations are dependent on mutant KRAS. Upon treatment of shRNAs to deplete KRAS in lung cancer cell lines harboring KRAS mutations, half of the cell lines maintained viability without expressing KRAS. This makes it difficult to develop treatment strategy against KRAS mutated tumors.. Although MEK-ERK signaling is an essential downstream of mutant KRAS, single treatment of MEK inhibitor exhibits variable responses and PI3K pathway activation strongly influences its sensitivity. Therefore, simultaneous downregulation of MEK-ERK and PI3K-AKT may have potential therapeutic value. Recent approach is to identify synthetic lethal interactions in cancer cells harboring KRAS mutation. In other words, it is to find which genes, when silenced, kill cells harboring mutant RAS gene but not cells without this mutation. However, the list of genes with synthetic lethal activity against RAS mutated tumors are expandingand includes THOC1, eNOS, Myc, Survivin, STK33, PLK1, SYK, RON, integrin b6, TBK1, NFkB, WT1, PKC delta, CDK4, JNK, ATR, GATA2. However, a subsequent and comprehensive study could not reproduce the synthetic lethal activity of STK33, throwing out the caveat that one should be cautious to interpret the RNAi data because individual shRNA can downregulate tens or hundreds of off-target genes . Above-mentioned experimental evidence suggests that RAS collaborate with many different molecules depending on cellular contexts to have oncogenic activity. This is why the development of RAS-targeted therapy is difficult and suggests that it would be necessary to develop combination therapy depending on different cellular context.

Abstract
KRAS mutations are found in ~30% of adenocarcinomas and ~5% of squamous NSCLC. They are more common in current or former smokers. Most KRAS mutations in NSCLC occur on codon 12 and less frequently codons 13 and 61. Prognostic Value of KRAS The prognostic significance of KRAS has been investigated extensively. Results have been inconsistent with heterogeneity among studies including differing endpoints and patient populations studied. A large meta-analysis of 28 studies reported that KRAS mutation was a negative prognostic factor for OS (p=0.01) when all cancers were considered, in adenocarcinoma (HR 1.52, CI 1.30-1.78, p=0.02) but not squamous histology (HR 1.49, CI 95%: 0.88–2.52; p=0.48). The International Agency for Research on Cancer assessed KRAS in 762 patients with resected NSCLC. Mutations were detected in 18.5%; KRAS was not prognostic for PFS (p=0.26). The LACE-Bio group performed a pooled analysis of 1,543 patients from four randomized trials of adjuvant chemotherapy vs observation. KRAS mutations were present in tumors of 300 patients (codon 12 275, codon 13 24, and 1 codon-14). This was the first study to assess the prognostic effect of different KRAS mutations. In observation patients, there was no prognostic difference for OS for codon-12 (HR=1.04) or codon-13 (HR=1.01) mutations, nor for specific codon-12 amino acid substitutions. KRAS was not prognostic in the adenocarcinoma subgroup (HR=1.0, p=0.97). This group was the first to report that OBS patients with KRAS-mutated tumors were more likely to develop second primary cancers (HR=2.76, p=0.005). This observation requires validation. Predictive Value of KRAS Mutation for Chemotherapy Several studies have assessed the predictive value of KRAS in NSCLC patients treated with chemotherapy, but few have had untreated control arms to be able to isolate the predictive from the prognostic effects of mutation status. Rodenhuis et al. assessed KRAS in 83 patients with advanced adenocarcinoma treated with ifosfamide/carboplatin/etoposide; 26% had mutations.[10 ]The presence of KRAS mutation was not significantly associated with response rate, PFS or OS (p=0.486, p=0.22 and p=0.29, respectively). The TRIBUTE trial in advanced NSCLC compared first-line carboplatin/paclitaxel +/- erlotinib. KRAS mutations were present in 21% of samples tested. Response rates in the chemotherapy-alone arm were 26% and 23% for patients with wild-type and mutated KRAS, respectively, with no significant survival difference (median OS 13.5 and 11.3 months, respectively). In a neo-adjuvant chemotherapy study, Boermann et al[12] reported ORRs of 80% and 77% in patients with KRAS wild-type and mutated tumors, respectively. PFS was longer in patients with wild-type tumors compared to those with mutations (PFS 21 vs 9 mo, p=0.003) although there was no difference in OS (p=0.07). The LACE-BIO pooled analysis revealed no significant effect of KRAS mutation on benefit from adjuvant chemotherapy with respect to OS or DFS, even in adenocarcinoma (interaction p=0.99). Analysis by KRAS subtype revealed a non-significant benefit from ACT in patients with wild-type KRAS (HR=0.89, p=0.15) but not codon-12 mutations (HR=0.95, p=0.77); with codon-13 mutations, ACT was deleterious (HR=5.78, p=0.001, interaction p=0.002). There was a trend towards benefit from ACT for codon-12 G12A or G12R (HR=0.66 p=0.48) but not G12C or G12V (HR=0.94 p=0.77) or G12D or G12S (HR=1.39 p=0.48), (comparison of 4 HRs, including WT p=0.76). Predictive Value of KRAS Mutation for Epidermal Growth Factor Receptor Inhibitors In TRIBUTE, patients with KRAS mutant tumors who received chemotherapy+erlotinib had shorter median TTP than those treated with chemotherapy+placebo (3.4 vs 6 months, p=0.03). OS also was significantly shorter in the KRAS mutant subgroup treated with chemotherapy+erlotinib than those treated with chemotherapy+placebo (4.4 vs 13.5 months, p=0.019). In the NCIC CTG BR.21 trial of erlotinib vs placebo in advanced NSCLC, KRAS mutations were found in 15% of response-evaluable patients in the erlotinib arm. Response rates were 10% and 5% for patients with wild-type and mutated KRAS, respectively (p=0.69). There was no significant difference in survival benefit from erlotinib based on KRAS status (interaction p=0.09) on multivariable analysis (p=0.13), despite a trend in univariate analyses (KRAS mutant HR 1.67, p=0.31; KRAS wild-type HR 0.69, p=0.03). In the ATLAS trial that compared maintenance bevacizumab+placebo to bevacizumab+erlotinib, 93 patients had tumors with KRAS mutations. There was no significant PFS benefit for bevacizumab+erlotinib (HR 0.93, p=0.7697), while in wild-type KRAS, there appeared to be some benefit for the combination (HR 0.67, p=0.01).[14] In the SATURN trial, stable and responding patients were randomized to receive maintenance erlotinib or placebo. KRAS mutation was detected in 18%. Modest PFS benefit from erlotinib was seen both in patients with mutant KRAS and wild-type tumors (interaction p=0.95). Data are limited regarding KRAS mutation subtype and response to EGFR-TKIs in NSCLC. One recent investigation of KRAS mutation status and response to EGFR-TKI in EGFR wild-type advanced NSCLC demonstrated that patients with codon 13 KRAS mutations had worse PFS (p=0.04) and OS (p=0.005) than patients with codon 12 mutations. However, there were only 14 and four patients having mutations in codons 12 and 13, respectively. Two meta-analyses have evaluated the association between KRAS and EGFR TKIs in NSCLC. Linardou et al. assessed 17 trials (1008 patients, 165 with KRAS mutation). Mutation was significantly associated with lack of response to TKIs. Mao et al. included 22 studies; 16% (231/1470) had KRAS mutations. ORRs were higher for KRAS wild-type compared to mutation (26% and 3%, respectively). The pooled relative risk for response was 0.29 (p<0.01). In Asians, relative risk was 0.22 (p=0.01), and 0.31 (p<0.01) in Caucasians. In BMS-099, advanced NSCLC patients were randomized to receive taxane/carboplatin +/- cetuximab. KRAS mutations were found in 17% of assessable samples. There was no significant association between KRAS status and response, PFS or OS. The FLEX study compared cisplatin/vinorelbine +/- cetuximab in EGFR-expressing NSCLC. KRAS mutations were detected in 19% of assessable samples. The addition of cetuximab to chemotherapy did not significantly affect survival, PFS or response in patients with KRAS wild-type or mutated tumors. Summary KRAS is at most, a weak prognostic marker in NSCLC. It should not be considered a tool to select patients for treatment at this time.

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Abstract
Managing Toxicities of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-small-cell Lung Cancer Treatment: Focus on Skin and Liver Toxicities Pan-Chyr Yang MD, PhD. Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan. Several recent prospective randomized controlled studies have confirmed the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), including Gefitinib, Erlotinib and Afatinib, in the treatment of non-small-cell lung cancer (NSCLC) harboring EGFR activating mutations (such as L858R or deletions in exon 19). Due to less systematic toxicity, treatment with EGFR TKIs is better tolerated, compared to platinum-based chemotherapy. However, signaling pathways downstream to EGFR are also important to the integrity and function of normal epithelium, and specific adverse effects thus can develop during EGFR TKI treatment. Acneiform rash and diarrhea are the most common adverse effects reported in the clinical trials. Although most adverse effects of EGFR TKIs can be well managed without treatment discontinuation, some uncommon adverse effects, such as hepatotoxicity and interstitial pneumonitis, can be serious and life threatening. Therefore, cautious monitoring for adverse effects is important to NSCLC patients receiving EGFR TKI treatment. Management of Skin Toxicity Various cutaneous adverse effects can occur during EGFR TKI treatment, including acneiform rash, dry skin (xerosis), pruritus, nail or periungual alternations, and hair changes. Acneiform rash usually involves the upper torso, and appears within 2 weeks of treatment initiation. Topical steroids (such as 2.5% hydrocortisone acetate cream), tacrolimus, or antibiotics (such as clindamycin 1% to 2%) are effective treatments for patients with mild acneiform rash. Oral doxycycline (100 mg twice daily) or minocycline (100 mg twice daily) can be used for those with moderate to severe eruptions. When purulent discharge or painful eruptions occurs, secondary infection should be suspected. Broad-spectrum empirical antibiotics are recommended for initial treatment of bacterial super-infection, and appropriate skin swab for culture is required for identification of the causative bacteria. For patients with pruritus during treatment with EGFR TKIs, topical steroid with moderate strength or anti-pruritics (such as 5% doxepin cream) can be used for symptomatic relief. Oral antihistamines may be required for those with more severe symptoms. Topical moisturizing cream or ointment and 12% ammonium lactate cream can help relieving xerosis associated with EGFR TKI treatment. For patients with paronychia associated with EGFR TKI treatment, topical antibiotics and ultrapotent steroids are recommended, and topical silver nitrate application can be used for more severe cases. Although cutaneous toxicities are frequent during EGFR TKI treatment, most of these cutaneous toxicities are mild to moderate in severity, and can be adequately treated without dose reduction or treatment discontinuation. Management of Liver Toxicity Hepatoxicity associated with EGFR TKIs is less commonly reported in clinical trials. However, recent two phase III Japanese clinical trials reported that severe hepatotoxicity (defined as serum hepatic aminotrasferase levels above five times the upper limit of normal) developed in 16% to 28% of patients receiving gefitinib treatment. Furthermore, patients with lethal hepatotoxicity associated with Erlotinib treatment were also reported. Therefore, it is important to regularly monitor serum levels of hepatic aminotransferases in NSCLC patients receiving EGFR TKI treatment. Once severe hepatitis develops during EGFR TKI treatment, timely discontinuation of EGFR TKIs is required, with thorough evaluation of other potential etiologies, such as acute viral hepatitis. It is not recommended to re-challenge the patients with the same EGFR TKIs, which may induce more severe hepatic damage even after dose reduction. The efficacy of steroids in preventing hepatotoxicity is unknown and is not consistent in different reports. Routine steroid treatment is thus not suggested in patients with hepatotoxicity associated with EGFR TKIs. Successful Erlotinib or Gefitinib treatment has been reported in some patients recovering from severe Gefitinib- or Erlottinib-associated hepatotoxicity, respectively. Since different CYP450 enzymes are involved in the metabolism of different EGFR TKIs, trials of different EGFR TKIs may be considered after recovery from hepatitis, especially in responders to EGFR TKI treatment. References: 1. Hirsh V. Managing treatment-related adverse events associated with egfr tyrosine kinase inhibitors in advanced non-small-cell lung cancer. Curr Oncol 2011;18:126-138. 2. Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer 2006; 6: 803-12. 3. Wang SH, Yang CH, Chiu HC, Hu FC, Chan CC, Liao YH, Chen HC, Chu CY. Skin manifestations of gefitinib and the association with survival of advanced non-small cell lung cancer in Taiwan. Dermatologica Sinica 2011; 29: 13-18. 4. Lacouture ME, Schadendorf D, Chu CY, Uttenreuther-Fischer M, Stammberger U, O’Brien D, Hauschild A. Dermatologic adverse events associated with afatinib: an oral ErbB family blocker. Expert Rev Anticancer Ther 2013; 13: 721-8. 5. Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med 2006;354:731-739. 6. Takeda M, Okamoto I, Tsurutani J, Oiso N, Kawada A, Nakagawa K. Clinical impact of switching to a second EGFR-TKI after a severe AE related to a first EGFR-TKI in EGFR-mutated NSCLC. Japanese journal of clinical oncology 2012;42:528-533.

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Abstract
MANAGING TARGETED THERAPY PATIENTS IN A NURSE LED CLINIC Numbers of lung cancer patients on targeted therapies are growing as testing becomes more widely available and cost effective. Lung cancer Clinical Nurse Specialists and Nurse Practitioners are in an ideal position to manage these patients for a number of reasons. Patients on Targeted Therapies present with unique toxicity profiles which CNS’s and NP’s are developing a growing level of expertise in managing. Toxicity profiles include rash, nausea, fatigue, cachexia, diarrhoea, deranged liver function tests, and shortness of breath. Nurses tend to be the most frequently contacted person between clinic visits, triaging and managing toxicities. They are ideally placed to proactively monitor patients, aiding continuity of care and reducing hospital admissions. Patients report improved communication, education around management, and continuity, with reduced treatment related anxiety, in nurse led clinics. Many CNS and NPs can provide a prescription service adding to continuity of care. Support for nurse led clinics is essential to ensure patient safety and should be run alongside the oncologist’s clinics. Competency of the nurse leading the clinic must be maintained through identified supervisors. Utilisation of evidence based tools help to ensure best practice is maintained.

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Abstract
Pain in lung cancer Lung cancer is the most common cancer globally with 1.6 million people diagnosed with the disease during 2008; over half of them in the developing world. Nearly 90% are due to smoking, or passively smoking, tobacco. The mortality to incidence ratio is 0.86, reflecting dismal survival [http//:globocan.iarc.fr/factsheet.asp] . Therefore, the focus of care remains one of palliation despite increased options for cancer directed treatment. Optimal symptom relief must play a central role. A systematic review of pain in people in with lung cancer found an overall weighted mean prevalence of pain in 47% patients (6 – 100%); the wide variation reflecting the different patient settings (1). However, for studies in general hospitals, just over one third of lung cancer patients had pain, and the weighted mean prevalence in a cancer treatment centre was 65%. Most pain is attributed to the cancer, either directly, or due to treatment (weighted mean prevalence; 13%). Pain is most common in the chest, then, pain in the spine. Patients may have multiple sites of pain, with other symptoms such as breathlessness, cough, and fatigue; pain considered to be one of the top three most distressing. Severe pain is associated with reduced survival, and interferes with function, enjoyment of life, mood and work(2). According to surviving relatives, of the 85% patients who had pain in the last year of life, over 50% found it very distressing(3). Management Assessment. All symptom management should start with a full assessment which extends beyond physical concerns into psychosocial and spiritual domains, and treatments (and involvement of relevant team members) tailored to the needs of the individual, remembering the effect on their family and friends. There are many extensive pain assessment tools which are not easy to use in daily clinical practice. Systematic assessment of every patient attending clinic, or admitted to hospital is often overlooked, but simple aide memoirs for the busy clinician are available and effective(4), or simple screening patient report scales. Where patient reported symptoms have been embedded in oncology clinical practice and linked to symptom management protocols, outcomes have improved(5-7). Symptom monitoring should be related to factors that patients rate as important such as effect on function and relationships with family and friends rather than a score(8). The linking of assessment to education (clinician and patient) and clinical guidance is important and shown to be more effective than education alone(9). Interventions for pain control Radiotherapy. Most pain is from the primary tumour, often with haemoptysis and cough. Palliative radiotherapy is effective but not extensively documented. One RCT study in non-small cell lung cancer shows improvement in pain in three quarters. Other symptoms also improved, along with function and wellbeing(10). Bony metastases are common in lung cancer, if present over 55% lead to one or more skeletal related events. Palliative radiotherapy is the most effective treatment. Onset of relief is between a few days and 1 month, and lasts between 3 to 6 months(11;12). A Cochrane review in 2000 calculated a number needed to treat to give complete relief in one patient at one month as 4.2 (95% CI 3.7 – 4.7)(13). A single fraction of 8Gy is as effective as higher multi-fractionated doses for the acute relief of pain, although of shorter duration(14). Opioids and other analgesics. The WHO analgesic ladder remains the standard approach to analgesic use in cancer pain with morphine still the most cost-effective first line strong opioid; cheaper than the equally effective oxycodone(15;16). In the presence of significant renal dysfunction, fentanyl, alfentanil and methadone are the least likely to cause harm (17). A systematic review confirms a small further benefit with the addition of a non-steroidal anti-inflammatory drug (NSAID), although the contributory studies were too small to comment on toxicity(18). Given the recent data on cardiovascular toxicity of NSAIDS, naproxen and low dose ibuprofen appear to be the safest in this group(19). Incident pain due to bone metastases is difficult to manage with analgesics alone because the direct relationship to periods of activity; the average duration of incident pain is 60 minutes and so may be improving before oral morphine may be fully absorbed. The newer transmucosal fentanyl preparations may be more helpful, with an onset of action of 10 minutes(20). Neuropathic pain often contributes to difficult to manage cancer pain. Opioids may provide benefit and a trial should be given. Standard adjuvant analgesics such as tricyclic antidepressants (duloxetine, amitriptyline) and anticonvulsants (gabapentin and pregabalin) and topical agents (capsaicin and lidocaine) may help but good quality trials in cancer pain are lacking(21). A recent RCT of ketamine for the palliation of refractory cancer pain found no benefit with ketamine(22). Another in patients with better performance status and where neuropathic pain is deemed to be the primary aetiology is almost closed to recruitment [ClinicalTrials.gov Identifier: NCT01316744]. Corticosteroids are commonly used for cancer pain although the evidence base is scant; a systematic review only found “low level evidence” for benefit (23). Bisphosphonates. Bisphosphonates are not routinely used for patients with lung cancer. A recent systematic review of bisphosphonate use in small cell lung cancer demonstrated improved pain control (RR 1.18; 95% CI 1.0 – 1.4), reduced skeletal related events (RR 0.81; 95% CIs 0.67 – 0.97) (24). However, many of the studies were of poor quality. Toxicity is usually restricted to transient flu-like or gastro-intestinal symptoms, but 15% of those with zoledronic acid developed renal dysfunction and 5% the distressing side-effect of osteonecrosis of the jaw. Newer agents such as denosumab may be tolerated better, but comparative trials in lung cancer are awaited. For the future In spite of these options, cancer pain, in general, is under-treated even where there is good access. Barriers include fear of, and poor education about, opioids in both patients and clinicians with consequent respective poor compliance and prescribing, and a lack of systematic screening of patient symptoms with full assessment if needed. Until assessment and management of pain is embedded into daily clinical practice, this feared symptom will remain a problem.

Abstract
Cancer-related fatigue (CRF) is a well-acknowledged, very common, phenomena arising from treatment of cancer. It is defined as ‘a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer treatment that is not proportional to recent activity and interferes with usual functioning’ [1]. In particular, the characteristics of CRF are different to those of fatigue experienced in the general population. In persons with lung cancer, the prevalence of CRF is very high, with 75 - 100% presenting with this symptom, and ≥50% reporting severity to be moderate to marked [2, 3]. The mechanisms underpinning CRF are multi-dimensional. These mechanisms include both central and peripheral components resulting from disturbances occurring across several systems, including physiological, biochemical, and psychological systems [4]. Factors that may contribute to CRF include side-effects of treatment such as anaemia, nutrition and fluid imbalance, sleep disturbances and systemic reactions to tissue injury induced by the disease and/or the treatment [5]. In addition, psychological factors can trigger or exacerbate CRF. Examples of psychological factors include anxiety and depression and difficulty in coping with treatments. Physical fatigue, often expressed as a feeling of weakness, lack of energy, or exhaustion associated with conducting activities of daily living, is thought to be due to a peripheral component. It is postulated that these sensations are a consequence of muscles having reduced capacity for a contractile response [4]. Several factors can conspire during cancer treatment to affect the contractile response of muscles, including insufficient oxygen transport and insufficient blood pumping to muscles, and severe impairment of skeletal-muscle function [5]. In persons with physical fatigue, sedentary habits reinforce fatigue, resulting in a vicious cycle. Exercise has the capacity to interrupt this downward decline. There is compelling evidence that exercise can address cancer-related physical fatigue. A recent Cochrane Review on the role of exercise for management of cancer-related fatigue identified 56 randomised controlled trials (RCTs); however, the majority were carried out in women with early breast cancer [6]. Not surprisingly, timing of interventions varied, with some occurring during treatment and others after cessation of adjuvant therapies. Mode and intensity of exercise also differed across studies: some interventions occurred in the home, while others were supervised at institutions or used a combined supervised/home based intervention. The major finding from this review was that aerobic exercise, including walking programs, or stationary arm or leg cycling significantly reduced fatigue both during and following cancer therapy. In addition, approximately half of the studies that included quality of life measures (n=17/35 studies) reported beneficial effects from exercise. In contrast, no consistent benefit from exercise was observed for anxiety or depression. Persons living with lung cancer, from Stage I to IV, appear to have the capacity to be physically active. In a systematic review on exercise interventions to improve exercise capacity and health-related quality of life in patients with non-small cell lung cancer, it was concluded that exercise is safe before and after treatments [7]. However, it was also noted that the studies reviewed were either case reports or small RCTs. Well-designed, appropriately powered RCT’s are required in this area. Two such studies are currently under way: Jones et al [8] are currently recruiting Stage I-IIIA non-small cell lung cancer patients treated surgically to participate in a study in which participants are randomised to one of four 16 week conditions: aerobic training alone; resistance training alone; combination of aerobic and resistance training; and attentioncontrol; and Vardy et al [9] are currently exploring the role of supervised aerobic physical activity with behavioural support specifically on fatigue. One finding from the systematic review [7] was that lung cancer patients who exercised following surgery, chemotherapy, or radiotherapy consistently reported improvements in fatigue. In addition, other symptoms such as dyspnoea, pain and cough were also reduced with exercise. The interventions were predominantly supervised aerobic training, lasting from 10 to 45 minutes, performed at moderate to high intensity, 3 times per week over a set period of weeks. Interval training of 3 – 5 minutes duration, repeated several times per day, is a common feature of exercise programs designed for lung cancer. In contrast, and similar to the findings from the Cochrane Review on exercise and fatigue [6], progressive resistance training was not effective in reducing fatigue in lung cancer patients who had completed 10 weeks of resistance training (n=17). Further clarity on the role of resistance training for management of fatigue in patients living with lung cancer will be determined from the study currently underway by Jones et al [8]. In conclusion, exercise is likely to be effective in reducing fatigue for persons living with Stage 1 – IV non-small cell lung cancer. However, it is important to recognise the support and supervision used in the interventions that demonstrated a significant reduction in fatigue. References: 1. Mock V. Evidence-based treatment for cancer-related fatigue. Journal of the National Cancer Institute. Monographs 2004:112-8 2. Iyer S, et al. The symptom burden of non-small cell lung cancer in the USA: a real-world cross-sectional study. Support Care Cancer 2013; epub ahead of print. 3. Sanders SL, et al. Supportive care needs in patients with lung cancer. Psychooncology 2010: 19:480-9 4. Ryan JL, et al. Mechanisms of cancer-related fatigue. Oncologist 2007:12 Suppl 1:22-34 5. Lucia A, Perez M. Cancer-related fatigue: can exercise physiology assist oncologists? The Lancet Oncology 2003:4: 616-25 6. Cramp F, Byron-Daniel J. Exercise for the management of cancer-related fatigue in adults. Cochrane Database Syst Rev 2012:11:CD006145 7. Granger CL, et al. Exercise intervention to improve exercise capacity and health related quality of life for patients with Non-small cell lung cancer: a systematic review. Lung Cancer 2011: 72: 139-53 8. Jones LW, et al. The lung cancer exercise training study: a randomized trial of aerobic training, resistance training, or both in postsurgical lung cancer patients: rationale and design. BMC Cancer 2010:10:155 9. Dhillon HM, et al. The impact of physical activity on fatigue and quality of life in lung cancer patients: a randomised controlled trial protocol. BMC Cancer 2012:12:572