Virtual Library

Abstract not provided

Abstract not provided

Abstract not provided

Abstract:
Introduction Approximately 68 particle therapy facilities are in operation worldwide. Among them, only 11 offer carbon-ion treatment (5 in Japan, 2 in Germany, 2 in China, 1 in Italy, and 1 in Austria; 6 also offer proton), and the remainder offer proton treatment. More than 150,000 patients have been treated with particle therapy worldwide from 1954 to 2015, 87% of which were treated with protons and 13% with carbon-ions or other particles. (from the website of the Particle Therapy Co-Operative Group: http://www.ptcog.ch/). The National Institute of Radiological Sciences (NIRS) in Chiba, Japan, has been treating cancer with high-energy carbon-ions since 1994. The majority of patients curatively treated with carbon-ions worldwide were treated at NIRS (1). Through the data they have generated, carbon-ion radiotherapy (CIRT) for non-small cell lung cancer (NSCLC) has been suggested as safe and efficacious. Here, I review those results and discuss this modern technology. Characteristics of CIRT In comparison with photon radiotherapy, CIRT has better dose distribution to tumors while simultaneously minimizing dose to surrounding normal tissues. Moreover, CIRT offers potential advantages over protons, which have similar dose distribution benefits. Carbon-ions provide a better physical dose distribution, because lateral scattering is lessened, and offer a higher relative biological effectiveness with a lower oxygen enhancement ratio; desirable features for eradication of radioresistant, hypoxic tumors. This difference between densely ionizing nuclei and sparsely ionizing x-rays/protons further offers potential radiobiological advantages, such as reduced repair capacity in irradiated tumors, decreased cell-cycle dependence, and possibly stronger immunological responses. CIRT of early NSCLC Surgical resection with lobectomy has been the standard treatment of choice for early-stage NSCLC. From a Japanese lung cancer registry study of 11,663 surgical cases in 2004, overall survival (OS) rates at 5 years for stages IA and IB disease were 82.0% and 66.8%, respectively (2). Radiotherapy is an option for patients who are not suitable for surgery or refuse it. Recently, hypofractionated radiotherapy is regarded as an alternative for surgery in cases of localized NSCLC, employing x-ray stereotactic body radiotherapy, protons, or CIRT. Regarding CIRT, for peripheral stage I NSCLC, the number of fractions delivered per treatment at NIRS has been reduced through consecutive trials from 18 to 9, then 4, and finally to a single fraction (3-7). This latest result , conducted via dose escalation study, was recently reported by NIRS, demonstrating results comparable to those with previous fractionated regimens (8). The Japan Carbon-ion Radiation Oncology Study Group (J-CROS) has further reported that the results of a multi-institutional retrospective study of CIRT for stage I NSCLC were similar with the results of previous single institutional reports (9). The results of CIRT in stage IA NSCLC are similar to the best stereotactic body radiotherapy results reported worldwide. For stage IB disease, CIRT results appear tentatively superior to those reported for photon stereotactic body radiotherapy in terms of local control and lung toxicity, but will require randomized controlled trials to verify. Despite this high local control, however, disease-specific survival is much lower in stage IB than in stage IA, due to distant metastatic recurrence. A combination of CIRT with systemic therapy is therefore essential to improve survival. CIRT demonstrates a better dose distribution than both SBRT and proton therapy in most cases of early-stage lung cancer. Therefore, CIRT may be safer for treating patients with adverse conditions such as large tumors, central tumors, and poor pulmonary function. CIRT of locally advanced NSCLC There has only been one report regarding CIRT for locally advanced NSCLC. A prospective nonrandomized phase I/II study of carbon-ion therapy in a favorable subset of locally advanced NSCLC was reported from NIRS (10). They showed that short-course carbon-ion monotherapy (72GyE/16Fr) was associated with manageable toxicity and encouraging local control rates. Among them, cT3-4N0M0 patients were particularly favorable candidates for CIRT. However, there is a relative dearth of evidence for CIRT in the setting of locally advanced NSCLC, and more trials, including those combined with systemic immunological or chemotherapy agents, are required. Future directions We have organized a multi-institutional study group of carbon-ion radiation oncology in Japan (J-CROS) and have been conducting a number of trials involving a multitude of tumor sites. A number are emerging as particularly attractive for CIRT with possibility of new levels of achievable disease control, including in NSCLC, head and neck cancer, locally advanced unresectable pancreatic cancer, hepatocellular carcinoma, locally recurrent rectal cancer, as well as others. The outcomes of CIRT for stage I NSCLC in Japanese multi-institutional datasets were retrospectively analyzed. As a result, CIRT is considered a low-risk and effective treatment option for patients with stage I NSCLC. Confirmative multi-institutional prospective studies via J-CROS began last year, so as to validate these results. References: 1. Kamada T, Tsujii H, Blakely EA, et al. Carbon ion radiotherapy in Japan: an assessment of 20 years of clinical experience. Lancet Oncol 2015; 16: e93-100. 2. Sawabata N, Miyaoka E, Asamura H, et al. Japanese lung cancer registry study of 11,663 surgical cases in 2004: demographic and prognosis changes over decade. J Thorac Oncol 2011; 6: 1229-35. 3. Miyamoto T, Yamamoto N, Nishimura H, et al. Carbon ionradiotherapy for stage I non-small cell lung cancer. Radiother Oncol 2003; 66: 127-140. 4. Miyamoto T, Baba M, Yamamoto N, et al. Curative treatment of Stage I non-small-cell lung cancer with carbon ion beams using a hypofractionated regimen. Int J Radiation Oncol Biol Phys 2007; 67: 750-758. 5. Miyamoto T, Baba M, Sugane T, et al. Carbon ion radiotherapy for stage I non-small cell lung cancer using a regimen of four fractions during 1 week. J Thorac Oncol 2007; 10: 916-926. 6. Sugane T, Baba M, Imai R, et al. Carbon ion radiotherapy for elderly patients 80 years and older with stage I non-small cell lung cancer. Lung Cancer 2009; 64: 45-50. 7. Karube M, Yamamoto N, Nakajima M, et al. Single-fraction carbon-ion radiation therapy for patients 80 years of age and older with stage I non-small cell lung cancer. Int J Radiation Oncol Biol Phys 2016; 95: 542-548. 8. Yamamoto N, Miyamoto T, Nakajima M, et al. A dose escalation clinical trial of single-fraction carbon ion radiotherapy for peripheral stage I non–small cell lung cancer. J Thorac Oncol 2016; 12: 673-680. 9. Shioyama Y, Yamamoto N, Saito J-i, et al. Multi-institutional retrospective study of carbon ion radiation therapy for stage I non-small cell lung cancer: Japan Carbon Ion Radiation Oncology Study Group. Int J Radiation Oncol Biol Phys 2016; 96: S10. 10. Takahashi W, Nakajima M, Yamamoto N, et al. A prospective nonrandomized phase I/II study of carbon ion radiotherapy in a favorable subset of locally advanced non-small cell lung cancer (NSCLC). Cancer 2015; 121: 1321-7.

Abstract not provided

Background:
Fiducial markers guide stereotactic body radiotherapy (SBRT) and can be used to localize lesions for surgical resection in the management of lung cancer. We report the safety, accuracy and common practice patterns of fiducial placement guided by electromagnetic navigation bronchoscopy (ENB).

Method:
NAVIGATE (www.clinicaltrials.gov, NCT02410837) is a prospective, multicenter, global, single-arm, observational cohort study of ENB using the superDimension™ navigation system (Medtronic, Minneapolis). This abstract presents the patient demographics, procedural characteristics, and 1-month outcomes in the subset of NAVIGATE subjects from the United States cohort who had fiducial markers placed. Continued enrollment in Europe and 2-year follow-up are ongoing. Study sponsored and funded by Medtronic.

Result:
258 subjects from 21 United States centers (29 operators) received fiducial markers during their ENB procedure. Most subjects received between 1 and 5 fiducial markers (mean 2.2±1.7). General anesthesia was used in 69.4%. Real-time confirmation by radial endobronchial ultrasound (r-EBUS) was used in 34.5% of ENB procedures. The median ENB procedure time (first locatable guide [LG] / extended working channel [EWC] entry to last LG/EWC exit) was 31.0 minutes. Among the 258 subjects undergoing ENB-guided fiducial marker placement, 213 subjects also had lung lesion biopsy. Based on subjective operator assessment, 99.2% of fiducial markers were accurately placed. Follow-up imaging an average of 4.7 days post-procedure showed that 94.3% (232/246) of markers were still in place. The ENB-related pneumothorax rate was 5.0% (13/258) overall and 3.1% were Grade ≥2 based on the Common Terminology Criteria for Adverse Events scale (i.e., requiring chest tube placement or hospitalization). The ENB-related Grade ≥2 bronchopulmonary hemorrhage and Grade ≥4 respiratory failures rates were 0.0% and 1.6%, respectively. Among the 39 subjects undergoing fiducial placement alone with no biopsy, there was 1 respiratory failure and no pneumothoraces or bronchopulmonary hemorrhages.

Conclusion:
We report the largest series to date of fiducial marker placement by ENB guidance. Our data suggest that ENB-guided fiducial marker placement is versatile and accurate, with low complication rates. Practice variations in number and type of fiducial placed between operators were noted in our data. We did not identify the type of radiotherapy system used at each institution or how many fiducial markers were useful during the therapy. In addition, not all SBRT systems require fiducial marker placement, and some fiducial markers were placed for surgical localization. Further investigation should explore these practice patterns to further hone the usefulness and accuracy of placement of fiducial markers for SBRT and surgical localization.

Background:
Pleural dye marking guided by electromagnetic navigation bronchoscopy (ENB) has been useful in identifying small peripheral lesions for sublobar resection in the management of non-small cell lung cancer and indeterminate lung nodules. We report the use of this procedure among the participants of the NAVIGATE study.

Method:
NAVIGATE (www.clinicaltrials.gov, NCT02410837) is a prospective, multicenter, global, single-arm, observational cohort study of ENB using the superDimension™ navigation system (Medtronic, Minneapolis). Enrollment of up to 1,500 subjects is planned at 37 sites in the United States and Europe. European enrollment and 2-year follow-up are in progress. This abstract presents a prespecified 1-month interim analysis of NAVIGATE subjects from the United States cohort who underwent ENB-guided pleural dye marking. Study sponsored and funded by Medtronic.

Result:
From April 2015 to August 2016 at 29 clinical sites, 1218 subjects were enrolled in the NAVIGATE United States cohort. In 7 clinical centers (7/29), 23 subjects (24 lesions) underwent pleural dye marking in preparation for surgical resection. Ten subjects underwent dye marking alone while 13 had dye marking concurrent with lung lesion biopsy and/or fiducial placement. The median nodule size was 10 mm (range 4-22) and 83.3% (20/24) were less than 20 mm in diameter. Most lesions (95.5%; 21/22) were located in the peripheral third of the lung. The median distance of the target lesion from the visceral pleura was 3.0 mm. The median total bronchoscopic procedure time was 22.0 minutes and the median ENB procedure time (first locatable guide [LG] / extended working channel [EWC] entry to last LG/EWC exit) was 11.5 minutes (range 4-38). Dye marking was considered accurate for surgical resection in 91.3% of the cases and the median time of dye marking to surgical resection was 0.5 hours (range 0.3-24). Seventy five percent of the lesions were malignant (18/24) and 50% were adenocarcinoma.

Conclusion:
Our data demonstrates that pleural dye marking with ENB guidance is useful for locating small peripheral lesions for surgical resection without adding significant additional time to the procedure. An interesting finding in our report is the underutilization of this procedure in the NAVIGATE cohort (23/1218). Given that sublobar and lung parenchymal sparing resections for non-small cell lung cancer are becoming more common, it is unclear why surgeons are not more frequently utilizing pleural dye marking. Further investigation concerning physician behavior and practice patterns in the use of lung sparing surgery needs to be explored.

Background:
Electromagnetic navigation bronchoscopy (ENB) is used to access lung lesions or lymph nodes for biopsy and/or to guide fiducial or dye marking for stereotactic radiation or surgical localization. CT-guided lung biopsy can be complicated by pneumothorax, particularly in patients with emphysema. We examined the safety of ENB in patients with COPD and/or poor lung function.

Method:
NAVIGATE (www.clinicaltrials.gov, NCT02410837) is a prospective, multicenter, global, single-arm, observational study of ENB using the superDimension™ system (Medtronic, Minneapolis). This NAVIGATE substudy analyzes the 1-month follow-up of the first 1,000 subjects enrolled in the United States and Europe. Subjects were determined to have COPD by medical history. Pulmonary function test results (PFTs) were collected if available. Procedure-related pneumothorax, bronchopulmonary hemorrhage, respiratory failure, and composite complications were prospectively captured. Study sponsored and funded by Medtronic.

Result:
1,000 subjects were enrolled at 29 clinical sites, including 448 with COPD and 541 without COPD (COPD data missing in 11). One-month follow-up was completed in 933 subjects (93.3%). Subjects with COPD tended to be older, male, and have history of tobacco exposure, asthma, and recent pneumonia. Nodule size, location, and procedure time were similar between groups. There was no statistically significant difference in the procedure-related composite complication rate between groups (7.4% with COPD, 7.8% without COPD, 9.1% in subjects missing COPD data, P=0.81). CTCAE Grade ≥2 pneumothorax was not different between groups (2.7%, 3.7%, 0.0%, respectively, P=0.63). Severity of FEV1 or DLCO impairment was not associated with increased composite procedure-related complications (ppFEV1 P=0.66, ppDLCO P=0.37). Figure 1



Conclusion:
Patients with a clinical diagnosis of COPD or with poor PFTs can undergo ENB without an increase in complication rates. Because the risk of pneumothorax is not elevated, in patients undergoing ENB in this analysis, ENB may be the preferred method to biopsy peripheral lung lesions in patients with COPD and/or poor PFTs.

Background:
Solitary pulmonary nodules are increasingly encountered in current medicine. There are interesting new technologies available for this difficult diagnostics category of pulmonary pathologies like endobronchial navigation techniques and transparietal CT guided biopsy. In order to increase diagnostic yield of those techniques precise biopsy instruments are needed.

Method:
We utilise new instrument based on near infrared diagnostics. This simple needle sheath can be used during routine bronchoscopy examination and enables simultaneous spectral measurement and obtaining of histology tissue samples in situ at the same time. This intelligent sheath with standard needle can be used both during fluoroscopy navigation and EBUS guided navigation to confirm correct biopsy instrument position during the sampling itself. According to our results diagnostic yield of navigation method is significantly increased using such device. Instrument itself consists of elastic tubing while along the length of tube on opposite sides of cross section perimeter there are two segments fixed with 6 optic microfibers covered with insulation as NIR spectroscopic probe. Core consists of the channel for of standard biopsy needle introduction. Instrument itself is introduced to the area of interest through the working channel of the bronchoscope.

Result:
We performed 40 consecutive examinations of SPN (diameter 1-3cm) using intelligent needle during navigational bronchoscopic procedure executing fluoroscopy and radial EBUS. Correct placement of biopsy instrument confirmed by NIR spectroscopy was possible in 32 cases. In all these cases positive cytology specimen containing diagnostic material was obtained.

Conclusion:
Intelligent NIR based biopsy needle appears to be good adjunct in the diagnosis of SPNs. More extensive studies are needed to prove diagnostic potency of this device.

Abstract not provided

Background:
Probe-based confocal endomicroscopy (pCLE) allows confocal microscopy of lung tissue in vivo but limited evidence is available. The objective was to discriminate pCLE patterns of lung cancer in vivo.

Method:
Fluorescence properties of methylene blue (MB) were examined ex vivo in confocal microscope. Next, 15 regions of the central airways were studied in vivo with pCLE and a representative image chosen for analysis with ImageJ software. Biopsy was performed for final diagnosis.

Result:
Ex vivo study showed no differences between 1% and 2% MB concentrations and rapid extinction of fluorescence after 10 minutes of MB application (figure). In vivo study included samples of bronchial mucosa (n = 6), inflammation (n = 3) and tumor (n = 6). pCLE image evaluation (table) showed inflammation and tumor nuclei were bigger (except SCLC) and occupied a greater area. Fluorescence of tumor nuclei was more intense. Non fluorescent area was inferior for both inflammation and tumor samples. Number of nuclei could not discriminate between normal and tumor.Figure 1 Table. Imaging features evaluated in pCLE frames

	Area occupied by nuclei (µm[2])	Intensity of nuclei (UA)	Mean size of nuclei (µm[2])	Non-fluorescent area (µm[2])	Number of nuclei (µm[2])
Bronchial epithelium (mean(SD))	97,769(9,451)	126(9)	107(10)	67,100(12,567)	937(84)
Inflammation (mean(SD))	117,381(22,166)	122(27)	127(15)	35,124(32,630)	933(225)
B cell lymphoma	138,354	145	185	49,269	746
Adenocarcinoma	155,033	198	177	5,225	875
Squamous cell carcinoma	102,805	145	155	54,301	663
Small cell lung cancer	107,201	157	63	11,257	1,687
Non-small cell lung cancer	113,173	187	122	32,359	926
Hamartoma	120,188	145	114	25,438	1,058

Conclusion:
1. MB fluorescence is unaffected by stain concentration 2. There is exponential extinction of MB over time 3. Lung cancer cell pattern distinction in vivo is feasible Funded by Fundació MaratóTV3, SEPAR and FUCAP

Background:
Endobronchial ultrasound (EBUS) transbronchial needle aspiration (TBNA) is the standard of care for diagnosis and mediastinal staging of non-small cell lung cancer (NSCLC). Studies suggest that elastography, an ultrasonic measure of tissue elasticity, may identify malignant lymph nodes (LNs) with sufficient accuracy to guide which LNs need sampling at EBUS and reduce the time and complexity of staging procedures. This study aims to confirm these findings while also describing technical factors that affect elastographic measurements.

Method:
All patients undergoing EBUS TBNA to investigate possible NSCLC were prospectively recruited. Elastographic analysis was performed prior to TBNA of LNs and later correlated with pathology from EBUS TBNA and/or surgical specimens. All LNs were classified qualitatively according to elastographic colour pattern: predominantly blue, predominantly green and mixed. Strain ratios (SR) were calculated to give quantitative measures of elasticity. Measures were compared to PET and sub-group analyses according to LN FDG avidity were performed. Finally the influence of various technical factors (probe pressure, Region of interest selection, and frame average function) were assessed.

Result:
There were 82 LNs from 50 patients who underwent EBUS elastography with the final diagnosis being malignant in 29(35%) and non-malignant in 57(69%). PET was available for 58 LNs. Diagnostic indices relating to elastographic features and effects of various technical factors are shown in Table 1.

Table 1 Diagnostic indices for elastographic identification of malignant LNs (A) and Effects of technical factors (B)

A. Variable	Sensitivity	Specificity	PPV	NPV
Elastography All	88%	47%	42%	90%
Elastography PET Positive	90%	64%	66%	90%
Elastography PET negative	63%	88%	70%	85%
Strain Ratio All	Pending	Pending	Pending	Pending
Strain Ratio PET positive	Pending	Pending	Pending	Pending
Strain Ratio PET negative	Pending	Pending	Pending	Pending
Sonographic features	81%	60%	54%	84%
PET All	82%	51%	52%	81%
B. Variation in technique	Difference	p value
Probe Pressure - colour map	Pending	Pending
Probe pressure - strain ratio	Pending	Pending
ROI pressure	Pending	Pending
ROI Placement	Pending	Pending
Frame average - colour map	Pending	Pending

Conclusion:
EBUS elastography can identify malignant LNs with equivalent power to sonography and FDG PET and may have a role in selecting which PET-negative nodes require sampling in staging procedures. It is highly dependent on technique which must be standardised to ensure accuracy of results. Please note: Data acquisition is still underway and planned to continue for a further 2 months. Analysis shall be complete by the time of the conference.

Background:
Solitary pulmonary nodules diagnosis and management is so challenging that nNew endoscopic techniques are being introduced to reduce uncertainty in peripheral pulmonary lesions (PPL) diagnosis and management. increase its diagnostic yield. Probe-based confocal laser endomicroscopy (pCLE) is a technique that can microscopically image the lung tissue in vivo during flexible bronchoscopy, though it can be difficult for pulmonologists to distinguish cellular patterns in a monochrome vision under respiratory and cardiac movements. . The goal of this work is to explore explore if Computed-Aided Diagnoses (CAD) tools can obtain a reliable diagnoses with pCLE in lung cancer.

Method:
A pilot study using 2 different methods for pCLE pattern analysis was performed:, one based on visual analysis by 3 experts and the other one based on computeron computerized analysis of visual patterns called Graphcom. Twelve 12 pCLE videos ( obtainedobtained using mMethylene blue dye (1%) and Alveloflex-Cellvizio 660nm miniprobe) were selected from patients with endobronchial lesionsperipheral SPNs (6 with lung adenocarcinoma cancer and 6 with inflammatory disease) during rigid bronchoscopy under general anesthesia. Afterwards, Vvideo sequences from pCLE were visually explored by one of the authors to select between 10 and 15 framesimages that presented a clear cellular pattern, without artifacts. . These images were shown to 3 observers who were familiar with confocal images but ignored the final histopathological diagnosis for a blind visual labellinglabeling. Images were also computationally analyzed using methods from social networks community analysis in a graph representation of pCLE images based on visual features to potentially overlapping groups of images that share common visual properties.

Result:
Our preliminary results indicate that on average visual analysis with 3 independent experts can only achieve a 60.2% of accuracy and has large variability amongst observers, while the accuracy of the proposed unsupervised image pattern classification rai(GraphCom) sesrises to 83,4.4%.

Conclusion:
Visual inspection of CLE images from lung tissue fails to provide accurate diagnosis. CLE images contain enough visual information for in vivo detection of neoplastic cell patterns that could be discriminated using cComputation methods and graph structural analysis applied to deep-learning feature spaces can increase diagnostic accuracy of pCLE images against visual analysis (83.4% vs 60.2%). Future studies are needed to apply this method in a real time scenario during bronchoscopy for PPL diagnoses.

Background:
Accurate mediastinal staging is crucial in potentially operable lung cancer to avoid non-therapeutic resection. Performance of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for staging of the radiologically normal mediastinum has been reported with inconsistent findings. We assessed the value of pre-operative systematic staging using EBUS-TBNA in cN0/N1 lung cancer.

Method:
For this systematic review and meta-analysis, we searched MEDLINE, PubMed, EMBASE, Cochrane databases from inception to October 2016. We included studies evaluating EBUS-TBNA for systematic mediastinal staging in cN0/N1 lung cancer. For each study, we extracted data on participant age and sex, radiological stage, EBUS-TBNA protocol, number and size of lymph nodes sampled, EBUS-TBNA stage, reference standard stage, and 2x2 tables. We evaluated the diagnostic accuracy of EBUS-TBNA for detection of occult mediastinal metastases. PROSPERO registration number CRD42017057020

Result:
We identified 1,173 articles, of which nine (1,146 patients) were included in meta-analysis. Mean prevalence of N2/N3 disease was 15% (6-24%). EBUS-TBNA had a pooled sensitivity 49% (95%CI 41-57%) (see figure 1), pooled specificity 100% (95%CI 99-100%), and mean negative predictive value 91% (82-100%) for detection of unsuspected N2/N3 disease. Number Needed to Test to detect occult N2/N3 disease was 14 (95%CI 10.8-16.3), NNT was reduced to 7 for studies which added endoscopic ultrasound to EBUS-TBNA. Moderate inter-study heterogeneitywas observed (I[2] 40.6%). Figure 1



Conclusion:
Pre-operative systematic staging by EBUS-TBNA of early lung cancer can reduce rates of non-therapeutic resection and decrease incidence of post-operative upstaging. Sensitivity for detection of radiologically occult mediastinal metastases appears lower than for targeted sampling of pathologic lymph nodes. Verification of negative results by mediastinoscopy in selected cases remains of value.

Abstract not provided

Background:
Chronic obstructive pulmonary disease (COPD) and lung cancer are associated through tobacco use. COPD is underdiagnosed in both the primary care and lung cancer populations. Diagnosis of COPD should lead to improved care and quality of life. Screening programs could provide an opportunity to capture undiagnosed COPD. We analyzed the Pan-Canadian Early Detection of Lung Cancer Study (PanCan Study) to evaluate the prevalence of COPD in a screening population.

Method:
The PanCan Study was a single arm lung cancer screening trial which recruited individuals to low dose CT scan, autofluorescence bronchoscopy, and biomarker screening. Eligible individuals were 50-75 years of age, had smoked within 15 years, and had a minimum six-year risk of lung cancer ≥ 2% based on a risk prediction model derived from PLCO study data, which included COPD as a risk factor. Consenting subjects completed a questionnaire including background medical conditions, high-risk work exposures, and smoking history. Baseline spirometry was performed, and COPD was defined by GOLD criteria. For individuals not receiving post-bronchodilator spirometry, COPD was defined as ‘probable’ if GOLD criteria were met pre-bronchodilator and there was no prior diagnosis of asthma. Individuals with definite or probable COPD were defined as having COPD.

Result:
Of 2537 individuals recruited, 2514 had available spirometry data. Mean age was 62.3 years, 55.3% were male, median pack-years smoked was 50, 62.3% were active smokers, 45.1% had symptoms of dyspnea, 52.4% cough, and 37.5% wheeze. 35.2% had worked in a high-risk occupation. Overall, 1136 (45.2%) met spirometry criteria for COPD. Of 1987 individuals without a prior history of COPD, 41.9% met spirometry criteria for COPD, of which 53.7% had moderate to severe disease. Of 527 individuals (21%) reporting a diagnosis of COPD at baseline, 57.5% met spirometry criteria for COPD, 32.2% did not, and 10.3% had a prior diagnosis of asthma. In a multivariate model for risk of COPD, age (odds ratio (OR)~per year~ 1.06), dyspnea (OR 1.42), being a current smoker (OR 1.43), and pack-years (log transformed OR 1.42) were significant (all p < 0.001) as were high-risk occupation (OR 1.24, p=0.013) and wheeze (OR 1.24, p = 0.024).

Conclusion:
A diagnosis of COPD by spirometry is common in a lung cancer screening trial population. Individuals with a pre-existing self-reported diagnosis of COPD often fail to meet spirometry criteria for their diagnosis. Testing a lung cancer screening population for COPD could significantly improve COPD diagnosis and treatment.

Background:
Patients with locally advanced Non-small cell lung cancer (aNSCLC) receive standard treatment with concurrent chemo-radiotherapy (CCRT). Different studies have tried to identify the changes in lung function after radiation exposition due to the high risk of pulmonary toxicity. The aim of this work is to evaluate lung function with a broad spectrum of respiratory tests as an objective way of assessing lung injury in patients with locally aNSCLC treated with CCRT.

Method:
A prospective study was conducted from June 2013 to July 2015. Fifty-two patients with locally advanced and oligometastatic NSCLC were included. The candidates received treatment with CCRT at the Instituto Nacional de Cancerología (Mexico). Participants were evaluated at baseline, end of RT, week 6, 12, 24 and 48 post-RT through forced spirometry with bronchodilator, body plethysmography, carbon monoxide diffusing capacity (DLCO), arterial blood gases, impulse oscillometry, 6-minute walk test and exhaled fraction of NO (FeNO). The study was registered in clinicaltrials.gov (NCT01580579).

Result:
Before treatment, 34.7% patients presented airflow obstruction (post-BD FEV~1~/FVC < 70%) which remained constant after RT (33.3%). For baseline results, the median of the % of the predictive value in FEV~1 ~post-BD was 97% (79-108), FVC 105% (90-116), TLC 101% (91-111) and DLCO 77% (55-103). At the end of CCRT, FEV~1 ~and FVC showed a significant reduction of 10% within week 12-48 (p=0.0004, p= 0.0005). TLC declined after week 6 post-RT, with a maximum drop of 15% at week 48 (p=0.0015). DLCO changes occurred from RT start to week 48, decreasing up to 20% at week 12 (p=0.0001). FeNO increased, exceeding 20% of its initial/baseline value with a peak at week 6 post-RT. Eighteen patients (34.7%) were hypoxemic (SO2 <90%) at the beginning of the trial, oxygen saturation had a statistically significant reduction at week 6 and week 48 (p<0.03, p<0.01). No significant differences were found in impulse oscillometry and 6-minute walk test. The results of the respiratory tests that decreased with the CCRT did not return to baseline at the end of follow-up.

Conclusion:
Regardless of pre-existing lung damage, the reduction in FEV~1~, FVC, DLCO, TLC and SO2 may represent increased inflammation, tissue remodeling and modification in gas exchange, however further studies are required. The nadir of the lung function occurred at 12 weeks from CCRT initiation. Increased FeNO values may represent a non-invasive marker of airway inflammation that correlates with RT lung injury mechanisms.

Background:
Mutation profiling of circulating tumor DNA (ctDNA) and pleural effusion sediment containing tumor cells (ETCs) were commonly applied in clinical practice. Several studies suggested that tumor-derived DNA from pleural effusion supernatant (etDNA) might be a better candidate for detecting gene alterations in lung cancer. However, little is known regarding the abundance and diversity of tumor DNA acquired among different types of liquid biopsy.

Method:
We performed targeted next generation sequencing (NGS)-based genetic profiling on tumor tissue, pleural effusion (etDNA & ETCs) and contemporaneous ctDNA from 63 lung cancer patients (58 adenocarcinoma, 2 adenosquamous carcinoma, 2 SCLC, 1 neuroendocrine carcinoma), among which 28 patients had paired tumor tissue samples. Genomic DNA from whole blood of each patient was used for germline control. Driver mutation and rearrangement profiling was validated using ARMS-PCR, FISH, or Ventana IHC assay in tumor tissue as golden standard.

Result:
We identified tumor-specific mutations in 98%, 89%, 86%, and 100% of patients in their etDNAs, ETCs, ctDNAs and tumor tissues, respectively (p<0.01). etDNAs showed a significantly higher tumor-specific mutation number per patient (Median: 5) compared to ETCs and plasma ctDNAs (Median of 3 for both), while the median number in tumor tissues is 4 per patient. The detection sensitivity for EGFR mutations in etDNAs is 95%, higher than that in ETCs and ctDNAs (89% and 63%, respectively). Two patients detected ALK fusion in tumor tissue were also positive in etDNA, only one patient was positive in ETCs and ctDNA, respectively. A total of 298 genetic alterations, including point mutations, indels, copy number variations (CNVs) and gene fusions, were identified in etDNAs from all the patients. However, only 74% and 57% of these alterations were detected in contemporaneous ETCs and ctDNA samples, with CNVs having the lowest detection sensitivity as 49% and 11%, especially in lung cancer patients without extrathoracic metastasis, as none of the CNVs detected in etDNAs were captured in plasma ctDNAs of these patients. Furthermore, driver mutations and rearrangements in etDNA showed a strong correlation to targeted therapy efficacy.

Conclusion:
This study demonstrated that etDNA had significantly higher tumor-specific mutation detection rate and sensitivity compared to ETCs and ctDNA. etDNA from supernatant of pleural effusion is a promising source for genetic testing to guide treatment-decision making in lung cancer. This study is funded by Shanghai Science and Technology Program (15ZR1406400).

Background:
Tumor genotyping is transforming lung cancer care but increasingly requires more tumor tissue. Advances in minimally invasive bronchoscopic techniques increase access to small lesions, but often result in smaller samples. With the advent of new cfDNA (“liquid biopsy”) genotyping technologies, we hypothesized that CSN might increase the yield from small FNAs, facilitating cancer genotyping.

Method:
We studied patients with known or suspected lung cancer undergoing FNAs. CSN, which is usually discarded, was collected under IRB approval. cfDNA was extracted after a hard spin (1600 Gs) and tested by both ddPCR (EGFR, KRAS mutations) and targeted next-generation sequencing (NGS).

Result:
14 patients with suspected or known lung cancer were studied at time of analysis (final diagnosis: 2 non-malignant, 9 adenocarcinomas, 1 small-cell carcinoma, 2 squamous cell carcinomas), including 12 EBUS-TBNAs and 2 CT-guided FNAs. Among 6 known KRAS and EGFR mutations, all could be detected with ddPCR of CSN, with allelic fraction (AF) ranging from 1%-46% (median 8.5%). No ddPCR false positives were seen across 9 cases. NGS analysis was piloted on 7 specimens; 5 failed due to insufficient residual DNA. In one specimen, an EGFR exon 19 deletion was detected at 6% AF (2% AF ddPCR). In the other, a BRAF V600E, PIK3CA E784D and TP53 V274F mutations were detected at 48% (46% AF ddPCR), 18% and 86% AF, respectively.

Conclusion:
Cytology supernatant, usually discarded, may be a rich source of fresh tumor DNA, increasing the yield from FNAs. This widely available biospecimen has potential for aiding resistance genotyping, reducing turnaround time of cancer genotyping, and possibly a future role in clarifying the malignant potential of non-diagnostic biopsies. Enrollment continues in order to optimize this biospecimen for NGS. Figure 1

Abstract not provided

Abstract not provided

Abstract:
Reasons surgeons “quit” cancer operations are typically related to finding additional sites of disease, inability to perform necessary dissection, or disappearance of previously identified disease. In the setting of N2 positive non-small cell lung cancer (NSCLC) the disappearance of disease is not a consideration, so occult sites of disease or inability to perform safe hilar or mediastinal dissection are the most common reasons to back out of an operation once started. Incredibly precise pre-resection imaging has made this an uncommon scenario. Imaging techniques include functional and molecular correlates, and 3 and 4 dimensional reconstructions, which improve detection of very small lesions and appreciation of tumor interactions with adjacent structures. That being said, N2 involvement denotes locally advanced and often aggressive disease and use multimodality treatments and therefore the risk for unexpected findings in the operating room which alter resectability are more frequent than in early stage disease. Occult or unexpected disease encountered by thoracic surgeons in the operating room typically involves the parietal pleura, as occult carcinomatous pleuritis. Additional pulmonary nodules and unanticipated milliary spread are far less common. Pleural studding is defined as M1a disease in the 8[th] edition of AJCC staging. Chemotherapy is the recommended treatment for radiographically identified pleural involvement, but management recommendations are slightly less clear for disease found at the time of surgery. Pulmonary resections are generally contraindicated, but several investigators report favorable outcomes for those who can undergo macroscopic complete resection.[1,2] Carcinomatous pleuritis can escape radiographic detection, the incidence of occult disease at thoracotomy ranges from 1.5% to 4.5% for all lung cancer resections,[3] and is associated with large tumors, non-squamous histology, and lymph node involvement.[2] Carcinomatous pleuritis can escape radiographic detection, the incidence of occult disease at thoracotomy ranges from 1.5% to 4.5% for all lung cancer resections,[] and is associated with large tumors, non-squamous histology, and lymph node involvement. Intraoperative pleural lavage cytology (PLC) is a technique used for detecting subclinical dissemination of malignant cells in the pleural cavity. The boundary between malignant pleural effusion and positive PLC is not particularly well defined and most reports demonstrate a negative impact on prognosis in resected patients, but positive PLC does not upgrade tumors in the current TNM staging system. It also does not preclude resection in a patient with otherwise resectable disease. Similar to pleural studding positive cytology is consistently found to be more common in patients with higher stage and nodal involvement.[4] The presence of bulky N2 disease can greatly increase the complexity of hilar and mediastinal dissection. Modern techniques and intraoperative tools have increased surgeons ability to remove structures once considered unresectable including the spine, carina, and superior vena cava, but direct tumor extension or nodal involvement of the trachea, heart or great vessels can make safe resection impossible. Preoperative imaging typically allows for appropriate planning and decision making about these types of complex resections and controversy exists as to appropriateness of such resections in the setting of N2 disease. Induction therapy can make the pre-operative assessment of involved structures more complicated, differentiation between tumor and treatment effect is not always clear and therefore many surgeons make resection decisions on pre-treatment imaging. A more common scenario in thoracic oncology is that of the patient with marginal pulmonary reserve in whom the hilar resection is complicated by extensive nodal involvement or treatment effect; a pneumonectomy is technically feasible and would result in complete resection, but the patient would not tolerate that extensive a resection. Sleeve resections are used whenever possible, but widespread hilar and mediastinal scarring can sometimes exclude any safe surgery other than a pneumonectomy. The amount of fibrosis and scarring encountered at resection following induction therapy remains unpredictable. It is known to increase with time, which is why resection is recommended within 12 weeks induction therapy, but within that window, it can be quite variable. Review of recent large prospective trials for resectable IIIA NSCLC can help shed light on how frequently and why surgeons cannot complete the planned resection for N2 positive NSCLC. In the recent SAAK trial which compared induction chemotherapy to induction chemoradiotherapy in high volume operative centers in Europe, all patients who were taken to surgery, had a pulmonary resection, but R2 resections occurred in 3% of the trimodality group and 8% of the bimodality, reasons for incomplete resection were not delineated.[5] In the recent report of pooled data from RTOG 0229 and 0839, evaluating surgical outcomes after high dose induction chemo-radiotherapy, 7 of the 99 patients brought to surgery were not resected, 2 due to occult pleural metastasis, 2 because of persistent N2 involvement in patient with limited pulmonary reserve, and 3 were “unresectable”, 2 because complete resection would require a pneumonectomy and they had poor pulmonary reserve and one due to extensive mediastinal fibrosis.[6] These trials were all limited to experienced thoracic surgeons, indicating that the inability to complete a planned resection for IIIA NSCLC remains a rare but real phenomenon even in skilled surgical hands. References 1. Fukuse, T., et al., The prognostic significance of malignant pleural effusion at the time of thoracotomy in patients with non-small cell lung cancer. Lung Cancer, 2001. 34(1): p. 75-81. 2. Iida, T., et al., Surgical Intervention for Non-Small-Cell Lung Cancer Patients with Pleural Carcinomatosis: Results From the Japanese Lung Cancer Registry in 2004. J Thorac Oncol, 2015. 10(7): p. 1076-82. 3. Fukui, T. and K. Yokoi, The role of surgical intervention in lung cancer with carcinomatous pleuritis. J Thorac Dis, 2016. 8(Suppl 11): p. S901-S907. 4. Toufektzian, L., et al., Pleural lavage cytology: where do we stand? Lung Cancer, 2014. 83(1): p. 14-22. 5. Pless, M., et al., Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet, 2015. 386(9998): p. 1049-56. 6. Donington, J., et al. safety and Feasibility of Lobectomy folowing Concurrent Chemotherapy and High Dose Radiation for Stage IIIA NSCLC: Pooled Surgical Results of NRG Oncology RTOG 0229 and 0839. in American Asociation for Thoracic Surgery. 2017. Boston, MA.

Abstract:
Various treatment strategies, including chemotherapy, radiotherapy and surgery have been developed for patient populations with N2 lymph node metastasis, especially clinical stage IIIA-N2 non-small cell lung cancer (cIIIA-N2 NSCLC). For potentially resectable patients, clinical trials including surgical treatment have been published. Among them, EORTC-08941, INT-0139, ESPATUE examined the efficacy of adding surgical treatment with chemotherapy and radiotherapy in randomized design. In the INT-0139 study, surgery after induction chemoradiotherapy (CRT) demonstrated a 7% gain on 5-year survival, however, it failed to show statistical significance mainly because of treatment-related death in patients received pneumonectomy after induction CRT. Although the contribution of surgery was recognized, the additional effect of surgery over CRT has not been confirmed consistently in other trials. On the other hand, trials investigating newer medical treatment and higher radiotherapy dose have been conducted for patients with unresectable stage III NSCLC. In this patient population, so-called third generation cytotoxic agents whose effects were confirmed in patients with advanced disease, including paclitaxel (WJTOG0105), docetaxel (OLCSG 0007), vinorelbine and pemetrexed (PROCLAIM) with platinum have been actively examined but failed to show improvement compared to older agents (etoposide, vindesine and mitomycin C). Furthermore, high-dose radiotherapy (74Gy) with platinum-doublet chemotherapy showed strikingly shorter survival than conventional radiation dose (60Gy) in RTOG-0617. After these continuous efforts, CRT stayed as standard for those patients with unresectable N2 disease. Besides CRT, induction therapy followed by surgery has also come to be recognized as a treatment option for potentially resectable N2 disease in major guideline including ACCP, NCCN and ESMO. However, no clear answer has been provided for the question: what is resectable N2 disease, and what is unresectable N2 disease? To refine the heterogeneity in cIIIA-N2 NSCLC patients and show clues to answer the question of resectable/unresectable, we analyzed the data of consecutive patients with cIIIA-N2 NSCLC diagnosed and treated by CRT in National Cancer Center Hospital, Tokyo, Japan. The appearance of the mediastinal lymph nodes (MLNs) was classified into discrete or infiltrative according to the criteria proposed by the ACCP. In addition, the extent of MLN involvement (MLNI) was classified as limited (close to the primary tumor) or extensive (including upper MLNI in the case of tumors in the lower lobes and vice versa). Those with a discrete appearance of the MLNIs and a limited extent of MLNIs at diagnosis could show favorable survival outcomes by CRT without surgery comparable to the data provided by induction CRT followed by surgery. Meanwhile, immune checkpoint inhibition by PD-1/PD-L1 antibody has been being actively examined as adjuvant for early stage resectable NSCLC patients and consolidation therapy for unresectable stage III NSCLC patients after CRT. The PACIFIC is a phase III randomized clinical trial investigating the efficacy of MEDI-4736 (PD-L1 antibody) as consolidative therapy in patients without progression after definitive CRT. Based on the press release by AstraZeneca, MEDI-4736 showed significant prolongation of progression-free survival, suggesting that there is a possibility of changing standard treatment. Under such circumstances that powerful medical treatment option will be introduced in unresectable N2 disease, there is increasing need for an appropriate guidance to select surgical candidates in potentially resectable population. Now is the time to respond to the question of resectable/unresectable that has not been answered for a long time.

Abstract not provided

Abstract:
What is Resectable N2 Disease, and What is Unresectable N2 Disease: A Surgeon's Viewpoint Jhingook Kim, MD (Samsung Medical Center, Sungkyunkwan University) The poor prognosis of N2 disease is related to the risk of occult systemic metastasis although N2 disease, by definition, is a localized disease. Therefore, multimodal treatment, including systemically chemotherapy and locally surgery or radiotherapy, is often required. However, the optimal multimodal approaches for N2 disease remain controversial. Although definitive concurrent chemoradiotherapy (CCRT) is considered the standard of care, its oncologic efficacy can be limited by the high rate of local failure. Adding surgical resection to this bimodal treatment as a neoadjuvant treatment setting or replacing the radiotherapy with surgery has been attempted and has achieved enhancement of local control and improved survival, but the main concern regarding this approach is the increased risk of postoperative mortality and morbidity. Since 1995, neoadjuvant CCRT followed by surgical resection has been the preferred treatment modality at our institution, and prospectively and consecutively performed for more than 800 medically fit patients with resectable NSCLC with N2 disease. Figure 1 Fig. 1. Summary of treatment scheme Based on the previous analysis of 574 patients (From 1997 to 2013, 59 years of mean age, 444 men), complete resection was obtained in 543 patients (95%) by lobectomy (418 patients; 73%), pneumonectomy (73 patients; 13%) and sleeve resection (25 patients; 4.3%). Postoperative complications and in-hospital mortality occurred in 199 patients (35%) and 21 (3.7%), respectively. Pathologic complete response was achieved in 72 patients (13%) and 304 (53%) experienced mediastinal clearance. The 5-year overall and recurrence-free survival rates were 47 and 29%, respectively, and the median overall survival and recurrence-free survival were 56 months and 18 months, respectively. The 5-year OS rates were 61% in ypN0, 49% in ypN1, and 35% in ypN2 (p = 0.001). The 5-year RFS rates were 45% in ypN0, 23% in ypN1, and 17% in ypN2 (p < 0.001). Older age, advanced pTstage, persistent N2, large cell carcinoma, and pneumonectomy were independent prognostic factors associated with worse OS and poorer RFS. Evidence such as acceptable early postoperative outcomes, satisfactory local control and encouraging long-term survival has supported the need to expand the indication or situation. When investigating the timing and patterns of recurrence after treatment, of 290 patients with recurrence, 25 (8.4%) experienced loco-regional recurrence, whereas 238 (80.4%) had distant metastases. The hazard rate function for overall recurrence revealed a peak at approximately 8 months after surgery and a marked decline after 2 years (figure 2). The peak recurrence frequency of distant metastasis differed at each site, with isolated brain metastases exhibiting the earliest peak (6 months) and a narrow recurrence interval (15 months). Interestingly, the dynamics of recurrence after trimodality therapy varies according to pathologic factors and response to induction therapy (not specifically related with pre-induction presentation), which may mean personalized consideration of the treatment including surgery. Figure 2 FIG 2. Comparison of the recurrence hazard rate according to the site of distant metastasis. Each organ has a different peak of recurrence, although the peaks and shapes of the hazard rate curves were similar between bone and supraclavicular lymph nodes. Therefore, in this session, we will discuss “resect or not to resect” in several specific situations such as 1) for the patients with invasive T3 or resectable T4 2) for the patients with multi-station, bulky lymph nodes (not every) 3) for the patients with central lung cancer with possible sleeve lobectomy 4) for the old patients (>75 year-old) with comorbidity By the rapid development of the medical sciences, especially in cancer medicine, there would be fundamental changes in the diagnosis and management of N2 disease. Especially, improvement in systemic treatment would have critical impact on the surgical role in locally-advanced lung cancer. Moreover, if systemic tumor burden or minimal residual disease could be assessed at the earliest, surgery would be applied with higher benefit, and thus, the survival outcome would be significantly improved. Therefore, there should be more studies of combined local control (surgery) and systemic control (chemo and/or immunotherapy); either as adjuvant, neoadjuvant or salvage purpose; either with or without radiotherapy; participated by thoracic surgeons, to maximize the survival of the patients from dreadful disease. References 1. Kim HK, Cho JH, Choi YS, et al. Outcomes of neoadjuvant concurrent chemotherapy followed by surgery for non-small cell lung cancer with N2 disease. Lung Cancer 2016; 96:56-92 2. Lee J, Kim HK, Park BJ, et al. Recurrence Dynamics after Trimodality Therapy (Neoadjuvant Concurrent Chemoradiotherapy and Surgery) in Patients with Stage IIIA (N2) Lung Cancer. Lung Cancer (submitted)

Abstract:
The natural history of GGO-containing tumors, i.e., subsolid nodules (SSNs), is a major concern not only in CT lung cancer screening, but in daily clinical practice. SSNs are classified into pure ground-glass nodules (GGNs) and part-solid GGNs on the basis of their consistency. SSNs are classified according to their status as transient or persistent. Articles in the literature related to the natural history or long-term follow-up results of SSNs are summarized in Table. In the largest CT lung cancer screening cohort reported to date, nonsolid nodules (synonymous with pure GGNs) and part-solid nodules were detected in 4.2% (2392 of 57,496) and 5.0% (2892 of 57,496), respectively, of the participants at baseline (Table). The numbers of SSNs reported in the articles ranged from 19 to 3433 (median, 139). The median follow-up periods ranged from 1.1 years to 12 years (median, 2.9 years). The percentages of pure GGNs that grew ranged from 3% to 58% (median, 15%). The percentages of lung cancers among the SSNs ranged from 1% to 71% (median, 7%). An inherent limitation of studies of the natural history of SSNs is that not all of the SSNs are pathologically confirmed. The changes in persistent SSNs on sequential thin-section CT images in the Research Center for Cancer Prevention and Screening (RCCPS) examinations have tentatively been classified into six types; increasing type, stable type, decreasing type, fluctuating type, sudden onset type, and overtaking type. Some of the SSNs were evaluated on the basis of semiautomatic volumetry. Although the natural history of SSNs had gradually been clarified, the complete natural history of SSNs as a whole remains unknown. In the current era of ultralow-dose chest CT at a chest x-ray equivalent dose, a lifelong follow-up study should be considered.

			SSNs¶			Grew	Lung Cancer
Author	Journal	Year	Total	Consistency,n	Follow-up Period (yr.)	n (%)	n (%)
Kodama	Ann Thorac Surg	2002	19	PGGN*, 19	Median, 2.7	11 (58)	5 (26)
Hiramatsu	J Thorac Oncol	2008	125	PGGN, 95	Median, 2.9	14 (15)	8 (6)
				PSN**, 30		12 (40)
Silva	J Thorac Oncol	2012	76	PGGN, 48	Mean, 4.2	8 (17)	4 (5)
				PSN, 28		12 (43)
Takahashi	Jpn J Radiol	2012	150	PGGN, 150	Mean, 5.5	19 (13)	8 (5)
Chang	Chest	2013	122	PGGN, 122	Mean, 4.9	12 (10)	11 (9)
Kobayashi	J Thorac Oncol	2013	108	PGGN, 82	Median, 4.2	29†(27)	25 (23)
				PSN, 26
Matsuguma	Chest	2013	174	PGGN, 98	Mean, 2.4	14 (14)	53 (30)
				PSN, 76		27 (36)
Lee	Respir Med	2013	175	PGGN, 143	Median, 3.8	28 (20)	26 (15)
				PSN, 32		18 (56)
Attina	Radiol Med	2013	146	PGGN, 140	Mean, 2.3	41 (29)	5 (3)
				PSN, 6		6 (100)
Kim	Ann Thorac Surg	2013	139	PGGN, 69	Mean, 3.7	2 (3)	7 (5)
				PSN, 70		21 (30)
Tamura	J Thorac Oncol	2014	63	PGGN, 63	Mean, 2.2	29 (46)	45 (71)
Eguchi	Lung Cancer	2014	124	PGGN, 124	Median, 4.8	64 (52)	32 (26)
Scholten	Eur Respir J	2015	117	PGGN, 69	Median, 7.9	33≠	28 (24)
				PSN, 48		46≠
Kakinuma	Radiology	2015	439	PGGN, 439	Median, 6.0	45 (10)	4 (1)
Silva	Diagn Interv Radiol	2015	95	PGGN, 95	Median,1.7ø	18 (19)	n/a
Yankelevitz	Radiology	2015	2877	Nonsolid$,2392^	Median[1]	1764[&]	84 (3)
				Nonsolid,485^^	Median[2]	163[&]
Lee	Eur Radiol	2016	213	PGGN, 136	Median, 2.3	18 (13)	49 (23)
				PSN, 77		24 (31)
Zhao	Br J Radiol	2016	70	PGGN, 62	Median, 2.1	6† (9)	5 (7)
				PSN, 8
Kakinuma	J Thorac Oncol	2016	1231	PGGN, 1046	Mean, 4.3	116 (11)	85 (7)
				HGGN***, 81		23 (28)
				PSN, 104		45 (43)
Cho	J Thorac Oncol	2016	453	PGGN, 438	Median, 6.4	11 (3)	7 (2)
				PSN, 15		4 (27)
Henschke	AJR	2016	3433	PSN, 2892^	Median[3]	2325[&]	107 (3)
				PSN, 541^^	Median[4]	164[&]
Sawada	Chest	2017	226	PGGN, 166	§, #	39†(17)	124(55)
				PSN, 60
Mets	Eur Radiol	2017	89	PGGN, 63	Median, 1.6	35†(39)	n/a
				PSN, 26

Footnotes. ¶ SSN, subsolid nodule; * PGGN, pure ground-glass nodule; ** PSN, part-solid nodule; n/a, not available. † This study did not report the numbers of pure and part-solid GGNs separately. ≠ Growth was calculated by comparing actual mass to mass when first detected and is expressed as a percentage. $ A synonym of PGG.; ^ Baseline; ^^ Annual repeat screening. ø Follow-up period of the “grew” group. [1 ]Among the 1764 cases in which the nonsolid nodules were stable or growing, the median time to pathologic diagnosis was 1.7 years; the median follow-up time in the cases without a pathologic diagnosis was 1.4 years. [2] The median time from the initial identification of the nonsolid nodules to pathologic diagnosis was 1.2 years; the median follow-up time in the cases without a pathologic diagnosis was 1.7 years. [&] This study did not report the number of SSNs that grew and number of stable SSNs separately. ***HGGN, heterogeneous GGN. [3] Among the 2325 cases in which the PSNs were stable or growing, the median time to pathologic diagnosis was 0.5 years; the median follow-up time in the cases without a pathologic diagnosis was 1.1 years. [4] The median time from the initial identification of the PSN to pathologic diagnosis was 0.8 years; the median follow-up time of 0.7 years for cases without pathologic diagnosis. § Fifty-seven patients had stopped receiving follow-up examinations after a median of 5.6 years because of the presence of stable disease in 42 and reduced disease in 15. # Forty-five patients were continuing to undergo follow-up examinations, and their median follow-up period was 12 years; 40 were stable and 5 showed growth.

Abstract:
The radiological term GGO or ground-glass opacity was established when high-resolution CT (HRCT) became part of standard practice, and describes “a hazy attenuation of lung, with preservation of bronchial and vascular margins: caused by partial filling of air spaces, interstitial thickening, partial collapse of alveoli, normal expiration, or increased capillary blood volume…” (1). As such GGO is a nonspecific finding but depending on the clinical circumstances it may suggest a specific diagnosis and have consequences for the diagnostic and therapeutic approach. Most primary lung tumours present with masslike areas of consolidation, however there are other patterns. A specific subtype of adenocarcinoma may present as GGO, and this was described as bronchioloalveolar carcinoma (BAC) (2). It reflects the unique lepidic growth pattern along the alveolar septa with a relative lack of acinar filling. The classification BAC was used for a broad spectrum of tumours including small non-invasive peripheral lung tumours, invasive adenocarcinoma with minimal invasion, mixed subtype invasive adenocarcinoma, mucinous and nonmucinous subtypes, and widespread disease. As in this larger group GGO is present in only a minority, it is difficult to conclude from the chemotherapy trials done specifically in BAC (3) what the efficacy of chemotherapy in tumours with as feature GGO is, nor has the pathological feature of lepidic growth been reported in these studies. Overall the response rate in BAC of single agents seems not to be different from other types of NSCLC. At a later stage, it seemed that gefitinib was especially effective in the non-mucinous subtype (4), in retrospect this might be explained by the molecular characteristics of both. EGFR mutation was more related to lepidic growth, whereas KRAS was especially found in mucinous types (5). It became clear that the term BAC leads to confusion and is representing a very heterogeneous group of tumours. It was therefore recommended to discontinue the use of the term BAC (6), and use a more descriptive classification based on histological findings. Within this new grouping the radiological description of ground-glass opacity was related to the pathological pattern of adenocarcinoma: pure GGO would favour adenocarcinoma in situ (AIS) or possibly minimally invasive adenocarcinoma (MIA), and GGO with a solid component > 5 mm in diameter would favour lepidic adenocarcinoma (7). The natural course of pure GGO or GGO with a small solid component is rather benign. In a large Japanese cohort followed for 4.3 + 2.5 years (mean) the frequency of change from pure GGO towards a - still small - solid component was found in 6.6% (69 out of 1046), of the cases initially diagnosed with a very small solid component change into part-solid nodules was seen in almost 20% (16 of 81) (8). All these observations come from resected tumours and cannot be diagnosed in small biopsies, this makes it difficult to characterize more advanced adenocarcinoma in the same way. The likely most GGO containing advanced tumours will be those diagnosed with (dominant) lepidic growth (9). Reports of chemotherapy efficacy are infrequent but do not show a real difference in sensitivity if treated with one of the commonly used regimens carboplatin – paclitaxel (10). Although the LACE-Bio study contains only small numbers of cases with lepidic growth, combining these patients with the ones with the prognostically less unfavourable histology (papillary, acinar) failed to demonstrate benefit of adjuvant chemotherapy (11). The frequency of finding more than one GGO (with or without a solid component) is rather high and reported as almost 30% (12). If this is in a patient with stage IV NSCLC it is questionable whether these are separate primaries or metastases. The behaviour of these lesions has not been systematically reported, personal observations confirm the rather indolent role of these lesions, usually without any pathological proof of malignancy, and no change during systemic therapy for an other stage IV tumour. The question whether the presence of GGO as such, either as part of the stage IV tumour or as a different lesion, should affect the choice of systemic therapy can not be answered. References: 1. Austin JHM, Müller NL, Friedman PJ et al. Glossary of terms for CT of the lungs: recommendations of the Nomenclature Committee of the Fleischner Society. Radiology 1996; 200: 327-331. 2. Jang HJ, Lee KS, Kwon OJ et al. Bronchioloalveolar carcinoma: focal area of ground-glass attenuationat thin-section CT as an early sign. Radiology 1996; 199: 485-488. 3. Miller VA, Hirsch FR, Johnson DH. Systemic Therapy of Advanced Bronchioloalveolar Cell Carcinoma: Challenges and Opportunities. J Clin Oncol 2005; 23:3288-3293 4. Cadranel J, Quoix E, Baudrin L et al. IFCT-0401 Trial. A Phase II Study of Gefitinib Administered as First-Line Treatment in Advanced Adenocarcinoma with Bronchioloalveolar Carcinoma Subtype. J Thorac Oncol. 2009;4: 1126–1135. 5. Yoshizawa A, Sumiyoshi S, Sonobe M et al. Validation of the IASLC/ATS/ERS lung adenocarcinoma classification for prognosis and association with EGFR and KRAS gene mutations: analysis of 440 Japanese patients. J Thorac Oncol. 2013; 8: 52-61 6. Travis WD, Brambilla E, Noguchi M et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011; 6: 244-85 7. Travis WD, Brambilla E, Nicholson AG, et al. The 2015 World Health Organization Classification of Lung Tumours: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thor Oncol 2015; 10: 1243-1260. 8. Kakinuma R, Noguchi M, Ashizawa K et al. Natural History of Pulmonary Subsolid Nodules: A Prospective Multicenter Study. J Thorac Oncol 2016; 11: 1012-1028. 9. Travis WD, Asamura H, Bankier AA et al. The IASLC lung cancer staging project: proposals for coding T categories for subsolid nodules and assessment of tumor size in part-solid tumors in the forthcoming eighth edition of the TNM classification of lung cancer. J Thor Oncol 2016; 11: 1204-1223. 10.Cadranel J, Gervais R, Merle P et al. Erlotinib versus carboplatin and paclitaxel in advanced lepidic adenocarcinoma: IFCT-0504. Eur Respir J 2015; 46: 1259–1261. 11. Tsao MS, Marguet S, Le Teuff G et al. Subtype classification of lung adenocarcinoma predicts benefit from adjuvant chemotherapy in patients undergoing complete resection. J Clin Oncol 2015; 33: 3439-3446. 12. Kim HK, Choi YS, Kim J et al. Management of Multiple Pure Ground-Glass Opacity Lesions in Patients with Bronchioloalveolar Carcinoma. J Thorac Oncol. 2010;5: 206–210.

Abstract:
A ground glass opacity (GGO) is a radiographic finding defined as hazy, increased attenuation of the lung with preservation of bronchial vascular margin. A subsolid nodule (SSN) includes pure ground glass nodules and partsolid nodules in which both solid and ground glass components are present. These nodules are nowadays more commonly found with the introduction of CT screening programs. The optimal management of patients with SSN is of growing clinical concern. The newly (1) introduced adenocarcinoma classification makes a clear distinction between pre-invasive lesions (atypical adenomatous hyperplasia), adenocarcinoma in situ (AIS: ≤ 3cm pure lepidic growth without invasion), minimally invasive adenocarcinoma (MIA: ≤ 3cm lepidic growth with ≤ 5mm invasion) and invasive adenocarcinoma (IA) of different subtypes. Preinvasive lesions or MIA have an excellent survival and might be treated with sublobar resection. IA (especially certain subtypes) are more aggressive and should be treated with lobar resection combined with systematic nodal dissection. Pure GGO lesions can be non-specific inflammation, fibrosis or neoplasm. Recent guidelines (2) recommends for pure GGO nodules ≥6mm follow-up scan at 6 to 12 months and then every 2 years until 5 years. In a retrospective study (3) 83 patients with pure GGO lesion that had surgery and proved to be adenocarcinoma were described. 79,5 % were non IA and 20,5 % (IA). In a multivariate logistic regression analysis both preop GGO size on CT and pleural retraction were predictive factors for IA. Pure GGO lesions ≥ 10 mm should be resected if they persist or grow on follow-up CT. Partsolid nodules. When a nodule is partially solid or when in a GGO lesion a solid part appears, the risk of IA increases. In a prospective multicentric study Suzuki et al looked at radiologic criteria for predicting pathologic early (non-invasive) adenocarcinoma (4). In this study, the consolidation/tumor (C/T)ratio was measured in lung and mediastinal window settings. Radiologic non-invasive longadenocarcinoma could be defined as a subsolid nodule ≤2cm with a (C/T) ratio of 0.25 or less. Asamura et al (5) re-evaluated the radiology pathology correlation in this study in term of the prognosis. The radiologic criteria of a C/T ratio of 0.25 or less in tumor ≤3cm as well as 0.25 or less in tumors ≤2cm could be used to define a homogeneous group of patients with an excellent prognosis after surgery. These criteria can be used to select patients with early lung adenocarcinoma in which a sublobar resection (wedge or segmentectomy) would be safely indicated. For lesions with a tumor diameter of 2.0cm and a C/T ration >0.25 a prospective randomized fase III study comparing lobectomy and segmentectomy is ongoing (6). The incidence of N2 disease in clinical T1-T2N0 was evaluated (7). The incidence of unforeseen N2 disease was 1.5% in pure GGO lesions. N2 disease was found in 4.3% of semi solid tumors and 12.6% in pure solid tumors. In a multivariate analysis, tumors with any GGO components were less likely to have N2 disease (Odds ratio 0.14, 0.001). A recent study (8) used a nomogram for predicting the risk of IA in patients with solitary peripheral subsolid nodules. In a multivariate analysis the occurrence of IA was significantly correlated with lesion size, spiculation, vascular convergence and pleural tag. There are different subtypes of IA. The micropapillary and solid types are aggressive subtypes with a high rate of N2 (9). These types cannot be used for sublobar resection. Huang et al (10) analyzed histology obtained by CT guided needle biopsy or EBUS. Concordant subtyping of adenocarcinoma between the predominant pattern on resections and biopsy section was only observed in 58.6% of the cases. For high grade adenocarcinoma detection, preoperative biopsy had a low sensitivity (16.5%). So preoperative obtained histology cannot show us which type of resection we should perform. The degree of invasion is often overestimated in frozen section. However, frozen section has a high specificity for micropapillary and subsolid pattern (11). If this subtype is found during surgery by frozen section, lobectomy and lymph node dissection should be performed. Conclusion By modern imaging subsolid nodules containing GGO lesions are more often seen. When the C/T ratio is more than 50% there is a high risk of IA with certain subtypes which are very aggressive. These lesions should be managed by lobectomy and lymph node dissection until results from prospective studies are known. For lesions ≤2cm, with C/T ratio ≤25% wedge or segmentectomy can be the appropriate intervention. When a limited resection is performed, the margins and the lymph nodes should be examined by frozen section. 1.Travis WD, Brambilla E, Noguchi M et al. International Association for the Study of Lung cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma. J Thorac Oncol 2011;6:244-285 2.MacMahon H, Naidich D, Goo JM et al. Guidelines for management of incidental pulmonary nodules detected on CT images : from the Fleischner Society 2017. Radiology 2017;284:228-243 3.Moon Y, Sung SW, Lee KW et al. Pure ground-glass opacity on chest computed tomography: predictive factors for invasive adenocarcinoma. J Thorac Dis 2016;8:1561-1570 4.Suzuki K, Koike T, Asakawa T et al. A prospective radiological study of thin-section computed tomography to predict pathological noninvasiveness in peripheral clinical IA lung cancer (Japan clinical oncology group 0201). J Thorac Oncol 2011;6:751-756 5.Asamura H, Hishida T, Suzuki K et al. Radiographically determined noninvasive adenocarcinoma of the lung : survival outcomes of Japan Vlinical Oncology Group 0201. J. Thorac Cardiovasc Surg 2013;146:24-30 6.Nakamura K, Saji H, Okada M et al. A phase III randomized trial of lobectomy versus limited resection for small-sized peripheral non-small cell lung cancer (JCOG0802/WJOG4607L). Jpn J Clin Oncol 2010;40:271-274 7.Gao SJ, Kim AW, Puchalsky JT et al. Indications for invasive mediastinal staging in patients with early non-small cell lung cancer staged with PET-CT. Lung Cancer 2017;109:36-41 8.Jin C, Cao J, Cai Y et al. A nomogram for predicting the risk of invasive pulmonary adenocarcinoma for patients with solitary peripheral subsolid lesions. J Thorac Cardiovasc Surg 2017;153:462-9 9.Hung JJ, Yeh YC, Wu YC et al. Factors predicting occult lymph node metastasis in completely resected lung adenocarcinoma of 3 cm or smaller. Europ J Cardio-Thorac Surg 2016;50:329-336 10.Huang KY, Ko PZ, Yao CW et al. Inaccuracy of lung adenocarcinoma subtyping using preoperative biopsy specimens. J Thorac Cardiovasc Surg 2017;154:332-9 11.Yeh YC, Nitadori JI, Kadota K et al. Using frozen section to identify histologic patterns in stage I lung adenocarcinoma ≤3 cm: accuracy and interobserver agreement. Histopathology 2015;66:922-938

Abstract:
With the advent of Chest CT screening, the identification of abnormalities has increased substantially. In addition to very small nodules of indeterminate significance, “ground glass opacities” (GGO) are often seen. Numerous series have been collected around the world attempting to define characteristics that predict the malignant potential of these GGOs. It is clear that a substantial fraction includes a component of invasive adenocarcinoma and warrant resection for cure prior to developing disseminated cancer. This presentation will review the literature for developing a rational algorithm for selection of those patients requiring which operation, as well as review outcomes. 1. Radiological determinants of malignancy using high-resolution CT and CT/PET 2. Criteria for patient section for resection or observation 3. Techniques for pre-resection localization for intraoperative identification of lesion 4. Appropriate selection lesions for extent of resection (lobe, segment or non-anatomic wedge) 5. Approach for resection 6. Outcomes after treatment Selected References Matsunaga T, Suziki K, Takamochi K, Oh S. What is the radiological definition of part-solid tumor in lung cancer? Eur J Cardiothorac Surg 2017; 51:242-247 Eguchi T, Kondo R, Kakkami S, Matsushita M, Yoshizawa A, Hara D, Matsuoka S, Tkeda T, et al. CT attenuation predicts the growth of pure GGO nodules Lung Can 2014;84:242-247 Suzuki K, Asamura H, Kusumoto M, Kondo H, Tsuchiya R. Early peripheral lung cancer: prognostic significance of GGO on thin section CT scan Ann Thorac Surg 2002;74:1635-9 Lee S, Leem C, Kim T, Lee K, Chung J, Jheon WS, Lee C. The long term follow-up of GGO detected on thin-section CT Respir Med 2013;107:904-10 Suzuki K, Shimohira M, Hashizume T, Ozawa Y, Sobue R, Mimura M, Mori Y, Ijima H, Watanabe K, Yano M, Yoshioka H, Shibamoto Y. Usefulness of CT-guided hookwire marking before VATS for small pulmonary lesions J Med Imag Rad Oncol 2014; 58:657-662. Mong-Wei L, Yao-Hui T, Yee-Fan L, Min-Shu H, Wei-Chun K, Jo-Yu C, Hsao-Hsun H, Yeun-Chung C, Jin-Shing C. Comuted tomography-guided patent blue vital dye localization of pulmonary nodules in uniportal thoracoscopy J Cardiovasc Surg 2016; 152:535-44 Fukui M, Suziki K, Matsunaga T, Oh S, Takamochi K. Surgical intervention for GGO-dominant lesions: observation or outright resection? Pan J Clin Oncol 2017;18:1-6 Cao C, Gupta S, Chandrakumar D, Tian D, Black D, Yan T. Meta-analysis of intentional sublobar resections versus lobectomy for very early stage non-small cell lung cancer Ann Cardiothorac Surg 2014; 3:134-141 Kodama K, Higashiyayma M, Tkami K, Oda K, Okami J, Maeda J, Koyama M, Nakayama T. Treatment strategy for patients with small peripheral lung lesions: Prospective study Eur J Cardiothoracic Surg2008; 34:1068-74 Yoshioka M, Ichiguchi O. Selection of sublobar resection for c-stage1A non-small cell lung cancer based on a combination of structural imaging by CT and functional imaging by FDG-PET Ann Thorac Cardiovasc Surg 2009; 15:82-8. Kohno T, Fujimoro S, Kishi K, Fujii T. Safe and effective minimally invasive approaches for small GGOs Ann Thorac Surg 2010; 89; 1114-7 Tsutani Y, Miyata Y, Nakayama H, Okurmura S, Adachi S, Yoshimura M, Okada M. Appropriate sublobar resection choice for GGO-dominant clinical stage 1A lung Adenocarcinoma Chest 2014; 145:66-71 Sook Y, Sung S, Mankoong M, Park K. The effectiveness of mediastinal node evaluation in a patient with GGO tumor J Thorac Dis 2016; 8:2617-2623 Wei S, Khao K, Guo C, Mei J, Pu Q, Ma L, Che G, Chen G, Wu Z, Wang Y, Kuo Y, Lin Y, Li W Lui L. Diagnosis and surgical treatment of lung GGO: a review of 663 cases. Sichan Da Xue Bao Yi Xue Ban 2017:48:359-362 Moon Y, Lee K, Moon S, Park J. Sublobar resection margin does not affect recurrence of clinical N0 non-small cell lung cancer presenting as GGO. World J Surg 2017;41:472-9 Hattori A, Matsunaga T, Takamochi K, Oh S, Suzuki K. Surgical Management of Multifocal Ground-Glass Opacities of the Lung: Correlation of Clinicopathologic and Radiologic Findings Thorac Cardiovasc Surg 2017; 65:142-14 Shimada Y, Saji H, Otani K, Maehara S, Maeda J, Yoshida K, Kato Y, Hagiwara M, Kakihana M, Kajiwara N, Ohira T, Akata S, Ikeda N. Survival of a surgical series of lung cancer patients with synchronous multiple ground-glass opacities, and the management of their residual lesions Lung Cancer 88 (2015) 174-180

Abstract:
Purpose/Objective(s): The popularization of computed tomography (CT) in clinical practice have increased a frequency of discovering ground-glass opacity (GGO)-containing tumor in lung. Surgery has been regarded as the general treatment including a purpose of histological examination for such tumors and its prognosis is better than that of solid-type tumors. Stereotactic body radiation therapy (SBRT) is a rapidly prevailing treatment modality in the radical treatment of mainly inoperable or high risk operable cases with stage I non-small cell lung cancer (NSCLC), but the most tumors treated with SBRT were solid type because SBRT has been performed principally for the pathology-proven tumors and it is generally difficult to acquire histological specimen in the tumors composed of GGO. Therefore a prognosis of the stage I NSCLC cases treated with SBRT when their tumors contained GGO has not been clear. The purpose of this presentation is to review the treatment outcomes for SBRT for the patients with GGO-containing tumor in our multi-institutional SBRT study group of Japanese Radiological Society (JRS-SBRTSG), and to discuss how we consider the validity of SBRT for them. Materials/Methods: GGO was defined as hazy opacity that does not obscure underlying bronchial structures or pulmonary vessels at high-resolution computed tomography. We have reviewed 174 patients (89 men, 85 women; mean age, 74 years) treated with SBRT whose lung tumor showed appearance of GGO accompanying solid component ratio to the whole tumor (S/T ratio) less than 50 % in diameter of the tumor and no metastases. SBRT was done because of the pathological proof, positive accumulation on PET study or growth of the tumor. In histology, 69 tumors were adenocarcinoma, 8 were squamous cell carcinoma, 5 were unclassified carcinoma and 92 cases were histology-unproven. The median tumor size was 23 mm (range, 9-53 mm). SBRT was performed using non-coplanar multiple static ports or dynamic arcs. A total dose of 40 -70 Gy (6-15 Gy / fraction) was prescribed in 4-10 fractions. Median biological effective dose (BED) was 108 Gy (range, 72-150 Gy) based on alpha/beta = 10 Gy. Survival, recurrence, and metastases rates were calculated using Kaplan-Meier method. Results: Median follow-up was 32 months. The 3-year local recurrence, regional lymph-node metastases, and distant metastases rates were 3.8%, 4.1%, and 8.6%, respectively. Mean S/T ratios of the subgroup with any recurrences and the subgroup with no recurrence were 22% and 4%, respectively. The rates of cause-specific and overall survival (OS) at 3 years were 98.1% and 85.6%, respectively. The 3-year OS rates of medically operable and inoperable subgroups were 96.2% and 85.6%, respectively. The 3-year OS rate of medically operable and histology-proven subgroup was 88.1%. The 3-year OS of female subgroup was 95.0% and it was significantly better overall survival rate than male. The treatment-related pneumonitis of grade 3 or more was observed in 3.4% of the total patients. Summary and Discussion: Natural course of GGO-containing tumor is much better than that of solid-type tumors. Sublober limited resection would be acceptable in the subgroup of stage I NSCLC if the tumor appears GGO for the most part because they have mostly no invasion nor metastases. SBRT is a so localized treatment only for the tumor that a study comparing SBRT versus limited surgery without regional lymph node resection might have a rationale of randomization for such candidates, however, we have to demonstrate the prognosis and risk factors regarding recurrence, survival, and late toxicity after SBRT with longer follow-up (more than 10 years). In conclusion, the outcomes of SBRT for patients with GGO-containing tumor (solid component was less than 50 % in total diameter) were excellent but some cases had local recurrence or metastases. GGO-containing in most of the tumor seldom produced local progression, lymph node metastases, or distant metastases after SBRT. Although more cases and longer follow up are mandatory, SBRT may be one of the radical treatment options for stage I NSCLC patients with GGO-containing tumor. We hope to have a further discussion regarding the validity of SBRT for them.

Abstract not provided

Abstract:
NSCLC is a heterogenous disease withvariable molecular mutations. Vi-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) is one of the most common oncogenic drivers, especially in lung cancer, found in around 25-30% adenocarcinomas. The other molecular abnormalities related to RAS pathway are EGFR (10-23%), BRAF (2%), MET (2%), HER2 (1%) and NRAS (0.2%). Within KRAS, the most common mutations are G12C (40%), G12V (21%), G12D (17%), G12A (10%) and other (12%) G12 and G13 mutations [Dogan. Clinical Cancer Research 2012; 18: 6169-6177]. KRAS mutations are associated with poorer outcomes in NSCLC. Renaud et al, showed that KRAS mutant patients had worser outcomes compared to wild type cases[1]. KRAS may be a negative predictor of responsiveness to cytotoxic therapy based off of retrospective data. In addition, Renaud and colleagues have shown that KRAS mutations may be predictive of resistance to radiation therapy. Identifying ways to target these KRAS mutations may lead to benefit for patients in combination with other traditional means of treatment. Directly blocking RAS activity has remained difficult to attain, due to a variety of mechanisms and yet to demonstrate efficacy clinically. Therefore, much more focus has been spent on downstream targets of KRAS. Selumetinib an oral inhibitor of the mitogen-activated protein kinase kinase (MEK) 1/2 had promising phase II results in combination with docetaxel in comparison to docetaxel alone. Unfortunately, in the multicenter Phase III, SELECT-1 trial with 510 patients, PFS and OS were no different in the selumetinib and docetaxel arm versus docetaxel alone. This may be in part due to an increase in RAF-depedent MEK phosphorylation that may interfere with its efficacy. Combining inhibitors that target different components or parallel pathways have yielded success in other tumors like melanoma with combination MEK and BRAF inhibition. For KRAS mutant tumors, the PI3K-AKT- mTOR pathway has also been examined as it has been thought it can bypass resistance to MEK inhibition. The combination of MEK in addition to PI3K-aKT-mTOR has yet to yield any clinically impactful results. Inhibtion of the cysteine residue on KRAS G12C, which makes up more than 40% of KRAS mutants, has been shown to have some activity preclinically [2, 3] Our preliminary data shows that, KRAS is frequently associated with co-occuring mutations. The most common of these were TP53 (n=15, 25%), ATM (n=9, 15%), LRP1B (n=9, 15%), ARID1A (n=8, 13%), STK11 (n=8, 13%), ARID1B (n=7, 12%), TERT (n=7, 12%), EGFR (n=6, 10%), RBM10 (n=6, 10%), SPTA1 (n=6, 10%). We still are not clear on the role of co-mutations and their specific function as sensitizers or agents resistance. It was previously shown that KRAS plus TP-53 mutations had impaired response to docetaxel monotherapy. The addition of selumetinib provided substantial benefit in mice models [4]. Also, STK11 mutations in conjunction with KRAS mutant NSCLC has been shown to infer resistance to PD-1/PDL-1 blockade [5]. Lung cancer frequently exhibits upregulation of angiogenesis and has been reported to be associated with a negative prognostic factor. Over the past decade, novel insights into the role of angiogenesis in NSCLC tumor growth and progression have provided a rationale for the development of anti-angiogenic agents. The use of anti-angiogenic agents to treat NSCLC gained clinical interest in 2006, when the results of the Eastern Cooperative Oncology Group (ECOG) Trial 4599 were published in the New England Journal of Medicine and showed for the first-time improved overall survival(OS) and progression-free survival after the addition of bevacizumab (Avastin, Genentech), a humanized monoclonal antibody that inhibits the process of angiogenesis by binding to the vascular endothelial growth factor A (VEGF-A) protein, to treatment with carboplatin and paclitaxel in 878 patients who had recurrent or advanced NSCLC [6]. Since then, no other anti-angiogenic agent (such as sunitinib, sorafenib, etc.) has been able to demonstrate improved OS for patients with lung cancer. This may be in part because the mechanisms of actions for those drugs is completely different from bevacizumab; they work by inhibiting the internal tyrosine kinase domain of the VEGF receptor and are also not completely selective for the VEGF receptor and also hit other targets (such as PDGF, FGFR, etc.) [6]. This may play a role in the increased toxicity for these inhibitors and the subsequent lower OS. Since the recent positive data showing benefit of first-line carboplatin, pemetrexed, and pembrolizumab may lead to expedited FDA approval, the utility of anti-angiogenic drugs may enter a renaissance as a second-line therapeutic option. However, another consideration has to be made in the pursuit of improved anti-angiogenic drugs where the clinical and financial “value” for the patient are factored in clinical decision making. Though the VEGF/VEGFR pathway is seen as a crucial mediator of tumor survival and growth, the treatments currently available are overshadowed by excessive costs and several cost-effective analyses of bevacizumab have shown that the use of the drug can cost up to 350,000 per life-year gained [7]. References 1. Renaud, S., P.-E. Falcoz, M. Schaeffer, et al., Prognostic value of the KRAS G12V mutation in 841 surgically resected Caucasian lung adenocarcinoma cases. Br J Cancer, 2015. 113(8): p. 1206-1215. 2. Ostrem, J.M., U. Peters, M.L. Sos, J.A. Wells, and K.M. Shokat, K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature, 2013. 503(7477): p. 548-51. 3. Patricelli, M.P., M.R. Janes, L.S. Li, et al., Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State. Cancer Discov, 2016. 6(3): p. 316-29. 4. Chen, Z., K. Cheng, Z. Walton, et al., A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature, 2012. 483(7391): p. 613-617. 5. Skoulidis, F., M.D. Hellmann, M.M. Awad, et al., STK11/LKB1 co-mutations to predict for de novo resistance to PD-1/PD-L1 axis blockade in KRAS-mutant lung adenocarcinoma, 2017, American Society of Clinical Oncology. 6. Socinski, M.A., ANGIOGENESIS INHIBITION FOR THE TREATMENT OF NON–SMALL CELL LUNG CANCER. CLINICAL ADVANCES IN HEMATOLOGY AND ONCOLOGY, 2016. 14(5): p. 336-338. 7. Goulart, B. and S. Ramsey, A trial-based assessment of the cost-utility of bevacizumab and chemotherapy versus chemotherapy alone for advanced non-small cell lung cancer. Value Health, 2011. 14(6): p. 836-45.

Abstract:
MET activation in non-small cell lung cancers (NSCLCs) can occur via mechanisms including mutation and amplification. MET exon 14 splicing alterations and MET amplification are clinically actionable genomic alterations. Response to MET-directed targeted therapy has been reported for both subsets. In a phase 1 study of crizotinib for patients with MET exon 14-altered NSCLCs, the overall response rate (ORR) was 39% and the median progression-free survival was 8 months (Drilon et al, ASCO 2016). In the same phase 1 study, the ORR for crizotinib in patients with MET-amplified NSCLC was 17% and 50% for tumors with a FISH MET/CEP7 ratio of >2.2 to <5 and ≥5, respectively (Camidge et al, ASCO 2014). Furthermore, acquired MET amplification is associated with resistance to EGFR tyrosine kinase inhibition in EGFR-mutant lung cancers. Response to combined EGFR- and MET-directed therapy has been reported in patients with EGFR-mutant lung cancers with acquired resistance to prior EGFR tyrosine kinase inhibitor therapy. Prospective clinical trials of various MET inhibitors as single-agents or in combination with other therapies are ongoing. A number of different MET inhibitors have been tested in the clinic, including multikinase inhibitors with activity against MET such as crizotinib and cabozantinib, MET-selective inhibitors such as capmatinib, and MET antibodies such as onartuzumab and embituzumab. Newer agents such as MET antibody-drug conjugates are being explored. Data on acquired resistance to MET-directed targeted therapy has begun to emerge. The MET D1228N and D1228V kinase domain mutations have been identified as acquired mechanisms of resistance to MET tyrosine kinase inhibition (Heist et al, J Thoracic Oncol 2016; Bachall et al, Cancer Discov 2017)). The detection of MET mutation and amplification in the clinic is thus important, but is associated with specific challenges, and requires a comprehensive approach to testing. Notably, molecular profiling should not be restricted to the classic population of younger, never or former light cigarette smoker patients with advanced lung adenocarcinomas where other drivers such as sensitizing EGFR mutations and ALK or ROS1 rearrangements are enriched; MET exon 14 alterations, for example, are found in older patients with a more substantial prior smoking history, and in sarcomatoid carcinomas of the lung. The role of MET immunohistochemistry in selecting patients for MET-directed targeted therapy in the absence of comprehensive molecular profiling remains controversial, although the experience with this approach in prior prospective clinical trials has been disappointing. Advances have clearly been made in the development of MET-directed targeted therapy for subsets of patients with advanced NSCLCs that are hopefully moving the field closer to the regulatory approval of one or more these agents in the future.

Abstract:
Aberrant activation of fibroblast growth factor (FGF) signaling due to up-regulation of FGF receptor gene (FGFR) expression, alternative splicing of FGFR transcripts, FGFR mutations or translocations, or increased availability of FGF has been found to contribute to prognosis in several types of tumors(1, 2). Our previous evidence suggest that these gene alterations increase the sensitivity to multi-kinase inhibitors (3, 4, 5). FGFR gene alterations are relatively frequent in lung squamous cell carcinoma (LSCC) and are a potential targets for therapy with FGFR inhibitors. However, little is known regarding the clinicopathologic features associated with FGFR alterations. The angiokinase inhibitor nintedanib has shown promising activity in preclinical and clinical studies for non-small cell lung cancer and other solid tumors (6,7,8). We have now applied next-generation sequencing (NGS) to characterize FGFR alterations in LSCC patients as well as examined the antitumor activity of nintedanib in LSCC cell lines positive for FGFR1 copy number gain (CNG). The effects of nintedanib on the proliferation of and FGFR signaling in LSCC cell lines were examined in vitro, and its effects on tumor formation were examined in vivo. A total of 75 clinical LSCC specimens were screened for FGFR alterations by NGS. Nintedanib inhibited the proliferation of FGFR1 CNG-positive LSCC cell lines in association with attenuation of the FGFR1-ERK signaling pathway in vitro and in vivo. FGFR1 CNG (10.7%), FGFR1 mutation (2.7%), FGFR2 mutation (2.7%), FGFR4 mutation (5.3%), and FGFR3 fusion (1.3%) were detected in LSCC specimens by NGS. Clinicopathologic features did not differ between LSCC patients positive or negative for FGFR alterations. However, among the 36 patients with disease recurrence after surgery, prognosis was significantly worse for those harboring FGFR alterations. Screening for FGFR alterations by NGS warrants further study as a means to identify patients with LSCC recurrence after surgery who might benefit from nintedanib therapy. 1) Mizukami T, et al. Mol Carcinog. 2017;56(1):106-117. 2) Matsumoto K, et al. Br J Cancer. 2012;106(4):727-32. 3) Arao T, et al. Hepatology. 2013;57(4):1407-15. 4) Sakai K, et al. Oncotarget. 2015;6(25):21636-44. 5) Kaibori M, et al. Oncotarget. 2016; 7(31):49091-49098. 6) Kudo K, et al. Clin Cancer Res. 2011; 17(6):1373-81. 7) Okamoto I, et al. Mol Cancer Ther. 2010; 9(10):2825-33. 8) M. Takeda K. et al. Ann Oncol. 2016; 27(4): 748–750.

Abstract:
Chromosomal rearrangements or deletions can generate novel gene fusions that lead to the expression of chimeric proteins with oncogenic activity in lung and other cancers. The paradigm for gene fusions in lung cancer is the EML4-ALK gene fusion which is found in approximately 5% of lung adenocarcinomas.[1] Once identified, drug development for this target proceeded rapidly and crizotinib was the first approved tyrosine kinase inhibitor for patients with ALK+ non-small cell lung cancer based on its ability to generate substation objective response rates and prolonged progression free survival (NSCLC).[3,4 ]The development of CNS penetrant and/or next generation ROS1 inhibitors including lorlatinib, entrectinib and TPX-0005 is ongoing. RET gene fusions are also found in 1-2% of NSCLC, but the use of multiple different RET inhibitors have failed to reproduce the success of targeting ALK or ROS1 fusions.[5 ]The development of more selective RET inhibitors such as LOXO-292, BLU-667, and RXDX-105 are currently in clinical trials for RET+ lung and other cancers. NTRK1 fusions were recently identified in NSCLC and homologous NTRK2 and NTRK3 fusions are found in multiple tumor types.[6,7, ]Early clinical trials of larotrectinib showed an impressive objective response rate of 76% for 12 different tumor histologies harboring NTRK1/2/3 fusions and the CNS-penetrant entrectinib is similarly being evaluated in a basket trial. Other rare, novel fusions have recently been identified in NSCLC including EGFR fusions or MET fusions.[7] Early evidence suggests that these fusions may also respond to cognate TKIs. EGFR fusions break the paradigm of ALK and ROS1 fusions in which the 5’ end of ALK or ROS1 is replaced with the 5’ portion of another gene. EGFR fusions retain most of the EGFR gene, with the unrelated gene sequencing fusing at the 3’ end of EGFR. A related oncogenic EGFR mutation in which the kinase domain of EGFR is duplicated in tandem has also been described and appears responsive to EGFR TKIs.[7] Additional fusions involving the receptor tyrosine kinase (RTK) encoding genes AXL, PDGFRA, and ERBB4 fusions have been described, but little is known about the true incidence in lung cancer.[8,9] The fusions described thus far all involve genes that encode RTKs, but additional gene fusions have also been identified in lung cancer including BRAF fusions.[7,9 ]BRAF fusions replace the 5’ region of BRAF, including the Ras-binding domain (RBD), with sequences from another gene. Anecdotal evidence suggest that these alterations may be responsive to MEK inhibition. Analogous splice alteration which remove a region including the RBD have also been described in cancer and are oncogenic. Finally, gene fusions involving NRG1, which encodes the HER3/4 ligand neuregulin-1, have been described, mostly in invasive mucinous adenocarcinomas of the lung.[9,10 ]Several challenges exist to the development of targeted therapies for these novel fusions. Even in the era of next-generation sequencing tests these alterations may go undetected due to limited testing of genes to those with approved therapies (ALK, ROS1, EGFR, and BRAF) and not all assays are designed to detect all of these alterations. Furthermore, the rarity of some of these alterations may make clinical trials for these novel fusions less appealing, although amalgamating some of these alterations with analogous mutations, e.g., MET gene fusions with MET exon 14 splice alterations or MET gene amplification, may allow for a more rapid path to approval. References 1. Chia PL, Mitchell P, Dobrovic A, et al: Prevalence and natural history of ALK positive non-small-cell lung cancer and the clinical impact of targeted therapy with ALK inhibitors. Clin Epidemiol 6:423-32, 2014 2. Camidge DR, Bang YJ, Kwak EL, et al: Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. The lancet oncology 13:1011-9, 2012 3. Davies KD, Le AT, Theodoro MF, et al: Identifying and targeting ROS1 gene fusions in non-small cell lung cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 18:4570-9, 2012 4. Shaw AT, Ou SH, Bang YJ, et al: Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 371:1963-71, 2014 5. Gautschi O, Milia J, Filleron T, et al: Targeting RET in Patients With RET-Rearranged Lung Cancers: Results From the Global, Multicenter RET Registry. J Clin Oncol 35:1403-1410, 2017 6. Vaishnavi A, Capelletti M, Le AT, et al: Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nature medicine 19:1469-72, 2013 7. Stransky N, Cerami E, Schalm S, et al: The landscape of kinase fusions in cancer. Nat Commun 5:4846, 2014 8. Seo JS, Ju YS, Lee WC, et al: The transcriptional landscape and mutational profile of lung adenocarcinoma. Genome Res 22:2109-19, 2012 9. Nakaoku T, Tsuta K, Ichikawa H, et al: Druggable oncogene fusions in invasive mucinous lung adenocarcinoma. Clin Cancer Res 20:3087-93, 2014 10. Fernandez-Cuesta L, Plenker D, Osada H, et al: CD74-NRG1 fusions in lung adenocarcinoma. Cancer Discov 4:415-22, 2014

Abstract:
Cancer stem cells (CSCs) are a subset of tumor cells that are responsible for initiating and maintaining the disease. In the clinical point of view, the most important characteristics of CSCs include their resistance to various therapeutic interventions[1)]. However, the underlying mechanisms of the resistance remain unclear. CD44 has been identified as a cell surface marker associated with cancer stem cells (CSCs) in several types of epithelial tumor. We have recently found that expression of CD44, in particular variant forms of CD44 (CD44v), contributes to the defense against reactive oxygen species (ROS) by promoting the synthesis of reduced gluathione (GSH), a primary intracellular antioxidant. CD44v interacts with and stabilizes xCT, a subunit of a glutamate-cystine transporter, and thereby promotes the uptake of cystine for GSH synthesis[2)]. Therefore, ablation of CD44 reduced GSH levels and increased ROS levels, leading to suppression of tumor growth and metastasis in both transgenic and xenograft tumor models[3,4)]. Our findings reveal a novel function for CD44v in protection of CSCs from high levels of ROS in the tumor microenvironment[5)]. Expression of CD44v and xCT is associated with tumorigenesis and therapeutic resistance[6,7)]. Based on these preclinical findings, we conducted clinical trials using an xCT inhibitor, sulfasalazine, for cancer patients having advanced gastric cancer and lung cancer. The clinical trials for gastric cancers revealed that sulfasalazine treatment reduceed the number of CD44v-positive cells in post-treatment tumor tissue[8,9)]. In terms of the clinical trial for lung cancer, chemotherapy-naive patients with advanced non-squamous nonsmall cell lung cancer were enrolled in a dose-escalation study (standard 3 + 3 design) of SASP in combination with cisplatin and pemetrexed[10)]. Fifteen patients were enrolled in the study and dose-limiting toxicity was observed in one of six patients at a SASP dose of 1.5 g/day, two of five patients at 3 g/day, and two of three patients at 4.5 g/day. The maximum tolerated dose was thus 3 g/day, and the recommended dose was 1.5 g/day. The overall response rate was 26.7% and median progression-free survival (PFS) was 11.7 months, much longer than that for cisplatin–pemetrexed alone in previous studies. It is possible that the prolonged PFS was due to a sulfasalazine-induced reduction in the number of CD44v-positive CSCs that are the origin of disease recurrence. References: 1) Sugihara E and Saya H: Complexity of cancer stem cells (Review article). Int J Cancer 132:1249-1259, 2013 2) Ishimoto T, Nagano O, Yae T, Tamada M, Motohara T, Oshima H, Oshima M, Ikeda T, Asaba R, Yagi H, Masuko T, Shimizu T, Ishikawa T, Kai K, Takahashi E, Imamura Y, Baba Y, Ohmura M, Suematsu M, Baba H and Saya H: CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc- and thereby promotes tumor growth. Cancer Cell 19: 387-400, 2011 3) Yae T, Tsuchihashi K, Ishimoto T, Motohara T, Yoshikawa M, Yoshida GJ, Wada T, Masuko T, Mogushi K, Tanaka H, Osawa T, Kanki Y, Minami T, Aburatani H, Ohmura M, Kubo A, Suematsu M, Takahashi K, Saya H and Nagano O: Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell. Nat Commun 3: 883, 2012 4) Yoshikawa M, Tsuchihashi K, Ishimoto T, Yae T, Motohara T, Sugihara E, Onishi N, Masuko T, Yoshizawa K, Kawashiri S, Mukai M, Asoda S, Kawana H, Nakagawa T, Saya H and Nagano O: xCT inhibition depletes CD44v-expressing tumor cells that are resistant to EGFR-targeted therapy in head and neck squamous cell carcinoma. Cancer Res 73: 1855-1866, 2013 5) Nagano O, Okazaki S and Saya H: Redox regulation in stem-like cancer cells by CD44 variant isoforms (Review article). Oncogene 32: 5191-5198, 2013 6) Seishima R, Wada T, Tsuchihashi K, Okazaki S, Yoshikawa M, Oshima H, Oshima M, Sato T, Hasegawa H, Kitagawa Y, Goldenring JR, Saya H and Nagano O: Ink4a/Arf-dependent loss of parietal cells induced by oxidative stress promotes CD44-dependent gastric tumorigenesis. Cancer Prev Res 8: 492-501, 2015 7) Tsuchihashi K, Okazaki S, Ohmura M, Ishikawa M, Sampetrean O, Onishi N, Wakimoto H, Yoshikawa M, Seishima R, Iwasaki Y, Morikawa T, Abe S, Takao A, Shimizu M, Masuko T, Nagane M, Furnari FB, Akiyama T, Suematsu M, Baba E, Akashi K, Saya H and Nagano O: The EGF receptor promotes the malignant potential of glioma by regulating amino acid transport system xc(-). Cancer Res 76: 2954-2963, 2016 8) Shitara K, Doi T, Nagano O, Imamura CK, Ozeki T, Ishii Y, Tsuchihashi K, Takahashi S, Nakajima TE, Hironaka S, Fukutani M, Hasegawa H, Nomura S, Sato A, Einaga Y, Kuwata T, Saya H and Ohtsu A: Dose-escalation study for the targeting of CD44v[+] cancer stem cells by sulfasalazine in patients with advanced gastric cancer (EPOC1205). Gastric Cancer 20: 341-349, 2017 9) Shitara K, Doi T, Nagano O, Fukutani M, Hasegawa H, Nomura S, Sato A, Kuwata T, Asai K, Einaga Y, Tsuchihashi K, Suina K, Maeda Y, Saya H and Ohtsu A: Phase 1 study of sulfasalazine and cisplatin for patients with CD44v-positive gastric cancer refractory to cisplatin (EPOC1407). Gastric Cancer 2017 (in press) 10) Otsubo K, Nosaki K, Imamura CK, Ogata H, Fujita A, Sakata S, Hirai F, Toyokawa G, Iwama E, Harada T, Seto T, Takenoyama M, Ozeki T, Mushiroda T, Inada M, Kishimoto J, Tsuchihashi K, Suina K, Nagano O, Saya H, Nakanishi Y and Okamoto I: Phase I study of salazosulfapyridine in combination with cisplatin and pemetrexed for advanced non-small cell lung cancer. Cancer Sci 108: 1843-1849, 2017

Abstract:
A better understanding of the interaction between tumors and the immune microenvironment has led to the successful development of immunotherapies for tumors traditionally considered poorly immunogenic, such as non-small cell lung cancer (NSCLC). Clinically approved immunotherapies for lung cancer are based on antibodies able to reactivate cytotoxic T cells by targeting the PD-1/PD-L1 immune checkpoint. However, the substantial proportion of tumors refractory to these treatments, together with the limited predictive value of PD-L1 expression, evidences the existence of additional immune suppressive regulatory systems. This calls for a more detailed understanding of the immune cell landscape related to lung tumors. Some studies have begun to dissect the details of immune cell distribution in lung cancer lesions using multiscale immune profiling strategies. Along with adaptive immune alterations in T cells, significant innate immune cell changes have been identified (1). We have recently reviewed the role played by the innate immune system in supporting tumor-promoting activities and an immunosuppressive microenvironment (2). Innate immunity includes soluble components and immune cell populations, such as myeloid cells. Specific subpopulations of myeloid cells have been identified as specialized immunosuppressive cells. These myeloid-derived suppressor cells (MDSCs) are immature myeloid cells arrested in different stages of differentiation. The recognition of these cells as a defined cell lineage remains controversial, but their cancer-specific phenotypic and functional characteristics are manifest (3). Chronic inflammation factors released by tumors induce the accumulation of these immature cells in the bone marrow, which are released to the circulation and recruited to tumors. MDCSs are thought to be major contributors to T-cell exhaustion. They deplete the tumor microenvironment of amino acids essential for T cell proliferation (e.g. arginine) and produce immunosuppressive cytokines (e.g. IL10 and TGFβ). Increased levels of MDSCs have been described in patients with NSCLC, are associated with poor prognosis and can mediate resistance to chemotherapy (4). Interestingly, in tumor models, accumulation of MDSCs has been proposed as a contributor to the incapacity of the anti-PD-1/PD-L1 blockade to completely reverse the suppressive activity (5). Therefore, stimulation of effector T cells while blocking the immunosuppressive activity of MDSCs represents a rational immunotherapy combination potentially effective for lung cancer. Several agents used in conventional cancer chemotherapy (e.g. gemcitabine, 5-fluorouracil or cyclophosphamide) have been found to reduce MDSC numbers and can be used to deplete this cell subpopulation. However, the use of these drugs results in a profound and unpredictable remodeling of the myeloid cell compartment in the tumor stroma, and careful evaluation of the appropriate timing and dosing is required (6). An alternative strategy recently proposed by us to successfully reverse the tumor immunosuppressive microenvironment is based on the inhibition of the complement system, another essential element of innate immunity. The complement system has developed as a first defense against pathogens or unwanted host elements. The three major pathways of complement activation (the classical, alternative, and lectin pathways) converge in the cleavage of C3 into C3b. C3b deposition leads to the formation of C3 convertases that amplify both opsonization and the complement response, and eventually promote C5 convertase formation and assembly of the membrane attack complex. In addition, enzymatic cleavage of C3 and C5 releases C3a and C5a, two multifunctional immunomodulators. Traditionally, tumor-associated complement activation has been considered as part of the body’s immunosurveillance against cancer. However significant work in recent years has identified new and surprising activities for complement within the tumor microenvironment. In the context of chronic inflammation, complement elements can promote an immunosuppressive response, induce angiogenesis, and activate cancer-related signaling pathways. In the seminal study that shifted the paradigm, Markiewski et al. reported that complement deficiencies were associated with impaired tumor growth in a syngeneic model of cervical carcinoma (7). This study demonstrated that the immunomodulator C5a, generated after complement activation within the tumors, is able to hamper antitumor CD8 T cell-mediated responses. Importantly, this activity was associated with the accumulation of MDSCs in the tumor stroma. In the case of lung cancer, reduction of tumor growth after blockade of the C5a receptor-1 (C5aR1) is accompanied by a decrease in the expression of immunosuppressive molecules and, again, a diminution in the percentage of MDSCs (8). These studies reveal the important role played by C5a/C5aR1 signaling in tumor immunity, and point to this pathway as a potential therapeutic target in the context of checkpoint inhibition. To support this hypothesis, we have recently evaluated the therapeutic efficacy of the combined administration of anti-PD-1 and anti-C5a drugs in a variety of syngeneic models of lung cancer. We demonstrated that the combination of C5a and PD-1 blockade synergistically impairs lung cancer growth and metastasis. This therapeutic effect is accompanied by a negative association between the frequency of CD8 T cells and MDSCs within the tumors, which may result in a more complete reversal of CD8 T-cell exhaustion (9). These studies suggest that inhibition of complement may overcome tumor resistance in cancer immunotherapy, providing support for the clinical evaluation of anti-PD-1 and anti-C5a drugs as a novel combination therapeutic strategy for lung cancer. In conclusion, immunotherapy strategies tailored to restore innate immune modifications might recondition the tumor immunosuppressed niche, strengthening anti-tumor T cell immunity after immune-checkpoint blockade. A more comprehensive knowledge of the dynamic spatiotemporal interactions between the tumors and the microenvironment would be required to predict response, facilitate further investigations in this field, and extend the benefit of immunotherapies to most patients. References 1. Lavin Y et at. Cell 2017;169:750-765. 2. Berraondo P et al. Immunol Rev 2016;274:290-306. 3. Escors T et al. Oncoimmunology 2013;2:e26148. 4. Huang A et al. Cancer Immunol Immunother 2013;62:1439-1451. 5. Youn JI et al. J Immunol 2008;181:5791-5802. 6. Berraondo P et al. Cancer Res 2007;67:8847-8855. 7. Markiewski MM et al. Nat Immunol 2008;9:1225-1235. 8. Corrales L et al. J Immunol 2012;189:4674-4683. 9. Ajona D et al. Cancer Discov 2017;7:694-703.

Abstract not provided

Abstract:
The tumor microenvironment differs significantly from the controlled environment of in vitro cell culture. Whereas cell lines are typically grown in plastic vessels containing a pH buffered, nutrient rich liquid medium with 10% fetal bovine serum and incubated at 37 ­ºC and 5% CO~2~, cancer cells in tumors experience different oxygen tension, growth substrate, nutrient, waste, and growth factor gradients, pH, and the presence of stromal support cells and infiltrating immune cells. The process of establishing a new cell line requires adaptation to this environment, which results in loss of genetic heterogeneity as well as irreversible epigenetic reprogramming that is maintained even when cultured cancer cells are re-introduced to an in vivo setting. Patient-derived xenografts (PDX) are direct human tumor xenografts established and maintained exclusively in mouse hosts. While these models can never perfectly recapitulate an autochthonous human tumor, they are increasingly used as tools in cancer research due to their utility in modeling therapeutic response with higher fidelity than either cell lines or cell line xenografts. A growing interest in defining the role of the tumor microenvironment and in testing the efficacy of immunotherapy in vivo has driven advances in PDX model development. The tumor microenvironment consists of stromal cell components including blood vessels, fibroblasts, and infiltrating immune cells as well as extracellular matrix, growth factors, and nutrients. In PDX, components of the tumor microenvironment are either provided by the mouse host or are excreted by the tumor cells themselves. However, paracrine effects between tumor and stroma may not be entirely replicated in a mouse host due to a lack of cross-species cytokine reactivity. The absence of compatible stroma may bias PDX engraftment toward tumors that are less dependent on paracrine factors or which are more adept at recruiting mouse stromal support cells through enhanced expression of mouse reactive factors. It remains a significant challenge to accurately assess the mechanistic activity of therapeutic approaches designed to inhibit these interactions in the absence of human tumor stroma. Anatomical context can also have significant impact on PDX tumor biology. PDX can be established as subcutaneous flank tumors or at any of a variety of orthotopic sites. Lung PDX are amenable to orthotopic growth in the lung, and can thus be used to model lung cancer growth and metastasis within its normal anatomical context. Orthotopic tumors can have vastly altered metastatic potential and organ preference as well as differential response to anti-cancer therapeutics in comparison to subcutaneous flank tumors. One of the primary limitations of PDX as a model for cancer is the need to use immunocompromised mouse hosts. The degree to which the immune system can be modeled with PDX is dependent on the mouse host chosen and the type of human immune cells used to reconstitute the human immune cell component. PDX can be established in a great variety of different strains of immunocompromised mice including athymic nude mice, severe combined immune deficiency (SCID) and non-obese-diabetic (NOD)-SCID strains, Rag null strains, and profoundly immunocompromised strains in which IL2-Rγc has been disrupted (NSG, NOG, BRG). Each of these strains differs with respect to the type and function of hematopoietic cells. For example, athymic nude mice have intact natural killer (NK) cells, whereas NSG mice do not; NSG mice therefore develop primary tumors and metastases at a much faster rate. Humanized mice are immunocompromised mice that have partially reconstituted human immune components for the purposes of modeling the behavior of the human immune system in a cancer context. NSG, NOG, and BRG mice have been engrafted with isolated peripheral blood mononuclear cells (PBMC) or tumor infiltrating lymphocytes (TIL) primarily to study mechanisms of lymphocyte recruitment; however, a major limitation of this approach is the rapid onset of graft versus host disease in the mouse host. Alternatively, different strains of mice can be engrafted with human CD34+ hematopoietic stem cells (HSC), which results in mouse hosts with fully human lymphocytes, monocytes, dendritic cells and in some cases NK cells. A variety of mouse strains engineered to express human cytokines such as IL-3 and GM-CSF have been developed to promote improved functional human immune system components. PDX models of lung cancer are growing in complexity, variety, and sophistication. These in vivo cancer models will be an integral component in a suite of tools for studying many aspects of lung cancer biology in a research environment. Recent advances in the humanization of mouse hosts promises texpand the possibilities of studying cancer immunology and immunotherapy of human tumors in an experimental setting in vivo.

Abstract:
The abundance of somatic alterations and their heterogeneity between SCLC patient tumors present the immense scientific and clinical challenges. Functional characterization of recurrent mutations in SCLC is an essential step towards understanding the pathogenesis. However, it remains extremely difficult due to the lack of systematic and informed ways of defining oncogenic drivers, especially those involved in early stage tumor development. While the inaccessibility of precancerous lesion in the patients has precluded characterization of lung cancer mutations, we have developed a precancerous cell-based model of SCLC development as a streamlined approach for characterizing novel mutations and determining mutation-driven oncogenic pathways [Kim et al. 2016, Genes and Development]. Using compound transgenic mice expressing neuroendocrine specific GFP in the GEMM of SCLC (Chga-GFP/Rb/p53/Rbl2), we isolated pulmonary neuroendocrine cells one month after adenoviral Cre-mediated tumor induction, at which time the lungs did not show macroscopic lesions (Figure 1). Notably, these cells from an early stage of tumor development grew as adherent monolayers in culture and did not form subcutaneous tumors in nude mice, whereas tumor cells formed floating aggregates and formed the subcutaneous tumors. These findings indicated that these neuroendocrine cells, lacking Rb and p53, were immortalized but not transformed. Therefore, we postulated that these cells were precancerous cells of SCLC (preSC). We then tested whether preSC could be transformed by an oncogene, using a retroviral vector carrying cDNA of L-Myc, one of the most frequently amplified genes in SCLC. The preSC transduced with retroviral L-Myc (L-Myc-preSC) formed spheres characteristic of SCLC cells in culture and palpable tumors resemble primary SCLC in the flanks of nude mice, whereas GFP-preSCs (control) were morphologically identical to uninfected preSC and did not form aggregates and subcutaneous tumor (Figure 2A). Comparative expression profiling of preSCs and L-Myc-preSC or tumor cells permitted identification of the genes and pathways related to oncogene-driven tumor progression. Defining the MYC-driven oncogenic pathways led to a preclinical test of an existing drug that successfully targeted human and mouse SCLC tumors. Furthermore, using this preSC-based model in combination with CRISPR/Cas9 methods of gene targeting and in vivo models, we found that several loss-of-function mutations found in the SCLC tumors were sufficient to cause the tumorigenic progression of preSCs (Figure 2B). In conclusion, this engineered preSC-based model facilitates functional validation of the recurrent mutations in SCLC and discovery of biomarkers and molecular pathways that will be further explored for mechanistic elucidation and targeted therapies.Figure 1

Abstract not provided

Abstract:
It is widely recognized that patient participation in clinical research is a significant challenge, with only less than 5% of adult patients with cancer entering on clinical trials. This issue is becoming exacerbated in the field of lung cancer. With the advent of new therapeutic options and strategies accompanied by endless potential combinations of these approaches, there are more important trials and research studies that need to be done than patients available to participate in them. To address this problem, Lung Cancer Alliance developed a unique, innovative program known as LungMATCH that combines direct patient services with increasing enrollment to clinical studies. LungMATCH provides patient education and navigation through the changing treatment landscape in lung cancer while informing and educating patients about research opportunities that they can discuss with their treatment team. There are multiple programs under the LungMATCH umbrella. These include a molecular testing service where patients can initiate the process of molecular testing themselves, a novel patient-friendly online clinical trial matching widget, and phone-based personalized treatment and trial specialists who are knowledgeable about the state of lung cancer today and the many clinical trials available. These specialists can empower a patient or caregiver to have an informed conversation with their treatment team. Notably, while providing the community with much-needed navigation services, the program also aims to accelerate research discoveries through patient enrollment on a registry protocol for the molecular testing component and increasing patient accrual to clinical trials. In the first six months since launch, there have been barriers to overcome and lessons learned but many successes. Over 50 patients have been referred to the molecular testing program. More than 10 times as many users are viewing clinical trial search results compared to a previous clinical trial matching tool. Patients who speak with the trial navigators report having conversations about clinical trials with their healthcare providers much more frequently than other callers. These initial data indicate that the program is filling a need in our community and can help provide support to patients and caregivers while accelerating lung cancer research.

Abstract:
Background: Decision makers in research, industry, policy and health-care settings are actively seeking robust sources of patient data to inform their practices. Patient registries are ideally positioned to capitalize on this growing interest by building high-impact source of patient information. Registries give patients a direct means to participate in the care continuum, leveraging their input and insights to focus priorities and improve outcomes. Definition: Patient registries are organized systems designed to directly involve patients in the collection of their disease data and engage the medical community in the analysis and use of this data to improve lung cancer patient care. By creating a centralized registry of robust, on-going data to which patients, health-care professionals, researchers, industry, and policy makers have open access, registries provide data-driven, longitudinal information to: • support and facilitate improved disease management and standard of care; • assess individual patients to help determine the best line(s) of treatment; • measure patient outcomes to assess the quality and efficacy of health care provided; • use aggregate data as a tool to find patterns (for example, by ethnicity, geographic location, sex, age, stage of diagnosis, treatment protocols, health care facility/clinic, etc.) that could better predict the medical future and lead to improved outcomes and quality of life for patients, both individually and as a group, over time. • eventually allow us to evaluate the clinical and cost effectiveness of different diagnostic tools, treatments, and services. Current Landscape: Launched in 2012, The Registry of Patient Registries run by the Agency for Healthcare Research and Quality[1] currently list over 3,100 registries on its site covering a wide variety of registry types, but with most being research or institution generated. According to the National Institutes of Health, “Registries can be used to recruit patients for clinical trials to learn about a particular disease or condition; to develop therapeutics or to learn about population behavior patterns and their association with disease development; developing research hypotheses; or for improving and monitoring the quality of health care.”[2] In more recent times we have seen a rise in the development of Patient Powered Registries which “are somewhat indistinguishable from traditional registries, with one exception: In patient-powered patient registries, patients and family members “power” the registry by managing or controlling the collection of the data, the research agenda for the data, and/or the translation and dissemination of the research from the data.[3] Like researcher-generated patient registries, there is no single complete listing or documented number of PPRs in the United States however one study of 201 disease advocacy organizations found that forty-five percent had supported a research registry or biobank.[4] With the definition, purpose and current landscape being covered, we can now look at how registries continue to evolve both to meet the most common concerns and to greatly impact a patient’s care and quality of life. Multiple data sources: By leveraging the power of digital technology many patient registries now supplement patient reported data with clinical data through integration with Electronic Heath Record (EHR) systems. This integration allows for the capture of additional data points and to verify patient reported data, specifically when the patient may be unsure of the answer. In addition, natural language processing now provides the capability to “pull” information from uploaded documents and reports such as CT scans, lab reports, x-rays, genomic tests. Having multiple data sources allows researchers to paint a more detailed picture of the patients within the registry and more accurately identify patterns and eventually interventions. Clinical trial matching functionality: As with the integration of EHR, digital technology is now facilitating clinical trial matching functionality directly into patient registries. This service now allows patients, based on the information provided to not only receive a list of potential matches, but even allows for direct communication to the investigators involved in the study. Building patient communities: Unlike research or institution generated studies, patient powered registries may serve as a tool for building connected patient communities particularly when matched with general social media platforms such as Facebook and LinkedIn or more specific patient communities such as Patients Like Me and Inspire. Because patient registries now ask participants to consent not only to sharing their data, but to be contacted by the provider, registries can quickly bring together patients from across the globe for a variety of purposes, including driving research into their specific disease. This is particularly important in lung cancer which we now know is not one disease, but a series of “rare diseases” based on genetic differentiation. Educating patients: Being able to communicate directly with patients not only helps facilitate the building of communities and clinical trial matching, it also allows the registry provider to disseminate customized, personalized education materials directly to the participant. Multiple studies have shown how access to such information improves not only quality of life, but satisfaction with care. Conclusion: Well-designed patient registries are based on the idea that to improve outcomes and quality of life, no silos within the care community should exist, collaboration is critical, and there must be open and shared access to all information. In addition, today’s registries should leverage technology to allow for multiple data sources, longitudinal data collection, two-way communication and clinical trial matching to better serve its participants. By putting these tools to work and providing accurate, digestible information in the hands of industry, health IT companies, physicians and other health care practitioners, registries will organize and engage the entire lung cancer community around the common goal of better care for patients. 1. 4. Landy D, Brinich M, Colten M, et al. How disease advocacy organizations participate in clinical research: A survey of genetic organizations. Genetics in Medicine. 2012;14(2):223–8.

Abstract:
INTRODUCTION: Patient-centricity means much more than episodic patient involvement in health care. A Patient-centric culture requires that patients play an active role in all health care subareas from identifying unmet needs, pre-clinical research, clinical research, drug authorization, drug reimbursement to drug prescription. This study focus on patient-centricity in clinical trials. While in former days a patient participating in a clinical trial very often felt like a “laboratory mouse” only being instructed what to do and often without any understandable information nowadays those responsible for research and drug development discover the advantages of patient involvement such as better recruitment, patient friendly protocols, a better retention rate etc. Till now the main focus was effectiveness and safety of drugs to be shown by cost-intensive clinical trials. Nowadays value of treatments and relevance of outcomes to patients are of special interest. Patient Advocacy organizations help with recruitment by informing their members about new clinical trials. Crowdsourcing techniques addressing different communities like medical experts, patients and researchers are used to provide responses to survey questions. Apart from the arising enthusiasm about the doubtlessly potential opportunities the necessary requirements and their costs such as patient education costs, efforts to establish long-term partnership with patient advocacy groups, implementing patient advisory boards, legal framework conditions which protect patients but do not hinder their active participation as stakeholders etc. should not be underestimated. Additionally, pharmaceutical companies need to implement patient-centricity as a strategy across their functional departments. Successful patient-centric clinical trials require the willingness of patients especially of those who experienced clinical trials to provide their input in order to support improvement. METHOD: An anonymous survey has been designed and submitted to patients who already participated in a clinical trial. As patient-centricity in clinical trials is not just a lung cancer but a general issue Patient Advocacy Groups for different diseases such as lung cancer, breast cancer, cancer in general, lung fibrosis, arthritis, HIV etc. have been involved in US and Europe and further countries aiming to learn more about patient experience in clinical trials. As there is an increasing number of industry-funded clinical trials[1] another online survey was submitted to pharmaceutical companies in order to to find out more about the daily practice. RESULTS: 40 of 61 participants who already have been on a clinical trial completed the survey. Almost 50% recently (2016 or 2017) participated in a clinical trial. 16 patients live in US, followed by 8 patients from Austria and single patients from different European countries, one from Australia and one from Israel. Almost 40% of the surveyed have not been asked for feedback concerning the procedure during or after participation in the trial. 87% of patients would take part again in a clinical trial due to reasons like getting effective treatment, new treatment, helping others etc. Previous studies have found that trial participants do not receive the trial results.[2 ]This study replicated this finding. Almost 50% have not been informed about the final trial results although the WMA Declaration of Helsinki 2013 requested that all medical research subjects should be given the option of being informed about the general outcome and results of the study.[3] There is a high rate of willingness (82%) to provide input from patient perspective to improve the design of clinical trials. The analysis of the survey did not show any relevant differences concerning geographic area. 7 research-based pharmaceutical companies completed the second survey. Asking in which parts of the trial process (clinical question, clinical trial design, patient recruitment, trial management) patients are actively involved two companies indicated that patients are not involved in any of the mentioned parts. About 70% of the surveyed request feedback from patients about the procedure of clinical trials (30% do not). 3 of 7 companies do not see any hurdles for driving forward patient-centricity, 3 companies mentioned hurdles like e.g. substantial differences in the patients´ attitudes / concerns / current management across different countries/regions, added complexity, clarity on compliance rules, contractual framework and often patient report disease impact is difficult to quantify (e.g. I´m feeling tired). The most important measures in the pharmaceutical companies are understanding of patient needs, inclusion of patient reported outcomes, patient satisfaction, safety of IMP (investigational medical product) and patient selection biomarkers. The 2 companies who do not actively involve patients in the different parts of the trial process mentioned patient selection biomarkers, safety of IMP, safeguarding of patient’s rights, data quality and integrity as important measures. Both did not see any hurdles to drive forward patient-centricity in clinical trials. CONCLUSION: Although the number of participants in both surveys is quite low, the informational results gained by the patient survey can shed some light to the patient experience concerning clinical trials, the willingness as well as the reasons to participate more than once in a clinical trial. “Effective treatment” as most frequently mentioned reason to participate in a trial indicates a lack of information about clinical trials. There is a vast majority of patients with clinical trial experience being willed to provide their input in order to improve the design of new clinical trials. On the other hand there are researching companies who do not involve patients/patient advocates in the clinical trial process at all and the results of the survey provides an indication of the inconsistent proceedings within the pharmaceutical industry. In order to increase patient-centricity in clinical trials it is necessary that all relevant stakeholders (patients, patient advocates, regulators, medical experts, pharmaceutical companies etc.) compile consensual guidelines that ensure inclusion of relevant and adequately validated PRO, accurate patient information about clinical trials (in different languages), the option to be informed about the trial results for trial participants, information and education about clinical trials and collection and usage of patient feedback. [1]Ehrhardt S, Lawrence J. Trends in National Institutes of Health Funding for Clinical Trials Registered in ClinicalTrials.gov. JAMA. 2015;314(23):2566-2567 [2 ]Partridge AH, Winer EP. Informing clinical trial participants about study results. JAMA. 2002;288(3):363-365 [3]https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/ (August 2[nd], 2017)

Abstract not provided

Background:
Retrospective studies indicate that selecting individuals for low dose computed tomography (LDCT) lung cancer screening based on a highly predictive risk model is superior to applying National Lung Screening Trial (NLST)-like criteria, which use only categorized age, pack-year and smoking quit-time information. The Pan-Canadian Early Detection of Lung Cancer Study (PanCan Study) was designed to prospectively evaluate whether individuals at high risk for lung cancer could be identified for screening using a risk prediction model. This paper describes the study design and results.

Method:
2537 individuals were recruited through 8 centers across Canada based on a ≥2% of lung cancer risk estimated by the PanCan model, a precursor to the validated PLCOm2012 model. Individuals were screened at baseline and 1 and 4 years post-baseline.

Result:
At a median 5.5 years of follow-up, 164 individuals (6.5%) were diagnosed with 172 lung cancers. This was a significantly greater percentage of persons diagnosed with lung cancers than was observed in the NLST(4.0%)(p<0·001). Compared to 57% observed in the NLST, 77% of lung cancers in the PanCan Study were early stage (I or II) (p<0.001) and to 25% in a comparable population, age 50-75 during 2007-2009 in Ontario, Canada’s largest province, (p<0·001).

Conclusion:
Enrolling high-risk individuals into a LDCT screening study or program using a highly predictive risk model, is efficient in identifying individuals who will be diagnosed with lung cancer and is compatible with a strong stage shift – identifying a high proportion at early, potentially curable stage. Funding This study was funded by the Terry Fox Research Institute and Canadian Partnership Against Cancer. ClinicalTrials.gov number, NCT00751660

Background:
In lung cancer screening, a nodule management protocol describes nodule assessment and thresholds for nodule size and growth rate to identify patients who require immediate diagnostic evaluation or additional imaging exams. The NELSON and NLST clinical trials used different selection criteria and nodule management protocols. Several modelling studies have reported variations in screening outcomes and cost-effectiveness across selection criteria and screening intervals; however, the effect of variations in the nodule management protocol remains uncertain. This study evaluated the effects of the eligibility criteria and nodule management protocols on the benefits, harms, and cost-effectiveness of lung screening scenarios in a population-based setting in Germany.

Method:
We developed a modular microsimulation model: a biological module simulated individual histories of lung cancer development from carcinogenesis onset to death; a screening module simulated patient selection, screening-detection, nodule management protocols, diagnostic evaluation and screening outcomes. Benefits included mortality reduction, life years gained, averted lung cancer deaths. Harms were costs, false-positives, overdiagnosis. Comparator was no screening. Evaluated 57 screening scenarios included variations in selection criteria and thresholds for nodule size and growth rate.

Result:
Five years of annual screening resulted in an 11.3–12.6% lung cancer mortality reduction in the screened population. The efficient scenario included volumetric assessment, a threshold for a volume of 300 mm[3], and a threshold for a volume doubling time of 400 days. Assessment of volume doubling time is essential for reducing overdiagnosis and false-positives. Incremental cost-effectiveness ratios of the efficient scenarios were 19,389–23,804 Euro per life years gained and 178,673–285,630 Euro per averted lung cancer death.

Conclusion:
Lung cancer screening can be cost-effective in Germany. Along with the eligibility criteria, the nodule management protocol influences screening performance and cost-effectiveness. Definition of the thresholds for nodule size and nodule growth in the nodule management protocol should be considered in detail when defining optimal screening strategies.

Background:
Screening of high risk smokers with computed tomography (CT) aims to identify early stage lung cancers in screening participants amenable to curative surgery. The National Lung Screening Trial (NLST) demonstrated a 20% reduction in lung cancer specific mortality in the CT arm compared to chest x-ray (control) arm. European screening trial results to date have failed to show any evidence of a reduction in lung cancer mortality. Reduction in lung cancer mortality comes from the combined effects of successful surgical removal of life-threatening early stage lung cancers and post-operative survival. In screening participants of the NLST, who are older chronic smokers, there exists a balance between mortality from lung cancer and mortality from non-lung cancer related causes.

Method:
This study aimed to validate a gene-based risk tool for dying of lung cancer and examine the outcomes from screening according to tertiles of risk. It also aimed to establish the utility of adding SNP-based data to risk prediction and efficacy in identifying which screening participants get the best outcomes from screening. Using prospective data from the NLST-ACRIN cohort (N=10,054), we examined the utility of combining risk genotypes with clinical risk variables in our risk model for dying of lung cancer. We then stratified screening participants into risk tertiles according to our risk model and compared the outcomes from CT versus CXR screening

Result:
The addition of risk genotypes (combined genetic risk score) to our clinical risk model for dying of lung cancer was significantly improved (AUC increased from 0.61 to 0.66, P=0.014). We show that screening participants in the middle risk tertile achieves a lung cancer specific mortality reduction of 55% and all-cause mortality reduction of 21%. In this group the number of lung cancers averted is maximised (12/1000 person screened) and number needed to screen to avert one lung cancer reduced to 84. We show that this is achieved through minimising pre-existing co-morbid disease and by maximising screen detected lung cancers amenable to CT detection and successful surgical intervention. We believe genetic data provides useful information on lung cancer biology.

Conclusion:
The “Sweet spot” of CT screening comes from identifying high risk smokers optimised according to co-existing premorbid disease (especially COPD), early stage lung cancers amenable to surgical cure and least likely to die of other complications of smoking. Gene-based risk testing appears superior to just clinical risk models alone in prioritising high risk smokers for screening.

Background:
Lung cancer (LC) is the commonest cause of cancer-related death in the world. Screening with low-dose computer tomography (LDCT) had been shown to reduce LC specific and all-cause mortality. Benefit is greatest in those at highest risk, such as current smokers from areas of high socio-economic deprivation, yet participation in these ‘hard-to-reach’ populations remains a challenge and must be improved if we are to succeed with screening. The aim of this NHS implementation project was to assess LC screening within the community in deprived areas.

Method:
Ever smokers, aged 55-74, registered at 14 participating general practitioner (GP) practices in deprived areas of Manchester were invited to attend and have a free ‘Lung Health Check’ (LHC) in a mobile unit located at their local shopping centres. Lung cancer risk score (PLCO~M2012~), respiratory symptoms and spirometry were assessed as part of the LHC with results communicated back to the GPs. Those at high risk of LC, i.e. 6-year lung cancer risk ≥1.51%, were offered immediate LDCT in a co-located mobile CT scanner. These were all reported by thoracic radiologists with an interest in pulmonary oncology. Specifically designed nodule algorithms were followed in the reporting.

Result:
The maximum available capacity of the project was filled within days of going live. 2,541 individuals attended for a LHC and consented to data analysis. The mean age was 64.1±5.5, 51.0% (n=1,296) were female, 35.1% (n=891) were current smokers and 74.5% (n=1,893) ranked in lowest deprivation quintile. Of these 56.2% (n=1,429) qualified for a LDCT scan (PLCO~M2012~ risk score ≥1.51%). 46 lung cancers were detected in 42 individuals, a prevalence of 3.0%, of which 80% (n=37/46) were early stage (I+II). A treatment with curative intent was offered to 89.1% (n=41/46) of screen detected cancers and the surgical resection rate was 65.2%, which is almost fourfold the UK national average (16.8%).

Conclusion:
Taking lung cancer screening into the community can identify and target those at most risk, using the PLCO~m2012~ model, resulting in a significant stage shift in screen detected lung cancers in deprived populations.

Abstract not provided

Background:
Low-dose computed tomography (LDCT) lung cancer screening is recommended by US guidelines for high-risk individuals. New solid nodules are regularly found in incidence screening rounds and have a higher lung cancer probability at smaller size than do baseline nodules, leading to the proposal of lower size cutoffs at initial new solid nodule detection. However, currently there is no evidence concerning the risk-stratification of new solid nodules at first LDCT screening after initial detection.

Method:
In the ongoing, multicenter, randomized controlled Dutch-Belgian Lung Cancer Screening (NELSON) Trial, 7,295 participants underwent the second and 6,922 participants the third screening round. We included participants with solid non-calcified nodules, that were registered by the NELSON radiologists as new or smaller than 15mm[3] (study detection limit) at previous screens and received a follow-up or regular LDCT screening after initial detection; thereby excluding high-risk nodules according to the NELSON management protocol (nodules ≥500mm[3]). Nodule volume was generated semiautomatically. For assessment of the predictive performance, the area under the receiver operating characteristics curve (AUC) of nodule volume, volume doubling time (VDT), and VDT combined with a predefined 200mm[3] volume cutoff were evaluated with eventual lung cancer diagnosis as outcome.

Result:
Overall, 680 participants with 1,020 low and intermediate risk new solid nodules were included. A total of 562 (55%) new solid nodules were resolving, leaving 356 (52%) participants with a nonresolving new solid nodule of whom 25 (7%) were eventually diagnosed with lung cancer in such a nodule. At first follow-up or regular LDCT screening after initial new solid nodule detection, VDT, volume, and VDT combined with the predefined ≥200mm[3] volume cutoff had a high discriminative performance for lung cancer (VDT, AUC: 0.91; volume, AUC: 0.88; VDT and ≥200mm[3] combination, AUC: 0.94). A cutoff combination of ≤590 days VDT or ≥200mm[3] at first LDCT after initial new solid nodule detection, classifying a nodule positive when at least one criterion was fulfilled, provided 100% (95% confidence interval [CI] 84-100%) sensitivity and 84% (95%CI 80-87%) specificity for discriminating lung cancer, with positively classified nodules having a lung cancer probability of 27% (95%CI 19-37%).

Conclusion:
More than half of new solid nodules identified in LDCT lung cancer screening are resolving nodules. At first follow-up, a cutoff combination of ≤590 days VDT or ≥200mm[3] volume can be used for risk stratification.

Background:
New solid nodules detected in low-dose computed tomography (LDCT) lung cancer screening have a higher lung cancer probability at a smaller size than baseline nodules and lower size cutoff values for risk stratification at initial detection have been proposed. So far, it is unknown whether nodule characteristics, such as morphology or location, could improve risk stratification by size in new solid nodules.

Method:
This study forms part of the ongoing, randomized controlled Dutch-Belgian Lung Cancer Screening (NELSON) trial. This analysis included solid non-calcified nodules detected during the three incidence screening rounds and registered by the NELSON radiologists as new or previously below detection limit (15mm[3]). Nodule volume was generated semiautomatically. The predictive performance of nodule characteristics (location, distribution [peripheral, nonperipheral], shape [round, polygonal, irregular], margin [smooth, lobulated, spiculated, irregular], visibility <15mm[3] in retrospect) combined with previously established volume cutoffs (<30mm[3], low risk; 30-<200mm[3], intermediate risk; ≥200mm[3] high risk) was evaluated by multivariable logistic regression analysis with eventual lung cancer diagnosis as outcome. Discrimination of lung cancer based on volume, the final parsimonious model, and the model stratified into three risk groups (low, intermediate, high) was assessed through the area under the receiver operating characteristics curve (AUC) and compared using DeLong's Method.

Result:
Overall, 1,280 new nodules were included with 73 (6%) being diagnosed as lung cancer eventually. Of the new nodules visible <15mm[3] in retrospect and now ≥30mm[3], 22% (6/27) were lung cancer. Discrimination based on volume cutoffs (AUC: 0.80, 95% confidence interval [CI] 0.75-0.84) and continuous volume (AUC: 0.82, 95%CI 0.77-0.87) was comparable (P=0.14). After adjustment for volume cutoffs, only location in the right upper lobe (odds ratio [OR] 2.0, 95%CI 1.2-3.4), nonperipheral distribution (OR 2.4, 95%CI 1.4-4.2), and visibility <15mm[3] in retrospect (OR 4.7, 95%CI 1.7-12.8) remained significant predictors. Discrimination based on the model (AUC: 0.85, 95%CI 0.81-0.89) was superior to the volume cutoffs alone (P=0.0002), but when stratified into three risk groups (AUC: 0.82, 95%CI 0.78-0.86) discrimination was comparable (P=0.2).

Conclusion:
At initial detection, nodule volume is the strongest predictor for lung cancer in new nodules. Nodule characteristics may further improve lung cancer prediction, but only have limited incremental discriminatory value additional to volume cutoffs in a three-category stratification approach.

Background:
Substantial variation exists in the processes of care for potentially curable NSCLC. We examined the impact of thoroughness of staging for patients undergoing NSCLC surgery in a large, heterogeneous population within a lung cancer endemic region of the US.

Method:
We evaluated all surgically resected patients in the Mid-South Quality of Surgical Resection (MS-QSR) cohort from 2009-2017. MS-QSR is a population-based cohort including all curative-intent NSCLC resections at 11 hospitals in the mid-south US. Patients were classified into 8 groups based on use (Yes/No) of the following staging modalities: PET/CT, pre-operative invasive staging, operative mediastinal nodal examination (MLE). We compared stage distribution, adjuvant therapy, and overall survival outcomes across groups using the chi-square test and adjusted Proportional Hazards Models.

Result:
The 2,370 patients had a median age of 67 years, were 53% male. The racial distribution was: 70% White, 25% Black, 5% Other. Clinical N-stage was similar between the 8 groups. We found statistically significant differences in pathologic stage distribution, adjuvant therapy usage, and overall survival across the 8 groups (Table 1). Patients who received PET/CT, invasive staging, and MLE (Group 1) had significantly higher pathologic N-stage distribution compared to the other groups due to substantial nodal upstaging. Group 1 had 76% eligibility and 31% use of adjuvant chemotherapy compared to 51% and 8% in the Group 8 (No PET/CT, No Invasive Staging, No MLE). Use and eligibility for adjuvant radiation therapy was also highest in Group 1. There was an overall difference in survival across the groups (p-value=0.0019) which remained significant after adjusting for age, sex, race, histology, and path stage (p-value=0.0013). After adjustment, Group 8 had a 14% increased hazard of death compared with Group 1. Figure 1



Conclusion:
A less thorough approach to staging may lead to less nodal upstaging and less eligibility for adjuvant therapy, which could have implications for long term survival.

Abstract not provided

Background:
There is currently no completed randomized controlled trial data comparing stereotactic ablative radiotherapy (SABR) and surgery in operable patients with early-stage non-small cell lung cancer (ES-NSCLC). Propensity score methods are increasingly utilized in oncology to balance the baseline characteristics of non-randomized cohorts, mimicking the setting of a clinical trial. No previous meta-analysis of propensity score analyses comparing a surgical and non-surgical modality has been conducted. Our goal was therefore to perform a systematic review and meta-analysis of all propensity score analyses comparing SABR and surgery in patients with ES-NSCLC.

Method:
A systematic review was carried out according to PRISMA guidelines by querying the MEDLINE and Embase databases from inception until December 2016. Hazard ratios (HR) with confidence intervals (CI) for overall survival (OS) and disease-specific survival (DSS) were directly extracted, if available, or estimated from Kaplan-Meier curves. Meta-analysis was carried out with inverse variance-weighted random-effects models.

Result:
After reviewing 1039 records, 17 PS-adjusted studies with a total of 20151 patients were included in the final analysis. Overall survival (OS) favoured surgery over SABR (HR = 1.52 [95% CI: 1.33-1.74], p < 0.001). However, the rate at which patients died from lung cancer (DSS) was not significantly different (HR = 1.13 [95% CI: 0.86-1.49], p = 0.38). On subgroup analysis, OS was superior for both lobectomy (HR = 1.61 [95% CI: 1.27-2.03], p < 0.001) and sublobar resection (HR = 1.33 [95% CI: 1.15-1.55], p < 0.001) versus SABR while DSS again did not significantly differ (HR = 1.35 [95% CI: 0.70-2.62] and HR = 1.18 [95% CI: 0.84-1.67], respectively). On secondary analysis, meta-analysis of proportions revealed a lymph node upstaging rate of 16.0% (95% CI: 13.6%-18.6%) and adjuvant chemotherapy usage rate of 11.5% (95% CI: 8.6%-14.8%) among patients who received surgery. On meta-regression, with every increase of 0.1 in the maximum allowable difference in propensity score within a matched pair - representing increases in imbalance between cohorts, DSS outcomes increasingly favoured surgery by 1.36-fold. Critical appraisal revealed inconsistent reporting of propensity score methods.

Conclusion:
Overall survival favoured surgery over SABR in this meta-analysis of 17 propensity score analyses. However, the effectiveness of SABR was reflected in a similar DSS to surgery, supporting ongoing clinical equipoise. A direct relationship between propensity score methodology and DSS outcomes were demonstrated. Whether this observed benefit in OS for surgery is real or due to limitations in the propensity score methodology requires confirmation through randomized data.

Background:
In last years, an increasing interest emerges on the role of sub-lobar resection and lobe-specific lymphnode dissection in the treatment of early stage lung cancer. The aim of our study was to define impact on Cumulative incidence of recurrence (CIR) of type of surgical resection and type of nodal staging. Furthermore, we evaluated the effect of interactions between the different kinds of procedure.

Method:
An analysis of 969 consecutive stage I pulmonary adenocarcinoma patients, operated in six Thoracic Surgery Institutions between 2001 and 2013, was conducted. Type of surgical resection included lobectomy and sub-lobar resection; pneumonectomy and bilobectomy were excluded from the analysis. Nodal staging procedures were classified in nodal sampling (NS), lobe-specific lymph node dissection (LS-ND) and systematic lymph node dissection (SND). Multivariable-adjusted comparisons for CIR was performed using Fine and Grey model, taking into account death by any cause as competing event. Test of interaction between type of surgical resection and type of nodal staging was carried out and results presented in a stratified way. Missing data were multiple-imputed, combined estimates were obtained from 5 imputed datasets.

Result:

Multivariable-adjusted Fine and Grey model for Comulative Incidence of Recurrence (take into account age, gender, smoking habit, side of intervention, pTNM stage, vascular invasion, pTNM stage, predominant histologic pattern and histologic grade)(Results of test of interaction presented in a stratified way)

Sub-lobar resection vs. Lobectomy HR (95%CI) P INTERACTION P-value Overall 1.52 (1.07 to 2.17) 0.02 0.268 SND 1.98 (1.14 to 3.42) LS-ND 1.87 (0.94 to 3.74) NS 1.08 (0.61 to 1.93) LS-ND vs SND HR (95%CI) P INTERACTION P-value Overall 1.74 (1.16 to 2.6) 0.007 0.903 Lobectomy 1.66 (1.03 to 2.69) Sub-lobar resection 1.58 (0.75 to 3.32) NS vs. SND HR (95%CI) P INTERACTION P-value Overall 1.49 (1.12 to 1.98) 0.007 0.131 Lobectomy 1.61 (1.18 to 2.19) Sub-lobar resection 0.88 (0.43 to 1.82)

Median follow-up was 63 months. Eight-hundred forty-six (87%) patients were submitted to lobectomy, while 123(13%) to sub-lobar resection. Four-hundred fifty-five (47%) patients received SND, 98(10%) LS-ND and 416(43%) NS. Two-hundred forty-seven (26%) patients developed a local/distant recurrence with a 5-year CIR of 24%. Multivariable-adjusted comparisons showed an independent negative effect of sub-lobar resection(HR 1.52;95%CI:1.07-2.17), LS-ND(HR 1.74;95%CI:1.16-2.6) and NS(HR 1.49;95%CI:1.12-1.98) on CIR(Table). Test of interaction showed an homogeneity of results among subgroups.

Conclusion:
In our series, lobectomy and systematic lymph node dissection confirmed to be the optimal strategy to achieve a favorable prognosis in stage I adenocarcinoma of the lung. The real value of sub-lobar resection and less aggressive nodal staging should be assessed by randomized clinical trial before being integrated in clinical practice.

Background:
The IFCT-0302 trial is the first large randomized phase III multicenter trial which compared two follow-up modalities after surgery for early stage non-small cell lung cancer (NSCLC).

Method:
After complete resection of a stage pI, II, IIIA or T4 (pulmonary nodules in the same lobe) N0-2 NSCLC (TNM 6[th] edition), patients were randomized (1/1) between 2 follow-up programs: - arm 1, clinical examination and Chest X-ray, - arm 2, clinical examination, Chest X-ray, thoraco-abdominal CT-scan plus bronchoscopy (optional for adenocarcinomas). In both arms, procedures were repeated every 6 months after randomization during the first 2 years, and yearly until 5 years. The primary endpoint was overall survival (OS). Distinction between lung recurrences and 2[nd] primary lung cancer was assessed by investigators, using the Martini and Melamed definition (J Thorac Cardiovasc Surg 1975).

Result:
1775 patients were randomized (arm 1: 888; arm 2: 887). Patient characteristics were well-balanced between the two arms: males 76.3%, median age 63 years (range: 34-88), squamous and large cell carcinomas 39.5%, stage I 68.1%, stage II 13.7%, stage III 18.3%, lobectomy or bilobectomy 86,6%. OS and DFS were not significantly different between arms (OS: HR=0.92, 95% CI: 0.8-1.07; p=0.27). Median disease-free survival was 4.95 years (95% CI: 4.4- not reached) in arm 1 and not reached in arm 2, respectively. A recurrence was diagnosed in 245 patients (27.6%) in arm 1, and in 291 patients (32.8%) in arm 2. Recurrences were symptomatic in 203 (82.9%) and 163 (56.0%) patients, respectively. The most frequent sites of recurrence were: ipsilateral lung (42.0 and 33.0%), brain (29.4 and 23.4%), and contralateral lung (24.9 and 22.3%), respectively. Treatment of recurrence achieved complete remission in 25 (10.2%) and 52 (17.9%) patients (p=0.01), respectively. Second primary cancers (SPC) were diagnosed in 101 patients (11.4%) in arm 1, and 97 patients (10.9%) in arm 2, with symptoms at diagnosis in 64 (63.4%) and 37 (38.1%) patients, respectively. The most frequent sites of SPC were: lung (25.7 and 41.2%), prostate (14.8 and 11.3%), and ENT (11.9 and 7.2%), respectively. Treatment of SPC achieved complete remission in 30 (29.7%) and 40 (41.2%) patients (p=0.10), respectively.

Conclusion:
Although OS and DFS were not significantly increased by thoraco-abdominal CT-scan-based follow-up, recurrences or SPCs were more frequently asymptomatic and amenable to curative treatment in patients followed by thoraco-abdominal CT scan compared to those followed by chest X-ray only.

Background:
Adjuvant chemotherapy remains the most important treatment for stage IIIA non-small cell lung cancer (NSCLC) after radical operation, but its benefits has reached plateau and high risk of recurrence. Previous studies SELECT and RADIANT have suggested a trend of improving DFS of erlotinib as adjuvant therapy for patients with activating mutations. This study is designed as prospective, open-label, randomized, multicenter phase II trial to investigate the efficacy and safety of erlotinib (E) as adjuvant therapy in comparison with vinorelbine/cisplatin (NP) chemotherapy in completely resected stage IIIA EGFR mutant patients.

Method:
Patients aged between 18 – 75 with ECOG PS 0–1, stage IIIA, EGFR-activating mutation (exon 19 or exon 21 L858R), reached R0 resection NSCLC were eligible. And patients were randomized(1:1) into either erlotinib (orally 150mg/day for 2 years, util relapse or unacceptable toxicity) or NP (vinorelbine 25mg/m[2] i.v. day 1, 8 and cisplatin 75mg/m[2] i.v. day 1, every 3 weeks for 4 cycles) group. Random assignment was stratified by EGFR mutation type (exon 19 vs exon 21), histology (adenocarcinoma vs non- ) and smoking status (smoker vs non-). The primary endpoint was 2-year disease free survival rate (DFSR), secondary endpoints include disease free survival (DFS), overall survival (OS), safety (NCI CTCAE 4.0) and quality of life (QoL), and exploratory biomarker analysis.

Result:
From Sep, 2012 to May, 2015, in total 102 patients from 16 centers across China were randomized to receive E (N=51) or NP (N=51). Median follow-up time was 33 months for E and 28 months for NP. Baseline characteristics of age, sex, PS, histology, smoking status, EGFR mutation subtypes were well balanced in each arm. Two-year DFSR was 81.35% (95%CI: 69.63-93.08) in E arm and 44.62% (95%CI: 26.86-62.38) in NP arm respectively (P<0.001) in ITT population. DFS was significantly prolonged with E vs NP (median, 42.41 vs 20.96 months, HR 0.271, 95% CI: 0.137-0.535; P<0.001). OS data from our trial are still immature. In current, the number of death events were 2 (E) and 13 (NP) arm. Safety profile was similar to previous studies of each agent in NSCLC, no new unexpected AE were observed in each arms.

Conclusion:
As compared with NP, E showed superior efficacy and should be considered therapeutic option for patients with R0 resected stage IIIA NSCLC with EGFR-activating mutation. (EVAN, NCT01683175).

Abstract not provided

Background:
A fourth of patients with cN1-NSCLC based on PET-CT imaging are at risk for occult mediastinal nodal involvement. In a previous prospective study, endosonography alone had an unsatisfactory sensitivity (38%) to detect mediastinal nodal disease. This prospective multicenter trial investigated the sensitivity of preoperative mediastinal staging by video-assisted mediastinoscopy (VAM) in patients with cN1 (suspected) NSCLC.

Method:
Consecutive patients with operable and resectable cN1 (suspected) non-small cell lung cancer (NSCLC) underwent a VAM or VAM-lymphadenectomy (VAMLA). All patients underwent FDG–PET and CT-scan. The primary study outcome was sensitivity to detect N2-disease. Secondary endpoints were the prevalence of N2-disease, negative predictive value (NPV) and accuracy of VAM(LA).

Result:
Figure 1 Out of 105 patients with cN1 on imaging, 26% eventually had N2-disease. Invasive mediastinal staging with VAM(LA) reached sensitivity of 73% to detect N2-disease. The median number of assessed lymph node stations during VAM(LA) was 4. In 96% ≥3 stations were assessed. VAMLA was performed in 31%, 69% underwent VAM.

		N	Prevalence of mediastinal disease	Sensitivity OR(95%CI)	Negative Predictive Value OR(95%CI)	Negative Posttest probability OR(95%CI)
Dooms et al. Chest. 2014; 147(1): 209–15.	Endosonography alone	100	24%	0.38 (0.18-0.57)	0.81 (0.71-0.91)	0.19 (0.13-0.27)
	Endosonograpy, if negative followed by mediastionoscopy			0.73 (0.55-0.91)	0.91 (0.83-0.98)	0.09 (0.04-0.17)
Current Study	Mediastinoscopy	105	26%	0.73 (0.54-0.86)	0.92 (0.83-0.97)	0.08 (0.03-0.17)

Conclusion:
VAM(LA) has a satisfactory sensitivity of 73% to detect mediastinal nodal disease in cN1-NSCLC and could be the technique of choice for pre-resection mediastinal lymph node assessment in this patient group with 26% chance of occult positive mediastinal nodes after negative PET-CT. (ClinicalTrials.gov NCT02222194)

Background:
The limited resection for lung cancer has become more prevalent for patients who show a compromised pulmonary or cardiac function. As of now standard care of lung cancer is lobectomy with lymph node dissection or sampling even for early lung cancer. Japan clinical oncology group (JCOG) study 0201 has proposed the criteria to diagnose pathological less-invasive lung adenocarcinoma by using consolidation to tumor ratio (CTR) on preoperative thin-sliced computed tomography (TSCT) scan. Three clinical trials have been ongoing based on this result, but the TNM classification was drastically revised in 2016, especially in T category. The aim of this study is to propose the new radiological criteria to predict pathological less-invasive lung cancer before surgery in accordance with the new TNM classification.

Method:
We analyzed the 744 patients who have peripheral Tis-T1cN0M0 non-small cell lung cancer with 3cm or less in size and underwent complete resection by lobectomy from 2003 to 2011. We defined a lung cancer with no nodal involvement and no vessel invasion pathologically as a pathological less-invasive cancer, and investigated the radiological criteria corresponding to the new T category by using TSCT to predict a pathological less-invasive cancer with the specificity of 97% or more. We also re-evaluated the criteria by adding the parameter of CTR and presence of ground-glass opacity (GGO), and prognostic parameters; overall survival (OS) and relapse-free survival (RFS).

Result:
The cTis/T1ami/T1a patients showed no pathological invasive cancer except for only 1 patient (specificity: 99%). In the cT1b/T1c patients, the specificity of cT1b with CTR 0.5 or less, cT1b with C/T ratio 0.75 or less, and cT1b with GGO presence were 100%, 97.1%, 94.4%, respectively. The new criteria of cT1a or less and cT1b with CTR 0.75 or less showed excellent prognosis for OS and RFS.

Conclusion:
As most of the patients with cTis/T1ami/T1a and cT1b with CTR 0.75 or less showed pathological less-invasive cancers and extremely good survival, they will be more likely to be obtained good outcomes by sublobar resection including wide-wedge resection as well. The further prospective study will be required to confirm the hypothesis.

Background:
It is necessary to apply a precise standard to predict the oncological outcomes among heterogeneous subgroups of N1 disease ranging from level 10 to 14. Although International Association for the Study of Lung Cancer (IASLC) proposed a new N descriptor in the 8[th] edition of the TNM Classification, lack of dissection on level 13 and level 14 may affect the efficacy of new classification. In this study, we tested a hypothesized classification strategy based on systematic dissection of N1 node from level 10 to level 14.

Method:
From March 2007 to December 2014, 156 consecutive patients of non-small cell lung cancer, treating with lobectomy and systematic mediastinal lymphadenectomy, were investigated. Nodes from level 10 to 12 were dissected during operation. Intrapulmonary lymph nodes (level 13-14) were retrieved after surgery. The data were prospectively collected and retrospectively analyzed. All cases were divided into two categories according to the 8[th] edition of the TNM Classification: pN1a was defined as N1 at a single station, while pN1b was defined as N1 at multiple stations. Then, in our proposed classification, N1a (modified) was defined as single level of N1 station involved (not including single level 10 or 11 spread) or level 13 and/or 14 involved, while N1b (modified) was defined as single level 10 or 11 spread or multiple levels of N1 node involvement (not including level 13 and 14 spread). The association between the N1 subgroup status and survival was explored separately using 8[th] IASLC classification and hypothesized classification.

Result:
In the whole cohort, a mean±SD of 13.1±7.1 N2 nodes and 12.0+5.2 N1 nodes per case were collected.There were 4.7±3.1 nodes from level 13 and 14. The difference in 5-year overall survival between pN1a and pN1b was not significant (73.9% versus 65.7%, p=0.371). However, the difference in 5-year overall survival between N1a (modified) and N1b (modified) was significant (79.1% versus 60.2%, p=0.018). Multivariate analysis showed the revised N1 classification was an independent prognostic factor for NSCLC (versus N1a, the hazard ratio [HR] of N1b for OS was 2.120, 95% confidence interval [CI]: 1.083-4.151, p=0.028). However, the 8[th] edition IASLC N1 descriptors was not an independent prognostic factor (versus pN1a, HR of pN1b was 1.419, 95% CI: 0.710-2.837, p=0.322).

Conclusion:
The hypothesized N1 classification in present study was shown to be a better descriptor to express the outcome than 8[th] edition of the TNM Classification of IASLC. More data are needed to validate this proposal.

Abstract not provided

Background:
Cohort G of the multicenter, open-label, phase 1/2 KEYNOTE-021 study (ClinicalTrials.gov, NCT02039674) evaluated efficacy and safety of pembrolizumab + pemetrexed and carboplatin (PC) compared with PC alone as first-line therapy for patients with advanced nonsquamous NSCLC. At the primary analysis of cohort G (minimum follow up, 6 months; median, 10.6 months), pembrolizumab significantly improved ORR (estimated treatment difference, 26%; P=0.0016) and PFS (hazard ratio [HR], 0.53; P=0.010). The HR for OS was 0.90 (95% CI, 0.42‒1.91). In a subsequent analysis (median follow-up, 14.5 months), the HR for OS was 0.69 (95% CI, 0.36‒1.31). We present results from the May 31, 2017 data cutoff.

Method:
Patients with stage IIIB/IV nonsquamous NSCLC, no prior systemic therapy, and no EGFR mutation or ALK translocation were randomized 1:1 (stratified by PD-L1 TPS ≥1% versus <1%) to receive 4 cycles of carboplatin AUC 5 + pemetrexed 500 mg/m[2] Q3W with or without pembrolizumab 200 mg Q3W. Pembrolizumab treatment continued for up to 2 years; maintenance pemetrexed was permitted in both arms. Eligible patients in the PC arm with radiologic progression could cross over to pembrolizumab monotherapy. Response was assessed by blinded, independent central review per RECIST v1.1. All P values are nominal (one-sided P<0.025).

Result:
123 patients were randomized. Median follow-up was 18.7 months (range, 0.8‒29.0 months). 40 of 53 (75%) patients in the PC arm who discontinued received subsequent anti-PD-1/anti-PD-L1 therapy (including 25 who received pembrolizumab in the on-study cross over). ORR was 57% with pembrolizumab + PC versus 32% with PC (estimated difference, 25%; 95% CI, 7%‒41%; P=0.0029). PFS was significantly improved with pembrolizumab + PC versus PC (HR, 0.54; 95% CI, 0.33‒0.88; P=0.0067) with median (95% CI) PFS of 19.0 (8.5‒NR) months versus 8.9 (6.2‒11.8) months. The HR for OS was 0.59 (95% CI, 0.34‒1.05; P=0.0344). Median (95% CI) OS was not reached (22.8‒NR) months for pembrolizumab + PC and 20.9 (14.9‒NR) months for PC alone; 18-month OS rates were 70% and 56%, respectively. Grade 3–5 treatment-related AEs occurred in 41% of patients in the pembrolizumab + PC arm versus 29% in the PC arm.

Conclusion:
Over the course of the 3 analyses, the HR for OS continues to improve for pembrolizumab + PC versus PC (HR: 0.90 to 0.69 to 0.59). The significant improvements in PFS and ORR with pembrolizumab + PC versus PC first observed in the primary analysis have been maintained with longer follow-up (median, 18.7 months).

Background:
The anti–PD-L1 mAb atezolizumab blocks the interactions between PD-L1 and its receptors, PD-1 and B7.1, thus restoring anti-tumor immunity. A Phase II study of atezolizumab monotherapy was conducted across multiple lines of therapy in PD-L1–selected patients with advanced NSCLC (BIRCH; NCT02031458). The primary analyses showed meaningful and durable clinical benefit with atezolizumab monotherapy in 1L and 2L+ NSCLC. Here we present updated survival data (median follow-up, 29.7 months) in patients receiving 1L atezolizumab.

Method:
Eligible patients had chemotherapy-naive, locally advanced or metastatic NSCLC without CNS metastases. Prior TKI therapy was required in patients with EGFR mutation or ALK rearrangement. PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (IC) was centrally evaluated (VENTANA SP142 IHC assay). Patients who were TC2/3 or IC2/3 (PD-L1 expression on ≥ 5% of TC or IC) were enrolled. Atezolizumab 1200 mg was administered IV q3w until disease progression or unacceptable toxicity. The primary endpoint was independent review facility (IRF)–assessed ORR. Secondary endpoints included investigator (INV)-assessed ORR, DOR, PFS (RECIST v1.1) and OS.

Result:
With a median follow-up of 29.7 months, median OS was 26.9 months (TC3 or IC3 subgroup) and 24.0 months (all treated patients); INV-assessed ORR was 35% (TC3 or IC3 subgroup) and 26% (all treated patients; Table). Among evaluable patients, the ORR was 31% for mutant EGFR (4/13) vs 23% for wild-type EGFR patients (24/103), and 31% for mutant KRAS (10/32) vs 24% for wild-type KRAS patients (16/66). No new safety signals were observed.

Conclusion:
With more than 2 years of follow-up, atezolizumab continued to demonstrate durable clinical activity in 1L NSCLC, regardless of EGFR and KRAS mutational status. These data suggest that atezolizumab monotherapy has promising activity as a frontline therapy. Ongoing Phase III trials are evaluating atezolizumab-based regimens vs chemotherapy in 1L NSCLC.

Endpoint (95% CI)	TC3 or IC3[a ](n = 65)	TC2 or IC2[b] (n = 73)	All Treated Patients (N = 138)
INV-assessed ORR, %	35% (23.9, 48.2)	18% (9.8, 28.5)	26% (19.0, 34.2)
EGFR mutant/wild-type, %	25%/33%	33%/15%	31%/23%
KRAS mutant/wild-type, %	38%/33%	25%/15%	31%/24%
mDOR, mo	16.5 (8.5, NE)	12.5 (8.3, 17.9)	13.1 (9.9, NE)
mOS, mo	26.9 (12.0. NE)	23.5 (18.1, NE)	24.0 (18.1, 31.9)
12-mo OS rate, %	61% (49.0, 74.0)	71% (59.8, 81.5)	66% (58.1, 74.6)
24-mo OS rate, %	52% (39.3, 65.2)	49% (37.0, 61.1)	50% (41.5, 59.2)
30-mo OS rate, %	48% (35.3, 61.5)	39% (27.2, 51.2)	43% (34.3, 52.1)
mPFS, mo	7.3 (4.9, 12.0)	7.6 (4.0, 9.7)	7.6 (5.7, 9.7)
12-mo PFS rate, %	38% (25.1, 49.9)	30% (19.2, 41.2)	34% (25.3, 41.9)
24-mo PFS rate, %	28% (16.5, 40.0)	13% (4.5, 21.5)	20% (12.9, 27.5)
30-mo PFS rate, %	19% (5.4, 33.5)	9% (1.4, 16.4)	14% (6.5, 21.9)
NE, not estimable. [a ]TC ≥ 50% or IC ≥ 10% PD-L1–expressing cells.[b ]TC2/3 or IC2/3 excluding TC3 or IC3.

Background:
Platinum-based doublet chemotherapy is the standard-of-care first-line treatment for most patients with advanced NSCLC, but responses are not durable (~4.5–6 mo). Chemotherapy may sensitize NSCLC tumors to immune checkpoint inhibitors. Nivolumab, a fully human programmed death (PD)-1 antibody, demonstrated long-term survival benefit in patients with previously treated advanced NSCLC. Here we report the 3-year update of safety and efficacy of first-line nivolumab combined with chemotherapy in the phase 1 CheckMate 012 study (NCT01454102).

Method:
Chemotherapy-naïve patients with stage IIIB/IV NSCLC were randomly assigned based on histology in 3 cohorts combining nivolumab Q3W with 3 platinum-based doublet chemotherapy regimens: nivolumab 10 mg/kg + gemcitabine-cisplatin (all squamous histology), nivolumab 10 mg/kg + pemetrexed-cisplatin (all non-squamous), and nivolumab 10 mg/kg or 5 mg/kg + paclitaxel-carboplatin (any histology). After 4 cycles of nivolumab plus chemotherapy, patients received nivolumab monotherapy until progression or unacceptable toxicity. The primary objective was safety. ORR, PFS, and OS were secondary/exploratory endpoints.

Result:
56 patients were treated. Median age was 63.5 years, 46% were male, and 14% were never-smokers; 29% of tumors had squamous histology. At database lock (September 19, 2016) the minimum follow-up was 45.5 mo. Median duration of chemotherapy treatment was ~12 weeks (4 cycles; range: 3–18 weeks) and median duration of nivolumab treatment was 17–22 weeks across cohorts (range: 3–204). No new safety signals were observed in patients receiving nivolumab maintenance compared with the September 2014 database lock. ORR was 46%. Median duration of response was 10.4 mo (95% CI: 5.1, 26.3). Median PFS was 6.0 mo (95% CI: 4.8, 8.3). Median OS was 19.2 mo (95% CI: 14.1, 23.8), and the 3-year OS rate was 25%. ORR and OS were similar in patients with tumor PD-L1 expression <1% (n=23) vs ≥1% (n=23): ORR 48% vs 52%; median OS 19.2 mo (95% CI: 12.2, 23.8) vs 20.2 mo (95% CI: 10.9, 27.2). The 3-year OS rate was 22% in both PD-L1 expression subgroups.

Conclusion:
Nivolumab plus chemotherapy resulted in prolonged survival in a subset of patients, with a 3-year OS rate of 25%. In all patients, ORR and OS were similar irrespective of tumor PD-L1 expression. These results support further evaluation of nivolumab-chemotherapy combinations as first-line treatment for advanced NSCLC, which are being explored in CheckMate 227 (NCT02477826).

Abstract not provided

Background:
Nivolumab is a standard option for second‐line treatment in pts with advanced NSCLC. Real‐life data are lacking regarding the efficacy of nivolumab and post‐nivolumab treatment.

Method:
This analysis included the first 600 consecutive pts with stage IIIB/IV NSCLC who received ≥1 dose of nivolumab 3mg/kg q2w through the French EAP from 01/2015 for Squamous ﴾Sq﴿ and 06/2015 for Non‐Sq NSCLC, until 08/2015.

Result:
Median age was 64 yo, there were 409 ﴾68%﴿ men, 521 ﴾87%﴿ smokers, 478 ﴾80%﴿ PS0/1 pts, 230 ﴾38%﴿ Sq and 370 ﴾62%﴿ Non‐Sq NSCLC, 130 ﴾22%﴿ pts with brain metastases. Nivolumab was administered as 2nd/3rd/≥4th‐line for 26%/33%/41% pts, respectively. Best response was PR/SD/PD for 17%/30%/37% of patients, respectively, with 16% not assessable. Toxicities occurred in 187 ﴾31%﴿ pts, including 10% grade ≥3 events. After a median follow‐up of 22.1 ﴾95% CI 21.6‐22.6﴿ months, median PFS and OS from the initiation of nivolumab were 2.1 ﴾95%CI 1.9‐2.3﴿ and 9.5 ﴾95%CI 8.4‐10.8﴿ months, respectively. In the 92 pts with PS2 at initiation of nivolumab, PR/SD rates were 7%/28%; median OS was 3.6 (95%CI 2.7-5.2) months. A total of 130 pts had brain metastases at initiation of nivolumab: PR/SD rates were 12%/25%; median OS was 6.6 (95%CI 3.8-8.3) months. Post‐nivolumab treatment was administered to 262 ﴾44%﴿ pts, and mostly consisted of gemcitabine ﴾19%﴿, docetaxel ﴾18%﴿, paclitaxel ﴾14%﴿, erlotinib ﴾12%﴿, vinorelbine ﴾9%﴿, platin‐based doublet ﴾8%﴿, or pemetrexed ﴾8%﴿. Access to post‐nivolumab treatment was higher in PS0/1 vs. PS2 pts ﴾48% vs. 23%, p<0.001﴿, but was not different according to histology or treatment line or disease control with nivolumab. Best response to post‐nivolumab treatment was PR/SD/PD for 15%/42%/42% of pts, respectively. In the whole cohort, median post‐nivolumab OS was 4.0 ﴾95%CI 2.8‐4.6﴿ months, and was significantly higher in case of PR to nivolumab ﴾HR=0.38; 95%CI 0.23‐0.64; p<0.001﴿, and if subsequent treatment was delivered ﴾HR=0.30; 95%CI 0.24‐0.38; p<0.001﴿; median post‐nivolumab OS in pts receiving post‐nivolumab treatment was 7.5 ﴾95%CI 6.8‐8.7﴿ months, and did not differ based on histology or treatment line.

Conclusion:
Efficacy and safety of nivolumab was in line with available data. Post‐nivolumab treatment may be delivered in many pts, including pts with PS2 and brain metastases, with favorable impact on response and OS. Data on the whole cohort of 900 pts enrolled in the EAP will be presented.

Background:
KEYNOTE-024 (ClinicalTrials.gov, NCT02142738) is a multicenter, international, phase 3, randomized, open-label, controlled trial of treatment with the anti‒PD-1 antibody pembrolizumab vs platinum-based chemotherapy as first-line therapy for patients with advanced NSCLC of any histology with PD-L1 tumor proportion score (TPS) ≥50% and without EGFR mutations or ALK translocations. Results from the primary analysis of KEYNOTE-024 demonstrated that after a median follow-up of 11.2 months, pembrolizumab significantly improved PFS (HR=0.50; P<0.001) and OS (HR=0.60; P=0.005) and was associated with a lower rate of treatment-related AEs compared with chemotherapy.

Method:
Patients were randomly assigned to receive either 35 cycles of pembrolizumab 200 mg every 3 weeks or 4–6 cycles of investigator's choice of carboplatin/cisplatin + gemcitabine, carboplatin + paclitaxel, or carboplatin/cisplatin + pemetrexed with optional pemetrexed maintenance (for those with non-squamous histology). Randomization was stratified by ECOG performance status (0 vs 1), histology (squamous vs nonsquamous), and geographic region (East Asia vs non–East Asia). Treatment continued until disease progression per RECIST version 1.1, intolerable toxicity, or withdrawal of consent. Patients in the chemotherapy arm who experienced disease progression could cross over to receive pembrolizumab monotherapy. Response was assessed every 9 weeks by blinded independent central review per RECIST version 1.1. The primary endpoint was PFS; secondary endpoints were OS, ORR, and safety.

Result:
305 patients were enrolled (pembrolizumab, n=154; chemotherapy, n=151). At the time of data cutoff (July 10, 2017) after a median follow-up of 25.2 months, 73 patients (47.4%) in the pembrolizumab arm and 96 patients (63.6%) in the chemotherapy arm had died. The hazard ratio for OS was 0.63 (95% CI, 0.47–0.86; nominal P=0.002). Median (95% CI) OS was 30.0 (18.3–not reached) months in the pembrolizumab arm and 14.2 (9.8–19.0) months in the chemotherapy arm. The Kaplan-Meier estimate of OS at 12 months was 70.3% (95% CI, 62.3%–76.9%) for the pembrolizumab group and 54.8% (95% CI, 46.4%–62.4%) for the chemotherapy group. 82 patients allocated to the chemotherapy arm crossed over to receive pembrolizumab upon meeting eligibility criteria. Treatment-related adverse events were less frequent in the pembrolizumab arm than in the chemotherapy arm (76.6% versus 90.0%, respectively) as were treatment-related grade 3-5 adverse events (31.2% versus 53.3%).

Conclusion:
With more than half of patients having OS events and prolonged follow‒up, first-line pembrolizumab monotherapy remains superior to platinum-based chemotherapy despite the crossover from the control arm to an anti-PD1 inhibitor as subsequent therapy.

Background:
Atezolizumab (anti–PD-L1) inhibits PD-L1 binding to PD-1 and B7.1, restoring anti-cancer immunity. OAK, a Phase III study of atezolizumab vs docetaxel demonstrated superior OS of atezolizumab. The characteristics of the long-term survivors (LTS) in the OAK primary population (n = 850) are evaluated and describe the largest cohort of cancer immunotherapy-treated NSCLC LTS yet reported.

Method:
Patients received IV q3w atezolizumab (1200 mg) until PD / loss of clinical benefit or docetaxel (75 mg/m[2]) until PD / unacceptable toxicity. No crossover was allowed. LTS were defined as patients with OS ≥ 24 months and non-LTS as those who died within 24 months of randomization. Patients with OS censored prior to 24 months were not included. Data cutoff, January 23, 2017.

Result:
A higher 2-year survival rate was observed for the atezolizumab-arm (31%) vs docetaxel-arm (21%). After a minimum follow-up of 26 months, there were 119 LTS vs 279 non-LTS in the atezolizumab-arm and 77 LTS vs 299 non-LTS in the docetaxel-arm. Characteristics of atezolizumab-arm LTS and non-LTS are shown (Table). Atezolizumab-arm LTS were enriched for non-squamous histology and high PD-L1–expressing tumors, but also included low/no PD-L1–expressing tumors (40.3%). Atezolizumab-arm LTS had higher ORR (39.5%) than non-LTS (5.0%) but included LTS subjects with PD. 52.9% atezolizumab-arm vs 71.4% docetaxel-arm LTS received anti-cancer non-protocol therapy (NPT) after discontinuation of protocol-defined therapy. 51.9% of docetaxel-arm LTS vs 12.7% non-LTS received non-protocol immunotherapy. Median treatment exposure in atezolizumab-arm LTS was 18.0 months. Atezolizumab-arm LTS had a comparable safety profile to all atezolizumab-treated population.

Conclusion:
Atezolizumab provides superior 2-year OS benefit vs docetaxel and is well tolerated. The majority of docetaxel-arm LTS received a checkpoint inhibitor as NPT. Atezolizumab LTS appeared to have favorable prognostic factors, including non-squamous histology, but notably were not limited to patients with RECIST v1.1 response or with PD-L1 expression.

Table. Characteristics of Atezolizumab-Arm Long-Term Survivors (LTS) vs Non-Long Term Survivors (Non-LTS)
	Atezolizumab LTS (n = 119) n (%)	Atezolizumab Non-LTS (n = 279) n (%)
Sex
Male	61 (51.3)	183 (65.6)
Female	58 (48.7)	96 (34.4)
Tobacco use history
Never smoker	29 (24.4)	47 (16.8)
Current/previous smoker	90 (75.6)	232 (83.2)
Histology
Non-squamous	101 (84.9)	195 (69.9)
Squamous	18 (15.1)	84 (30.1)
No. of prior therapies, 1	89 (74.8)	209 (74.9)
ECOG performance status at baseline
0	60 (50.4)	89 (31.9)
1	59 (49.6)	190 (68.1)
EGFR mutation status, positive	11 (9.2)	26 (9.3)
PD-L1 IHC subgroup
TC3 or IC3	28 (23.5)	39 (14.0)
TC1/2/3 or IC1/2/3	71 (59.7)	156 (55.9)
TC0 and IC0	48 (40.3)	119 (42.7)
Best overall response
Complete response	5 (4.2)	0 (0)
Partial response	42 (35.3)	14 (5.0)
Stable disease	47 (39.5)	97 (34.8)
Progressive disease	25 (21.0)	142 (50.9)
IC, tumor-infiltrating immune cell; TC, tumor cell. TC3 or IC3 = PD-L1 ≥ 50% TC or 10% IC; TC1/2/3 or IC1/2/3 = PD-L1 ≥ 1% on TC or IC; TC0 and IC0 = PD-L1 < 1% on TC and IC. NCT02008227.

Background:
Patients (pts) with oligometastatic NSCLC may benefit from LAT (e.g., surgery, stereotactic radiation (SRT)). It is unclear if systemic therapy can provide additional benefit after LAT. We are running a Phase II study to evaluate the efficacy of pembrolizumab after LAT, hypothesizing that immunotherapy will be effective in the setting of a minimal disease burden.

Method:
Eligibility stipulates oligometastatic NSCLC (up to 4 sites) with completion of LAT to all known sites of disease. Within 4-12 weeks of completing LAT, pts begin pembrolizumab 200 mg every 21 days for 6 mos, with a provision to continue for a full year in the absence of progression or toxicity. Progression free survival (PFS) and overall survival (OS) are measured from the start of LAT. A sample size of 42 pts provides 80% power for a test at 5% 1-sided type I error to increase PFS to >=10 mos compared to a historical control PFS of 6.6 mo.

Result:
Since January 2015, 39 pts have been enrolled. The median age is 64 years; 54% are male; 90% Caucasian. Current and former smokers comprise 90% of the cohort, with a median of 32 pack yrs. Most common metastatic sites are lung (15 pts), brain (13), and bone (8). LAT has included surgery (24 pts), SRT (23), and concurrent chemoradiotherapy (17). Attributable adverse events (AEs) have been mostly mild and self-limited. There has been one episode of Grade 3 pneumonitis and one episode of Grade 3 adrenal insufficiency. Median follow-up from start of LAT is 16 mos. To date, 11 pts have had progression or death. The median PFS has not yet been reached. The PFS rates (+ SE) at 6, 12 and 18 mos are 92%+5%, 64%+9% and 64%+9%, with 16 and 5 pts at risk beyond 12 and 24 mos, respectively. To date, 8 pts (21%) have died. The median OS has not yet been reached. The OS rates (+ SE) at 6, 12 and 18 mos are 100%, 90%+6% and 75%+9%, with 22 and 5 pts at risk beyond 12 and 24 mos, respectively.

Conclusion:
Use of pembrolizumab after LAT for oligometastatic NSCLC is feasible and well tolerated. In a preliminary analysis, PFS appears favorable. Continued follow-up is necessary to confirm these findings. It is expected that accrual will be complete as of September 2017. Updated survival estimates will be presented.

Abstract not provided