Virtual Library

Background
Crizotinib is approved multinationally to treat advanced ALK-positive non-small-cell lung cancer (NSCLC). Most patients with crizotinib-treated ALK-positive NSCLC ultimately develop progressive disease (PD). We investigated whether continuing ALK inhibition beyond PD is clinically beneficial and the clinicopathologic characteristics associated with patients who experience clinical benefit.

Methods
Patients with advanced ALK-positive NSCLC enrolled in two ongoing multicenter, single-arm trials (the molecularly enriched expansion cohort of the phase I trial PROFILE 1001 and the phase II trial PROFILE 1005) who developed RECIST-defined PD were allowed to continue crizotinib if, in the investigator's opinion, they were deriving ongoing clinical benefit. In the present retrospective analyses, continuation of crizotinib beyond PD (CBPD) was defined as >3 weeks of crizotinib treatment after PD documentation. Baseline and post-progression characteristics, sites of PD, progression-free survival (PFS), and overall survival (OS) were compared in patients who continued CBPD versus those who did not. The impact of continuing CBPD on OS after adjusting for potential confounding factors was assessed.

Results
Among 194 crizotinib-treated patients with RECIST-defined PD, 120 (62%) continued CBPD. A higher proportion of patients who continued CBPD responded to initial crizotinib treatment (74% vs. 55%), had an ECOG performance status of 0/1 at PD (96% vs. 82%), and had brain (56% vs. 28%) and/or bone (20% vs. 9%) as sites of PD compared with patients who did not continue CBPD. CBPD patients also had numerically longer median PFS from initial crizotinib treatment (7.3 months vs. 5.7 months) and significantly longer OS from the time of PD (median 16.4 months vs. 3.9 months; HR, 0.27; 95% CI: 0.17−0.42; P<0.0001; Figure 1). Multiple-covariate Cox regression analysis revealed that CBPD remained significantly associated with improved OS post-PD after adjusting for relevant factors. Figure 1. OS of patients who continued CBPD versus those who did not, from the time of PD. Shaded areas are 95% Hall-Wellner confidence bands. Figure 1

Conclusion
Continuing ALK inhibition after PD may provide survival benefit to a majority of patients with advanced ALK-positive NSCLC. Prolonged PFS on initial crizotinib, good performance status at PD, and progression in brain and/or bone are characteristics that were commonly found in patients who benefited from continued ALK inhibition.

Background
Crizotinib is an oral tyrosine kinase inhibitor targeting ALK and is approved multinationally for the treatment of advanced ALK-rearranged non-small cell lung cancer (NSCLC) due to its efficacy in controlling systemic tumor burden. The clinical effects of crizotinib in patients with brain metastases have not been previously studied in detail. To evaluate the clinical outcomes of patients with brain metastases on crizotinib, we conducted a retrospective analysis of pooled data from PROFILE 1005 (NCT00932451; a large ongoing global open-label, single-arm phase II study of crizotinib in patients with ALK-rearranged NSCLC who have received one or more treatment regimen for advanced/metastatic disease) and PROFILE 1007 (NCT00932893; an ongoing global randomized phase III study that compared crizotinib with standard second-line chemotherapy [docetaxel or pemetrexed] for advanced ALK-rearranged NSCLC; Shaw et al, N Engl J Med 2013). Subgroup analysis in PROFILE1007 showed that progression-free survival was longer with crizotinib than with chemotherapy for both patients with brain metastases (HR 0.67) and patients without brain metastases (HR 0.43) at baseline.

Methods
Patients with previously treated (but ALK-inhibitor-naïve) advanced ALK-rearranged NSCLC enrolled in either PROFILE 1005 or PROFILE 1007 (and randomized to crizotinib) were included in this analysis. Patients with asymptomatic brain metastases were eligible for both studies. The starting dose of crizotinib was 250 mg twice daily. Tumor assessments were evaluated by investigators based on RECIST. Baseline brain imaging (with either computed tomography or magnetic resonance imaging) was required in both studies, and if brain metastases were detected, subsequent brain imaging was required at 6-week intervals. Otherwise, imaging to assess brain metastases on treatment was performed as clinically indicated. Brain metastases were monitored as non-target or target lesions.

Results
A total of 275 patients, 31% of 888 patients included in this retrospective analysis, had asymptomatic brain metastases at baseline. Of the 888 patients included, 109 patients (12%) had no prior radiotherapy and 166 patients (19%) had prior radiotherapy for their brain metastases. Among the 109 patients with previously untreated asymptomatic brain metastases, the systemic disease control rate (DCR; % complete responses + partial responses + stable disease) at 12 weeks was 63%, with a systemic objective response rate (ORR) of 53%, and the intracranial DCR at 12 weeks was 56%, with an intracranial ORR of 7%. Among the 166 patients with previously treated brain metastases, the systemic DCR at 12 weeks was 65%, with a systemic ORR of 46%, and the intracranial DCR at 12 weeks was 62% weeks, with an intracranial ORR of 7%. Additional data, including outcomes for patients without brain metastases at baseline, will be presented.

Conclusion
In this large retrospective analysis, crizotinib was associated with an initial intracranial DCR of approximately 60% at 12 weeks in patients who were ALK-inhibitor-naïve and had untreated or previously treated brain metastases identified prior to initiation of therapy. Prospective studies may help to determine if crizotinib can delay the natural occurrence or progression of brain metastases in advanced ALK-positive NSCLC.

Background
Rearrangements of the ROS1 receptor tyrosine kinase gene identify a subset of NSCLC sensitive to the small-molecule ALK and MET inhibitor crizotinib, approved multinationally for the treatment of advanced ALK-positive NSCLC. Here we present updated efficacy and safety data for crizotinib in an expanded cohort of patients with advanced ROS1-rearranged NSCLC.

Methods
ROS1 status was determined by break-apart FISH assays, and patients were enrolled into an expansion cohort of an ongoing phase I crizotinib study (PROFILE 1001; NCT00585195, Pfizer). Where available, samples were also tested for concurrent ALK rearrangement and MET amplification. Patients received crizotinib 250 mg BID, and responses were assessed using RECIST v1.0.

Results
At the data cut-off, 35 of 40 patients with ROS1-positive NSCLC were evaluable for response. Median age was 51 years (range 31–77), 80% of patients were never-smokers, and 98% had adenocarcinoma histology; 40% had received one prior regimen, and 45% had received 2–6 regimens for advanced/metastatic disease. 25 samples tested for concurrent ALK rearrangement (24 by FISH and 1 by PCR) and 12 samples tested for concurrent MET amplification (11 by FISH and 1 method not recorded) were all negative. The objective response rate (ORR) was 60% (95% CI: 42–76), with 2 complete responses, 19 partial responses, and 10 cases of stable disease. Median progression-free survival (PFS) had not been reached, with 25 patients (63%) still in follow-up for PFS; six patients (15%) experienced disease progression, and two (5%) died before progression occurred; 6-month PFS probability was 76% (95% CI: 55–88). The disease-control rate was 80% at 8 weeks and 66% at 16 weeks. The most common treatment-related adverse events (AEs) were visual impairment (80%), diarrhea (35%), and nausea (30%), with most patients (68%) reporting only AEs of grade 1 or 2 severity. Peripheral edema (28%) and elevated transaminases (18% AST, 15% ALT) were also reported, similar to previous experience with crizotinib. There were no treatment-related serious AEs and one patient discontinued treatment due to treatment-related nausea. Accrual of patients with ROS1-positive NSCLC is ongoing.

Conclusion
Similar to results obtained in ALK-positive NSCLC, crizotinib had marked antitumor activity with a high ORR (60%) in patients with ROS1-positive NSCLC, with a generally tolerable and manageable AE profile. These data suggest that crizotinib is an effective therapy for patients with advanced ROS1-positive NSCLC.

Background
XALKORI[Ò] (crizotinib) is a selective small-molecule inhibitor of the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase (RTK) and its oncogenic variants (ie, ALK fusion events and selected ALK mutations). Crizotinib is also an inhibitor of the hepatocyte growth factor receptor (HGFR, c-Met), c-ros oncogene 1 (ROS1), and Recepteur d’Origine Nantais (RON) RTKs. Clinical studies were conducted globally to determine the maximum tolerated dose, pharmacokinetics, antitumor efficacy and safety of crizotinib in patients with ALK-positive NSCLC and other tumors sensitive to crizotinib. The major objectives of this analysis were (1) to develop a population PK model that describes crizotinib plasma PK using pooled PK data across studies in cancer patients;.and (2) to identify potential covariates which may account for the inter-individual variability in crizotinib PK.

Methods
Population pharmacokinetic models were developed from a dataset comprised of 8,973 pharmacokinetic samples from 1,214 cancer patients receiving crizotinib at a starting dose of 250 mg BID in Phase I, II, and III trials. The effects of pre-defined covariates pertaining to demographic characteristics, baseline renal (creatinine clearance) and hepatic function (AST, albumin, and total bilirubin) on the pharmacokinetics of crizotinib were tested in the models.

Results
The study population consisted of 533 males (44%) and 681 females (56%). The patients were characterized by a wide range of body weights (33 to 160 kg) and ages (19 to 83 years). There were 189 (15.6%) elderly patients (over 65 years). The majority of patients in the analysis were White (52.8%) and Asian (43.1%), followed by Black (1.8%), Hispanic (1.2%), and Other (1%). Crizotinib PK was characterized by a two-compartment model with first-order absorption and a time-dependent decrease in apparent (oral) clearance (CL/F) from baseline following multiple 250 mg BID dosing. The interindividual variability was moderate, with 40% for CL/F and 52% for the apparent central volume of distribution (V2/F), respectively. The typical PK parameters for a 65 kg non-Asian male cancer patient with baseline creatinine clearance 91.6 mL/min and total bilirubin 0.41 mg/dL were 136 L/hr, 76 L/hr, 3,520 L, and 0.73 hr-1 for the CL/F after the first dose, CL/F at steady state, V2/F, and absorption rate constant (Ka), respectively. Age, AST, albumin, smoking, or ECOG performance status were not significant covariates for crizotinib CL/F (P>0.001). Asian race, gender, body weight, creatinine clearance, and total bilirubin described a portion of the variability in CL/F, and Asian race and gender also explained some of variability in V2/F. Asian race had the greatest effect on crizotinib exposure, with a 97% probability that a typical area under the plasma drug concentration-time curve at steady state (AUCss) in an Asian patient would be >25% higher than a typical AUCss value in a Non-Asian patient. None of the other covariates investigated were found to markedly affect the systemic exposure of crizotinib.

Conclusion
There was moderate inter-patient variability in crizotinib disposition. No starting dose adjustments of crizotinib 250 mg BID are recommended based on age, gender, body weight, or race.

Abstract not provided

Background
AP26113 is a novel tyrosine kinase inhibitor (TKI) that exhibits pan-ALK inhibitory activity against all 9 clinically-identified crizotinib-resistant mutants, including the L1196M gatekeeper, in preclinical experiments. AP26113 also inhibits ROS1 and selectively inhibits mutant EGFR (EGFRm) in preclinical experiments, including the T790M resistance mutation, without affecting the native receptor.

Methods
We report data from the dose finding component (3+3 design) of a phase 1/2 open-label, multicenter study in patients with advanced malignancies (except leukemia) refractory to available therapies or for whom no standard treatment exists. Dosing was once daily (QD) or twice daily.

Results
As of 17 April 2013, 55 patients were enrolled: 30mg (daily dose) n=3, 60mg n=3, 90mg n=8, 120 mg n=15, 180mg n=15, 240mg n=9, 300mg n=2; 62% female, median age 58 yrs; diagnoses: non-small cell lung cancer (NSCLC, n=47), other (n=8). 33 patients discontinued: 22 disease progression, 6 adverse event (AE), 4 deaths (2 possibly related: sudden death, hypoxia), 1 withdrawal by subject. The most common AEs included fatigue (40%), nausea (36%), and diarrhea (33%), which were generally grade 1/2 in severity. The most common grade 3/4 AE was pneumonia (5%). Two patients experienced dose limiting toxicities: grade 3 ALT increase in 1 patient (240mg QD); grade 4 dyspnea and grade 3 hypoxia in 1 patient (300mg QD). Twenty-eight patients had ALK+ history (24 NSCLC, 4 other). Among 24 evaluable ALK+ patients, 15 responded. Responses were observed in 2/4 (50%) ALK+ TKI-naïve patients and 13/17 (76%) ALK+ patients with prior crizotinib therapy and no other ALK inhibitor exposure. Among ALK+ NSCLC patients with prior crizotinib only, 12/16 (75%) responded. The longest response is 40+ weeks (ongoing). 4 of 5 ALK+ patients with untreated or progressing CNS lesions at baseline and with follow-up scans had evidence of radiographic improvement in CNS, including 1 patient resistant to crizotinib and LDK378 (overall response = stable disease). CNS lesion improvements in all 4 patients are ongoing, with durations ranging from 15+ to 28+ weeks. Twenty patients had EGFRm history (19 NSCLC, 1 SCLC); 18 had ≥1 prior EGFR TKI. Of 18 evaluable EGFRm patients, 1 patient (prior erlotinib) responded at 120mg QD (duration 26+ weeks, ongoing), 7 patients had stable disease, including 4 with T790M by history (1 ongoing at 240mg QD, duration 16+ weeks). The maximum tolerated dose has not been defined; however, based on safety, efficacy, and pharmacokinetics, the recommended phase 2 dose (RP2D) is 180mg QD. Updated data will be presented.

Conclusion
AP26113 has promising anti-tumor activity in patients with ALK+ NSCLC and other ALK+ tumors, with initial evidence of activity in EGFRm patients, and is generally well tolerated. Five phase 2 cohorts are enrolling at the RP2D (180mg QD): 1) ALK inhibitor-naïve ALK+ NSCLC, 2) crizotinib-resistant ALK+ NSCLC, 3) single EGFR TKI-resistant NSCLC with documented T790M, 4) other tumors with AP26113 targets, 5) crizotinib-naïve or –resistant ALK+ NSCLC with active CNS metastases. Further phase 1 testing at 240mg QD will occur in EGFRm patients with documented T790M. NCT01449461

Background
EGFR T790M mutation and MET amplification have been implicated as mechanisms of acquired resistance to first-generation EGFR tyrosine kinase inhibitors (TKIs) in advanced NSCLC. We evaluated the feasibility of combining dacomitinib and crizotinib to overcome acquired resistance in patients with NSCLC whose last prior treatment was either single-agent erlotinib or gefitinib. Dacomitinib is an orally bioavailable, irreversible, small-molecule inhibitor of all kinase-active HER-family tyrosine kinases (EGFR/HER1, HER2, and HER4) with in vitro activity against T790M-mutated EGFR. Crizotinib is an ALK, ROS1, and MET TKI with demonstrated efficacy in the treatment of advanced ALK-positive and ROS1-positive NSCLC and several MET-amplified tumor types. Here we update previous data reported for PROFILE 1006 (Jänne et al, ESMO 2012; Pfizer, NCT01121575).

Methods
The study comprised a 3+3 design dose-escalation phase followed by an expansion phase of two concurrent cohorts: A) combined dacomitinib plus crizotinib and B) single-agent dacomitinib until progression, followed by combined dacomitinib plus crizotinib. The study enrolled patients with advanced NSCLC who had progressed after ≥1 line of chemotherapy/targeted therapy. The expansion phase was restricted to patients with acquired resistance to single-agent erlotinib or gefitinib, which was defined as PD following either a response or SD for 6 months. Patients in the expansion phase had a mandatory tumor biopsy for biomarker analysis at study entry. Endpoints included safety, best overall objective response rate (ORR), progression-free survival, and biomarkers in tumor and blood that are potentially predictive of antitumor activity.

Results
33 patients were enrolled in the dose-escalation phase of the study. Dose-limiting toxicities (DLTs) were the following grade 3 events: diarrhea (n=1), elevated ALT (n=1), and mucositis (n=1). The dacomitinib 30 mg qd plus crizotinib 200 mg bid combination showed no DLTs in 10 evaluable patients and was taken forward into the expansion phase. At the time of data cut-off on 31 December 2012, 27 patients had enrolled in the expansion phase (23 in cohort A and 4 in cohort B). Patient characteristics were as follows: M/F, 11/16; median age, 60 years (range 42–82); ECOG PS 0/1/2, 4/19/4; Caucasian/Asian, 22/5; never-smokers/ex-smokers/smokers, 18/7/2; number of prior systemic therapies 1/2/3/>3, 9/8/3/6. Nine patients (33%) in the expansion phase had started ≥4 cycles (approximately 12 weeks) of the combination. There were 20 evaluable patients in expansion cohort A, with an ORR of 5%. A further 8 patients (40%) experienced SD, and 1 of these patients had an unconfirmed PR. Tumor samples were available for biomarker analyses from 18 patients in expansion cohort A. Analyses to date revealed 1/17 patient samples had MET amplification (MET:CEP7 ratio >2); 1/5 had EGFR amplification; 7/12 harbored the EGFR T790M mutation; 1/11 displayed a KRAS mutation; 18/18 were negative for ALK rearrangement by FISH.

Conclusion
The dacomitinib 30 mg qd plus crizotinib 200 mg bid combination was administered with a manageable tolerability profile and was associated with clinical activity in patients with EGFR TKI-resistant advanced NSCLC. Analysis of predictive tumor biomarkers is underway in all patients in the expansion phase.

Background
To determine the frequency and predictive impact of ROS1-rearrangements on treatment outcomes in never-smoker patients with lung adenocarcinoma.

Methods
We concurrently analyzed ROS1- and ALK- rearrangements and mutations in the epidermal growth factor receptor (EGFR), and KRAS in 208 never-smokers with lung adenocarcinoma. ROS1- and ALK- rearrangements were identified by fluorescent in situ hybridization.

Results
Of 208 tumors screened, seven (3.4%) were ROS1-rearranged, and 15 (7.2%) were ALK-rearranged. CD74-ROS1 fusions were identified in two patients using reverse transcriptase polymerase chain reaction. The frequency of ROS1-rearrangement was 5.7% (6/105) among EGFR/KRAS/ALK-negative patients. Patients with ROS1-rearrangement had a higher objective response rate (ORR; 60.0 vs. 8.5%; P=0.01) and a longer median progression-free survival (PFS; not reached vs. 3.3 months; P=0.008) to pemetrexed than those without ROS1/ALK-rearrangement. The PFS to EGFR-TKIs in patients harboring ROS1-rearrangement was shorter than those without ROS1/ALK rearrangement (2.5 vs. 7.8 months; P=0.01).

Conclusion
The frequency of ROS1-rearrangements in clinically selected patients is higher than that reported for unselected patients, suggesting that ROS1-rearrangement is a druggable target in East-Asian never-smokers with lung adenocarcinoma. Given the different treatment outcomes to conventional therapies and availability of ROS1 inhibitors, identification of ROS1-rearrangement can lead to successful treatment in ROS1-rearranged lung adenocarcinomas.

Background
In case of progression under initial treatment, repeat biopsy is a new option procedure in advanced non-small cell lung cancer (NSCLC). Its justification is based on the assessment of biological markers (comparison to the initial status, emergence of resistance to chemotherapy or new biomarkers). The aim of this pragmatic prospective multicenter study was to assess feasibility and clinical utility of re-biopsy in real world setting in advanced NSCLC.

Methods
Patient’s main inclusion criteria was advanced NSCLC with an indication of repeat biopsy by the referent clinician. The primary outcome was the percentage of successful procedures; secondary outcomes were localization of the new biopsy, type of procedure, new biological status (comparison to initial status, new biomarkers, resistance biomarkers) and tolerance of the procedure.

Results
From May 2012 to May 2013, 18 centers included 102 patients. The characteristics of the 67 first patients were: male: 40%; age: 64.8 ± 10.9 years; PS 0/1: 87%; adenocarcinoma: 85%; EGFR mutated: 46.2%; no biological available assessment: 16.4%; controlled disease as best response to first line: 70%. Repeat biopsy was possible in 80.6%. The main failure reasons were: inaccessible lesion: 4.5%, medical contraindications: 14.9%. Main procedures were: bronchial endoscopy: 48.1%, trans thoracic needle biopsy: 24.1%. The procedure permits to find, in EGFR wild type population, 3 patients with a driver oncogene (1 HER2, 1 Ros1, 1 EML4 ALK); in EGFR mutated patients, 2 T790M mutations and to obtain in 3 patients with no biological data’s at the diagnosis, a biological profile. Complications were very low: 2 cases of moderate bleeding and 1 case of pneumothorax.

Conclusion
Repeat biopsy is a feasible procedure with acceptable adverse events. Recommendations should be realized on the indications of re-biopsy, the timing and the recommended site (primary versus metastasis, progressive target versus no progressive). Analysis of the complete population (n=102) will be presented at the meeting. Supported by an academic grant from Boehringer Ingelheim Company and Hoffmann-La Roche Company.

Abstract not provided

Background
Median survival of non-small cell lung cancer (NSCLC) patients with brain metastases is poor. We examined concurrent erlotinib and whole brain radiotherapy (WBRT) followed by maintenance erlotinib in patients with untreated brain metastases, given the potential radiosensitising properties of erlotinib and its direct effect on brain metastases and systemic activity.

Methods
Eighty NSCLC patients with KPS≥70 and multiple brain metastasis were randomised to placebo (n=40) or erlotinib (100mg, n=40) given concurrently with WBRT (20 Gy in 5 fractions). Following WBRT, patients continued with placebo or erlotinib (150mg) until disease progression. The primary end-point was neurological progression-free survival (nPFS).

Results
Fifteen patients (37.5%) from each arm were alive and without neurological progression 2 months after WBRT. Median nPFS was 1.6 months in both arms; nPFS HR 0.95 (95% CI, 0.59-1.54; p=0.84). Median overall survival (OS) was 2.9 and 3.4 months in the placebo and erlotinib arms; HR 0.95 (95% CI, 0.58-1.55; p =0.83). The frequency of EGFR mutations was low with only 1 out of 35 (3%) patients with available samples had activating EGFR-mutations. Grade 3/4 adverse event rates were similar between the two groups (70% in each arm), except for rash 20% (erlotinib) vs. 5% (placebo), and fatigue 17% vs. 35%. No significant QoL differences were found.

Conclusion
Our study showed no advantage in nPFS or OS for concurrent erlotinib and WBRT followed by maintenance erlotinib in patients with predominantly EGFR wild-type NSCLC and multiple brain metastases. Future studies should focus on the role of erlotinib with or without WBRT in patients with EGFR mutations.

Background
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have shown efficacy in advanced NSCLC with brain metastases (BM). Icotinib is a new EGFR-TKI. A randomized, double blind phase III trial proved that icotinib was non-inferior to gefitinib in terms of median progression free survival (PFS) in advanced NSCLC. We have conducted a phase II study to evaluate the efficacy and safety of icotinib in combination with WBRT in Chinese NSCLC patients with BM, and investigated the cerebrospinal fluid (CSF) concentrations of icotinib. .

Methods
From January 2012 to January 2013, 20 patients aged 18-75 years with Eastern Cooperative Oncology Group performance status 0-2 and BM from NSCLC,were recruited regardless of EGFR status. The treatment comprised icotinib 125mg, TID concurrently with WBRT (30Gy/10f/2w). CSF and plasma samples were collected at the same time from 10 patients at least 5 days after icotinib treatment. The concentrations of icotinib in the CSF and plasma were measured by high performance liquid chromatography coupled with tandem mass spectrometry. The primary end point was progression-free survival (PFS) determined by RECIST. Additional end points were response rate, safety and CSF concentrations of icotinib. EGFR mutation status was tested by Amplification Refractory Mutation System( ARMS)

Results
The median PFS was 7.3 months [95% confidence interval (CI) 4. 2-9.8]. Patients with EGFR mutation-positive disease had significantly longer median PFS versus EGFR wild-type disease [NR versus 4.2 months (95% CI 2.9-5.1); P = 0.000]. The most prevalent site of first failure was extracranial in seven patients (70.0%）. The CNS response rates were 25% complete response (n=5), 55% partial response (n= 11), 15% stable disease (n=3), and 5% progressive disease (n =1). The overall response rate was 80% (n = 16). The most common adverse events were rash (40.0%), diarrhea (15.0%),nausea(45.0%), vomiting(20.0%), headache(35.0%), fatigue (45.0%). And no patient experienced grade ≥ 3 toxicity. The mean plasma and CSF concentrations of icotinib were 936.47 ± 503.80 and 8.93 ± 8.01ng/ml, respectively, and the mean ratio of CSF-plasma concentration was 1.04% ± 0.95.

Conclusion
Icotinib was well tolerated and showed promising activity in combination with WBRT in patients with BM from NSCLC. The concentrations of icotinib in CSF were much lower than that of plasma. Further randomized trials are warranted.

Background
Afatinib, an irreversible ErbB Family Blocker, was superior to pemetrexed/cisplatin in previously untreated patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) in a global Phase III trial, LUX-Lung 3. In patients with the two most common EGFR mutations (Del19, L858R) median progression-free survival (PFS) was 13.6 vs. 6.9 months (HR=0.47, 95% CI: 0.34–0.65; p<0.0001). Here we present the results for subgroups of patients with or without brain metastases (BM) with NSCLC harbouring common EGFR mutations.

Methods
In LUX-Lung 3 EGFR mutation-positive patients were randomized 2:1 to afatinib 40 mg daily or up to 6 cycles of pemetrexed/cisplatin at standard doses. Patients with stable BM (asymptomatic, stable >4 weeks with no treatment required) were allowed. Presence of BM was documented by the investigator during screening. Tumour assessments were performed every 6 weeks until 48 weeks and every 12 weeks thereafter until progression, and reviewed independently and by the investigator.

Results
308 patients with common EGFR mutations were randomized (afatinib: 204, pemetrexed/cisplatin: 104), including 35 with baseline BM (afatinib: 20, pemetrexed/cisplatin: 15). Of these, Del19 mutation was detected in 11 (afatinib) and 8 (pemetrexed/cisplatin) patients and L858R in 9 (afatinib) and 7 (pemetrexed/cisplatin) patients. The baseline characteristics of patients with or without BM were comparable (females: 74% vs. 66%, median age: 61 vs. 62 years, ECOG 0: 31% vs. 41%, median time since diagnosis: 1.2 vs. 1.1 months, respectively). Within the BM group, baseline characteristics were balanced between treatment arms with the exception of ECOG 1; 80% of afatinib-treated patients had ECOG 1 compared with 53% of those treated with pemetrexed/cisplatin. Median PFS by independent review was 13.7 (afatinib) vs. 8.1 (pemetrexed/cisplatin) months in patients without BM (HR=0.47, 95% CI: 0.33–0.68; p<0.0001), and 11.1 (afatinib) vs. 5.4 (pemetrexed/cisplatin) months in patients with BM (HR=0.52, 95% CI: 0.22–1.23; p=0.13). Objective response in patients without BM was 59% (afatinib) vs. 23% (pemetrexed/cisplatin), odds ratio=4.8, p<0.0001, and 70% (afatinib) vs. 20% (pemetrexed/cisplatin), odds ratio=11.0, p=0.007, in patients with BM. Investigator review showed a median PFS of 13.6 (afatinib) vs. 6.9 (pemetrexed/cisplatin) months in patients without BM (HR=0.38, 95% CI: 0.27–0.53; p<0.0001), and 6.7 (afatinib) vs. 5.4 (pemetrexed/cisplatin) months in those with BM (HR=0.67, 95% CI: 0.29–1.57; p=0.36). By investigator review, progressive disease in the brain was observed for 4.2% (7/167) and 3.7% (3/82) of patients without BM at baseline for afatinib and pemetrexed/cisplatin, respectively. All but one of these patients (on afatinib) had intracranial progression only. The median (range) time to progression in the brain in this small group was 11.6 (1.3, 20.2) months (afatinib) and 5.5 (2.6, 8.2) months (pemetrexed/cisplatin).

Conclusion
In patients with previously untreated NSCLC harbouring common EGFR mutations afatinib remains efficacious regardless of the presence or absence of BM. Control of synchronous asymptomatic BM with afatinib compares favourably with existing data for cranial radiation therapy.

Abstract not provided

Background
Customization is feasible in adjuvant setting (tissue availability). SCAT trial has completed planned recruitment with 500 p. For resected NSCLC with nodal involvement adjuvant platinum-based CT improves outcomes but survival remains suboptimal. Compliance may be a key issue for efficacy in adjuvant setting. mRNA BRCA1 levels are prognostic in early NSCLC and could be a predictive marker for CT activity. In advanced disease patients with low BRCA1 benefit from cisplatin doublets meanwhile p with high levels attained longer survival with taxanes.

Methods
Phase III trial testing 4 cycles non-selected vs customized adjuvant CT. Entry criteria: NSCLC, R0 resection, pN1 or pN2, KI > 70, recovered from surgery, adequate hematologic, renal and liver functions, no prior CT or RT, age > 18 y, informed consent. Stratification: N1 vs N2, histology (squamous vs non-squamous), resection (lobectomy vs pneumonectomy). Central lab mRNA BRCA1 levels and quartile distribution. Primary end-point: OS. Secondary end-points: DFS, toxicity, recurrence pattern. Design: R: 1:3. Control treatment: Cis-Docetaxel (CD). Experimental arm: Q1: Cis-Gemcitabine (CG); Q2-3: Cis-Docetaxel; Q4: Docetaxel (D). PORT in pN2 patients. Compliance treatment and toxicity profile analyzed by arm and correlation with potential prognostic factors explored

Results
500 included p; 108 control arm, 392 experimental arm. Median follow-up 18.6 m (2-59 m). Median mRNA BRCA1 levesl 15.78 (0.73-132) Q1 212 (42.4%), Q2-3 150 (30%), Q4 138 (27.6%). Mean BRCA1: Adenocarcinoma: 8.45 vs Squamous 19.6 (p< 0.001). Overall low levels BRCA1: 43.8%. EGFR mut 5.6% 297 p evaluated for compliance planned adjuvant treatment: M/F ratio: 82.5/17.5%. Median age: 62 (range 36-80). PS 0/1/2: 55.9/43,1/1%. Histology: Adenocarcinoma 47.5%, Squamous 44.1%. Stages: IIA/IIB/IIIA: 11.1/38.4/50.2%. Surgical procedure: Lobectomy 72.1%; Pneumonectomy 27.9%.. Toxicity. G3-4 AE: Neutropenic fever: CD 10% vs D 4.4% vs CG 0%. (p=0.0056); Nausea/vomits: CG 11.1% vs CD 10.4% vs D 0%. (p=0.0198); Hypersensitivity: D 5.97% (NS). Dose-reduction: 34.24% control vs 18.30% experimental (p=0.0044). Full 4 cycles CT compliance: CD control 80.83%, CG 91.2%, CD experimental 79.2%, D 88.1% (p=0.052). No differences in dose-reductions. CT compliance lobectomy 86.4% vs 85.5% pneumonectomy (NS). CT compliante < 70 y 91.1% vs 66.6% > 70 y (p<0.01)PORT compliance 55.31% of planned cases.

Conclusion
Planned trial recruitment achieved with median f-u 18.6 m. Majority of resected NSCLC showed low levels expression BRCA1. Adenocarcinoma lower levels than Squamous. Safety profiles differences observed between treatment schedules: neutropenic fever (CD), nausea/vomits (CG). Customized treatment requires less dose-reductions. Trend to poor compliance with Cis-Doc. No relation between extensión of surgery and adjuvant Tx compliance . Compliance CT significantly lower for age > 70 y. Low compliance for PORT.

Background
Although UFT is approved in eastern countries, most guidelines do not recommend any adjuvant treatment in resected Stage I NSCLC. Pazopanib (P) is a potent, orally active multi-target receptor tyrosine kinase inhibitor of VEGFR-1, -2, -3, platelet derived growth factor (PDGFR) type-α and –β, approved in metastatic renal cell carcinoma and sarcoma. Neoadjuvant P demonstrated single-agent activity in patients with early stage NSCLC. We report the feasibility and tolerance of adjuvant P in stage I NSCLC.

Methods
In this double-blind randomized multicenter phase II/III trial, completely resected patients (pts) with stage I NSCLC (7[th] TNM edition) were randomized to receive either placebo or P 800 mg/d during 6 months. The Fleming’s two stage phase II primary endpoint was compliance (i.e. % of pts able to receive at least 3 months of P, whatever the dose). After 64 pts included (interim analysis), IDMC recommended to start with P 400 mg/d because of initial insufficient compliance. A one-step Fleming design was used with the new dose. Phase II design was not comparative.

Results
143 pts were randomized in 29 centers between March 2009 and August 2012, 71 and 72 in the placebo and P arms respectively. Most pts were male (61%) and smokers (91%), median age was 60. Pathological stage was IA in 111 pts (78%) and 16% were squamous cell carcinomas. Compliance for P800 was adequate in 38% (95% confidence interval [21-56]) vs. 87% [71-96] in placebo; for P400 in 69% [50-84] (p=0.01, compared to P800) vs. 93% [77-99] in placebo. Dose modifications were seen in 44% and 34% of P800 and P400 groups. The proportion of patient with at least one grade 3/4 toxicity was 53% [35-71] in P800 (13% [4-29] for placebo) and 38% [21-56] in P400 (27% [12-46] for placebo). No toxic deaths were observed. Only 2 pts has grade 4 toxicities in P800 (fatigue in P arm, GGT in the placebo arm). Most common toxicities G3 in P800 were diarrhea (9%), hypertension (9%), and increased transaminases (16% vs. 0% in P400); in P400 gastro-intestinal disorders (16%, 6% diarrhea) and hypertension (6%).

Conclusion
IFCT-0703 is the first feasibility study demonstrating that full dose of P is safe but not feasible in the adjuvant setting in NSCLC. Compliance and tolerance with reduced dose appeared acceptable for adjuvant settings.

Background
In general thoracoscopic lobectomy (VATS) is considered being associated with advantages compared to conventional thoracotomy when it comes to postoperative outcomes such as pain, duration of hospitalization and overall complications. It is also believed that a reduction in these complications leads to better patient compliance with adjuvant chemotherapy. However, this assumption is based on single-institution case-control studies and selection bias is possible. This is a study on the differences in patient compliance with adjuvant chemotherapy following lobectomy by VATS or thoracotomy. Data are obtained from a complete national registry on lung cancer patients.

Methods
To investigate if the surgical approach alone had an impact on patient compliance to adjuvant chemotherapy we investigated patients who underwent lobectomy for clinical stage I non-small cell lung cancer. The patient population in this study had; however, unsuspected nodal involvement and adjuvant chemotherapy was indicated. Patients were analyzed for type of adjuvant chemotherapy as well as failure to begin or complete full treatment. A clinical oncologist who was blinded for surgery approach reviewed all patient files in order to investigate the data on chemotherapy.

Results
From 2007-2011 lobectomy for clinical stage 1 disease was performed in a total of 1513 patients by VATS (N=718/ 47.5%) or thoracotomy (N=795/ 52.5%). Unsuspected nodal disease was diagnosed in 278 (18.4%) patients, 11 patients were excluded. They had either distant metastasis or radiotherapy due to nonradical resection. This left 267 patients for further analyses, adjuvant chemotherapy was delivered to 155 (58.1%) and 98 (36.7%) completed 4 cycles as planned. There was no significant difference in patient compliance with chemotherapy and surgical approach (p=0.35). Survival was significantly influenced by comorbidity, histology and compliance with chemotherapy (p<0.001) in a Cox proportional hazard analysis; Survival was not influenced by sex, age or surgical approach.

Conclusion
In this study with complete national data we did not confirm the assumption that patient compliance with adjuvant chemotherapy was better after thoracoscopic lobectomy compared to conventional lobectomy. Survival was significantly influenced by compliance with chemotherapy but not surgical approach.

Background
Most patients with early-stage lung cancer will die of recurrent disease despite multimodality therapy with curative intent. KRAS is the most commonly mutated oncogene in lung adenocarcinomas, and patients with resected disease are a unique population amenable to a personalized clinical trial approach. GI4000 is a vaccine created from whole, heat killed recombinant Saccharomyces cerevisiae yeast, overexpressing KRAS Q61L plus Q61(R or H) and either a G12C, G12D, G12V, or G12R mutation. This study aimed to assess the feasibility and immunogenicity of the GI4000 vaccine in patients with KRAS-mutant lung cancers and to compare the outcomes of patients to matched controls.

Methods
Patients with Stage I-III KRAS-mutant lung cancers who completed curative therapy were enrolled. Each patient was routinely administered the genotype-matched vaccine from the GI4000 series subcutaneously starting 1-4 months after standard treatment completion: weekly x 3, monthly x 6 and every 3 months for a total of 3 years (19 doses). KRAS-antigen T-cell response was assessed by interferon-γ ELISpot assay in peripheral blood mononuclear cells. The study was powered to detect an immune response rate of ≥25% (N=24 patients). A comparison group matched for age, sex, KRAS genotype and stage was used to compare recurrence and survival using the Kaplan-Meier method with a hazard ratio for survival adjusted for age, sex and stage.

Results
In 28 months, 33 patients were screened and 24 patients enrolled. The study met its primary endpoint with 63% of evaluable patients (50% of all patients) developing an antigen-specific immune response. 19 patients had evaluable baseline samples, 9/13 with a negative response at baseline developed a treatment emergent response and 3/6 with a pre-existing baseline response had an increased response over baseline that met pre-specified immunologic criteria. There were no treatment-related Grade 3/4 or severe AEs. The median number of vaccinations received was 15 (range 1-19). 1 patient withdrew consent due to local injection site reaction and 2 died of recurrent disease during study. The baseline characteristics and clinical outcomes of the trial patients and a group of matched controls is presented in the Table below.

GI4000 vs. Matched controls	GI4000 N=24 N(%)	Matched controls N=64 N(%)
Stage I II III	_____ 12 (50) 5 (21) 7 (29)	_____ 42 (66) 2 (3) 20 (31)
Age at diagnosis (median)	63	66
Sex Male Female	_____ 7 (29) 17 (71)	_____ 21 (33) 43 (67)
Recurrence free survival per year 1 2 3	_____ 86% 68% 60%	_____ 85% 71% 69%
Overall survival per year 1 2 3	_____ 100% 100% 92%	_____ 93% 88% 83%
Hazard ratio for survival (p-value)	0.58 (0.29)

Conclusion
The GI4000 vaccine is safe, feasible and immunogenic after completion of curative-intent therapy in patients with KRAS-mutant lung cancers. Recurrence rates are equivalent but overall survival trends favorably when compared to matched controls. Exploratory analysis of survival in the immune responders versus matched controls is underway. A randomized study with prospective biomarker analyses is warranted.

Background
Postoperative adjuvant chemotherapy is extensively received due to its extension of the time to recurrence and enhancement of survival rate in non-small cell lung cancer (NSCLC). However, it has reached the plateau at current, the beneficial cases are few, and drug-resistance and over-treatment phenomena are present in most of patients, hence it is necessary to seek a new postoperative adjuvant chemotherapy to improve the survival rate. Angiogenesis is one premise of malignant tumors to occur, develop and metastasize, but vascular endothelial growth factor (VEGF) is one of the most important tumors in the process of neovascularization. Under normal conditions, VEGF is hardly expressed in a lot of normal tissues in vivo, while highly expressed in the tumors like osteosarcoma, bladder cancer, breast cancer and colorectal cancer. Recombinant human endostatin (endostar) can significantly intervene the angiogenesis-promoting effect to block the nutritional supply of tumors and inhibit tumor proliferation or metastasis. We compare the curative effect of endostar plus adjuvant chemotherapy and adjuvant chemotherapy alone in the treatment of patients with completely resected NSCLC at stage IB-IIIA.

Methods
This is an open, multicenter, randomized (1:1) study, stratified by gender, stage and histology. Completely resected pts (stage IB to IIIA) were randomized to receive adjuvant NP plus Endostar (Vinorelbine 25mg/m2 on d1 and d8 plus Cisplatin 75 mg/m2 on d1, and iv plus Endostar 7.5mg/m2 per day iv for consecutive 14 days. Every 21 days as one cycle for 4 cycles) or NP regimen alone. The primary endpoint was disease-free survival (DFS). Secondary endpoints included tumor response rate, overall survival and safety.

Results
250 pts (1:1) were included between 07/2007 and 06/2009. Two arms were well-balanced with regard to age, gender, histology, staging, and resection type. The follow-up time is 42 months. The two groups had no significant difference in the incidence of toxicity reaction. Endostatin plus NP can prolong the DFS of patients with complete resectable NSCLC at stage IIIA (19.33±3.73m vs 17.10±9.68m) with high security, but no statistical difference. Cases with high expression of VEGF showed a better DFS than cases with low expression in Endostatin plus NP group (48.45±3.52m vs 40.18±4.54m, P < 0.05). The level of peripheral circulating endothelial progenitor cells (EPCs) in NSCLC patients is significantly higher than that in healthy volunteers. EPCs level was associated with NSCLC stage. The EPCs levels after treatment significantly decreased than that before treatment (P=0.014) in beneficiaries of NP or NP plus with endostar. The time to progression (TTP) was longer in patients with lower levels of EPCs (<0.35%) before chemotherapy or endostatin treatment (P<0.001).

Conclusion
This preliminary result showed vascular targeted therapy in postoperative adjuvant therapy of lung cancer has a good application prospect. VEGF and EPCs play important roles in the development of lung cancer. Deep studies should be taken for the other related molecular targets in the future.

Abstract not provided

Background
We conducted a phase III randomized controlled study to investigate the efficacy of post-surgical adjuvant chemo-immunotherapy using activated killer T cells and dendritic cells (AKT-DC) obtained from regional lymph nodes of lung cancer patients. The target of immunotherapy is the residual micrometastases after surgery and the resistant clones to chemotherapy.

Methods
Between April 2007 and July 2012, 103 patients with post-surgical non-small cell lung cancer were randomly assigned to receive either chemo-immunotherapy (group A) or chemotherapy (group B). Immunotherapy was consisted of adoptive transfer of autologous activated killer T cells and dendritic cells (AKT-DC) obtained from regional lymph nodes of lung cancer patients. The primary end point of this study was overall survival. Secondary end points were recurrence free survival, toxicity, and adverse effects of immunotherapy.

Results
Two and five years over all survival were 93.4% and 81.4% in group A and 66.0% and,48.3% in group B respectively. The difference was statistically significant (log-rank test p=0.0005, generalized Wilcoxon test p=0.0005) in favor of chemo-immunotherapy group A. Hazard ratio was 0.229 (95% CI 0.093 to 0.564).Two year recurrence free survival was 68.5%(53.2 to 79.7%: group A) and 41.4% (27.5 to 54.7: group B). The difference was statistically significant (log-rank test p=0.0020 and HR 0.423(95% CI 0.241 to 0.743) in favor of group A. [Adverse effects of immunotherapy.] Chill and shiver: Out of total 762 courses, 52 courses (6.8%) were accompanied with chill and shiver and 47 courses (6.2%) fever (>38) thereafter. Out of 50 cases treated by immunotherapy, 28 cases had no side effect and 22 cases had at least more than one side effect of chill, shiver and/or fever.

Conclusion
Immunotherapy using this modality is effective in recurrence control of post-surgical lung cancer patients by inhibiting the growth of disseminated micrometastases.

Background
The NCIC CTG JBR.10 trial demonstrated that adjuvant chemotherapy (ACT) improves survival in resected stage IB/II non-small cell lung cancer (NSCLC) compared to observation. A 15-gene expression signature was developed from the trial population and subsequently validated to stratify patients with resected NSCLC into low and high risk prognostic groups. The signature may also be predictive for greater benefit from ACT in high risk patients (Zhu et al. JCO 2010), but this has not yet been validated. This gene expression signature may offer a risk stratification strategy to identify patients most likely to benefit from ACT. We conducted an exploratory economic analysis to assess the impact of the use of this gene signature compared to current clinical staging to guide ACT decisions in resected early stage NSCLC.

Methods
We developed a decision analytic model populated by the NCIC CTG JBR.10 trial cost and outcome data, including direct medical costs and overall survival (OS). Utility for each health state was estimated from quality of life data to generate quality-adjusted survival. The analysis was performed over a lifetime horizon from the perspective of the Canadian public health care system, expressed in 2013 Canadian dollars. Survival and costs were discounted at 5% per year. We determined the incremental cost-effectiveness ratio (ICER) and incremental cost-utility ratio (ICUR) of ACT versus observation in resected stage IB/II NSCLC in the following two scenarios: (1) gene signature-directed ACT, where patients classified as having high risk of recurrence receive ACT and those at low risk are observed; and (2) clinical stage-directed ACT, where gene signature profiling is not performed – those with stage IB tumours >4cm or stage II NSCLC receive ACT, and those with stage IB tumours <4cm are observed. Nonparametric bootstrapping to estimate 95% confidence intervals (CI) and multi-way sensitivity analyses were performed.

Results
The analysis included 52 patients in the gene signature-based strategy and 125 patients in the stage-based strategy with available direct medical costs and gene signature data. The mean survival gain of ACT versus observation was 2.28 years using gene signature-directed selection, and 1.59 years using stage-directed selection. The discounted ICER of ACT versus observation was $8,327/life-year gained (LYG; 95% CI, $395 to $19,590) using the gene signature-directed approach, and $5,623/LYG (95% CI, -$2,161 to $14,354) for the clinical approach. There was no significant difference in the ICER between the two strategies (p=0.52). The discounted ICUR was $11,315/quality-adjusted life-year (QALY; 95% CI, $211 to $27,314) using the gene signature-directed approach, and $7,728/QALY (95% CI, -$3,080 to $19,825) for the clinical approach. Sensitivity analyses showed that the ICER was most sensitive to changes in the survival hazard ratio (i.e. treatment benefit) and utility, but less sensitive to the cost of the gene signature (range $0 to $10,000 per case, with corresponding ICER $15,794 to $28,194/LYG, respectively).

Conclusion
This exploratory analysis suggests that use of the 15-gene expression signature to guide decisions for ACT in resected stage IB/II NSCLC patients could be highly cost-effective. Further validation of the signature’s impact on ACT outcomes is needed.

Background
Mediastinal lymph nodes staging in NSCLC is of paramount importance. Although relatively precise, diagnostic modalities still employ certain level of invasiveness. Artificial Neural Network (ANN) is a well established predictor tool which, due to underlying distribution and relationship among the given variables, allow for construction of multidimensional models trained in prognosis of given outcome. Their performance in mediastinal staging based on radiological data only, currently remains unknown.

Methods
Samples from 467 lymph nodes were obtained from 160 patients with primary NSCLC by means of endobronchial ultrasound guided-transbronchial needle aspiration (EBUS-TBNA), mediastinoscopy or lymphadenectomy during thoracotomy and microscopically analyzed. ANN models were created and prospectively validated on unmatched cohort of 50 consecutive patients (158 groups of lymph nodes). To identify factors correlated with nodal involvement single factor tests and logistic regression analysis were performed.Figure 1 Figure 1. The multilayer perceptron (MLP). Artificial Neural Network (ANN) structure for predicting metastatic involvement of mediastinal lymph nodes in NSCLC patients.

Results
Size and standard uptake value (SUV) of the node along with primary tumour T characteristics were identified as the most sensitive variables regardless of the analysis conducted. Two ANN models predicted metastatic involvement with 89% and 92% accuracy. Single factor tests maintained high accuracy only for 2 out of 4 most sensitive variables (SUV >2.8 and length >15mm) in prospective validation. Additionally, logistic regression analysis allowed for construction of scoring model with certain parameters corresponding to risk thresholds of metastatic disease.Figure 1 Figure 2. Artificial Neural Network (ANN) characteristics. ROC curves for 2 manually designed ANNs (A); Sensitivity analyses of coefficients (B) and overall characteristics of ANNs performance (C).

Conclusion
ANN is a repeatable and accurate diagnostic tool in mediastinal staging in NSCLC patients. Before its role in clinical practice will be established in large multi-centre study, findings of this preliminary report should be considered as exploratory only.

Background
Pleural lavage cytology (PLC) is considered to be a prognostic factor for non-small cell lung cancer (NSCLC) patients. There has been no report describing the relationship between adjuvant chemotherapy and the presence of PLC.Backgroud: Pleural lavage cytology (PLC) is considered to be a prognostic factor for non-small cell lung cancer (NSCLC) patients. There has been no report describing the relationship between adjuvant chemotherapy and the presence of PLC.

Methods
From January 2000 to December 2009, we retrospectively reviewed the medical record of lung adenocarcinoma patients who underwent tumor resection and were positive for PLC immediately after thoracotomy.

Results
There were 53 patients (4.8%) out of 1114 lung adenocarcinoma patients had PLC positive findings, including 31 male and 22 female patients, with a mean age of 66.6 years. Median follow up period was 33.6 months. Adjuvant chemotherapy was administered intravenously to 24 patients and they were classified as adjuvant chemotherapy group. The rest of 29 patients were classified as surgery alone group. Pathological stage of I / II / III was 12 (41%) / 8 (28%) / 9 (31%) in surgery alone group and 7 (36%) / 8 (30%) / 9 (38%) in adjuvant chemotherapy group. The regimen of chemotherapy was as follows; 8 patients received cisplatin plus gemcitabine, 7 patients received carboplatin plus paclitaxel, 7 patients received gemcitabine, and 2 patients received others. 5-year survival rate was 50.3% and 29.7% (p=0.09) and 5-year recurrence free survival rate was 34.6% and 15.7% (p<0.01) in adjuvant chemotherapy group and surgery alone group. Even in stage I cases, there was a tendency that adjuvant chemotherapy group had better 5-year recurrence free survival than surgery alone group (60.1% and 29% p=0.11). In the COX proportional hazard multivariate analysis for recurrence free survival revealed that adjuvant chemotherapy (hazard ratio (HR) 0.45, p=0.03), tumor size >30mm (HR 2.23, p=0.02), and lymph node metastasis (HR 2.67, p<0.01) were significant independent prognostic factors.Figure 1

Conclusion
Adjuvant chemotherapy was considered to be effective for PLC positive lung adenocarcinoma patients. Even in stage I cases, our results implicated that adjuvant chemotherapy was beneficial.

Background
Non-small cell lung cancer (NSCLC) with postoperative recurrence (POR) is generally believed to have an incurable disease. However, several studies have indicated that only a limited number of distant recurrences (oligorecurrence) may benefit from local therapy to the distant site of disease. We investigated factors associated with postrecurrence survival (PRS) in recurrent NSCLC, and particularly the role of local therapy to the metastatic site.

Methods
From 2000 through 2009, a total of 1542 patients with NSCLC underwent complete surgical resection. Of those, we reviewed the records of 356 patients with POR.

Results
Type of POR included locoregional only in 114 (32%), distant in 242 (68%). Of the 242, there were 65 oligorecurrences. Initial recurrence therapy found local treatment for 68 (surgery 5, radiation 12, surgery with chemotherapy and/or radiation 12, chemoradiotherapy 39). Multivariate analysis demonstrated that older age (HR1.522), advanced stage (HR1.371), shorter disease-free interval (DFI; HR1.733), non-adenocarcinoma (HR1.442), systemic treatment (-) (HR1.481), EGFR-TKIs (-) (HR1.563), local treatment (-) (HR1.705) and bone metastases (HR2.140) had a significant association with poor PRS, and oligorecurrences state appeared as an independent PRS factor in patient with distant recurrence (HR1.836). Median PRS times were 36.3 months for 37 patients with DFI > 16 months and receiving local treatment, and 16.0 months for other (p<0.001) in all patients (Fig.1), and 36.5 months for 29 patients with DFI > 16 months and oligorecurrence, and 14.6 months for other (p<0.001) in patient with distant recurrence (Fig.2). There was no significant difference in survival for the patients with oligorecurrence according to whether or not receiving local treatment. Figure 1Figure 2

Conclusion
This study showed that local therapy improved PRS in patients with POR. Optimization of personalized systemic treatment depends on patient selection, and therapeutic strategy for adding an aggressive local treatment options based on a careful follow-up is important.

Abstract not provided

Background
The PI3K-AKT-mTOR signaling pathway is dysregulated in a wide variety of cancers. Pathway activation in mesothelioma may occur through diverse cellular mechanisms, including activation of receptor tyrosine kinases that signal through Ras and PI3K/Akt/mTOR, and loss of PTEN expression. GDC-0980 is a potent and selective oral dual inhibitor of class I PI3K and mTOR kinases that has demonstrated broad activity in various xenograft cancer models.

Methods
A phase I dose-escalation study was conducted in 2 Stages: Stage 1 evaluated oral, daily (QD) doses of 2-70 mg GDC-0980 given 21/28 or 28/28 days in a 3+3 dose escalation design. Stage 2 evaluated disease specific cohorts at the recommended phase 2 dose (RP2D), including a MPM cohort at 30 mg GDC-0980 QD 28/28 days. Safety and tolerability of GDC-0980 was assessed as well as pharmacokinetics (PK) and pharmacodynamics (PD) assessment of PI3K pathway inhibition by FDG-PET. Anti-tumor activity was assessed by modified RECIST; CT scans were centrally reviewed retrospectively by a radiologist with MPM expertise. Archival tumor tissue was evaluated for PIK3CA mutation by allele specific PCR or Sanger sequencing and PTEN expression was assessed by immunohistochemistry.

Results
33 MPM patients were enrolled: 6 in Stage 1 at 8-70 mg and 27 in Stage 2 at 30mg GDC-0980. Safety and tolerability of GDC-0980 in Stage 1 was similar in MPM compared to other solid tumor patients, with the exception of a Grade 5 pneumonitis that occurred in a MPM patient at 40 mg GDC-0980 QD. Based on Stage 1 tolerability data, a RP2D of 30 mg QD was evaluated in Stage 2 for MPM patients. The most frequent Grade ≥3 drug-related adverse events (AEs) at 30 mg GDC-0980 were rash (19%), with one patient (4%) having to discontinue GDC-0980. Other AEs were fatigue (15%), and hyperglycemia, diarrhea, and colitis (7% each). Reversible Grade 2 pneumonitis was reported for 2 patients (7%). Population PK analysis was used to assess the behavior of GDC‑0980 in MPM patients. Additionally, PK/PD relationships will be discussed for efficacy and safety, including exposure‑response, where appropriate. Archival tissue was analyzed for 29 MPM patients. Two samples had PIK3CA mutations (R88Q and E545G) and one sample showed loss of PTEN expression. PI3K pathway inhibition by FDG-PET responses was observed in 8 of 24 MPM patients with available scans. Anti-tumor activity was observed in both stages. Two patients achieved a partial response (PR) in Stage 1, one patient at 50 mg and one patient with the PIK3CA mutation R88Q at 8 mg GDC-0980. Two PRs were observed at the RP2D of 30 mg in Stage 2. Eleven (41%) MPM patients at the RP2D remained on study for >6 months, and 2 (7%) patients remained on study >12 months.

Conclusion
GDC-0980 was generally well tolerated in MPM patients at the RP2D. Anti-tumor activity, evidenced by tumor regression and prolonged disease control, has been observed. PIK3CA mutations and PTEN loss were uncommon.

Background
Preclinically, arginine deprivation has shown activity as a novel antimetabolite strategy for MPM patients who are deficient for the rate-limiting enzyme in arginine biosynthesis argininosuccinate synthetase (ASS1). Here, we examine the efficacy and safety of the arginine-lowering agent ADI-PEG20 (Polaris Group, San Diego, US) among patients with MPM.

Methods
We performed a multicentre randomised phase II clinical trial, based on patients with good performance status (0 or 1), non-resectable disease, ASS1-deficient MPM, and measurable disease. Patients were randomized 1:2 to receive best supportive care (BSC) or BSC+ADI-PEG20, stratified by: gender, histology (sarcomatoid versus non-sarcomatoid), prior treatment (chemonaive or previous platinum combination therapy), and centre. The primary endpoint, progression-free survival (PFS), is assessed by modified RECIST, and secondary endpoints include overall survival, tumor response rate, and toxicity. Translational endpoints included measurement of plasma arginine, citrulline and ADI-PEG20 antibody levels, assessment of metabolic response by [18F]Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) and ASS1 methylation status using Illumina’s 450K DNA methylation array. The target sample size was estimated to detect a PFS hazard ratio of 0.60. [Trial funded by Cancer Research UK].

Results
ASS1 deficiency was detected in 98 of 214 patients (46%) of which 68 were randomized on the trial (44 ADI-PEG20+BSC and 24 BSC alone). 66 patients have progressed so far (42 ADI-PEG20+BSC vs. 24 BSC alone), and 32 patients were alive (23 ADI-PEG20+BSC vs. 9 BSC alone). The hazard ratio for PFS was 0.53 (95%, CI 0.31 to 0.90, p=0.02) with a median PFS of 98 days for patients randomized to ADI-PEG20+BSC compared with 59 days for patients receiving BSC alone. ADI-PEG20 toxicity in patients with MPM has been consistent with previous trials of ADI-PEG20 in melanoma and liver cancer: commonly skin injection site reactions (grade 1-2), infrequent episodes of neutropenia (range: grade 1-4), anaphylactoid reactions (2 patients with grade 3 episodes) and serum sickness (1 patient). The best response by modified RECIST was stable disease. Metabolic responses (in 39 evaluable ADI-treated patients) were as follows: 46% with partial response (18/39), 31% with stable disease (12/39), 15% progressive metabolic disease (6/39) and 8% mixed metabolic response (3/39) by FDG-PET assessment. There was a significant difference between IHC assessed ASS1-negative and ASS1-positive patients and the methylation status of the ASS1 gene (p=0.025).

Conclusion
ADI-PEG20 is generally well tolerated and shows evidence of clinically significant activity in patients selected for arginine-dependent MPM demonstrating differential methylation of ASS1. Arginine deprivation may have a role in the future management of MPM either alone or in combination with selected therapies.

Background
Malignant pleural mesothelioma is an incurable thoracic neoplasm for which combination chemotherapy offers limited improvement in survival. Novel agents that offer synergy with standard systemic cytotoxic therapy are under investigation. Among these agents are a variety of immunotherapeutics which can be administered either locally or in a systemic fashion.

Methods
We conducted a Phase I/II “in situ vaccination” clinical trial commencing in March2011 involving repeated intrapleural administration of a replication-defective recombinant adenoviral vector containing the human interferon-alpha (hIFN-α2b) gene at a dose of 3x10[11 ]viral particles concomitant with a 14-day course of high-dose cyclo-oxygenase-2 (COX-2) inhibitor (Celecoxib). This was followed by standard first-line or second-line chemotherapy agents. Primary outcome measures were safety, overall best response rate, and survival.

Results
We completed accrual (n=25) in the first-line chemotherapy arm, in which all patients received pemetrexed-based chemotherapy regimens. This group included patients who previously received pemetrexed chemotherapy but did not subsequently receive this agent for >6 months. In the second-line chemotherapy arm, 13of a planned 15 subjects have enrolled (with 12 evaluable), all of whom received gemcitabine-based chemotherapy (Table 1). In both arms, the combination of intrapleural Ad.IFN-α2b vector, high-dose celecoxib, and systemic chemotherapy proved safe. Adverse events during the chemotherapy portion of the study were comparable to historical controls.Most patients experienced expected mild toxicities from vector (cytokine release syndrome, interferon production), including nausea, fatigue, anemia, lymphopenia (grade 3-4) and hypoalbuminemia. Serious adverse events included: pleural catheter infection (n=2); hypoxia (n=2); supraventricular tachycardia (n=1); and esophagitis (n=1), none directly attributable to the vector or vector administration. Serial chest CT and PET/CT scans demonstrated an overall response rate of 31% by Modified RECIST criteria and disease control rate (DCR) of 78% (partial and complete responses plus stable disease) at initial follow-up scan after the first two cycles of chemotherapy. Partial responses were seen in 9/25 evaluable patients with pemetrexed-based chemotherapy and 1/12 with gemcitabine. Patients who received first-line pemetrexed-based chemotherapy (n=14) had a median survival of 10.5 months, 95% ci=(5.5,inf), whereas second-line patients (n=21; 12 gemcitabine)had a median survival of 15.0 months, 95% ci=(9.0,inf).

	Pem/Platin (N=25)	Gemcitabine (N=13)
Male %	64% (16/25)	84.6% (11/13)
Median Age	67 (51-86)	65 (43-81)
Histologic Subtype %	Epithelioid - 17 (68%) Biphasic - 4 (17%) Sarcomatoid - 4 (17%)	Epithelioid - 11 (84.6%) Biphasic - 2 (15.4%) Sarcomatoid - 0
Stage	I - 2 (8%) II - 6 (24%) III - 13 (52%) IV - 4 (16%)	III - 4 (30%) IV - 9 (70%)
Prior Treatment	Chemotherapy - 4 (16%) RP/PDT - 4 (16%) XRT - 5 (20%)	Chemotherapy - 13 (100%) RP/PDT - 7 (53%) XRT - 2 (15%)
Platin Agent	Cisplatin - 12 Carboplatin - 10 Cis-Carbo - 1 None - 2	Cisplatin - 0 Carboplatin - 2 None - 8
Median Cycles of Chemo	6 (1-6)	3 (0-6)

TABLE 1

Conclusion
The combination of intrapleural Ad.IFN-α2b vector, Celecoxib, and systemic chemotherapy proved safe. Disease control rates observed in this study compare favorably with historical data andthe especially encouraging OS in the second-line chemotherapy group argue strongly for proceeding with a multi-center randomized clinical trial of chemo-immunogene therapy versus chemotherapy alone.

Background
Identifying tumorigenic mutations in malignant pleural mesothelioma (MPM) is essential to advance therapy. Somatic mutations in the BRCA-1 associated protein-1 (BAP1) gene occur in about 20% of MPM tumors (Bott et al., Nature Genetics, 2011). In a retrospective analysis evaluating demographics, exposures, and survival, a history of smoking was the only clinical feature associated with the presence of BAP1 mutations (Zauderer et al., in press, J Thorac Oncol, 2013). Germline BAP1 mutations have also been identified in families predisposed to MPM (Testa et al., Nature Genetics, 2011). BAP1 germline mutations have also been associated with other tumors including atypical Spitz nevi, uveal melanoma, and renal cell carcinoma. These discoveries suggest that BAP1 mutations in mesothelioma represent part of a new hereditary cancer syndrome but the exact clinical phenotype remains unclear. To establish the frequency of germline BAP1 mutations in MPM patients and to accurately assess exposure history and family histories in these patients, we have undertaken a clinical trial to prospectively collect this information from patients with MPM.

Methods
All consenting patients provide a saliva or blood specimen from which germline DNA is extracted. Existing tumor samples are collected and analyzed for BAP1 mutation. Everyone completes a questionnaire regarding asbestos exposure, personal cancer history, and family history of malignancy. First, we will perform a de-identified assessment of the prevalence of germline BAP1 mutation. Patients whose tumors harbor BAP1 mutation and/or meet prespecified high risk criteria will be approached for identified germline testing after appropriate pre-test counseling. Mutations identified through research testing with be confirmed with clinical testing and additional genetic counseling will be undertaken. Testing will be offered to family members of patients with identified BAP1 germline mutations. Please see Figure 1 for study flow. Figure 1

Results
During the first 3 months that this protocol was open, we accrued 26 patients with mesothelioma, 15 of whom qualify for identified research testing. We will present results from ongoing testing at the meeting.

Conclusion
Recruiting patients to perform both de-identified and identified germline testing is feasible. Given the paucity of information regarding penetrance and appropriate screening interventions, BAP1 germline testing should continue only in the context of research programs. Additional preclinical work is ongoing to exploit this potential therapeutic target. Supported, in part, by a grant from the Mesothelioma Applied Research Foundation.

Abstract not provided

Background
The National Lung Cancer Audit is run jointly by the Royal College of Physicians and The Information Centre for health and social care with the aim of recording outcomes in lung cancer (and mesothelioma) on a population scale, explaining the wide variations seen within the UK and between the UK and other countries and ultimately improving outcomes. This abstract presents results for England only, focusing on mesothelioma.

Methods
All patients with mesothelioma seen in in secondary care 2006-2011 were analysed. A hierarchy of diagnosis from surgical histology to non-surgical histology to clinical diagnosis was used to exclude patients with potentially conflicting diagnoses. These records were further analysed to extract data on age/sex distribution, referral source, histological subtype, treatment regime and survival rates.

Results
There were 8,503 patients with mean age 72yrs (83% male), representing around 65% of expected incident cases (a substantial number diagnosed at autopsy and not included in the audit). 45% have right-sided disease, 28% were left-sided, and 1% were bilateral (data missing in 26%). The majority of patients (47%) were referred by their primary care physician, but at least 20% present to secondary care as emergencies. Overall, 89% of cases were histo-cytologically confirmed with that figure appearing to rise slowly over the audit period from 81% (2006) to 92% (2011). Survival data is shown below.

	n (%)	Median survival (days)	1 year survival (%)
All patients	8,503 (100%)	278	41
Survival was slightly better in females (median 304 days vs 274 days HR 0.91, p=0.002)
Subtype	n (%)	Median survival (days)	1 year survival (%)
Unspecified	3,798	276	39.5
Epithelioid	2,300	388	53.2
Sarcomatoid	439	123	16.4
Biphasic	268	274	36.0

37% of patients received no anti-cancer treatment, but 28%, 26% and 30% of patients received “surgery”, chemotherapy or radiotherapy at any time. Most surgical operations (60%) were pleurodesis. Median survival varied by first treatment modality: surgery 378 days, chemotherapy 399 days, radiotherapy 308 days, no anti-treatment 140 days. Survival was highest in patients having “surgery” and chemotherapy (491 days). Use of chemotherapy varied across 28 regional cancer networks from 14% to 41% of patients, but overall increased over the audit period from 13% to 34%.

Conclusion
Mesothelioma is predominantly a cancer of elderly males, with a striking tendency for right-sided disease. Only 11% have no histological confirmation, but where this is obtained, the epithelioid subtype has best prognosis. Low rates of anti-cancer treatment may reflect therapeutic nihilism as well as patient fitness, but there is an encouraging trend towards wider use of chemotherapy which was associated with a greater than doubling in survival compared with no treatment.

Background
Despite advances in therapy, the prognosis of MPM remains poor (median overall survival (OS) of 9-12 months). Nevertheless, as described in surgical series, a small proportion of patients survive far longer. Previously identified prognostic factors in patients undergoing extra-pleural pneumonectomy (EPP) include histological subtype, gender and neutrophil-lymphocyte ratio (NLR). Similar factors including stage and performance status have also been shown to be prognostic in chemotherapy studies. We aim to assess in the general MPM patient population, what factors predict for better prognosis independent of the treatment path chosen.

Methods
We reviewed records of patients registered (2002 -2009) with the NSW Dust Diseases Board; a government compensation body for NSW workers with occupational asbestos exposure. We evaluated a priori prognostic factors including age, gender, histological subtype, staging on CT imaging and NLR using Kaplan Meier and Cox regression analysis, and by treatment interventions, smoking and asbestos exposure history. Exploratory subgroup analyses compared these factors in long-term (>20 months) survivors versus the remainder of the study population.

Results
We identified 913 patients: 90% male; median age 71.9 years; histological subtype (epithelioid 54%; biphasic 11%; sarcomatoid 16.3%; unknown 19%); stage on CT imaging (Tx-I-II 49%; III-IV 51%). 51% of patients received chemotherapy and 6% underwent EPP (of which 67% received chemotherapy. Median age of first occupational asbestos exposure was 18 years, cumulative duration of exposure, 24 years and latency from exposure to diagnosis, 50 years. Median OS was 10.0 months, 15.0 months (range(1-120) in patients receiving chemotherapy and/or EPP and 5.8 months (range 0-125) in patients receiving neither. On univariate analysis, younger age (<70 vs. >70yrs at diagnosis; 13.1 vs. 8.5 months; p<0.001); female gender (12.0 vs. 9.8months; p<0.001); epithelioid subtype (11.8 vs. 7.2 months ;p>0.001); and NLR <5 (12.9 vs. 7.5months; p<0.001) were associated with prolonged OS. Patients who underwent chemotherapy (13.6 vs. 7.2 months; p<0.001) and EPP (17.9 vs. 9.6 months; p<0.001) also had an improved survival. Smoking history (current/ex vs. never) and cumulative asbestos exposure did not affect survival. A trend to improved survival was noted with early stage disease (11.2 vs. 9.1 months; p=0.284) and younger age at first exposure (<18 vs. >18 years of age; 10.9 vs. 9.4 months; p=0.091). On multivariate analysis, age, gender, histological subtype, NLR, EPP and chemotherapy administration remained significant. 24% of patients demonstrated survival over 20 months. Of those, 14% underwent EPP, and 63% received chemotherapy. On multivariate analysis, epithelioid histology (p<0.001), chemotherapy use(p=0.002), undergoing EPP(p=0.01) and NLR<5(p=0.007) were independently associated with survival over 20 months.

Conclusion
In this large, population based cohort of MPM patients, we have validated age, gender, histological subtype and NLR as significant prognostic factors. Patients undergoing interventions such as EPP or chemotherapy demonstrated more favourable survival, however it is important to note that 86% of long survivors did not receive radical surgery, and 37% did not receive chemotherapy. As such, we hypothesise that apart from active treatment and inherent selection criteria, there are additional factors, such as favourable tumour biology, that seem to positively influence survival of MPM patients.

Background
Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer associated with exposure to asbestos. Currently rates of MPM are rising and estimates indicate that the incidence of MPM will peak in western world within the next 10-15 years. Untreated, MPM has a median survival time of 6 months, with poor survival rates for most patients after 24 months of diagnosis. Nuclear Factor kappa B (NF-kB) is a pro-inflammatory transcription factor which is activated in many cancer types, including MPM. The NF-kB pathway regulates important cellular processes including survival and proliferation signals, which are often found to be dysregulated in cancer. Furthermore, we and others have shown that increased NF-kB activation is linked to development of cisplatin resistance. We aim to outline the potential role of NF-kB as a mediator of cisplatin resistance in MPM and determine its value as a potential candidate for therapeutic intervention.

Methods
NF-kB expression was examined in a cohort of MPM patients (n=200) by IHC, and correlated with clinicopathological variables and survival. NF-kB expression was examined in both a panel of MPM cell lines and isogenic parent/cisplatin resistant cell lines by Western blot analysis. The effect of NF-kB inhibition on cellular proliferation was measured by BrdU assay, in a panel of MPM and isogenic parent/cisplatin resistant cell lines, using the novel NF-kB inhibitor Dehydroxymethylepoxyquinomicin (DHMEQ). In addition, the effect of DHMEQ on nuclear translocation of NF-kB was examined by high content screening (HCS).

Results
Cytoplasmic or membranous immunostaining was seen in the majority of tumour samples (96.5%), but nuclear localisation of NF-kB was seen in only 11% cases. Kaplan-Meier survival analysis showed that nuclear NF-kB expression correlated with reduced survival (p=0.05). There was no significant correlation between the level of expression of NF-kB and standard clinicopathological parameters. NF-kB was expressed in all MPM cell lines tested to a varying extent (n=20), with no associations to histology. NF-kB levels were shown to be elevated in cisplatin resistant cell lines when compared to the isogenic parent from which they were derived. DHMEQ was shown to reduce nuclear translocation of NF-kB, inhibiting cell proliferation in all cell lines but to a lesser extent in NCI 2596 cells which have low NFkB expression.

Conclusion
Nuclear NFkB expression is a poor prognostic factor in MPM. DHMEQ, which inhibits nuclear translocation of NF-kB, inhibits cell proliferation in MPM cell lines. Furthermore, increased NF-kB expression in resistant cells suggests this pathway may play a role in development of cisplatin resistance in MPM. Inhibition of NF-kB may therefore prove to be of potential therapeutic benefit in MPM treatment and re-sensitisation of resistant MPM to cisplatin.

Abstract not provided

Background
Tumor response criteria provide a framework for therapeutic decisions and clinical trials management in oncology. The standard response classification categories (partial response (PR), stable disease (SD), and progressive disease (PD)) were defined by the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines based on relative changes in linear measurements of tumor diameter on computed tomography (CT) scans. An increase in linear dimension of at least 20% is categorized as PD, a decrease in linear dimension of at least 30% is categorized as PR, and a change in linear dimension not great enough to exceed either of these thresholds is categorized as SD. With improvements in imaging technology and enhancements in computer algorithms, the extraction of tumor volume from CT scans has become more practical. The possibility that tumor volume may eventually become the preferred tumor measurement metric rather than linear dimension necessitates the development of volumetric response criteria. Although extrapolation of the RECIST response criteria to volume is straightforward for spherical nodules, tumors as non-spherical as mesothelioma likely will require unique volumetric response criteria.

Methods
A semi-automated computerized method was used to determine the mesothelioma tumor volume from CT scans (baseline and all available follow-up scans) retrospectively collected from 70 patients undergoing standard-of-care chemotherapy. Relative changes in tumor volume from baseline were categorized as PR, SD, or PD based on different combinations of percent change thresholds. Overall patient survival was correlated with best response using Harrell’s C statistic. The response criteria for PD and PR were each varied in 1% increments to obtain optimized classification criteria.

Results
The process that systematically evaluated various combinations of response criteria identified an increase in tumor volume of at least 58% and a decrease in tumor volume of at least 17% for PD and PR, respectively, as the criteria that were best correlated with patient survival. These criteria yielded a C statistic of 0.76, where a C statistic value of 1.0 would indicate perfect separation of response groups with respect to subsequent survival times. This result may be compared with the C statistic value of 0.61 obtained when volumetric response criteria extrapolated directly from the RECIST criteria (+73% for PD and -66% for PR) were applied to this cohort.

Conclusion
The evolution toward volumetric assessment of tumor burden and response to therapy necessitates the derivation and validation of volume-specific tumor response criteria to distinguish among PR, SD, and PD. The present study motivates such response criteria for mesothelioma and indicates that mesothelioma volumetric response criteria differ substantively from a simplistic extension of the RECIST criteria to three dimensions. Future prospective studies will be required to validate these criteria.

Background
Clinical T classification of Malignant Pleural Mesothelioma involves qualitative estimation of tumor involvement of the thorax and does not accurately predict prognosis (JTO 7(11):1631-9, 2012). We explored whether novel quantitative assessment of standard CT images might improve the prognostic accuracy of clinical T classification.

Methods
All patients who underwent primary extrapleural pneumonectomy (EPP) or pleurectomy (PDC) between 2001-2012 with available preoperative CT for retrospective review were included. Tumor volume was derived using Vitrea software (Vital) and binned into 3 categories (≤75cc, >75≤500cc, >500cc). Maximal thickness among measurable interlobar septae was measured on CT and binned into 2 categories (≤5mm, >5mm). Kaplan-Meier estimates of overall survival were computed for each combination of volume and septum thickness categories. Combinations with similar estimated survival functions were combined to create criteria for T classification levels. Cox regression was used to evaluate the relative hazard for death and disease recurrence associated with classification levels.

Results
406 patients met inclusion criteria (278 EPP, 128 PDC; 317 male; 297 epithelial histology on biopsy; median age 64). Alignment of survival functions yielded combinations of volume and septum thickness categories defining T1 through T4. These classifications were associated with progressively increasing hazard for death and recurrence (Table).

		Overall Survival			Time to Recurrence
T status	N	Median(mths)	HR	95% C.I.	Median(mths)	HR	95% C.I.
T1	85	37	1.0	-	16	1.0	--
T2	118	21	1.5	1.0 - 2.1	11	1.6	1.1-2.1
T3	105	14	2.5	1.7 - 3.5	8	2.3	1.7 -3.2
T4	98	10	4.2	3.0 - 6.1	5	4.1	3.0 - 5.8

Conclusion
Tumor volume and septum thickness are readily measured on standard CT imaging and provide robust prognostic information not accounted for by current clinical T classification criteria. As quantitative measurements, they should be minimally affected by inter-observer variability. The feasibility and value of these simple and cost effective adaptations to clinical staging should be evaluated as the TNM staging system is revised.

Background
Little is known about the significance of metastases to the posterior intercostal lymph nodes, located within the intercostal spaces at the level of the rib heads, in patients with malignant pleural mesothelioma. These nodes are not part of any staging system. This report is an initial attempt to determine the significance of these lymph nodes.

Methods
We sampled posterior intercostal lymph nodes from 48 patients undergoing radical pleurectomy for malignant pleural mesothelioma. Statistical analyses were then performed correlating metastases to these lymph nodes with progression free and overall survival.

Results
26/48 (54%) patients had positive posterior intercostal lymph nodes. Standard staging revealed: 6/48 (13%) N0, 3/48 (6%) N1, 39/48 (81%) N2, 9/49 (19%) stage III and 39/48 (81%) stage IV. Presence of positive posterior intercostal lymph nodes was not associated with stage (Fisher exact P=0.48), but was associated with N status. N1 and N2 were associated with higher rates of positive posterior intercostal lymph nodes (Fisher exact P=0.011). At a median follow-up of 9.6 months, progression-free survival was 0.83 years, 95% CI: (0.74, 1.30) years; median overall survival was 1.89 years, 95% CI: (1.29, ND) years. Patients with negative posterior intercostal lymph nodes had a median progression-free survival of 1.25 years, 95% CI: (0.95, 1.95) years, while that for patients with positive posterior intercostal lymph nodes was 0.73 years, 95% CI: (0.61, 1.40) years (p=.017 by log-rank test). Patients with negative posterior intercostal lymph nodes had a median overall survival of 3.43 years, 95% CI: (1.89, ND) years, while that for patients with positive ICLNs was 1.01 years, 95% CI: (0.61, 1.40) years (p=.007 by log-rank). In a Cox regression model that adjusted for stage, positive posterior intercostal lymph nodes were associated with an increased risk of failure (HR=2.71, 95% CI=1.15.6.39, P=.048) and death, (HR=3.3, 95% CI: 1.3, 8.1, P=0.0098. Figure 1

Conclusion
Bearing in mind the limitations of this retrospective study with short-term follow-up, these results suggest that the posterior intercostal lymph nodes may have independent prognostic significance. This data has served as a trigger for us to now routinely include the posterior intercostal lymph nodes in our thoracic lymphadenectomies in patients undergoing surgery for malignant pleural mesothelioma. Further investigation of this nodal station is indicated and it is likely that these nodes should be included in any future staging system for malignant pleural mesothelioma.

Background
Studies have assessed correlation between radiographically estimated tumor volume (TV) and outcomes for malignant pleural mesothelioma, no standard radiographic model exists for estimating TV. Although radical pleurectomy yields a surgical specimen essentially all cancer, thereby allowing accurate determination of TV, empirically-derived intraoperative TVs have never been reported. We compare multiple radiographic estimates of TV with TVs determined at resection to determine which radiographic approach most accurately predicts intraoperative TV, and we correlate TV with survival.

Methods
Actual TVs were measured for 41 consecutive radical pleurectomy specimens by volume displacement. Radiographic TV estimates were performed by radiologists/radiation oncologists blinded to intraoperative TVs. Radiographic estimates were obtained with: Live Wire algorithm (automated tumor delineation after manual algorithm training), radiology TeraRecon (tumor automatically circumscribed with subsequent manual tracing corrections), and radiation oncology Eclipse (non-automated tumor delineation).

Results
Median age was 63yrs, with 80% male and 83% having epithelial histology. Stage distribution was: 3-Stage I (7%), 4-Stage II (10%), 29-Stage III (71%), and 5-Stage IV (12%). Median (interquartile range) intraoperative TV was 600(400,800)cm[3]. Median TV of 800(575,1100)cm[3] among nonepithelial compared to 500(350,838)cm[3] for epithelial was not significantly difference (p=0.099). TVs were largest for stage III (p=0.01). Median TVs for Live Wire, TerraRecon, and Eclipse were 260(147-452), 293(161-465), and 447(247-559)cm[3], respectively. Pearson correlation coefficients were 0.60, 0.75, and 0.78, with all models underestimating intraoperative TVs (Figure 1A). Among 34 epithelial patients (mean/median follow-up 9.8/8.0mo), median survival was not reached (only 9 recurrences). Epithelial patients with large (>500cm[3]) intraoperative TVs had numerically worse progression-free (p=0.148) and overall (p=0.161) survival than patients with TVs ≤500cm[3](Figure 1B), but limited events precluded statistical significance. Larger radiologic TVs similarly correlated with shorter survivals. Figure 1

Conclusion
This is the first study to compare radiographic estimates of TV to actual TV determined by volume displacement of radical pleurectomy specimens, arguably the TV measurement gold standard. This study is also the first to compare estimated TVs using multiple established and previously reported radiographic techniques. Our results demonstrate a clear trend toward greater overall and progression-free survival for actual TVs <500cm[3]. All radiographic techniques underestimated actual TV, with estimates progressively closer to the actual volume with each technique as they became less automated and more manual. Further analysis is ongoing to determine if any radiographic method can serve as an accurate surrogate for actual TV and if models correlate as closely with outcomes as actual TVs.

Abstract not provided

Background
Lung squamous cell carcinoma (SqCC) is the second most prevalent type of lung cancer. Currently, no targeted-therapeutics are approved for treatment of this cancer, largely due to a lack of systematic understanding of the molecular pathogenesis of the disease. To identify therapeutic targets and perform comparative analyses of lung SqCC, we probed somatic genome alterations of lung SqCC cases from Korean patients.

Methods
We performed whole-exome sequencing of DNA from 104 lung SqCC samples from Korean patients and matched normal DNA. In addition, copy number analysis and transcriptome analysis were conducted for a subset of these samples. Clinical association with cancer-specific somatic alterations was investigated.

Results
This cancer cohort is characterized by a very high mutational burden with an average of 261 somatic exonic mutations per tumor and a mutational spectrum showing a signature of cigarette-smoke exposure. Seven genes demonstrated statistical enrichment for mutation (TP53, RB1, PTEN, NFE2L2, KEAP1, MLL2 and PIK3CA). Comparative analysis between Korean and North American lung SqCC demonstrated similar spectrum of alterations in these two populations, in contrast to the differences seen in lung adenocarcinoma. We also uncovered recurrent occurrence of therapeutically actionable FGFR3-TACC3 fusion in lung SqCC.

Conclusion
These findings provide new steps towards the identification of genomic target candidates for precision medicine in lung SqCC, a disease with a significant unmet medical need.

Background
Previously we reported that the frequency of mutations in EGFR and KRAS in non-small cell lung cancer (NSCLC) is Latinoamerica,finding the frequency of EGFR mutations in Latin-America between Asian (40%) and European (15%) populations. We report the update frequency of mutations in Latin America.

Methods
3606 biopsies of NSCLC patients from Latin-America (Argentina, Colombia, México and Peru) were used by extracted genomic DNA which was used to perform direct sequencing of EGFR gene (exons 18 and 21) and KRAS gene in 2385 samples.

Results
Of all patients the median age was 62.2 ±12.3, 52.6% were women, and 51% had smoking history. Frequency of EGFR mutations in NSCLC was 24.4% [CI 95% 22.7-24.1] (Argentina 14.4%, Colombia 24.9%, Mexico 34.4%, Peru 67.0%). The frequency of KRAS mutations was 7.1%. EGFR mutations were independently associated with gender (29.8% vs 16.3%; p< 0.001), older age (<60 vs >60; p= 0.001), non-smokers 25.9% vs 15.7%; p= 0.001), ethnicity (Hispanic 37.7%, Caucasic 13%, Afro-American 0%, non-determinate 22.9%; p< 0.001), histology (adenocarcinoma 23.8%, squamous 4.4%, large cells 33.3% and non differenced 22.2%) and absence of KRAS mutation. Overall response rate to tyrosine kinase inhibitors (EGFR-TKIs) in EGFR mutated patients (n=56) was 62.5% [95% CI 50-75] with a median overall survival of 16.5 months [95% CI 12.4-20.6].

Conclusion
Our findings confirm the high frequency of EGFR Mutation in Latino-america and low frequency of K-RAS mutation, particularly in patients of Hispanic ethnicity. Differences in risk factors associated with lung cancer in our population and ethnic variability could explain these findings.

Background
Approximately 1.2 million people are diagnosed with lung cancer every year. The identification of genomic alteration can impact therapeutics. EGFR mutation status predicts how patients can respond to EGFR tyrosine kinase drugs (EGFR-TKI). EGFR positive patients have an improved response rate to erlotinib or gefitinib; KRAS mutated tumors are not sensitive to EGFR-TKI. Recently, it has been published that patients with mutations inHER2 have a high response rate to trastuzumab. The prevalence of EGFR and KRAS mutations are well known to be associated with sex, histological type of tumor, smoking status and also ethnic origin. HER2, BRAF and PI3K are relevant gene candidates to emerging therapies. Mutation prevalence of the latter genes has not yet been investigated in large populations.

Methods
We have analyzed 1375 consecutive patients with metastatic lung adenocarcinomas having the screening of EGFR, KRAS, BRAF, PI3K and HER2 gene mutational status in the Paul Brousse platform between November 2011 and April 2013. The DNA mutation screening was performed using the HRM technology and their identification were analyzed by allelic discrimination and/or sequencing. Our database included all mutations results as well as anonymous diagnosis and socio-demographic data. The birth location has been self-reported.

Results
Of the 1375 tumors, the frequencies of EGFR, KRAS, BRAF or HER2 mutations were those usually reported in Caucasian population. Mean age was 65.2 years (SD = 11.2), 821 were male and 519 female. Among our population, 140 patients reported of African birth location, 1220 of European birth location and 15 of Asian birth location.

TABLE 1. Mutation prévalance and birth location
	European birth location	African birth location	Asia birth location	Total
EGFR (n/%)	129 (10.6)	13 (9.3)	5 (33.3)	147/1375 (10.7)
KRAS (n/%)	318 (26.3)	21 (15.0)	*	340/1366 (24.9)
BRAF (n/%)	23 (1,9)	1 (0,75)	*	24/1345 (1.8)
HER2 (n/%)	13 (1.1)	4 (2.9)	*	19/1327 (1.7)
PIK3CA (n/%)	20 (2.0)	5 (4,2)	*	25/1159 (2.2)
*Low effective

The percentage of EGFR mutations was higher in Asiatic patients, as previously reported. Interestingly the KRAS mutation rate was significantly lower in the African patients (15.0%, CI: 10.0 – 21.9) than in the European patients (26.3%; I: 23.9 – 28.8; p = 0.004). HER2 and PI3K mutation prevalences were more than doubled in African population compared to European population (Fisher's Exact Test, respectively p = 0.10; p = 0.17).

Conclusion
Our data show different EGFR, KRAS, and HER2 mutation rates according to the geographical birth location of patients. Interestingly, we noted a significant decreased Kras and higher HER2 and PI3K mutations prevalence in African birth location mutation rates compared to the other populations studied. The incidence of these mutations had not been extensively studied in the population of African birth location. That could suggest, especially in this population, the importance of systematic HER2 and PI3K screening to investigate specific targeted therapy.

Background
Treatment paradigms for non–small-cell lung cancer (NSCLC) have shifted from one based only on histology to one that incorporates molecular subtypes involving particular genetic alterations such as activating mutations in EGFR or translocations of ALK. The list of therapeutically targetable lesions is rapidly increasing including mutations in genes such as EGFR, HER2, KRAS, ALK, BRAF, PIK3CA, AKT1, ROS1, NRAS, FGFR1 and MAP2K1. Analysis of these potential targets is becoming a challenge in terms of work load, tissue availability as well as cost. Within the Network Genomic Medicine Lung Cancer (NGM), a regional molecular screening network of the Center for Integrated Oncology Köln Bonn, we aimed to improve on the sequential analysis of a set of 9 target amplicons by Sanger sequencing using bench top ultra-deep parallel sequencing platforms. We aimed to reduce 1) the time requirement for comprehensive molecular diagnostics, 2) the minimal amount of formalin fixed paraffin embedded (FFPE) derived input DNA, 3) while at the same time increasing the number of target regions analysed.

Methods
We established a multiplex PCR to amplify up to 640 lung cancer relevant target regions from at least 20ng of FFPE derived tumor DNA. The amplicon libraries were ligated to adapters encompassing medical identifier sequences that allowed multiplexing of up to 48 patients. The resulting libraries were sequenced on a benchtop Illumina platform (MiSeq). Mutations identified by parallel sequencing were confirmed by Sanger sequencing.

Results
330 patients were analyzed both by traditional single PCR based Sanger sequencing of 9 amplicons and the newly established parallel sequencing protocol. We found that the NGS approach worked reliably, was less prone to sequencing analysis errors and that the time needed to complete the mutation screening was significantly reduced to 7 working days from previously 21 days. A total of at least 300ng of DNA was needed to complete the analysis of 9 amplicons by Sanger sequencing compared to 20 to 100ng of DNA needed for up to 640 amplicons analyzed by parallel sequencing.

Conclusion
Newly multiplex PCR based parallel sequencing allows rapid comprehensive mutation testing in routine molecular pathological diagnostics even on small FFPE embedded transbronchial biopsies.

Abstract not provided

Background
Molecular subtypes of NSCLC are delineated through single driver alterations, although this likely underestimates the extent of inter-tumor heterogeneity. The goal of this study was to evaluate the potential impact of co-occuring mutations and copy number alterations in a series of tumours from both East-Asian (EA) and Western-Europe (WE) origins.

Methods
230 non-squamous non-small cell lung carcinomas (NSCLC) were analysed using the MassARRAY LungCarta™ panel (Sequenom) which examines 214 mutations in 26 oncogenes and tumour suppressor genes. Results were integrated with copy number alterations evaluated using Affymetrix Genome-Wide Human SNP 6.0 arrays and clinical variables.

Results
Out of the 230 tumours tested, 185 mutations were observed, with 138 tumours (60%) with at least one mutation – 97 tumours (42.2%) with a single mutation in a single gene, 36 tumours (15.7%) with two mutations (either in the same gene or two different genes), four tumours (2.2%) with three mutations and one with four mutations. The most frequent mutations were EGFR (38.5% EA;10.1% WE), KRAS (10.9% EA;31.6% WE), P53 (8.8% EA;15.1% WE), MET (14.3% EA;2.2% WE), STK11 (9.9% EA;2.8% WE) and PIK3CA (2.2% EA;4.3% WE). Co-occurring mutations were found in up to 30% of tumors, although the likelihood differed for each gene: KRAS (16/54, 31%), EGFR (18/49, 37%), MET (6/16, 38%), P53 (13/29, 45%), STK11 (8/13, 62%) and PIK3CA (5/8; 62%). Among the eight tumors harbouring PIK3CA mutations, five cases had a co-mutation (four cases with EGFR, one case with KRAS). In EGFR mutant cancers, co-occuring mutations include p53 (10%), PIK3CA (8%), STK11 (6%) and MET (4%). Significant relationships were also detected between EGFR mutation and CNAs on chromosomes 1p, 7p, and 13q. There were also significant relationships between KRAS mutation and CNAs on chromosomes 1q and 3q. For stage I, we found a worse prognosis for patients with at least one mutation. PIK3CA was significantly correlated with poor prognosis. Consistent with recent pooled analysis, KRAS alone is not prognostic but when CNAs and mutation status are combined, patients having both KRAS mutation and the highest related CNA (3q22.3 copy loss) showed a significant poorer prognosis.

Conclusion
This study highlights the wide diversity of mutation profiles within molecularly-defined NSCLCs, revealing co-mutations and associations with numerical chromosomal abnormalities that are clinically relevant. This diversity should be taken into account when designing stratified treatment approaches and underscores the need for customized assays that broadly screen for “actionable” mutations and copy-number alterations.

Background
The European Thoracic Oncology Platform LungScape database contains 2614 cases of primary resected lung carcinoma from 16 centres with patient demographics, pathological tumour data and detailed clinical follow-up. A total of 1281 cases of adenocarcinoma with >2 years clinical follow-up were selected for analysis of ALK status by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Test positive cases were matched, in order of importance at ratio 1:2, by stage, gender, smoking status, study centre, year of surgery and age with test negative cases -both for IHC and for FISH testing.

Methods
Testing was performed in all centres using the same protocol (IHC: Novocastra 5A4 clone antibody at 1:10 dilution, Novolink detection system. FISH: Abbott Vysis ALK break-apart probe). Each centre passed an external QA test using unknown cases in a tissue microarray before conducting the LungScape tumour testing. IHC was scored according to three intensity scores (1+, 2+, 3+) using ‘objective’ methodology previously described [1]. Maximum staining intensity was recorded. Any IHC staining was defined as IHC positive result. FISH preparations were assessed according to the Vysis protocol on all 82 IHCpositive cases plus their 164 IHCnegative matches.

Results

	IHC cases, n=1281	FISH positive(264 tested)
IHC negative	1199 (93.6%)	0 (0.0% of 164 controls)	FISH specificity: 100%
IHC 1+	43 (3.35%)	2 (4.6% of IHC 1+)
IHC 2+	16 (1.25%)	6 (37.5% of IHC 2+)
IHC 3+	23 (1.8%)	20 (87% of IHC 3+)
IHC any positive	82 (6.4%)	28 (34.1% of IHC+)	FISH sensitivity: 34.1%

FISH sensitivity was 87% for IHC 3+. IHCpositive/FISHnegative cases (n=54) were mostly IHC 1+ (75.9%), sometimes IHC 2+ (18.5%) and rarely IHC 3+ (5.5%). The frequency of never smokers was higher in the ALK IHCpositive group (29.3%) versus IHCnegative group (18.3%) {p=0.011}. Age, gender and tumour stage did not differ between IHC groups. The hazard of an event for IHCpositive cases decreases by 32% in relapse-free survival {RFS; p=0.03} and by 38% in either time-to-relapse {TTR; p=0.02} or overall survival {OS; p=0.016}. Multivariate models -adjusted for patient and tumour characteristics- indicated that IHC-ALK was a significant predictor for all three time-to-event outcomes (RFS, TTR, OS). In stratified Cox analysis, significantly higher OS was retained in the IHCpositive (HR=0.59, p=0.04) and FISHpositive (HR=0.34, p=0.03) cases in the matched cohorts, while conditional logistic regression yielded non-significant associations with 3-year survival status.

Conclusion
In this large cohort of surgically resected primary lung adenocarcinoma: ALK IHC positivity was 6.4%. IHC 3+ staining (prevalence 1.8%) showed 87% probability of ALK FISH positivity ALK IHC positivity was higher in never smokers and related to better clinical outcome ALK testing can be reliably implemented across multiple laboratories {1} Ruschoff et al. Virchows Arch. 2010;457(299-307).

Background
Pulmonary carcinoid tumors account for up to 5% of all lung malignancies in adults and comprise 30% of all carcinoid malignancies. They are defined histologically as typical carcinoid (TC) and atypical carcinoid (AC) tumors, and are characterized by neuroendocrine differentiation and the potential to metastasize. Relatively little is known about bronchopulmonary carcinoid tumorigenesis, and understanding of these tumors has yet to benefit from the insight of genomic studies. This unfortunately has translated into relatively limited treatment options for these patients and no recent advances in therapy. We aimed to characterize genomic alterations in pulmonary carcinoid tumors under the hypothesis that a better molecular understanding may lead to improved therapeutic approaches and patient outcomes.

Methods
We characterized genomic alterations in pulmonary carcinoid tumors using whole genome, exome, and RNA sequencing, in addition to mRNA expression and SNP genotyping from specimens of normal lung, typical and atypical carcinoid, and SCLC. Fresh-frozen specimens from 54 patients with primary lung neuroendocrine tumors were obtained from our lung specimen registry and clinical data collected. This included a total of 31 typical and 11 atypical carcinoid tumors with associated normal tissue, and 12 SCLC. Whole transcriptome mRNA expression profiling and SNP genotyping for evaluating copy number variation was performed using Illumina array platforms. For a subset of tumors, whole genome sequencing was performed through Complete Genomics, and exome and RNA sequencing performed through BGI and the Mayo Clinic Genomics Facility. These data were correlated with the histologic subtype, stage and survival data available from this cohort of patients.

Results
Gene expression clearly identified distinct profiles differentiating carcinoid tumors from SCLC, though not between typical and atypical carcinoids. Copy number variations (CNV) were widely prevalent in SCLC, less frequent in AC, while TC had the lowest frequency of CNV. Validated sequencing data from exome and WGS platforms revealed a number of novel mutations for pulmonary carcinoid tumors, including ADNP, BRIP1, cyclin B3, CREBL2, GLI3, HERC1, IRAK3, NEDD4L, PRRX2, and ZDBF2, among others. RNA sequencing data did not reveal any novel fusions from analysis to date. Despite a low overall mutation frequency versus other forms of lung cancer, each carcinoid tumor had at least one potential driver mutation, suggesting possible targeted therapy opportunities for a disease where currently none exist.

Conclusion
Despite a low overall mutation frequency and an absence of frequently recurring mutations from the tumors sequenced to date, targeted therapy opportunities may exist through mutation profiling in broncopulmonary carcinoid tumors.

Abstract not provided

Background
Activation of the RET gene by fusion has been described in 1-2% of unselected population of non-small-cell lung cancer (NSCLC) and there is early evidence suggesting that patients with RET activated tumors obtain clinical benefit from RET inhibitors. The major fusion partner is KIF5B, but CCDC6, NCOA4 and TRIM33 have also been reported. The prevalence of RET fusions in different lung cancer subtypes and clinicopathologic characteristics of remain unclear. In this study, we sought to identify RET rearrangements in NSCLC using FISH and to investigate the association with histology and clinical features.

Methods
A 3-target, 3-color FISH probe set [3’RET in red, 5’RET in green, 5’KIF5B in yellow] was developed to simultaneously detect (a) disruption between 3’ and 5’ RET and (b) specific fusion between 5’KIF5B-3’RET. This probe set was used to interrogate a cohort of Caucasian NSCLC patients using tumor microarray. Inclusion of specimens on the tissue microarray was independent of gender, age, smoking history, histology and any known molecular profile and was only based on patient informed consent and tissue availability.

Results
Among 348 evaluable NSCLC patients, 6 (1.7%) were found to be positive for RET rearrangement (RET+): 2 showed typical KIF5B:RET pattern, 2 showed patterns consistent with CCDC6: RET fusion; and 2 had split 3’-5’ without suggestion of the fusion partner identity. The histology was adenocarcinoma in 4, large cell carcinoma in 1 and squamous cell carcinoma in 1. All RET+ tumors were wild type for EGFR and negative for ALK and ROS1 rearrangements. The mean age of RET+ patients at the time of diagnosis was 62 years (49-74) and they were predominantly male (5) and former (4) or current smokers (1). The 10p11-q11 region displayed high level of genomic instability, with RET doublets, KIF5B and RET doublets, unbalanced KIF5B copy number gain, fusion KIF5B with 5’ and 3’RET, and abnormal separation between KIF5B and RET in 8.5%, 5.1%, 9.6%, 2.3%, and 2% of specimens, respectively. These atypical patterns will be further investigated by RT-PCR.

Conclusion
The customized 3-target, 3-color probe set successfully detected KIF5B:RET rearrangements and identified patterns suggestive of RET rearrangements with non-KIF5B partners in small subset of unselected NSCLC. Interestingly, only a minority of RET + patients were never smokers and 1/3 of them had non-adenocarcinoma histology. Despite the benefits of using enrichment strategies based on clinicopathologic variables for molecular testing of NSCLC in search for personalized therapy, these findings argue against using variables such as smoking status and histology for screening selection when the aim is to detect all potential RET+ patients.

Background
The presence of mutations of epidermal growth factor receptor (EGFR) is related to phenotypical characteristics such as ethnicity, gender and smoking status. Such observations led us to explore associations between genetic polymorphisms and EGFR mutational status.

Methods
We set up a set of samples from 677 primary pulmonary adenocarcinoma. We tested two genetic polymorphisms (rs2736100 and rs10937405), which were discovered previously as to be associated with the risk of lung adenocarcinoma. The association between EGFR mutational status and genetic polymorphisms were evaluated using logistic regression analysis.

Results
In 673 patients, four exons (18, 19, 20, 21) of EGFR were completely evaluated. Presence of EGFR mutations were found in 382 (56.8%) patients. In logistic regression analysis, female gender (aOR, 1.7 with 95% CI, 1.0-2.9) and smoking status (ex-smoker, aOR, 0.6 with 95% CI, 0.4-1.1; current smoker aOR, 0.4 with 95% CI, 0.2-0.8) were associated with presence of EGFR mutations. None of two single nucleotide polymorphism (SNP) sites showed significant association. In the analysis of individual type of EGFR mutations, however, we found a significant association between EGFR exon 18 mutations and a SNP rs27366100T/G located in TERT. The G/G genotype showed a 2.8-fold increase in the occurrence of the EGFR exon 18 mutations compared to T/T+G/T genotypes (aOR, 2.8 with 95% CI, 1.2-8.7). Additionally, C/T+T/T genotypes of rs10937405C/T SNP in TP63 showed frequnt occurrences of EGFR exon 21 mutations compared to CC genotype (aOR, 1.5 with 95% CI, 1.0-2.3).

Conclusion
Our findings suggest that the somatic mutations of EGFR may be closely associated with genetic polymorphisms. Further investigation of this field may enable us to identify patients who may get a benefit from EGFR inhibitors.

Background
Chromosomal rearrangements which generate constitutively activated ROS1 receptor tyrosine kinase (6q22.1) have been found in several tumor types, including non-small cell lung cancers (NSCLC). In clinical trials, the oral kinase inhibitor crizotinib has shown promise in treating tumors with ROS1 rearrangements. Currently, fluorescence in situ hybridization (FISH) using dual-color, break-apart (BA) probes is used to detect ROS1 rearrangements in clinical samples; however, further optimization of this method is necessary to ensure patients are accurately diagnosed. This study explores BA FISH assay characteristics in NSCLC samples.

Methods
Tumor sections from 464 NSCLC patients were screened for ROS1 rearrangement using ROS1 BA FISH. Of these samples, 206 were co-screened for ALK rearrangement. The copy number of fused and isolated 3’/5’ signals, as well as the incidence of atypical patterns (doublet and clustered multiple fusions) was investigated. Cells were considered ROS1 positive (ROS1+) when ≥ 15% of nuclei displayed split 5’/3’ signals or single 3’ signals. Specific fusion transcripts in ROS1+ cases were identified by RT-PCR or inverse PCR.

Results
ROS1 rearrangements (ROS1+) were found in 21 patients (5%). The copy number of native ROS1 differed significantly between positive and negative tumors (mean of 1.5 versus 2.5, p<0.0001). The percent of cells with FISH patterns compatible with ROS1 rearrangement ranged from 30% to 100%, with a mean of 81%, in ROS1+ patients. The distribution of positive cells between scored regions within ROS1+ tumors was investigated for 13 cases and found to follow a normal distribution, ruling out intra-tumoral heterogeneity. Among ROS1+ specimens, 71% had a split signal pattern, 19% displayed a single 3’ pattern, and 10% had both a split and single 3’ pattern of positivity. For positive tumors, ROS1 fusion partners were identified as SDC4 (S2;R32 and S2;R34), EZR (E10;R34) and CD74 (C6;R32 and C6;R34). Atypical negative patterns such as fused doublets, clusters, 3’ doublets, 5’ doublets, and single 5’ signals were observed in 4%, 1%, 1%, <1%, and <1% of negative patients. ALK and ROS1 were scored simultaneously in the same cells in 206 patients, including 5 ROS1+ and 10 ALK+; no double positive cases were found. In ROS1 negative specimens, mean native ALK copy numbers were significantly higher than native ROS1 in ALK negative samples (3.2 versus 2.3, p<0.0001).

Conclusion
ROS1+ tumors were detected in 5% of patients in this large NSCLC cohort. Since these patients were subject to various selection strategies, this frequency cannot be transferred to an unselected NSCLC population. The low native ROS1 copy number in the rearranged cells and lack of evidence of intra-tumoral heterogeneity suggests ROS1 rearrangements occur early in tumorigenesis, consistent with their known oncogenic driver role. Data from this sample also show that, in FISH negative cases, ROS1 copy number was lower than native ALK. This suggests ROS1 may exist in a relatively more stable portion of the genome, potentially explaining why ROS1 rearrangements exist at a lower frequency than ALK rearrangements in NSCLC.

Abstract not provided

Background
Lung cancer computed tomography (CT) screening is a controversial topic. Results from the National Lung Screening Trial showed that low dose CT (LD-CT) can reduce lung cancer mortality by at least 20%. However a critical issue is the high rate of indeterminate lung nodules and false positive cases. The aim of the study was to evaluate the diagnostic accuracy of CT/PET for lung cancer diagnosis in the context of lung cancer screening.

Methods
Between 2004 and 2005, 5203 asymptomatic high-risk individuals (≥20 pack-years, age ≥50 years) were enrolled to undergo annual LD-CT for 10 years. Nodules ≤5 mm were scheduled for repeat LD-CT a year later. Nodules >5.0≤8.0mm received LD-CT 3-6 months later. Nodules >8.0mm or growing nodules underwent CT-PET. Results from all PET scans performed during the screening workup of COSMOS participants were reviewed. Those performed for suspected collateral disease (pleura, mediastinum, other cancers) were excluded. Outcome was based on the pathological findings for patients who underwent surgery or on findings at follow-up. Outcome was considered negative for those with negative CT findings for at least two years. PET results were visually evaluated by expert radiologists.

Results
383 nodules in 351 patients were studied by CT/PET. In 5 occasions, PET evaluation was dubious. 197 nodules turned out to be malignant. Overall sensitivity, specificity and accuracy of CT/PET to distinguish between benign and malignant nodules was 64%, 89% and 76% while it was 82%, 92%, 88% when considering only PET scans performed during baseline screening work-up. Diagnostic performance was high (sensitivity 87%, specificity 73%) for nodules larger than 15 mm in their maximum diameter, reaching 98% sensitivity for solid nodules larger than 15 mm. The diagnostic performance of the test was significantly lower for nodules investigated at annual repeat CT compared to baseline CT (p<0.0001, sensitivity ranging from 30 to 71%) and for non-solid compared to solid nodules (p=0.0001; sensitivity 22% for non-solid versus 79% for solid nodules).

Strata	PETs	VN	FN	FP	VP	Sensitivity	Specificity	Accuracy	p-value accuraccy
Overall	378	164	70	21	123	64%	89%	76%
Diam <10mm	145	75	40	4	26	39%	95%	70%
Diam 10-15mm	104	51	19	4	30	61%	93%	78%
Diam >15mm	117	30	10	11	66	87%	73%	82%	0.06
Solid	263	123	26	16	98	79%	88%	84%
Non solid	48	15	25	1	7	22%	94%	46%
Partially solid	65	25	19	3	18	49%	89%	66%
Non/Part solid	114	41	44	4	25	36%	91%	58%	<0.0001
Age <60	147	64	31	14	38	55%	82%	69%
Age >60	231	100	39	7	85	69%	93%	80%	0.02
Inferior lobe	139	69	29	8	33	53%	90%	73%
Superior lobe	208	85	33	9	81	71%	90%	80%
Other location	30	10	8	3	9	53%	77%	63%	0.09
Left lobe	148	64	27	8	49	64%	89%	76%
Right lobe	206	90	35	10	71	67%	90%	78%	0.70
Baseline	148	81	11	7	49	82%	92%	88%
2[nd] year	57	17	11	3	26	70%	85%	75%
3[rd] year	62	19	28	3	12	30%	86%	50%
4[th] year	44	10	10	4	20	67%	71%	68%
5[th] year	47	31	6	4	6	50%	89%	79%
6[th] year	20	6	4	0	10	71%	100%	80%	<0.0001
Male	264	113	44	12	95	68%	90%	79%
Female	114	51	26	9	28	52%	85%	69%	0.05
Non/part solid <15mm	72	27	34	2	9	21%	93%	50%
Non/part solid >15mm	37	10	9	2	16	64%	83%	70%
Solid <15mm	177	99	25	6	47	65%	94%	82%
Solid >15mm	80	20	1	9	50	98%	69%	88%	<0.0001

Conclusion
CT/PET is a highly sensitive test for the differential diagnosis of screening-detected cancer, in particular at baseline CT, for solid nodules and those with a diameter larger than 15mm. Sensitivity of CT/PET for sub-solid nodules is very low suggesting that other diagnostic tests, such as volume doubling time, should be used.

Background
Early diagnosis of lung cancer is associated with a better survival. The measurement of volatile organic compounds (VOCs) in exhaled breath using an electronic nose may prove to be a novel, effective and simple technique for screening and diagnosing lung cancer. The aim was to test the validity of the VOC profile in discriminating subjects with early stage lung cancer (I and II) (ESLC) from healthy ever smokers (HS).

Methods
243 subjects: 54 ESLC and 189 HS provided a breath sample after tidally breathing through an inspiratory port filter for 5 minutes. It was analysed using a 32 sensor Cyranose 320 (Smiths Detection). Subjects were divided into training (n=159) and independent test set (n=84) groups. Canonical discrimination analyses were performed to determine significance of difference between subject groups and calculate cross validated accuracy (CVV) of the groups using leave one out classification method. Area under the curve (AUC) of Receiver Operating Characteristic Curves were also determined (SPSS V17.0).

Results
Validation of the training VOC profile model using an independent test group showed 79% accuracy (p=0.001) in distinguishing ESLC (n=20) from HS (n=64). (AUC 0.933). There was no significant difference in age, lung function and smoking history between the training and test groups.

Conclusion
Exhaled breath VOC profile model to discriminate between ESLC subjects and HS was validated in an independent group with a high accuracy. A clinically high sensitivity of the VOC profile model to discriminate between ESLC and HS can be achieved by selecting an appropriate cut point. The cyranose has potential to be a clinically useful diagnostic and screening tool for early stage lung cancer.

Background
Implementing effective lung cancer screening programs requires extensive knowledge on the natural history of lung cancer and the sensitivity of the proposed screening modality. Data from the National Lung Cancer Screening Trial (NLST), the Prostate, Lung, Colon and Ovarian Cancer Study (PLCO) and Surveillance Epidemiology and End Result (SEER) data from 2004-2008 are used to investigate the screening sensitivity (by stage and histological type) of Computed Tomography (CT) and chest radiography (CXR) and the mean preclinical sojourn time (MPST) of lung cancer (by gender, stage and histological type).

Methods
The MISCAN-Lung model was used to reproduce the lung cancer incidence by method of detection (clinical or screen-detected), gender, histology and stage in both trials, by calibrating screening sensitivity and natural history parameters.

Results
Major differences in sensitivity between CT and CXR are estimated for the less advanced stages, for example the sensitivity for stage IA adenocarcinoma is estimated to be 56.63% for CT compared to 16.91% for CXR. The model suggests that the MPST varies by histological type and gender. The largest difference between genders was estimated for adenocarcinoma for which the MPST in pre-clinical stages IA to IV was estimated to be 4.48 years for men compared to 6.01 years for women.

Conclusion
This study provides detailed insights in the natural history of lung cancer and the differences in the effectiveness of screening between the NLST and PLCO trials. This knowledge may help to determine effective lung cancer screening programs.

Background
Introduction: Based on a 20% reduction in lung cancer deaths in the CT screening arm of the National Lung Screening Trial (NLST), yearly CT screening for lung cancer is now widely recommended. Recently, a multivariate risk model for lung cancer (LC), be used to identify smokers at greatest risk, has been proposed to better select smokers for CT ([#]Tammemagi et al. JNCI 2011;103:1058).This risk model includes age smoking history, history of COPD, BMI, recent CXR and educational level. This model has been validated in the NLST where recent CXR and educational level was omitted due to the unavailability of this data. In this sub-study of the NLST, we examine the role of the known clinical risk factors for lung cancer and whether they mediate risk for lung cancer via risk for COPD. To test this we compared risk factors between LC cases and controls after stratifying cancer-free screening participants (controls) by spirometry-defined COPD.

Methods
Using a sub-group of the NLST (drawn for validation of a gene-based risk stratification tool), we compared known risk factors for LC (recently validated in the PLCO[#] study) in 345 screen-detected lung cancer cases and 1482 randomly selected cancer free screening controls stratified by COPD (pre-bronchodilator GOLD 1-4). These variables included age, pack years, family history of LC (FHx), self-reported COPD and BMI.

Results
When the LC risk variables were compared between LC cases (N=345) and the cancer-free screening controls, stratified from baseline data into controls with COPD (N=489) and without COPD (n=993) (see Table1), we found the following; age and pack years but not FHx were significantly higher in those with COPD and LC compared to cancer-free controls with no COPD, self reported COPD was 2 fold higher in COPD controls and LC cases compared to controls without COPD, and BMI was significantly lower in the LC cases and those with COPD compared to cancer-free controls with no COPD. Figure 1

Conclusion
These data from the NLST suggest the risk of LC is strongly mediated by variables underlying risk of COPD (age, pack years and BMI). [#]Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO)

Abstract not provided

Background
The existence of healthcare disparities by race and ethnicity is well documented, often attributed to a lack of economic and educational parity among groups, and manifested by unequal healthcare access and delivery. Inexplicably however, in many countries the wealthiest and most educated populations have the worst health outcomes. We hypothesize that minority status within a country rather than race, ethnicity, socioeconomics or educational level is more closely associated with poor health outcomes globally and functions independently of other variables.

Methods
Minority and majority populations in 34 countries/territories were evaluated for smoking prevalence and age-adjusted lung cancer incidence rates. A global, systematic review of over 1000 sources of epidemiological data was performed using rigorous screening criteria including only national data in original form (national cancer registry, census, or health surveys), from an official government agency, or from peer-reviewed publications. Relative risks (RR) of smoking and lung cancer were computed for all minority groups with the majority population as the referent null. Relative wealth based on median per capita income and relative schooling based on educational attainment were also calculated. Minority groups were only included if so defined by both the Minority Rights Group International and the CIA World Fact Book.

Results
Data were collected from approximately 60% of the global population including all six WHO world regions and every populated continent. The RR of smoking for at least one minority group was greater than that of the referent majority in every country or territory analyzed. The RR of lung cancer for at least one minority group was greater than that of the referent majority in all but three countries/territories. These results were remarkably consistent and durable with RR ≥ 1.0 for smoking prevalence and lung cancer incidence in nearly all countries despite minority status being defined differently in many nations whether by race, ethnicity, religion, language, indigenous affiliation, or immigrant status. These results were further corroborated by age-specific lung cancer incidence for selected countries/territories. Racial and socioeconomic status differentials were insufficient explanations for these observations. In the U.S., for example, blacks are generally less wealthy and educated than whites and have higher smoking prevalence and lung cancer incidence rates. However, in neighboring Bermuda and distant South Africa where blacks are the majority, whites have both higher smoking prevalence and lung cancer incidence rates despite being far wealthier and educated. This relationship of increased smoking and lung cancer rates in wealthier, more educated minorities is replicated in nine of the 34 countries in this study.

Conclusion
Our results show an empirical relationship between minority status and both increased smoking prevalence and lung cancer incidence rates in minority populations globally. This suggests that minority status may be a potent, behavioral driver leading to elevated health risks in minority populations around the world. Moreover, minority status seems to be independent of traditional socioeconomic variables, and alone may be a powerful predictor of disparate health outcomes in many diverse nations, distinctive societies, and unique cultures on a global scale.

Background
There are population-specific differences in the presence of lung cancer, these are related with: health outcomes, quality of health care and access to health care services that exist across racial and ethnic groups. Disparities represent a lack of efficiency within the health care system and therefore account for unnecessary costs. Few publications are available about disparities in African-American (AA) populations with lung cancer and very few about Hispanic (H) populations with this disease.

Methods
We reviewed registry data on 2,255 pts with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) treated during last 10 years (2002-2011) at Memorial Health Care System. The main objective of the study was to evaluate differences in lung cancer survival according to ethnicity. Chi-square was used to compare distribution of tumor stage. Survival curves were compared using log-rank test for each of the tumor stages. Adjusted hazard ratios (AHR) and 95% confidence intervals (95% CI) were reported based on the results of a multivariate Cox regression model for overall survival (OS) with adjustment for gender, age at diagnosis, race, stage and health insurance

Results
A total of 1940 pts (86%) had the diagnosis of NSCLC, the rest were SCLC. There were 1170 (52%) females. Non-Hispanic whites (NHW) were 1,791 pts (79%), Hispanics (H) 266 (12%) and African-American (AA) 149 (7%). Fifty eight percent of patients had stage III/IV at diagnosis. 2054 of the pts were insured (91%). There was a significant difference in age at diagnosis among H (66.5 y), AA (64.4y) and WNH (69.5y). The probability of being diagnosed at a late stage (IIIB/IV) was two times higher among AA compared to NHW (OR= 1.77, p<0.05) or H (OR) = 1.67, p <0.05). There was no survival difference between NSCLC and SCLC (19m vs. 16m). Females with NSCLC lived significantly longer than males (Adjusted Hazard ratio (AHR= 1.14 p<0.01). The same was true for SCLC (AHR = 1.43 p < 0.01). Significant predictors for worse survival for patients with NSCLC were: older age at diagnosis (AHR = 1.01, p<0.001), male gender (AHR=1.12, p<0.05) and late stage at diagnosis (AHR=2.27, p<0.001). Insurance and ethnicity were not significant predictors of survival.

Conclusion
There are significant disparities in presentation and outcomes among minority patients (AA and H) with lung cancer. We will further evaluate if other social or genetic factors can explain these disparities.

Background
Writing on behalf of the I-ELCAP Investigators. The goal of CT screening is to maximize lung cancer cure rates by early diagnosis and treatment of lung cancer. To achieve this, a regimen of screening is important, particularly for small nodules. To better understand the importance of a regimen, we compared two large databases of screen-diagnosed lung cancers, the International Early Lung Cancer Action Program (I-ELCAP) and the National Lung Screening Trial (NLST) CT arm as the former had a specified diagnostic workup algorithm while the latter did not mandate any specific approach.

Methods
We compared all lung cancers including small-cell and carcinoids, that were diagnosed under screening, that is, either screen-diagnosed because of a positive result of the CT screening or symptom-prompted after a negative CT screening. We compared the stage and size distribution of the screen-diagnosed cancers in the International Early Lung Cancer Action Program (I-ELCAP) from 1993 to 2011 and those in the NLST-CT arm from 2002 to 2006. In I-ELCAP, the screenings were performed according to a common protocol in which the diagnostic workup for a participant was defined by a specified protocol which has been continually updated whereas in the NLST, “… no specific diagnostic evaluation approach was mandated.”

Results
In I-ELCAP, a total of 799 patients were diagnosed under screening of which 11 (1.4%) were interim-diagnoses; 8 prior to the first annual repeat screening and 3 between annual rounds, leaving 788 screen-diagnosed patients. In the NLST CT arm, 1060 patients were diagnosed with lung cancer, but only 692 were diagnosed under screening. There were 18 interim-diagnosed cases before the first annual repeat screening and 26 between the 2 annual repeat screenings, a total of 44 (6.4%) interim-diagnosed cases for this cohort. This left 649 screen-diagnosed patients. The frequency of clinical Stage I was 82% (95% CI: 79%-84%) vs. 69% (95% CI: 65%-72%) in I-ELCAP and NLST, respectively. Average tumor size (95% confidence interval) was 17.3 mm (16.6-18.1) vs. 23.1 mm (21.7 -24.4), respectively. Surgical resection was performed in 86% (676/788) and 77% (497/649) of the screen-diagnosed patients, respectively. The frequency of pathologic Stage I (clinical, if not resected) was 73% (95% CI: 70%-76%) vs. 63% (95% CI: 59%-67%).

Conclusion
Stage I disease, both clinical and pathologic, was significantly higher in I-ELCAP than NLST. The tumor size was significantly lower in I-ELCAP than NLST, all strongly suggestive of the importance of a specified regimen of screening. This is further substantiated by the reported 71% for pathologic Stage I (clinical, if not resected) by the NELSON study which is close to that reported by I-ELCAP as the NELSON also followed a well-defined regimen of screening.

Background
Low-dose CT screening for lung cancer can reduce mortality among high-risk people but to reduce unnecessary evaluations with attendant risks, alternative thresholds for defining positive result and cancer diagnoses needs to be further understood. The purpose of the study is to assess the frequency of positive results and potential delays in diagnosis in the baseline round of screening using more restrictive thresholds.

Methods
Among the participants who were randomly assigned to the CT arm of the National Lung Screening Trial (NLST) cohort, we identified the frequency of solid and part-solid pulmonary nodules and the rate of lung cancer diagnoses using a 5.0, 6.0, 7.0. 8.0 and 9.0 mm threshold for the largest noncalcified nodule identified in the baseline CT scan. we compared these results with those previously published for the I-ELCAP cohort.

Results
The frequency of positive results in the baseline round, using the definition of positive result (any parenchymal, solid or part-solid, noncalcified nodule > 5.0 mm), was 15.9% (4,104/25,814). Using alternative threshold values of 6.0, 7.0, 8.0 and 9.0 mm, the frequencies (95% CI) of positive results were 10.5% (10.2, 10.9), 7.2% (6.9, 7.5), 5.3% (5.0, 5.6) , and 4.2% (3.9, 4.4), respectively. Use of these alternative definitions would have reduced the workup by 33.8%, 54.7%, 66.6%, and 73.8%, respectively. Concomitantly, proportion of lung cancer diagnoses made within first 12 months would be delayed for 0.9%, 2.6%, 6.1%, and 10.0% of the patients, respectively. These results are similar to those found in I-ELCAP.

Conclusion
These results are similar to those found in I-ELCAP and suggest that even in the higher-risk participants enrolled in the NLST, higher threshold values can be used. This reduction in the positive result rate compared to the 28% positive result rate reported in the NLST, which used a 4mm threshold, is considerable.

Abstract not provided

Background
Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) are smoking related diseases and the presence of COPD increases itself the risk of developing lung cancer, probably due to underlying inflammation. LC is typically detected at late stages of the disease and carries a dismal prognosis. There is an unmet need for useful early detection methods of lung cancer in high risk subjects, such as smokers.

Methods
The expression of inflammatory proteins was studied in bronchoalveolar lavage samples (BAL) by antibody arrays in a prospective discovery cohort of 60 patients with the following inclusion criteria: age > 40 years, diagnostic broncoscopy due to hemoptysis or pulmonary nodule, smokers or ex-smokers pack of more than 30 pack-years, divided into four groups (control, LC, COPD, LC & COPD). Relevant biomarkers were validated by western blot. Additional validation was carried out by ELISA in two independent controlled cohorts of 139 (control, LC, COPD, LC & COPD) and 160 patients (control, all LC histological subtypes).

Results
CCL-1 and IL-11 were selectively expressed in samples of adenocarcinoma patients, with or without COPD (p<0•001) in the discovery cohort. These proteins exhibited a remarkable diagnostic performance for lung adenocarcinoma in an independent cohort of 139 patients. ROC curves showed that the optimum diagnostic cutoff value for IL-11 was 42 pg/mL (area under curve [AUC] 0•93 [95% CI 0•896-0•975], sensitivity 90%, specificity 86%), and for CCL-1 was 39•5 pg/ml (0•83 [95% CI 0•749-0•902], sensitivity 83%, specificity 74%). Further validation of the ELISA biomarkers at the mentioned cutoffs was performed in an additional cohort of 160 patients (20 controls, 66 LC, 74 LC & COPD). There was a significant correlation between BAL levels of IL-11 and CCL-1 (r2= 0•76, p<0•001), and the use of both biomarkers increased the diagnostic accuracy to 96,1% in the two validation cohorts. Appropriate diagnostic performance was observed for all subgroups regardless of stage at diagnosis, involvement of bronchial tract, pack-years smoked, and number of cells in BAL.

Diagnostic performance of IL-11 and CCL-1 in the first validation cohort (N=139)
Adenocarcinoma vs all patients	AUC (95%IC)	Sensivity (95%IC)	Specificity (95%IC)	PPV (95%IC)	NPV (95%IC)	Positive LR	Negative LR
IL-11	0.93 (0.896-0.975)	90.2% (79%-95.7%)	88.7% (80.6%-93.5%)	80.7% (68.7%-88.9%)	94.5% (87.8%-97.6%)	7.95 (4.53-13.98)	0.11 (0.05-0.26)
CCL-1	0.83 (0.749-0.902)	80% (66.4%-87.7%)	74.1% (63.9%-82.2%)	72.1% (59.2%-73.4%)	86.3% (76.6%-92.4%)	3.02 (2.05-4.47)	0.29 (0.17-0.52)
IL11 and CCL-1		71.2% (57.7%-81.7%)	94.4% (88.4%-97.4%)	86% (72.7%-93.4%)	87.2% (79.9%-92.1%)	12.8 (5.77-28.41)	0.31 (0.20-0.47)
IL-11 and/or CCL-1		94.3% (84.6%-98.1%)	74.1% (65.1%-81.4%)	64.1% (53%-73.9%)	96.4% (89.9%-98.8%)	3.64 (2.63-5.04)	0.08 (0.03-0.23)
Diagnostic performance of IL-11 and CCL-1 in the second validation cohort (N=160)
Adenocarcinoma vs all patients	AUC (95%IC)	Sensivity (95%IC)	Specificity (95%IC)	PPV (95%IC)	NPV (95%IC)	Positive LR	Negative LR
IL-11	0.95 (0.92-0.98)	90.6% (79.7%-95.9%9	83% (86.8%-87.7%)	60.8% (49.7%-70.8%)	96.8% (92.7%-98.6%)	5.32 (3.81-7.41)	0.11 (0.05-0.26)
CCL-1	0.91 (0.87-0.96)	91.7% (80.4%-96.7%)	77.5% (71.0%-82.9%)	51.2% (40.8%-61.4%)	97.3% (93.3%-99%)	4.08 (3.09-5.04)	0.11 (0.04-0.28)
IL11 and CCL-1		71.2% (57.7%-81.7%)	96.3% (92.5%-98.2%)	84.1% (70.6%-92.1%)	92.3% (87.7%-95.3%)	19.1 (9-41.13)	0.3 (0.19-0.46)
IL-11 and/or CCL-1		92.3% 82.6%-98.1%)	84% (78%-88.5%)	62.5% (51.5%-72.3%)	98.1% (94.6%-99.4%)	5.88 (4.21-8.22)	0.07 (0.02-0.20)

Conclusion
IL-11 and CCL-1 are highly specific biomarkers with great accuracy for the diagnosis of lung adenocarcinoma in BAL specimens. Further study of these proteins as markers for early diagnosis and screening in plasma and other biological materials is warranted.

Background
Selenium is known as a chemoprotective anti-cancer agent. The impact of low selenium serum level on the frequency of early lung cancer (LC) detection rate in patients participating in a low dose chest CT (LDCT) screening program is assessed.

Methods
A program of early LC detection was conducted in a single city of 400000 inhabitants from 2008 till 2011 (Protocol I). Enrollment criteria included both sexes aged 55-65 years with a history of 20 pack-years of tobacco smoking. All detected lesions were followed up in accordance with IELCAP protocols. A new pilot study (Protocol II) launched in 2012 was based on preselection of the participants by measure of their selenium serum level. Only individuals with a low selenium level (< 75 microgramms/ml) were invited for CT scans. Other enrollment criteria were the same as in Protocol I. All cases requiring surgery were referred to a single local thoracic surgery department. The following data were analyzed: number of all detected lesions as well as LC detected in both protocols.

Results
Protocol I: 15020 patients were screened by LDCT. 6240 pulmonary lesions were detected with the majority (59%) smaller than 5mm. 182 patients (2.9% of all detected lesions) were referred for thoracic surgery. 119 primary LC were diagnosed and treated. Protocol II: 2440 patients have had selenium serum level measured. 720 of them were screened by LDCT. 210 lesions were detected with 49% smaller than 5mm. 14 patients (6.8%) were referred for thoracic surgery. 9 primary LC were diagnosed and treated surgically. Protocol II was more specific because number of all detected lesions was significantly smaller than in Protocol I (p < 0.0001, OR: 0.55; CI: 0.46 – 0.64) but the LC detection rate in Protocol II was more than twice as high as in Protocol I (p = 0.0226, OR: 2.38; CI: 1.19 – 4.76).

Conclusion
The detection rate of LC in the program of early detection based on LDCT is higher if the protocol is supported by preselection of high risk tobacco - smoking patients based on a low level of selenium in serum.

Abstract not provided

Background
Tumor-derived autophagosomes, referred to as DRibbles, are novel cancer vaccines that have been shown to be effective against 5 preclinical models of established tumors. We hypothesize that DRibbles’ efficacy stems from their ability to present stabilized tumor-derived short-lived proteins (SLiPs) and defective ribosomal products (DRiPs) that are, due to their short-lived nature, normally not processed and presented by professional antigen presenting cells. These SLiPs and DRiPs represent a potential pool of tumor antigens against which the host is not tolerant. A pilot clinical trial of an autologous DRibble vaccine demonstrated feasibility and suggested immune effects in 4 patients with advanced NSCLC (WCLC 2013, submitted). In order to expand the DRibble strategy to patients without an autologous tumor source, we have produced an allogeneic DRibble vaccine (DPV-001) from two NSCLC cell lines and developed a panel of 13 NSCLC cell lines expressing relevant antigenic targets that will be used to monitor induction of tumor-specific immunity.

Methods
The two NSCLC cell lines used to produce the DPV-001 vaccine (UbiLT3 and 6) were cultured with bortezomib and ammonium chloride to block the proteasome and prevent lysosomal degradation of SLiPs and DRiPs. Gene expression profiles were performed for each lot produced (Human Gene 1.0 ST arrays). Stability of indicator tumor antigens was assessed by Western blots. Toll-like receptor (TLR) agonist activity was assessed using HEK blue cells transfected with specific TLRs. After informed consent, a panel of NSCLC cell lines was established from 13 patients (tumor tissue or pleural fluid). These cell lines were HLA-typed for use in immunologic monitoring studies. cDNA was synthesized in triplicate from total RNA extracted from each cell line in log phase growth. Samples were then analyzed using human microarrays containing approximately 17,000 oligonucleotides (CBER array). Data files were uploaded into the mAdb database and analyzed by software provided by the Center for Information Technology (CIT), NIH. Group t-test was used to compare gene expression differences between NSCLC and normal lung tissues and between cell lines.

Results
Analyses confirm reproducible gene expression profiles from both cell lines during DPV-001 manufacture, and stability studies demonstrate that the vaccine remains stable for 23 months. The vaccine contains at least nine NCI-prioritized cancer antigens and agonists for 5 TLRs. Gene expression profiles of the 13 NSCLC cell lines identified 46 commonly overexpressed genes, all of which are expressed in the DPV-001 vaccine.

Conclusion
The DPV-001 vaccine provides a source of broad-spectrum relevant NSCLC antigens. We are conducting a multicenter, randomized, phase II trial of adjuvant DPV-001 vaccine in patients with definitively treated stage IIIA/B NSCLC. T-cell immune responses will be monitored using HLA matched cell lines from the indicator panel of 13 NSCLC cell lines. NIH grants R21 CA123864 (WJU) and R43/44 CA121612 (SA, TH), Kuni Foundation (WJU), Murdoch Trust, Robert Franz, Wes and Nancy Lematta, Lyn and Jack Loacker, and the Chiles Foundation. Clinicaltrials.gov study identifier pending

Background
Successful translation of adoptive T-cell therapy for solid cancers is predicated on the ability to generate a potent antitumor immune response and establish T-cell persistence. Thoracic malignancies typically lack expression of costimulatory ligands but do express negative regulators of T- cell function—factors that may impede T-cell therapy. We hypothesized that cancer antigen–targeted T cells engineered with activating CD28 costimulatory signaling would eradicate tumor and establish long-term functional persistence.

Methods
Mesothelin-specific chimeric antigen receptors (CARs) were engineered without (Mz) or with (M28z) a CD28 costimulatory domain. CAR-transduced human T cells were evaluated in vitro for cytotoxicity ([51]Cr-release assay), cytokine release (Luminex cytokine-release assay), and proliferation (cell-counting assay). In vivo assessment included monitoring of tumor progression by bioluminescence imaging (BLI), flow cytometric analysis of splenic/peripheral blood T-cell phenotypes, and Kaplan-Meier analysis of median survival, in NOD-scid IL-2Rγ-null mice bearing orthotopically implanted mesothelin-expressing mesothelioma cells (MSTO-211H: CD80/86-, TGF-β+, PD-L1+) and treated with human T cells transduced to express either Mz, M28z, or a control vector.

Results
In vitro, M28z CAR–transduced T cells exhibited equivalent cytotoxicity but enhanced Th1 cytokine secretion and antigen-specific proliferation, compared with Mz transduced T cells. In vivo, mice treated with a single low dose of M28z CAR–transduced T cells achieved tumor eradication and prolonged survival (median survival not reached; p=0.01), compared with mice treated with an equal dose of Mz-transduced (median survival, 63 days; tumor eradication in 20% of mice) or control CAR–transduced (median survival, 36 days) T cells (Figure 1A, 1B). Furthermore, CD28 costimulation enhanced CD62L[-]CD45RA[-] effector memory T-cell persistence (Figure 1C), leading to a robust T-cell proliferative response and superior control of tumor burden on tumor rechallenge 87 days after T-cell administration (Figure 1D, 1E). Figure 1

Conclusion
CD28 costimulation plays an important role in achieving long-term antitumor efficacy and functional persistence in mesothelin-targeted T-cell therapy. These data provide the scientific rationale for our upcoming clinical trial for pleural malignancies.

Background
Noninvasive T-cell imaging technology allows monitoring of adoptive T-cell responses without the need for invasive biopsies. Herein, we report dynamic imaging of tumor-targeted T cells in preclinical models by use of luminescent-enhanced firefly luciferase vector, and we further demonstrate the successful use of a clinical-grade herpes simplex virus type 1 thymidine kinase (HSV1-tk)–incorporated vector for monitoring of T-cell trafficking, antigen-specific proliferation, and biodistribution.

Methods
T cells transduced with mesothelin-targeted chimeric antigen receptors (M28z) were either cotransduced with an enhanced firefly luciferase vector (effLuc-M28z) or singly transduced with HSV1-tk-M28z (TK-M28z). To simultaneously visualize tumor during T-cell PET imaging, cancer-cell imaging was performed using MSTO-GFP/ffLuc+ (MSTO-211H cells transduced to express mesothelin and the green fluorescent protein/firefly luciferase fusion protein). In vitro, uptake of [18]F-FEAU radiotracer by T cells was measured by [3]H channel counting. In vivo studies used either SCID-beige or NSG mice bearing pleural or flank tumors. Bioluminescence imaging (BLI) quantification was determined by the mean number of photons per second in the region of interest. PET imaging with [18]F-FEAU was performed in a 3-dimensional microPET scanner. T-cell imaging results were validated by flow cytometric and immunohistochemical analysis of harvested tissue.

Results
Quantification studies showed a linear relationship between photon emission and T-cell number both in vitro and in vivo. In vivo, evaluation of T-cell biodistribution kinetics, by intravenous administration of effLuc-M28z T cells into mice bearing flank tumors, demonstrated initial accumulation of T cells in the lungs, liver, and spleen and progressive accumulation in the tumor (Figure 1A). Pleurally administered effLuc-M28z+ T cells displayed an increasing BLI signal (5-fold; p<0.01) in response to antigen 72 hours after administration, compared with pleurally administered effLuc+ T cells alone (control) (Figure 1B). T-cell accumulation in pleural tumor and extrathoracic sites (spleen) was confirmed by flow cytometric analysis of tissues harvested at serial time points (Figure 1C). These results were reproduced with clinical-grade vector TK-M28z+ T cells administered intrapleurally in mice bearing pleural tumor. Serial [18]F-FEAU PET imaging showed antigen-specific T-cell accumulation with decreasing tumor burden, as seen by corresponding tumor BLI (Figure 1D). Figure 1

Conclusion
We provide an optimized method for monitoring of T-cell trafficking, localization and proliferation in thoracic malignancies. Our findings—derived using a clinical-grade imaging construct and substrate—provide convincing evidence for the use of noninvasive T-cell monitoring in our upcoming adoptive T-cell therapy clinical trial.

Abstract not provided

Background
Activation of anaplastic lymphoma kinase (ALK) via the EML4 translocation occurs in a proportion of non-small cell lung cancers (NSCLC). Whilst inhibitors of ALK such as crizotinib have been successful in the clinic, most patients ultimately relapse due to resistance via a number of different mechanisms. EML4-ALK and many critical components of signalling pathways involved in resistance are clients for the chaperone HSP90. This offers an alternative approach for targeting both ALK inhibitor-sensitive and -resistant disease through inhibition of HSP90 alone or in combination with an ALK inhibitor. AT13387 is a potent second-generation HSP90 inhibitor currently being clinically tested in a number of indications, including ALK-positive NSCLC as single-agent and in combination with the ALK inhibitor, crizotinib. Here we describe its activity in preclinical models of ALK-positive NSCLC and investigate its potential in combination with crizotinib.

Methods
The activity of AT13387 was investigated in vitro in the EML4-ALK translocated H2228 cell line. Protein levels were determined by western blotting. In vivo, AT13387 was evaluated in an H2228 tumor xenograft and an EML4-ALK translocated patient-derived xenograft model by measuring inhibition of tumor growth.

Results
AT13387 potently inhibited the proliferation of the crizotinib-sensitive EML4-ALK NSCLC cell line, H2228, in vitro with an IC~50~ value of 69 nM. The HSP90 client proteins, EML4-ALK and AKT, along with their phospho-forms, were depleted on treatment of these cells with AT13387. A simultaneous reduction in levels of phospho-ERK, phospho-AKT and phospho-S6 indicated that ALK signalling was inhibited, whilst induction of HSP70 confirmed HSP90 inhibition. In vivo, AT13387 demonstrated activity in ALK-dependent xenograft models, including an ALK-dependent patient-derived xenograft model. When mice bearing H2228 tumor xenografts were treated with AT13387 (70 mg/kg or 55 mg/kg ip once weekly), significant inhibition of tumor growth was observed. As expected, treatment with crizotinib (50 mg/kg po daily) caused partial tumor regression in this model (75% regression after 8 weeks of treatment). However, when AT13387 (55mg/kg weekly) was combined with the crizotinib treatment, a further enhancement of the inhibition of tumor growth over either of the monotherapies (88 % regression after 8 weeks) was observed, with 5 out of 7 tumors achieving complete regression, suggesting that the upfront addition of AT13387 to crizotinib treatment could lead to an improved response and potentially delay the emergence of resistance. In addition, this combination was well-tolerated.

Conclusion
AT13387 was shown to be effective in models of ALK-positive NSCLC as monotherapy or in combination with crizotinib, supporting the ongoing Phase II trial of AT13387 in ALK-positive NSCLC as single agent and in combination with crizotinib. These data suggest that treatment with an HSP90 inhibitor such as AT13387, alone or in combination with crizotinib, has therapeutic potential in ALK-positive NSCLC and that, furthermore, upfront combination of the two agents could extend the duration of response.

Background
Non-small cell lung cancer (NSCLC) patients with tumors bearing “driver” mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase (TK) domain have very high response rates to small molecule EGFR TK inhibitors (TKIs). However, all patients eventually develop resistance to the TKIs, and more recent reports have shown that patients who have stopped TKI therapy may be sensitive again upon re-treatment. While several genetic mechanisms of resistance have been documented, including the gate keeper T790M mutation and Met amplification, cell line studies in vitro have also implicated alternate epigenetic mechanisms that may explain the clinical progression observed in patients with EGFR mutations treated by TKIs. Studies in vivo using patient-derived primary lung tumor xenograft models have not been reported.

Methods
Patient-derived primary tumor xenografts were established from surgically resected early stage NSCLC implanted subcutaneously in non-obese diabetic severe combined immune deficient (NOD-SCID) mice. Tumors were passaged after reaching the humane endpoint 1.5 cm maximum diameter. EGFR TKI therapy was initiated when tumors reached ~6 mm diameter. Treatment included daily oral gavage for erlotinib (50 mg/Kg) and dacomitinib (3 mg/Kg). Cetuximab was administered weekly intraperitoneally (50 mg/Kg).

Results
Among 33 tumors with EGFR mutations engrafted into the mice, only 6 (18.2 %) formed tumors that could be propagated beyond first passage. Three models have been studied for their responses to EGFR TKIs. Model 148 with L858R mutation showed intrinsic pan-resistance to erlotinib and dacomitinib, as well as to cetuximab. This model was derived from a patient who received pre-operative erlotinib in a window of opportunity trial and did not respond. The patient relapsed after surgery and did not receive additional TKI therapy. Model 137 with exon19 E746-A750 deletion mutation demonstrated complete response to both erlotinib and dacomitinib. However, microscopic examination of tissue from the implantation site revealed viable tumor cells, consistent with the inability of TKI to completely eradicate tumor cells even when complete response is observed clinically. The patient subsequently developed disease recurrence and responded to third line gefitinib treatment. Model 164 has double exon19 L747-T751 deletion/T790M mutations. As anticipated, the xenograft failed to respond to erlotinib but responded dramatically to cetuximab alone. Importantly, model 164 xenograft showed transient stabilization of the tumor growth when treated by dacomitinib, but eventually developed progressive growth after 2 weeks of treatment. Resistance was reversible each time the dacomitinib-resistant tumor was propagated, without drug in new mice. The reversibility of resistance observed upon re-initiation of dacomitinib treatment suggests an epigenetic mechanism for TKI resistance. This patient developed recurrence after surgery and failed to respond to second line erlotinib treatment.

Conclusion
Patient-derived primary lung cancer xenografts may provide important patient-like models to study mechanisms of resistance to targeted therapies, and to test novel treatment strategies that may improve further treatment efficacy.

Abstract not provided

Background
The purpose of this study is to examine the patterns of recurrence for stage I lung adenocarcinoma and to identify clinicopathologic factors associated with post-recurrence survival (PRS).

Methods
We performed a retrospective review of 1027 patients with stage I lung adenocarcinoma who underwent a surgical resection between 1999 and 2009 (median follow-up 35 months). The manner of recurrence detection, either by scheduled CT scan, presentation with new symptoms, or by other means, was noted. Tumors were classified using the new IASLC/ATS/ERS nomenclature and grading as low (adenocarcinoma in situ, minimally invasive adenocarcinoma, or lepidic-predominant), intermediate (papillary-predominant or acinar-predominant), and high (micropapillary-predominant, solid-predominant, colloid-predominant, or invasive mucinous) grade. The Kaplan-Meier method was used to analyze recurrence-free survival (RFS). Log-rank tests and Cox proportional hazard models were used to analyze the association between predictive factors and PRS.

Results
Of the 1027 patients with follow-up data available, 151(15%) had recurrent disease (table), five-year RFS was 80%. Of the 151 patients with recurrence, 80 (52%) were detected by a scheduled CT scan (51 locoregional and 29 distant). Symptomatic recurrences were seen in 70 (46%) patients (9 locoregional and 61 distant). Overall, 5-year PRS was 27.8%. On multivariate analysis, recurrences identified by new symptoms (HR, 2.15; 95% CI, 1.36- 3.40; p=0.001), a recurrence free interval ≤ 24 months (HR, 2.52; 95% CI, 1.31- 4.84; p=0.006), and tumors with high architectural grade (HR, 1.69; 95% CI, 1.07- 2.67; p=0.024) and vascular invasion (HR, 1.79; 95% CI, 1.14- 2.81; p=0.012) were significantly associated with a worse PRS (Figure).Figure 1Figure 2

Conclusion
Our study demonstrates the recurrence patterns in patients who underwent surgical resection for stage I lung adenocarcinoma. We identify a symptomatic recurrence, a recurrence-free interval ≤ 24 months, high architectural grade, and vascular invasion, as independent factors associated with worse post recurrence survival.

Background
Since the incidence of lung cancer death increases from 50 years-old, the surgical results of young lung cancer patients remains unclear.

Methods
Seven hundred and four patients with lung cancer, aged up to 50 years, were enrolled from among the 11,663 patients registered in the Japanese Lung Cancer Registry Study 2004, and their clinical data were compared with those of 10959 patients older than 50 years.

Results
In the young/old groups, pneumonectomy was performed in 5.7%/3.2%; adjuvant therapies were given preoperatively in 10.4%/4.7% (p<0.001) and postoperatively in 31.4%/24.5% (p<0.001). The proportions of patients with p-stage IIIA and adenocarcinoma histology were higher in the young group. The 5-year overall survival rate (5Y-OS) was 94.8%/86.2% for p-stage IA (p<0.001), 87.0%/73.2% for p-stage IB (p=0.001), 61.0%/61.6% for p-stage IIA (p=0.595), 71.0%/48.4% for p-stage IIB (p=0.003), 49.6%/39.4% for p-stage IIIA (p=0.020), and 80.0%/24.8% for p-stage IIIB (p=0.012); it was 83.5%/80.7% for females (p=0.106) and 75.1%/62.3% for males (p<0.001) in the young/old groups. The postoperative survival was significantly better with all operative procedures in the young group. The 5Y-OS after recurrence was better in the young group (17.9%, p=0.016). In the young group, the 5Y-OS was better in females (83.5%) than in males (75.1%, p=0.002), and for patients with adenocarcinoma (80.3%) than for those with squamous cell carcinoma (68.5%, p=0.013). Age up to 50 years was identified as an independent prognostic factor on multivariate analysis. Figure 1

Conclusion
The postoperative survival in lung cancer patients aged up to 50 years was better than that in patients older than 50 years.

Background
Outcome after surgery is the result of many components of the care pathway.. The Thoracic Surgery Community of Practice of Cancer Care Ontario developed quality indicators which reflected processes of care as well as outcomes.

Methods
A systematic review of the literature identified potential indicators in the care of lung cancer patients which were relevant to thoracic surgery. These were then evaluated using a modified Delphi process. Seventeen indicators were chosen from seven domains: pre-operative assessment, staging, surgery, pathology, adjuvant therapy, surgical outcomes and miscellaneous based on actionability, validity, usefulness, discriminability, and feasibility. Data obtained from administrative databases is reported for 4 process indicators and 3 outcome indicators.

Results
Of the 3242 patients diagnosed with Stage I and Stage II non-small cell lung cancer in 2009 and 2010, 2172 (67%) received a surgical consultation and 1524 (47%) underwent resection within 3 months of diagnosis. For the 1075 Stage I and Stage II patients over age 75 only 634 (59%) received a surgical consultation and 322 ( 32%) underwent resection. Of the 2302 patients resected in total (all stages), only 736 (32%) had invasive mediastinal staging(IMS) prior to resection:15% for sublobar resections; 30% for stage I; and 42% for stage II. Surprisingly only 42% of patients with stage III disease had IMS. IMS was also performed in an additional 23% of patients for whom stage data was unavailable. In a similar cohort of patients resected in 2011-2012, only 28% had ≥10 lymph nodes removed at the time of resection but this did not include nodes assessed by IMS. However, for 20% of patients lymph node resection data was not available or could not be determined. Positive resection margins were reported in 7% of patients, however in a further 7% of patients margins could not be assessed. 30 day mortality for lobectomy was 1.9%, reoperation rate was 2.8% (2.0% for same day as resection).

Conclusion
Initial results of 7 quality indicators in thoracic surgery identified some quality gaps in processes of care as well as limitations in databases. Evaluation of process indicators allowed feedback to thoracic surgeons and pathologists who identified quality improvement opportunities. Rate of surgical consultation and resection for stage I and II disease was lower than expected as were rates of invasive mediastinal staging especially for patients with stage III disease for whom cytologic or histologic confirmation is recommended. To address variable intraoperative lymph node assessment, systematic lymph node sampling or complete mediastinal lymphadenectomy was recommended to standardize intraoperative lymph node assessment. Quality improvement opportunities for pathologists also included dissection of intralobar lymph nodes, standardization of pathological processing and margin assessment. Feedback of quality indicator data was important in stimulating quality improvement initiatives by thoracic surgeons and pathologists.

Abstract not provided

Background
Limited resection of primary lung cancer or sublobar resection of pulmonary metastatic tumor can result in cut-end recurrence. It is important to confirm the absence of tumor cells at the cut-end. Since 2004, all autostapling cartridges used for wedge or segmental resection of pulmonary malignancies are washed with 50 ml saline. Washing saline is centrifuged and the sediment is stained using Papanicolaou’s method and examined for cancer cells during surgery to confirm negative margin. The aim of this study is to evaluate the efficacy of the intraoperative autostapling cartridge lavage cytology in preventing surgical cut-end recurrence.

Methods
The intraoperative cytology analysis was performed in 271 patients undergoing wedge or segmental resection for 319 lesions including primary lung cancers and pulmonary metastatic tumors between April 2004 and April 2010. We retrospectively reviewed the clinicopathologic features of patients with positive cytology results and those who developed recurrence at the surgical margins.

Results
The median age of the 271 patients at surgery was 67 years (range: 31−92 years). The median size of the 319 lesions was 1.4 cm (range: 0.4−3.5 cm), and there were 149 primary lung cancers and 170 pulmonary metastatic tumors (primary site: 116 colorectal and 54 others). Twenty-two lesions (7%) showed positive cytology results (11 primary and 11 metastatic). In primary lung cancers, tumor size (≧ 21 mm, p = 0.02), moderate to poor differentiation (p ＜ 0.01), vascular invasion or lymphatic permeation (p ＜ 0.01), and visceral pleural invasion (p ＜ 0.01) were significant predictors of a positive result. In contrast, there were no significant predictors in pulmonary metastatic tumors. The cut-ends of the 19 lesions among the 22 positive cytology margin lesions were additionally resected, but those of the remaining 3 lesions were not because of impaired respiratory function. With the median follow-up period of 42 months, surgical cut-end recurrence occurred in 2 of the 19 lesions for which additional resection had been performed (11%, 1 primary and 1 metastatic). Of the 3 lesions for which additional resection was impossible, cut-end recurrence developed in 2 (67%, 1 primary and 1 metastatic). Among the 297 lesions showing negative cytology result, cut-end recurrence occurred in 5 (2%, 4 primary and 1 metastatic).

Conclusion
Intraoperative autostapling cartridge lavage cytology in sublobar resection for primary or metastatic lung tumor may be useful in preventing surgical cut-end recurrence.

Background
There is little information about prognosis after pulmonary resections for non-small cell lung cancer (NSCLC) in patients with interstitial lung disease (ILD). In this study, we examined the long-term outcome and the factors that affect long-term survival after resection for NSCLC in patients with ILD.

Methods
Between September 1996 and May 2011, 71 NSCLC patients were diagnosed as having ILD based on the CT and pathological findings. The extent of ILD on CT was scored visually at the level of 3 cm above the diaphragm as follows: minimal, <2 cm from the subpleura at the base of the lungs; moderate, >2 cm from the subpleura, but less than one-third of the lung area at the base of the lungs; severe, more than one-third of the lung area at the base of the lungs. Various clinical values such as gender, age, preoperative chemotherapy, severity of ILD on CT, preoperative pulmonary function test results, arterial blood gas studies, operative procedure, pathologic stage, cell type, and adjuvant treatment were evaluated using univariate and multivariate analysis.

Results
The mean age was 65.9 years, and the majority of patients were male(65:91.5%). In-hospital mortality was 9.9% (7/71). The causes of early mortality included pneumonia (n=4), acute respiratory distress syndrome (n=2), and acute exacerbation of ILD (n=1). The 5-year overall survival rate was 43.1% (stage I: 59.4%, stage II: 41.3%, stage III: 35.0%, respectively). In univariate analysis, the risk factors for long-term mortality were lower preoperative FEV~1~, FVC, severe ILD on CT, presence of pathologic pulmonary fibrosis, and non-squamous cell type. In multivariate analysis, severity of ILD on CT and non-squamous cell type remained as poor prognostic factors.Figure 1

Conclusion
Although patients with ILD undergoing pulmonary resection for NSCLC has resulted in a high in-hospital mortality, long-term survival can be expected in highly selected patients. NSCLC patients with severe ILD on CT findings and those with non-squamous cell type should be carefully selected for major pulmonary resection.

Background
Posterolateral thoracotomy has been extensively used for non-cardiac thoracic surgery. Although this procedure provides excellent access for cancer surgery, it is responsible for considerable postoperative pain and contributes to postoperative pulmonary insufficiency. Post-thoracotomy pain has been reported to occur in 10 to 70% of patients. Intercostal nerve injury has been implicated as a major factor in the etiology of post-thoracotomy pain. We performed a study to compare post-thoracotomy pain in patients undergoing posterolateral thoracotomy with and without the preservation of the intercostal neurovascular bundle.

Methods
This randomized double-blind phase II trial was carried out in a tertiary-referral cancer centre. We included adult patients undergoing posterolateral thoracotomy for pulmonary resection. Patients were randomized into two groups – standard posterolateral thoracotomy (PoT) where no attempt was made to preserve the intercostals neurovascular bundle or modified nerve-sparing thoracotomy (NeST) which involved preservation of the intercostal neurovascular bundle while opening the intercostal space and closure by drilling holes in the lower rib, thereby avoiding pericostal sutures. All surgeries were performed under general anaesthesia with fentanyl, morphine, diclofenac and paracetamol for intra-operative analgesia. Post-operatively, all patients received round-the-clock paracetamol and diclofenac with an intravenous morphine patient-controlled analgesia pump for additional analgesia. Worst and average pain scores (on a Numerical Rating Scale) and morphine requirements on the first three post-operative days were assessed. Patients and assessors were blinded to study group. Chronic pain was assessed 6 months after surgery using a standard questionnaire. The primary outcome was the mean worst pain score over the first three post-operative days. Secondary outcomes were mean average pain score over the first three post-operative days, morphine consumption and incidence of post-thoracotomy pain at 6 months.

Results
We recruited 90 patients between May 2010 and July 2012. Groups were comparable in terms of age, gender, weight and type of surgery. There was no significant difference between the PoT and the NeST group in mean worst pain scores over the first three post-operative days (3.83 versus 3.71, difference 0.12, 99% CI -0.7 to 0.9). Mean average pain scores were also similar between the groups (1.85versus 1.77, difference 0.08, 99% CI -0.4 to 0.6) as was the mean morphine consumption in milligram per kilogram body weight (1.40 versus 1.45, difference of -0.05, 99% CI -0.4 to 0.3). Chronic pain was present in 18 of 39 assessable patients (46.1%) in the PoT group and 17 of 41 assessable patients (41.2%) in the NeST group (difference 4.7%, 99% CI -22.8% to 30.7%).

Conclusion
Preservation of the neurovascular bundle during thoracotomy using a modified nerve-sparing approach has no impact on acute or chronic post-thoracotomy pain or analgesic requirements as compared to a standard posterolateral approach.

Abstract not provided

Background
To investigate the relationship between the different levels of biologically effective dose (BED) and the outcome of stereotactic body radiation therapy (SBRT) for Stage I non–small-cell lung cancer (NSCLC).

Methods
Eligible studies were identified on Medline, Embase and the Cochrane Library from January 2001 to March 2013. According to the quartile of included studies, BED was divided into four dose groups: low (＜100Gy), medium (100–112.3Gy), medium to high (112.3–135Gy), high (>135Gy). To obtain pooled estimates of overall survival (OS), local control rate (LCR), cancer-specific survival(CSS), regional failure rate(RFR), distant failure rate (DFR)，data were combined in a random effect model. The difference in pooled estimate among BED groups was assessed with the Pearson chi-squared test. The meta-regression model was used to explore the relationship between the characteristics of the studies and the prognostic index.

Results
Fifty-nine observational studies with a total of 5,562 patients were included in the meta-analysis. Pooled estimates of 2-year and 3-year OS in the medium BED (79%, 71%) group were higher than in the low (64%, 57%) or medium to high BED (69%, 57%) or high groups (66%, 56%), respectively (p＜0.001, p＜0.001, p＜0.001,respectively). Pooled estimates of 2-year LCR in the medium BED (89%) group was lower than in medium to high BED (94%)or high groups (94%), respectively (p=0.003,0.009 respectively). While no significant differences were observed between each two of four different levels of BED and the 3-year RFR.

Conclusion
Based on the meta-analysis, a statistically significant OS benefit at 2 and 3 years can be demonstrated in the treatment of Stage I NSCLC with the delivery of medium BED compared with low, medium to high BED or high BED. The medium BED (range, 100–112.3Gy) for SBRT may currently be more beneficial and reasonable in Stage I NSCLC.

Background
To select the most favorable treatment regimen based on the rate of grade 3 or higher protocol-specified adverse events (psAEs) at 1 year.

Methods
Pts with documented baseline medical conditions precluding lobectomy and biopsy-proven peripheral (greater than 2 cm from the central bronchial tree) T1/T2, N0 (clinically node negative by PET), M0 tumors were eligible. Patients (pts) were randomized to receive either 34 Gy in one fraction (arm 1) or 48 Gy in 4 consecutive once-daily fractions (arm 2). Rigorous central accreditation and quality assurance assessments were used to assure pts were treated according to protocol guidelines. The study was designed to detect whether psAEs rate>17% at a 10% significance level (1-sided) and 90% power. Secondary endpoints included primary tumor control (PC) rate, 1-year overall survival (OS), progression-free survival (PFS). The regimen selection criteria were based on pre-specified rules of psAEs and PC for each arm. Formal comparisons were not performed.

Results
The study opened in September 2009 and closed in March 2011 after accruing a total of 94 pts. Median follow up was 20.6 months. Of 86 evaluable pts, 41 were in arm 1 and 45 in arm 2. Baseline pt and tumor characteristics were balanced between both arms. 4 (9.8%) pts on arm 1 (95% CI: 2.7-23.1%; p=0.151) and 6 (13.3%) pts on arm 2 (95% CI: 5.1-26.8%; p=0.337) experienced psAEs. 39 (95.1%) pts on arm 1 and 45 (100%) pts on arm 2 received planned SBRT treatment. Contouring compliance indicated 100% and 95.6% of targets and 89.5% and 82.2% of normal tissue structures were outlined per protocol/minor deviations, for arms 1 and 2, respectively. OS at 1 year was 85.4% (95% CI: 70.3-93.1%) for arm 1 pts and 91.1% (95% CI: 78.0-96.6%) for arm 2. PFS at 1 year was 78.0% (95% CI: 62.1-87.9%) for arm 1 and 84.4% (95% CI: 70.1-92.3%) for arm 2. The PC rates at 1 year were 97.1% (95% CI: 85.1-99.9%) for arm 1 and 97.6% (95% CI: 87.1-99.9%) for arm 2.

Conclusion
At one year, 34 Gy in one fraction met pre-specified criteria with respect to adverse events and primary control, and therefore is selected as the experimental arm for a planned phase III trial. Supported by RTOG U10 CA21661 and CCOP U10 CA37422 grants from NCI.

Background
Lung tumor control has improved with advances in radiotherapy delivery (RT). Respiratory motion inders improvements. An Anchored Beacon® transponder (Varian Medical Systems, Palo Alto, CA) can track lung tumors in real time during RT. This study evaluates the safety of these bronchoscopically implanted transponders in 50 lung tumor patients undergoing RT

Methods
Each patient underwent implantation of 3 anchored transponders in the lung. A delivery catheter was inserted into the bronchoscope and using fluoroscopic guidance +/- radial endobronchial ultrsound (EBUS) and/or electromagnetic guidance (superDimension): the catheter was positioned in a 2-2.5 mm diameter airway, within 3 cm of the tumor. The transponder was deployed by depressing a plunger within the delivery catheter. The catheter was then withdrawn. CT's were acquired before RT and every 1-2 weeks during treatment. Transponder positions were measured.

Results
50 patients (28 female/ 22 male) with median age 64 had transponders inplanted. Follow-up ranged from 0- 15.5 months (median 9.2). Positional stability of the Anchored transponders over the course of RT was confirmed. Inter-transponder distance from serial CT scans have been evaluated in 47 of 49 patients who underwent RT. Inter-transponder distances were stable over the course of radiation therapy for 140/141 (99%) of Anchored transponders. 2 Anchored transponders migrated, one after completion of RT. Safety: 2 patients (4%) sustained pneumothorax with insertion. Each resolved within one day with chest tube placement and withdrwal. One patient sustained a cardiac arrest prior to bronchoscopy for implantation. 2/147 (1%) sustained migration. Patient A coughed one transponder. which was placed in too large and proximal airway. Patient B was found the have the transponder migrating to the pleural space associated with a suppurative lung infection 3 months post-treatment.

Conclusion
Bronchoscopic implantation of Anchored transponders can be performed with few complications. Anchored transponders are positonally stable in the lung with a 99% retention rate. There are multiple advantages to real-time localization and tracking of lung tumors. The Anchored transponder demonstrated a high safety profile and significantly low migration.

Abstract not provided

Background
Stereotactic ablative radiotherapy (SABR) is now a guideline-recommended treatment for early-stage lung cancer (ES-NSCLC), achieving 5-year local control rates of approximately 10%. The timely detection of local recurrence (LR) and early salvage following SABR is impaired by fibrotic changes, which occur commonly. Seven high-risk CT features (HRFs) that suggest LR include; enlarging opacity, cranio-caudal growth, sequential enlarging opacity, enlarging opacity after 12 months, bulging margin, loss of linear margin and loss of air bronchograms. We validated these, performing blinded clinician assessment in patients with and without LR.

Methods
ES-NSCLC patients treated with SABR, who developed pathology-proven LR (n=12), were matched 1:2 to patients without clinical LR (n=24), based on tumor location, SABR fractionation, PTV size and follow-up duration. Three radiation oncologists assessed serial follow-up CT images for HRFs, while blinded to outcomes. The sensitivity and specificity of HRFs and combinations of these were determined.

Results
The median follow-up was 24 months (range 6-67) and both cohorts were well matched. All HRFs were significantly associated with LR (p≤0.002), Table 1. The best individual predictor of LR was opacity enlargement after 12 months (100% sensitivity, 83% specificity), however this was detected slowest, at a median 22 months. The earliest HRF detected was cranio-caudal growth detected at a median 13 months. The HRFs enlarging opacity and cranio-caudal growth were each detected at least 3 months prior to the actual diagnosis of LR 42% of the time. The odds of LR increased 4-fold for each additional HRF detected (p<0.001). The sensitivity and specificity of detecting multiple HRFs is shown in Table 2, with ≥3 HRFs being the best predictor of LR (sensitivity 92%, specificity 92%). Figure 1 Figure 2

Conclusion
LR following SABR can be accurately predicted by the presence of HRFs on surveillance CT scans. This approach may reduce unnecessary confirmatory procedures, and facilitate earlier salvage treatment.

Background
Radiographic changes following lung SBRT have been previously categorized into 4 groups: modified conventional pattern (A), mass-like fibrosis (B), scar-like fibrosis (C) and no evidence of increased density (D) (Dahele et al.).The purpose of this study was to assess the inter-rater reliability of this categorization in patients with early stage non-small cell lung cancer.

Methods
79 patients treated with SBRT for early stage NSCLC at a single institution who had a minimum follow-up of 6 months were included in this study. Serial post-treatment CT images were presented to expert clinicians (up to 6) familiar with post-SBRT radiographic changes and were scored by each individual in a blinded fashion according to the published categorization of A, B, C or D. The proportion of patients categorized as A, B, C or D at each interval was determined. Krippendorff's alpha (KA) was used to establish inter-rater reliability at each time point. A leave-one-out analysis was performed at each time point on each rater to determine the sensitivity of the KA score to an individual rater. To explore if a training effect existed the KA of the first and last 20 patients scored by the raters was determined.

Results
There were 351 ratings on 67 patients at 12mo, 250 ratings on 49 patients at 24mo, 169ratings on 31 patients at 36mo and 80 ratings on 14 patients at 48mo. The proportion of patients scored in each category of A,B,C &D is reported in Table 1. Table 1: Scale Category by Time-Point

	A (Modified-Conventional)	B (Mass-like Fibrosis)	C (Scar-like Fibrosis)	D (No Evidence of Increased Density)
6 months	43%	9%	6%	42%
12 months	50%	16%	11%	23%
18 months	46%	18%	16%	20%
24 months	46%	22%	17%	15%
36 months	40%	24%	21%	15%
48 months	29%	24%	31%	16%

Category A was the most common at all time points except 48 months when category C was the most common. KA was 0.28, 0.27, 0.18 and 0.27 at 12, 24, 36 and 48 months respectively. The range of KA in the leave-one-out analysis was 0.25-0.31, 0.24-0.27, 0.15-0.22 and 0.24-0.31 at 12, 24, 36 and 48 months respectively. The KA of the first 20 patients vs the last 20 patients was 0.34 vs 0.47 at 12 months.

Conclusion
The predominant pattern of post SBRT radiographic changes evolves over time. In this study categorization of late post-SBRT radiographic changes has moderate inter-rater agreement. There is a suggestion of a training effect with more experience. However, categorization of late radiographic changes following SBRT is challenging and may require specific training.

Background
Symptomatic rib fractures occur in approximately 5% of patients treated with SBRT for early stage NSCLC. Only in small patient cohorts has the dose-effect relation of radiation induced rib fractures been determined. Recent developments in automatic rib segmentation allow determining the dose-effect relation in a large patient cohort, which is the aim of this study.

Methods
From 2006-2012 453 patients with early stage NSCLC were treated with SBRT (3x18 Gy). Follow-up (FU) consisted of a physical examination and a CT scan 4 months after treatment and every 6 months up to two years and yearly thereafter. For the first 101 patients with FU>6 months, all ribs were automatically segmented using 15 atlases of manually delineated ribcages. A non-rigid registration followed by a multi-level label fusion produced for each patient a set of ribs. The physical dose distributions were NTD (Normalized Total Dose) corrected with α/β=3 Gy. Cox proportional hazard regression analysis, which takes into account the time to event with patient as random intercept, was used to find the optimal dose parameter. Evaluated were the dose received by x% of the rib D~x~ (x ranged 1-30%) and equivalent uniform dose (EUD) (volume effect 1/n ranged 0.1-60). The Lyman-Kutcher-Burman (LKB) model based on this optimal dose parameter was used to model the dose-effect relationship. Using maximum-likelihood estimation, parameters were median toxic dose (TD~50~), steepness parameter m and 1/n were optimized.

Results
In 354 patients with FU>6 months (median 22 months), 38 patients(11%) were diagnosed with a total of 49 rib fractures, symptomatic (grade 2) for 9 patients(2.5%). Included in the dosimetric analysis were 2410 ribs (14 ribs outside field-of-view). 26 ribs in 15 patients(15%) were fractured, symptomatic for 4 patients(4%). In the univariate analysis, all dose parameters significantly correlate with rib fracture (p-values<0.001). Hazard ratios (95%CI) for the parameters with highest log likelihood: D~1~=1.022 (1.017-1.027) and EUD~0.033~=1.021 (1.016-1.026). Multivariate analysis identified EUD as the predictor with the highest log-likelihood and was used in the LKB model. The optimal LKB parameters to predict rib fracture in this dataset were (95% CI): TD~50~=395.5 Gy (244.3-555.1), m=0.348 (0.311-0.384) and 1/n=32.3 (4.82-inf). The risk of rib fracture was <5% in case the NTD-corrected EUD<170 Gy.Figure 1

Conclusion
In this subgroup of NSCLC patients treated with 3x18Gy, the risk of rib fracture was significantly correlated to the dose, and was <5% in case the biological dose is kept under 170 Gy.

Abstract not provided

Background
The updating of written clincial practice guidelines regularly is difficult and expensive. New evidence in cancer treatment is published frequently. Guideline booklets are difficult to disseminate widely and stakeholder feedback is mainly pre-publication. To enable lung cancer guidelines to be rapidly updated and widely disseminated and therefore more likely to be utilised, Cancer Council Australia developed a web-based wiki platform for guidelines and is evaluating its impact.

Methods
The initial methodology paralled the steps in published written guideline development but these were integrated with the wiki capability. An expert group, whose competing interests were documented, were identified, the key clinical questions and search strategies were developed for each question and literature searches recorded on the wiki. An online literature screening and critical appraisal process was developed. This provides data on which papers were used to form the guidelines and why papers were either selected or rejected depending on their quality. Evidence-based recommendations were formulated and evidence tables automatically generated. The wiki was closed in that only the invited experts could write or change a guideline but any stakeholder could comment on the guidelines at any time and the writing group would review and respond to comments. The initial vesion of the guidelines were distributed for targetted review by expert groups. We used web analytics to monitor usage. The writers remain engaged to appraise new papers and update the guideline rapidly as necessary. All previous versions could be accessed.

Results
Evaluation of the lung caner treatment guidelines developed on the wiki, showed that 22 authors had identified 67 clinical questions covering treatment of all stages of lung cancer. The literature search and screening process resulted in 2035 potentially relevant articles being forwarded for detailed methodological evaluation with another 571 added through snowballing and other methods. To fine-tune the initial draft content, the working party used the wiki to exchange 156 internal comments in 9 weeks. When the guidelines were released for the initial 30-day public consultation period, 1055 users visited lung cancer content pages. The majority of users (487) accessed the guidelines directly as a result of targeted emails, while 387 found the site by Google searches. Most respondents were from Australia (799) and New Zealand (60) with the United States (47) having the largest user group of respondents from the other countries who visited the site. A survey of the usability of the site indicated widespread acceptance. The average time on a content page was 1:27minutes. The landing page was the most popular content page with 3426 page views and an exit rate of 18.85%, which indicates that the landing page served as an important tool for visitors to navigate the guidelines. To date there were 38 external comments which occasioned 31 edits by the working party.

Conclusion
Adopting a platform built on MediaWiki, and moving to electronic guidelines has allowed rapid updates as new evidence becomes available and wider dissemination than print formats. The next strategy to boost uptake is to write Qstream education modules to accompany the guidelines.

Background
The “CLiC” Study seeks to characterise cough and identify its predictors using subjective and objective cough assessment tools, including the recently validated Manchester Cough in Lung Cancer Scale (MCLCS). Results will enable the identification of robust endpoints and therapeutic targets for novel antitussive interventional trials.

Methods
Patients with lung cancer (LC) and complaining of cough were recruited irrespective of stage and treatment, from two cancer centres. Demographic and clinical data were collected. Patients completed the MCLCS, Cough Severity Diary (CSD), cough severity Visual Analogue Scale (VAS) and the Brief Reflux Inventory (BRI, a validated 5-item questionnaire assessing gastro-oesophageal reflux disease (GORD)). The oncology specific European Organization for Research and Treatment of Cancer Quality of Life (QoL) Questionnaire (EORTC QLQ) C30 with the module (LC13), (including item 31: "In the past week, how often did you cough?") was also completed. Cough was graded according to Common Toxicity Criteria for Adverse Events (CTCAEv4.0). A sample size of 178 patients was required for analysis of 160 (based on Peduzzi J Clin Epidem 1996) for 10 participants per correlate per outcome in binary logistic regression, assuming a 10% attrition rate, the prevalence of severe cough to be 50% and 8 cough predictors.

Results
We recruited 179 patients (Oct'11-Nov'12). The median age was 65 yrs (range 25-83 years), with 53% patients male. The majority (79%) had non small cell lung cancer (NSCLC) and advanced stage disease (>IIIA 60%). In total, 36% were receiving cancer therapy at entry. Overall, 60% felt their cough warranted treatment. Having ensured validity of the cough assessment tools, the mean cough severity score (VAS) (n=171) was 43.4mm (SD 29.6). The mean cough-specific QoL score (MCLCS) was 25.3 (SD 8.8, with a range 1-50, high scores representing worse QoL).

Table showing association between cough predictors and cough severity (VAS) and cough specific QoL (MCLCS) scores on univariate analysis[*]
	Cough Severity (VAS)	Cough Specific QoL (MCLCS)	Comment
Age (≤70yrs vs >70yrs)	p=0.365#	p=0.834#
Gender	p=0.048#	p=0.171#	women worse cough severity
Smoking Status (current, ex, never)	p=0.191##	p=0.356##
Performance Status (WHO PS 0-3)	p<0.0001##	p<0.0001##	poorer PS worse cough severity poorer PS worse cough related QoL
Histology (NSCLC vs SCLC)	p=0.348#	p=0.274#
Stage (early vs advanced)	p=0.358#	p=0.301#
Tumour Location (central vs peripheral)	p=0.486#	p=0.040#	central tumours poorer cough related QoL
COPD (Chronic Obstructive Pulmonary Disease) (self-reported)	p=0.578#	p=0.128#
LRTI (Lower Respiratory Tract Infection) (self-reported)	p=0.022#	p=0.044#	LRTI worse cough severity LRTI worse cough related QoL
Asthma (self-reported)	p=0.021#	p=0.054#	asthma worse cough severity
GORD (BRI questionnaire)	p<0.0001#	p<0.0001#	GORD worse cough severity GORD worse cough related QoL
Nausea (EORTC QLQ C30)	p=0.004##	p=0.017##	Increased nausea worse cough severity. Increased nausea worse cough related QoL
Oral Steroids	p=0.434#	p=0.017#	On steroids worse cough related QoL
Over the Counter Antitussives	p=0.011#	p=0.067#	On antitussives worse cough severity
Opiates	p=0.497#	p=0.018#	On opiates worse cough related QoL
*Not all analysed cough predictors shown # Mann-Whitney-U Test ## Kruskal-Wallis Test

Conclusion
This is the largest single study to use validated cough-specific assessment tools in LC to characterise and assess potential influences on cough. LC patients have a severe cough, with comparable VAS scores to those of patients presenting to specialist chronic cough clinics. New antitussive therapies are needed. Key predictors of cough severity and reduced cough-specific QoL are performance status (PS), nausea and GORD. Preclinical research suggests that the neurokinin-1 pathway may mediate the vagal cough reflex pathway. Our results further support this hypothesis and imply that the neurokinin-1 pathway may be a relevant therapeutic target. The association with GORD may be explained by the shared vagal innervation of the airway and upper gastrointestinal tract.

Background
Cough is a common lung cancer (LC) symptom, yet effective therapies are lacking. The development and testing of novel therapies relies upon appropriate tools for the assessment of cough. CLiC is the first study to evaluate two new tools 1) objective ambulatory cough monitoring (ACM) from acoustic recordings (VitaloJAK™) and 2) the Manchester Cough in Lung Cancer Scale (MCLCS) quality of life (QoL) questionnaire. These provide complementary assessments of cough frequency and its impact upon the patient.

Methods
Patients with LC and complaining of cough were recruited, irrespective of stage or treatment, from two cancer centres. Demographic and clinical data were collected. All patients completed the MCLCS, Cough Severity Diary (CSD) and cough severity Visual Analogue Scale (VAS). The European Organization for Research and Treatment of Cancer QoL Questionnaire (EORTC QLQ) C30 with the module (LC13), (including item 31: "In the past week, how often did you cough?") was also completed. The Common Toxicity Criteria for Adverse Events (CTCAEv4.0) was used to grade cough. A subgroup underwent ACM and MCLCS on Days 0&60.

Results
We recruited 179 patients (Oct'11-Nov'12): median age 65yrs (range 25-83 years), 53% male. Majority (79%) had non small cell lung cancer, 60% advanced stage (>IIIA), 36% were on cancer therapy.

Table showing correlations between subjective cough assessment tools
	EORTC QLQ C30 cough item 31	CTCAE Cough Grading	MCLCS Manchester Cough LC Scale	CSD Cough Severity Diary
VAS Cough Severity	0.54**§ n=171	0.50**§ n=170	0.67**§ n=163	0.70**¥ n=84
EORTC QLQC-30 cough item Q31		0.45**§ n=173	0.57**§ n=165	0.52**§ n=85)
CTCAE Cough Grading			0.56**§ n=164	0.59**§ n=85
MCLCS Manchester Cough LC Scale				0.76**¥ n=82
** p<0.0001 ¥high correlation §moderate correlation

Table showing correlations between objective ACM and subjective cough tools
	VAS Cough Severity	MCLCS Manchester Cough LC Scale	Log Cough/hr Asleep	Log Cough/hr Awake	Log Cough/hr 24-hour
VAS Cough Severity		0.73** n=37	0.33* n=37	0.61** n=37	0.57** n=37
MCLCS Manchester Cough LC Scale			0.24 n=35	0.51* n=35	0.44* n=35
Log Cough/hr Asleep				0.52** n=35	0.62** n=35
Log Cough/hr Awake					0.97** n=37
** p<0.0001 * p<0.05

Intra-class correlations demonstrated good repeatability over time between Days 0&60 for cough frequency (24hour: r=0.77, p<0.0001, awake: r=0.79, p<0.0001, sleep: r=0.66, p=0.004) and MCLCS: r=067,p<0.001 .The median cough scores/hour were 14.1(24hour: range 0.7-156), 18.5 (awake: range 1-233) and 6.0 (asleep: range 0-110).

Conclusion
We have demonstrated moderate to strong correlations between established measures of cough and two novel assessment tools, suggesting the validity of MCLCS and ACM. Their good repeatability suggests they have excellent potential for the assessment of novel treatments in future intervention studies for LC-related cough. In contrast, standard oncology tools are blunt and poorly discriminate cough.

Background
Patients with newly diagnosed advanced lung cancer may experience severe impacts on their quality of life (QOL). However, relatively few studies have examined the longitudinal patterns of QOL and their relationship to patients’ symptoms during the first 12 months of cancer diagnosis. Thus, the purposes of this study were to (1) examine the overall pattern and the potential sub-patterns (if any) of QOL in these patients during the first 12 months of cancer diagnosis; and (2) identify those important characteristics of each QOL sub-pattern and their relationship to patients’ symptoms.

Methods
This is a 12-month prospective longitudinal study. Newly diagnosed advanced lung cancer patients (Stage IIIB & IV) were eligible to be recruited and followed for 12 months on 5 time points (Pre-treatment, 1, 3, 6 and 12 months since treatments). The overall QOL was measured by the overall QOL item in the EORTC QLQ-C30 (0-100 scoring, higher is better). The QOL patterns and factors related to the patterns were analyzed by Latent Class Growth Analysis (LCGA). Potential factors (independent variables) used to predict the overall QOL change and each QOL sub-pattern (dependent variables) included: physical function, selected symptoms, emotion distress, self-efficacy (on coping with cancer) and important demographic and treatment related variables.

Results
A total of 200 subjects completed the 5 follow-up assessments. Generally, patients had moderate level of QOL across the 12 months. There were three QOL sub-patterns were identified. In the pattern I (around 50% of subjects), patients reported moderate to relatively good levels of QOL (scoring around 70-80) across the 12 months. In the pattern II (around 45% of subjects), patients reported moderate levels of QOL (scoring around 50-70 QOL). In the pattern III (<10% subjects), patients reported poor level of QOL (scoring around 40 or less). Overall, symptoms including fatigue, pain, lack of appetite and dyspnea were significantly related to the changes of QOL. Other factors also included psychological distress, uncertainty and self-efficacy (level of confidence) in coping well with lung cancer.

Conclusion
The results provide a relatively comprehensive picture about the overall QOL and the sub-patterns of QOL for those newly diagnosed advanced lung cancer patients. The results further support the giving timing and tailoring interventions are needed to better improve lung cancer patients’ QOL. (Acknowledgement: National Health Research Institute,NHRI,Taiwan).

Abstract not provided

Background
Breathlessness in patients with lung cancer is common symptom affecting 50-70% of patients, rising to 90% for those with advanced lung cancer. Managing breathlessness is complex, treatment options are limited and treatments are sometimes unsuccessful. Inspiratory muscle training (IMT) is a non-pharmacological method that has shown positive results in Chronic Obstructive Pulmonary Disease and mixed results in other respiratory illnesses. As this treatment method has never been tested in patients with lung cancer, the aim of the current study was to assess how feasible this treatment is in the lung cancer population and explore changes in outcome variables, before launching a larger randomized trial.

Methods
Pilot feasibility randomized trial in patients with lung cancer having stable disease. The experimental group received training using a pressure threshold device (commercially available from Phillips Respironics). Patients were instructed to do 5 sessions weekly for 12 weeks for a total of 30mins per day, divided over 2 sessions. Patients in the control group received standard care and received the treatment at the end of their trial participation. Outcome measures were completed at baseline and monthly for 3 months, and included: physiological parameters (FEV1,FVC); perceived severity of breathlessness in six 10-point VAS assessing average breathlessness over past 24 hours, worst breathlessness over past 24hrs, breathlessness now, distress from breathlessness, ability to cope with breathlessness and satisfaction with breathlessness management; modified Borg scale; quality of life using the short form-Chronic Respiratory Disease Questionnaire (with subscales on dyspnea, fatigue; emotional function and mastery of breathlessness); Hospital Anxiety & Depression Scale, and safety.

Results
46 patients (M=37, F=9) at a mean age of 69.5 years old and a mean of 16 months post-diagnosis who were not currently receiving chemotherapy/radiotherapy were recruited from 3 centres in the UK and Cyprus. Seventy-percent had NSCLC and advanced disease. There were no changes in FEV1 and FVC levels between groups. There were time by intervention interaction effects in average breathlessness and worst breathlessness in past 24hrs (p<0.01) with the intervention arm showing stable breathlessness and the control group deteriorating, but no between-group differences. Statistical and clinically important differences were seen with regards to ability to cope with breathlessness (p=0.02), satisfaction with breathlessness management (p=0.024), fatigue (p=0.007), emotional function (p=0.006), breathlessness mastery (p=0.031), anxiety (p=0.027) and depression (p=0.048). The m-Borg difference between the 2 groups at 3 months was 0.80, which is borderline clinically significant but not statistically significant. Changes were more evident in the 3-month assessment. IMT was safe with only a small number of patients complaining of muscle fatigue and dizziness.

Conclusion
This trial shows the IMT is feasible and safe in patients with lung cancer with significant benefits particularly in their ability to cope with breathlessness and emotional distress. The details of this trial allow us to refine the treatment protocol and findings guarantee a fully-powered larger trial (N should be around 196 with m-Borg as primary outcome).

Background
Central airway obstruction is seen in around 30% of patients with primary lung cancer. This is often a life-threatening presentation of the disease due to imminent airway loss and therefore requires urgent intervention. Direct bronchoscopic techniques including airway stenting can offer an immediate improvement in symptoms and quality of life, in addition to providing time for further treatment modalities. Here we report outcomes from a large single centre five year experience of tracheobronchial stent insertion for palliation of advanced primary lung cancer.

Methods
A retrospective review of all patients undergoing tracheobronchial stent insertion between January 2007 and January 2012 was performed. Patients undergoing stent insertion for benign or secondary malignant disease were excluded. A total of 70 patients underwent 80 stenting procedures with an average age of 66 years. Patient notes were used to collect patient demographic, disease and stenting data. Outcomes included post-procedure length of stay, complications, need for further intervention and overall survival.

Results
Disease was identified within the trachea in 18 cases, bilaterally within the bronchi in 10 cases and in the left or right bronchus in 23 and 28 cases respectively. Expandable, nitinol stents were used for all patients with either a proximal or distal release system. Uncovered stents (57), covered stents (20) or a mixture of the two (3) were placed. The average length of stay was 2.5 days (range 0-17); however, 69% of patients were discharged on the same day or on day one following the procedure. There were no cases of stent migration identified. The most common complication was retained secretions requiring repeat bronchoscopy which occurred in 5 cases. One patient required telescopic insertion of a second stent due to malposition of the first. Median survival was 2.6 months with a 20% one-year survival. There were 4 in hospital deaths.

Conclusion
Central airway obstruction secondary to primary lung cancer can cause disabling dyspnoea and impending suffocation. Interventional bronchoscopic techniques, in particular airway stenting, can provide immediate relief of these symptoms. The survival data here reflects the advanced stage of disease in this patient group and, although unlikely to improve survival, airway stenting can offer the opportunity for further adjuvant treatment in some cases. More importantly perhaps, 91% of patients were discharged home following the procedure allowing an improved in quality of life. In our experience, tracheobronchial stent insertion can be used effectively to achieve these outcomes with minimal complications and a short hospital admission. Figure 1

Background
Tracheobronchial stent insertion is safe and effective in managing central airway obstruction in advanced lung carcinoma. Airway stenting offers both immediate relief of severe dyspnoea and time for adjuvant therapy. It is commonly used in specialist thoracic centres with a variety of stent models employed. A large number of centres still use fluoroscopic guidance for stent positioning, leading to increased radiation exposure for both patients and staff. The aim of this study was to compare outcomes in patients undergoing stent insertion with or without radiological guidance.

Methods
70 patients were identified who underwent a total of 79 stent procedures. The cohort was divided into two groups based on whether stents were inserted under radiological guidance or direct vision at bronchoscopy. Retrospective analysis of notes was performed to collect data with regards to stenting strategy and post-operative course. The primary outcomes were length of stay, complications, repeat procedure and survival.

Results
Of the 79 stent procedures, 41 were with radiological guidance (group 1) and 38 were under direct vision only (group 2). There was an equal distribution with regards to the position of the stents (Table 1). Both techniques were well tolerated with minimal complications and no stent migration. Post-procedure length of stay was 2.73 days in group 1 and 2.26 days in group 2, with no significant statistical difference seen (p=0.93). There was also no difference in need for further stent intervention. A comparison of survival is shown in Figure 1. Figure 1 Figure 2

Conclusion
Airway stenting is a vital technique in the management of impending central airways obstruction. Although traditionally carried out under radiological guidance, we found no differences in complications, need for repeat procedure or survival when using direct vision. This not only saves radiation exposure to patients and staff, but also improves the cost-effectiveness and logistics of planning these urgent cases.

Background
Amino-biphosphonates are third-generation bisphosphonates which act by inhibition of osteoclasts. We have presented at two previous ATS conferences (Dimitroulis I.A. et al 2009, 2011), the role of each amino-biphosphonate separately. We set out to investigate the superiority or inferiority of Ibandronic acid (Ibandronate) over Zoledronic acid (Zoledronate), in terms of efficacy in reducing bone pain, and complications in patients with skeletal metastases due to Lung Cancer.

Methods
Ninety six patients with Skeletal Metastases due to Lung Cancer were enrolled, and were randomized on a 1:1 basis to receive infusions of Ibandronate (50 pts) or Zoledronate (46 pts) intravenously, every 21 days. Infusion time for Zoledronate (4mg) was 15 minutes, and for Ibandronate (6mg) one hour. Patients (pts) were analysed for pain relief, skeletal-related events (SREs) and adverse events. All pts underwent dental and cardiac examination before enrollment, and completed blood tests every 21 days. Bone scan was performed every 6 months. Blood tests (including close monitoring of calcium levels and renal function) were performed before each amino-biphosphonate administration.

Results
Patients in both arms were well matched for their diagnosis, stage of disease, burden of skeletal disease, and performance status. Median follow-up was 24 months. At 24 months, mean increases in British Pain Inventory pain scores were lower with Zoledronate compared to Ibandronate (0.43 vs 0.89 [p=0.03]). Analgesic effect as defined by the 4 point analgesic scale was less with Zoledronate as compared to Ibandronate. Incidence of SREs was not significantly different between two arms (35% for Zoledronate vs 38% for Ibandronate [p=0.2]). Median time to the first SRE was not reached in either arm. At 18 months of median follow up, percentages of patients with skeletal-related events were 41% in the Zoledronate arm vs 45% in the Ibandronate arm (p=0.05). Zoledronate caused fever in six (12%) patients and hypocalcemia in one patient. Ibandronate caused hypocalcemia in one patient (2.2%). No cases of jaw osteonecrosis, atrial fibrillation or renal failure (all of them possible side-effects of amino-biphosphonates) were observed.

Conclusion
Zoledronate is the preferred amino-bisphosphonate for its shorter infusion time, availability and relative benefits. It is slightly better than Ibandronate in reducing bone pain and preventing skeletal-related events. The only possible drawback is that, locally, Zoledronate is 1.3 times more expensive than Ibandronate (according to the mean European Economic Community price).

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