Virtual Library

Background:
The eighth edition TNM classification for lung cancer subclassified T2 into T2a (>3 to ≤4cm) and T2b (>4 to ≤5cm). T1 tumor(<3cm) with visceral pleural invasion(VPI) should be classified as T2a or T2b remain unclear. To elucidate this, we analyzed the survival of non–small-cell lung cancer(NSCLC) patients from Surveillance, Epidemiology and End Results (SEER) registry and our institute.

Method:
Within the SEER database, we selected 24245 resected pN0 NSCLC patients from 2010 to 2013 with a special interest in the prognostic impact of VPI. The VPI was defined as including PL1 and PL2 according to the TNM system. The classification of T1 tumor with VPI was investigated via discriminative power of survival curves. The further validation set was selected from Guangdong Lung Cancer Institute (GLCI).

Result:
The overall survival (OS) and lung cancer specific survival (LCSS) of T1-VPI and each stage (size only) were compared. The survival differences were statistically significant between T1-VPI and T1c, as well as T1-VPI and T2b. There were no significant survival differences between T1-VPI and T2a (OS: p=0.706; LCSS: p=0.792). And we retrospectively collected pN0 NSCLC patients between 2011-2013 from GLCI. The progression-free survival(PFS) and OS differences were also observed between T1-VPI and other groups except T2a (PFS: p=0.852; OS: p=0.970).

Conclusion:
In the 8th TNM classification for lung cancer, in which T1 tumors with VPI are upgraded to T2a, rather than T2b. Figure 1

Background:
Recent studies have reported that sublobar resection is not inferior to lobectomy for small-sized non-invasive adenocarcinoma; however, the adequacy for small-sized invasive adenocarcinoma (IAD) remains unclear. We have reported that, in patients with pathological stage I IAD, the presence of ≥ 5% solid (SOL) histologic subtype is a significant predictor of recurrence, especially for the patients undergoing sublobar resection (Figure A). The objective of this study was to identify the clinical factors associated with the presence of SOL in patients with IAD.

Method:
We retrospectively reviewed patients with therapy-naïve, pathological stage I (≤2-cm) lung adenocarcinoma, who had undergone complete resection from 1998-2015. Each tumor was evaluated by comprehensive histologic subtyping according to the 2015 WHO classification and re-evaluated preoperative thin-sliced computed tomography to determine solid size and reclassified them according to the new TNM classification. We defined carcinoembryonic antigen (CEA) cut-off value as 2.2 ng/mL. Recurrence-free probability was estimated using the Kaplan-Meier method.

Result:
IAD patients with available image was 160 cases (94 male and 66 female, 96 smokers, and median age: 69 years). Clinical T classification in the 7th edition was T1a:142, T1b:17, T2a:1, and in the 8th edition Tis:17, T1mi:3, T1a:37, T1b:100, T1c:3. The presence of ≥ 5% solid component (SOL) was identified in 70 patients (44%). In patients with IAD, the presence of ≥ 5% SOL was associated with increased risk of recurrence compared to those with SOL <5% (P=0.001, Figure B). The presence of ≥ 5% SOL was significantly associated with sex, smoking, clinical T classification in the 8th edition, and high CEA level (P = 0.001, P < 0.001, P < 0.001, P = 0.013, respectively).

Conclusion:
In patients with pathological stage I IAD, clinical  T classification in the 8th edition, and high CEA level significantly correlated with the presence of ≥ 5% SOL, which was associated with recurrence after surgery. Figure 1

Background:
Current practice guidelines recommend uniform follow-up protocol for all stage I lung adenocarcinoma (ADC) patients who underwent surgical resection. We hypothesized that the annual recurrence hazard of resected pathological stage I lung ADC patients vary according to the IASLC/ATS/ERS histological subtype.

Method:
Pathological stage I lung ADC patients who had undergone complete resection (R0) without induction therapy (N=1572, 1995-2012) were analyzed.

Result:
Among 1572 patients, 271 (18.5%) recurrences were identified (median follow-up 64.0 months) with highest peak of recurrence within first two years following resection. Patients who had undergone sublobar resection showed higher recurrence rate than those who had undergone lobectomy (Fig. 1A). The recurrence hazard increased as a function of the percentage of micropapillary (MIP) pattern (Fig. 1B), while the solid pattern contributed to the early recurrence (Fig. 1C). According to the presence of MIP and/or solid (SOL) pattern, the recurrence hazard is well stratified. Tumors without micropapillary and solid subtype show no peak with 2% of annual recurrence hazard within 10 years following resection, while tumors with both MIP and SOL patterns have the highest peak within 2 years compared to other MIP and SOL combinations.

Conclusion:
Patients with resected pathological stage I lung ADC show structured recurrence dynamics well stratified with the high risk histological subtypes, providing clinically useful prognostic information for patients and physicians. Figure 1

Background:
Stereotactic body radiation therapy (SBRT) is an option for treatment of patients with non-small cell lung cancer (NSCLC). Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive, diagnostic modality for mediastinal and hilar staging of NSCLC. We evaluated the diagnostic value of EBUS-TBNA in SBRT candidates and compared it to that of computed tomography (CT) and positron emission tomography (PET) scans.

Method:
Inclusion criteria for this single institutional retrospective study included 1) biopsy-proven or clinically suspicious NSCLC with diameter <6 cm; 2) no evidence of distant metastasis; 3) EBUS-TBNA staging between April 2008 and November 2014; 4) medically SBRT-eligible other than nodal staging. CT and PET positive nodes were defined as short axis ≧1cm and standardized uptake value ≧2.5, respectively. Node positive by clinical-pathologic confirmation (NPCP) was defined as confirmed malignancy by EBUS-TBNA or clinically diagnosed recurrence in hilar or mediastinal lymph nodes within one year after SBRT. The survival after SBRT was compared between CT or PET node-positive but EBUS-TBNA result-negative patients, and a matched cohort (tumor size; radiation dose; operability) who underwent SBRT in our institution within the same time period but without EBUS-TBNA staging.

Result:
There were 35 eligible patients (mean age 77±8.2, 24 male). Thirty-two (91.4%) patients had pathological confirmation of NSCLC (mean diameter 2.5±1.0 cm) (T1a N=12, T1b N=15, T2a N=7, T2b N=1). Thirty (85.7%) patients were medically inoperable. After EBUS-TBNA, 20 out of 24 patients who had positive nodes in CT (N=13) or PET (N=17) were ultimately pathologically N0. All eleven image-negative patients were N0 following EBUS-TBNA. Thirty-one patients (20 image positive plus 11 image negative) underwent SBRT. Sensitivity/specificity of CT, PET and EBUS-TBNA for NPCP were 42.9/64.3%, 100/64.3% and 57.1/100%, respectively. Positive predictive value of CT and PET for NPCP was 23.1% and 41.2%, respectively. Negative predictive value of CT, PET and EBUS for NPCP was 81.8%, 100% and 90.3%, respectively. A 1:4 (Case; N=20, Control; N=76) match was obtained. Regional failure-free survival (p=0.71, HR=0.88 CI 0.45-1.74) and disease-free survival (p=0.77, HR=1.10 CI 0.58-2.11) of the Case were not significantly different from the ones of Control. There were no major complications related to EBUS procedures.

Conclusion:
EBUS-TBNA can be considered for invasive staging in SBRT-eligible NSCLC patients with radiographically positive lymph nodes because of its safety and possibility of false positive imaging. If EBUS-TBNA result is negative, these patients may remain candidates for SBRT with comparable outcomes to those who are conventionally selected for SBRT.

Background:
According to the 8th Edition of the TNM Classification of Lung Cancer, a tumor of >7 cm in diameter is upstaged to T4 from T3 based on the prognostic analysis of patients with pT1–4N0M0R0. However, there are two major problems with this classification. The first is selection bias; very few patients with non-size-based T4 undergo resection, whereas most patients with large tumors have surgery. The second is a diagnostic problem. Additional tumor nodules in a different ipsilateral lobe (pm2) are also T4 descriptors; however, multiple primary lung cancers may be misdiagnosed as T4 lung cancer with intrapulmonary metastasis.

Method:
A total of 378 patients with pT3–4N0–1M0 (according to the new classification) underwent complete or incomplete resection from 1992 to 2011. T4 was subdivided into invT4 (local invasion), multiple-pmT4 (pm2 with multiple nodules), single-pmT4 (single pm2), and sizeT4 (>7 cm).

Result:
The number of patients with invT4/multiple-pmT4/single-pmT4/sizeT4/T3 was 13/12/9/61/283; 5-year overall survival (OS) was 23%/25%/67%/46%/64%; and 5-year disease-free survival (DFS) was 15%/17%/67%/39%/55%, respectively. Patients with invT4 and multiple-pmT4 had poorer prognosis than those with sizeT4 in multivariate analysis (OS, hazard ratio = 2.6, p < 0.05; DFS, hazard ratio = 3.2, p < 0.01). Figure 1



Conclusion:
The extremely favorable outcome of single-pmT4 suggests the possibility of it being mixed up with multiple primary cancers. Non-size-based T4 patients had poorer prognosis than did sizeT4 patients even in surgical candidates, and the outcome of non-surgically treated patients seemed still worse. Tumors of >7 cm in diameter should not be treated the same as a non-size-based T4 and should be reclassified as T3b.

Background:
Mediastinal lymph node staging in NSCLC is crucial to set treatment options. But correct nodal staging is also challenging, especially, in regions of endemic for granulomatous diseases. The purpose of the study is to evaluate the value of PET-guided EBUS-TBNA and the efficacy of PET/CT for prediction of cytopathological results of lymph node staging in NSCLC.

Method:
38 patients who underwent F-18 FDG PET/CT for initial staging of NSCLC and subsequent mediastinal node staging by EBUS-TBNA for clarification of the hilar,mediastinal nodes between Sep.2013 and Jul.2014 were retrospectively reviewed. The clinical nodal staging with PET/CT were correlated with cytopathological results after TBNA. Overall sensitivity, specificity, PPV, NPV,and accuracy were evaluated.

Result:
From 38 PET scans, total 112 thoracic lymph node stations had noticeable focal hypermetabolisms.82 FDG avid stations were suspected to have metastasis,16 stations were considered as inflammatory nodes,and 14 stations were reported as equivocal findings. The majority of the primary lung pathology which showed equivocal nodal PET findings were adenocarcinoma (9/14). Total 58 thoracic lymph nodes (PET positive 38, PET negative 12, and equivocal PET finding in 8 nodes, respectively) were aspirated in 38 patients. Malignancy was detected in 39 (67.2%) out of 58 lymph nodes. (Figure 1. flow chart)Figure 1 2 patients up-staged from N1 to N2,1 patient up-staged from N2 to N3,and 1 patient down-staged from N3 to N2 after PET-guided EBUS-TBNA. From 8 lymph nodes that showed equivocal PET finding,6 were enlarged and showed heterogenous hypoechogenicity on EBUS.4 node of those were proved to be cytologically metastatic lymph nodes. The sensitivity, specificity, PPV, NPV and diagnostic accuracy of PET-guided EBUS-TBNA on a node-based analysis was 94.9%, 63.2%, 84.1%, 85.8%, and 84.5%, respectively when we combined EBUS findings with PET.



Conclusion:
PET-guide EBUS-TBNA offers an effective, accurate, and minimally invasive strategy for evaluating lymph node staging in NSCLC.

Background:
Based on a 20-30% prevalence of occult mediastinal disease, current guidelines recommend preoperative invasive mediastinal staging in patients with central tumour location and negative mediastinum on PET-CT. A uniform definition of central tumour location is lacking. Our objective was to determine the best definition in predicting occult mediastinal disease.

Method:
A single institution prospective database was queried for patients with (suspected) NSCLC staged cN0 after PET-CT and referred to invasive staging and/or primary surgery. We evaluated 5 definitions of central tumour location (table 1).

Result:
Between 2005 and 2015, 822 patients were eligible. Radio-occult lesions were excluded from analysis (n=9). Preoperative histology was NSCLC in 49% and unknown in 51%. The lesion was subsolid in 7%. Tumour stage was cT1, cT2, cT3 and cT4 in 43%, 28% 17% and 11%, respectively. Invasive mediastinal staging (EBUS and/or mediastinoscopy) was performed in 31%. Surgical resection was performed in 97%, a median of 5 (IQR 3-6) nodal stations were examined. The final pathology was squamous NSCLC, non-squamous NSCLC, or other in 38%, 54% and 7%, respectively. Any nodal upstaging was found in 21% (13% pN1 and 8% pN2-3). Central tumour location demonstrated, compared to peripheral location, a 4 times higher risk for any nodal upstaging but not for N2-3 upstaging (table 1).

Conclusion:
When modern PET-CT fusion imaging points at clinical N0 NSCLC, the prevalence of occult mediastinal nodal disease was only 8% in our patient cohort. None of the five definitions of centrality we studied was predictive for occult pN2-N3. Overall nodal upstaging was 21%, however, and all definitions of centrality then had discriminatory value. These data question whether the indication of preoperative invasive mediastinal staging should be based on centrality alone. Table 1 Figure 1

Background:
Among patients with lung adenocarcinoma, some of them diagnosed as clinical N0 (cN0) are staged as pathological N2(pN2 ; unexpected N2 disease). The aim of this study is to analyze preoperative factors of unexpected N2 disease.

Method:
We retrospectively reviewed 361 cN0 lung adenocarcinoma patients who underwent curative resection between January 2005 to December 2016 in our institution. Patients were staged according to findings of computer tomography (CT), positron emission tomography (PET), and/or transbronchial needle aspiration (TBNA). We analyzed their clinical features, comparing pN0 group with pN2 group. Especially, we focused on the diameter of solid component by TNM classification 8[th] edition.

Result:
There were 37 patients (10.2%) with unexpected N2 disease. Of the 37 patients, 10 patients (27.0%) had metastasis in Single-station N2 without N1 involvement (skip N2 disease), 14 patients (37.8%) had in Single-station N2 and 13 patients (35.1%) had in Multiple-station N2. There was no difference in the tumor size between pN0 and pN2 (p=0.100). However, the diameter of solid component was larger in pN2 than in pN0 (p<0.001), C/T ratio (p<0.001), maximum standard uptake value (p<0.001), and CEA (p=0.005) were higher in pN2 than in pN0. Multivariate logistic regression analysis identified the diameter of solid component and CEA as significant associated factors for unexpected N2 disease (p=0.006, p=0.01).

Conclusion:
The possibility of unexpected N2 disease increases with the larger diameter of solid component or higher CEA. Particularly, in order to discover unexpected N2 disease in lung adenocarcinoma, it is reasonable to evaluate T-factor by TNM classification 8[th] edition.

Background:
Computed tomography (CT) lymphography by transbronchial injection of a water-soluble extracellular CT contrast agent was developed as a new method for identifying sentinel nodes (SNs) in patient with non-small cell lung cancer (NSCLC). SNs were identified in 87.8% of patients, and the accuracy rate of SN identification was 97.5%. CT lymphography images sometimes show enlargement of lymphatic vessel (Fig), and we noticed this finding is related to lymph node metastasis. Lymphatic vessel enlargement was seen in 80% of lymph node metastasis positive cases whereas only 24.2% of lymph node metastasis negative cases showed lymphatic vessel enlargement (p=0.027). The aim of this study was to investigate the relationship between the finding of lymphatic vessel enlargement seen in CT lymphography and tumor lymphangiogenesis including lymphatic vessel density or vascular endothelial growth factor (VEGF)-C. Figure 1



Method:
Lymphatic vessel enlargement was defined as a finding of an enhanced lymphatic vessel ≥ 3mm on CT lymphography. We examined formalin fixed paraffin embedded tumor samples of 36 patients who received CT lymphography preoperatively. Lymphatic vessel density was determined based on the number of peritumoral vessels immunoreactive to anti-D2-40 antibody. The percentage of tumor cells exhibiting cytoplasmic staining for VEGF-C was evaluated and ≥ 30% was defined as VEGF-C positive.

Result:
Twelve out of 36 (33.3%) cases showed finding of the lymphatic vessel enlargement on CT lymphography. Peritumoral lymphatic vessel density of VEGF-C positive patients was significantly higher than that of VEGF-C negative patients (28.4 ± 11.6 vs 17.0 ± 10.5, p=0.005). Lymphatic vessel enlargement was more frequently seen in VEGF-C positive patients than in VEGF-C negative patients (53.8% vs 21.8% ± 10.5, p=0.056).

Conclusion:
Our study suggests VEGF-C secreted by tumor cells play a key role in the lymphatic remodeling and lymphatic vessel enlargement seen in CT lymphography may be a risk factor for lymph node metastasis of NSCLC.

Background:
Non - small cell lung cancer(NSCLC) is known to have a high propensity for metastasis to brain. Conventional wisdom and guidelines recommend MRI brain as routine staging investigation for patients planned for radical treatment. However there is little data about the detection rate of brain metastasis using MRI brain in asymptomatic patients with operable/early stage NSCLC.

Method:
We conducted a prospective observational study to assess the incidence of MRI detected brain metastasis in early operable lung cancer. Consecutive patients presenting to the outpatient department with biopsy proven NSCLC were screened. All patients planned for radical treatment underwent PET CECT and MRI brain as per institutional protocol. Patients with early stage disease( Stage I to IIIA) on PET CECT with no symptoms suggestive of brain metastasis were included in the study. Data regarding histopathology, T stage, N stage, SUV uptake of primary, clinicoradiological stage, neurological symptoms and MRI brain findings was collected.

Result:
1944 consective biopsy proven patients of NSCLC presenting in the outpatient department from Jan 1st 2015 to Dec 31st 2015, were screened. 168 patients in stage I to IIIA as per PET CECT, without obvious evidence of brain metastastis were included in the study, 81(48.2%) were in stage I&II and 87(51.7%) were in stage IIIA. Among the remaining 1776 patients, 213 patients had brain metastasis at presentation. Two patients with early stage disease and symptomatic solitary brain metastasis were treated with radical intent and excluded from the study. The incidence of MRI detected asymptomatic brain metastasis in the study population(Stage I to IIIA) was 6/168 (3.5%) and all were in stage IIIA. MRI brain did not pick up any brain metastasis in asymptomatic Stage I&II NSCLC patients. No co-relation could be found between grade of tumour, SUV of primary, T stage or N stage with the incidence of brain metastasis. Three patients in the study population developed brain metastasis while on treatment.

Conclusion:
Although this study is limited by the small sample size, the role of MRI brain in staging of early stage NSCLC (Stage I & II) needs to be re evaluated in light of the low yield seen in asymptomatic patients. Rigorous evaluation of the patient's history and clinical symptoms may obviate the need of MRI brain in this subset. This may become increasingly relevant with the implementation of lung cancer screening programs.

Background:
Lung cancer survival depends on accurate staging and treatment selection. Because staging and treatment are increasingly multi-modal, we examined staging and treatment selection practices with or without MD care in a single healthcare system.

Method:
Eligible patients had untreated lung cancer, ECOG performance status of 0-2, and gave informed consent. Comparisons were made between patients seen in a co-located MD clinic (MDC) and those receiving standard care (SC). Some SC patients were discussed at a multidisciplinary tumor conference (MDTC), thus allowing comparison of MD care to pure SC and MDTC. Diagnostic, staging, treatment procedures and patient outcomes were prospectively recorded. Staging thoroughness was defined as biopsy of stage-defining lesion; bimodality staging (PET+CT or CT+invasive staging biopsy); trimodality staging (PET+CT+invasive staging biopsy). Stage migration was determined comparing baseline stage (from first radiologic scan) to final clinical stage prior to treatment. Stage-appropriate treatment was defined by NCCN guidelines using final, pre-treatment stage. Chi-squared test and multivariable logistic regressions adjusted for age, sex, and histology were used to examine differences between patient cohorts.

Result:
Of 527 patients, 178 were MDC, 77 MDTC, 272 SC. Race and gender were similar but median age (67 v 66 v 69 (p=0.0032) and insurance distribution (p=0.0021) differed across groups. MDC tended to have more thorough staging than MDTC and SC. Significant differences were observed in staging migration and appropriate treatment, favoring MDC and MDTC patients (Table 1). After adjusting for age, sex, and histology, MCD and MDTC were 2-3 times more likely to have more thorough staging and overall stage appropriate treatment (Table 1). Figure 1



Conclusion:
Care within a structured MDC environment (whether co-located MDC or MDTC) was associated with significantly more thorough staging processes and higher rates of stage-appropriate use of treatment modalities than usual care. Survival analysis will be reported when data are mature.

Background:
Radiologically pure solid tumors are heterogeneity because of including various histological type, however, small-sized tumors are difficult to be preoperatively diagnosed histology. The aim of this study was to identify preoperative predictors for pathological malignant of pure solid lung cancer in clinical early stage.

Method:
The data from a multi-center database of 220 patients who underwent anatomical resection for radiologically pure solid, tumor size 2 cm or less, and clinical N0 lung cancer were retrospectively analysed. Factors affecting survival were assessed using Cox regression analysis. Predictors were found by drawing the receiver operating characteristic curves (ROC) and evaluated the possible cutoff value for independent prognostic factor.

Result:
Pure solid tumors included 164 (74%) adenocarcinoma, 33 (15%) squamous cell carcinoma, 16 (7%) neuroendocrine tumor, 5 (2%) pleomorphic carcinoma, and 3 (1%) adenosquamous cell carcinoma. In multivariate analyses, high malignant grade histology such as micropapillary and solid predominant adenocarcinoma, adenosquamous cell carcinoma, neuroendocrine tumor, or pleomorphic carcinoma and pathological lymph node metastasis were an independent prognostic factors for recurrence-free survival. The ROC showed that 3.55 in maximum standardized uptake value (SUV max) was cut-off value for detecting high malignant grade histology or lymph node metastasis (area under the curve, 0.71; 95% confidence interval, 0.63 – 0.78). Tumors with SUV max ≥ 3.55 had significantly more high-grade histology, the presence of lymphatic and vascular invasion, and lymph node metastasis and poorer recurrence-free survival rate than SUV max < 3.55 (Figure). Figure 1



Conclusion:
The prognosis of radiologically pure solid tumor with small size and clinical N0 lung cancer was stratified according to SUV max. SUV max could evaluate pathological malignant grade and help the decision of appropriate surgical procedure.

Background:
The 8th edition of the TNM staging system for lung cancer has been published. In the new staging system, the N component remains the same as in the previous version. However, the number of involved nodal stations has been previously shown to be correlated with patient outcomes. In the present study, we retrospectively investigated the correlations between the anatomical location versus the total number of metastatic lymph nodes and the outcomes of patients with non-small cell lung cancer.

Method:
We retrospectively collected 237 samples (16.1%) from patients with pN1 and N2 primary lung cancer who underwent complete resection between 2004 and 2013. In those samples, we divided N1 samples into N1ss (single station N1) and N1ms (multiple station N1). We also divided samples into hilar N1 (#11, #10; N1h) and peripheral N1 (#14, ＃13, and #12; N1p) subgroups. pN2 lymph nodes were divided into “single station N2 with skip metastasis” (N2ss1), “single station N2 with N1 metastasis” (N2ss2), and N2ms. The clinicopathological factors and outcomes for each group were statistically analyzed.

Result:
In this study, per patient, a mean of 17.9 lymph nodes were dissected and the mean number of lymph node metastases was 3.9. The pN1 and pN2 groups consisted of 74 and 163 cases, and their 5-year survival rates were 74.7% and 54.8%, respectively (p = 0.021). The 5-year survival rates of the N1p and N1h groups were 74.7% and 63.6%, respectively. Although the N1h group showed a tendency towards poorer outcomes, no statistically significant difference between the groups was observed (p = 0.114). The 5-year survival rates of the N2ss1 and N2ss2 groups were 65.4% and 62.4%, respectively, and the N2ms group had poorer outcomes (45.0％, p = 0.010). In our cohort of patients with N1 and N2 lymph node metastasis, the number of metastatic lymph nodes was not correlated with patient outcomes.

Conclusion:
In the cases of pN1, patients with N1h had poorer outcomes than those with N1p. In the cases of pN2, patients with N2ms had poorer outcomes than those with other subsets of pN2. From a prognostic point of view, classification based on the anatomical location of metastatic lymph nodes may be important. Further accumulation and examination of cases will be necessary to confirm our findings.

Background:
Patients with N1 non-small cell lung carcinoma (NSCLC) represent a heterogeneous subgroups.we reviewed our previous cases of pT1N1M0 and pT2N1M0 NSCLC and the influence of the type of lymph node involvement on survival and recurrence was investigated.

Method:
A total of 106 consecutive patients who underwent complete tumor resection and mediastinal lymph nodes dissection for pT1N1M0 and pT2N1M0 NSCLC between 1981 and 2015 were retrospectively reviewed.

Result:
The overall 5-year survival of patients with T1-2N1M0 disease was 32.4%. the 5-year survival rate differed significantly according to the type of lymph node involvement. The 5-year survival rate for patients with hilar lymph node involvement, interpulmonary lymph node involvement was 50.2%, 30.1%,the survival curves of two groups had significant differences. In T1 patient, the 5-year survival rate for patients with hilar lymph node involvement, interpulmonary lymph node involvement was 46.2%, 30.1%. In T2 patient, the 5-year survival rate for patients with hilar lymph node involvement, interpulmonary lymph node involvement was 40%, 12%.

Conclusion:
In patients with N1 NSCLC, survival differs according to the type of lymph node involvement.patients with only inter-pulmonary lymph node involvement have a better prognosis, whereas patients with hilar lymph node involvement have a poorer prognosis. In T2 patients, hilar lymph node involvement represents poorer disease. Patients with pN1 disease represent a heterogeneous group that may be subdivided according to the level of the involved N1 station.

Background:
To determine whether percutaneous transthoracic needle biopsy (PTNB) increase the risk of (a) isolated pleural recurrence and (b) concomitant pleural seeding and metastasis in stage I non-small cell lung cancer (NSCLC).

Method:
In this institutional review board-approved retrospective study, medical records of total of 830 consecutive patients with stage I NSCLC who underwent curative resection between 2004 and 2010 were reviewed. Median duration of follow-up was 1843 days (interquartile range, 1006-2734). Multiple logistic regression analyses were performed to identify risk factors of pleural recurrence.

Result:
Of 830 patients, 540 patients (65.1%) underwent PTNB before surgery, while 290 patients (34.9%) underwent non-PTNB procedures including bronchoscopic biopsy or exploratory thoracotomy. An isolated pleural recurrence was found in 26 patients (3.1%, [95%CI, 2.1-4.6%]) (20 in PTNB group, 6 in non-PTNB group). There was no significant association between PTNB and isolated pleural recurrence (P=0.197). Concomitant pleural recurrence occurred in 42 patients (5.1%, [95%CI, 3.8-6.8%]) (34 in PTNB group, and 8 in non-PTNB group). Subpleural location (p=0.007), tumor consistency (solid, part-solid, nonsolid) (p=0.046), PTNB (p=0.027), pathologic T stage (p<0.001), microscopic pleural invasion (p<0.001) and microscopic lymphatic invasion (p=0.019) were associated with concomitant pleural recurrence. The most significant factor of pleural recurrence was only microscopic pleural invasion (Odds Ratio, 4.28; 95% CI, 2.20 to 8.29) (P<0.001) on multiple logistic analysis. Among 540 patients undergoing PTNB, transfissural approach did not have significant association with pleural recurrence (P=0.220), while the most sole significant factor was microscopic pleural invasion (Odds Ratio, 3.40; 95% CI, 1.54 to 7.51) (P=0.002).

Conclusion:
PTNB did not increase the risk of isolated or concomitant pleural recurrence in early stage NSCLC. Higher incidence of concomitant pleural seeding in PTNB group was presumably attributed to peripheral lung cancer, potentially accompanying microscopic pleural invasion.

Background:
The prediction of RP has become an important topic in medical field. Currently, the clinical assessment of lung injury is analyzing the dose-volume threshold based on the 3D-CRTor IMRT by controlling the percent lung volume receiving a certain amount of dose. Many literatures failed to provide an exact correlation coefficient due to data missing and nonlinear deviation in the modeling of RP prediction. Compared with the conventional radiation techniques, the low dose volume of lung is greatly enlarged especially for patients treated with VMAT or tomotherapy (TOMO). EUD is equivalent dose of inhomogeneous radiation that has the same radiobiological effect.The tissue characteristic parameter α in EUD shows the tolerance of tissue for radiation dose and the higher α, the better tolerance. Different α value are used to classify the tumor tissue, normal tissue and the serial and parallel organ in normal tissue according to “Stevens law”. The tumor tissue has a negative α value which means that in dose will lead to uncontrolled tumor. The serial organ in normal tissue has a high α value for its abnormal sensitivity to high dose. And the parallel organ has a small α for its low sensitivity.

Method:
65 patients receiving radiation therapy for lung cancer using VMAT were divided into two groups according to whether radiation pneumonitis occurred after radiation therapy. The dose-volume histogram (DVH) and its associated parameters of the patients were abstracted and analyzed by self-complied analysis program. The LEUD values of the two groups were calculated with α ranging from -50 to 50. The optimal α value was obtained when the relative LEUD difference between the two groups reached maximum.

Result:
The maximum relative LEUD difference between the group of radiation pneumonitis (GRP) and non-radiation pneumonitis (G-NRP) is obtained at α=0.5 (LEUD (GRP) =627.94 cGy, LEUD (G-NRP) = 510.23 cGy, relative LEUD difference =23.07%). The relative LEUD difference (R) reaches the maximum at α=0.5. the R tends to decrease slowly till the end of the parameter range of this study (α=50). The traditional correlation analysis of physical dose-volume threshold shows that the LEUD (α=0.5) is related to physical dose metrics including , and mean lung dose (MLD) with average person =0.929.

Conclusion:
The LEUD (α=0.5) (limited below 510 cGy) is possible to distinguish GRP from G-NRP for the thoracic tumor patients. The combination of LEUD and conventional physical dose metrics shows clinical prospective value for RP caused by non-uniform radiation.

Background:
No standard fractionation of radiotherapy (RT) has been established for solitary lung tumors after complete resection of non-small cell lung cancer (NSCLC). We retrospectively compared stereotactic body radiotherapy (SBRT) with conventionally fractionated radiotherapy (CFRT) with regard to efficacy and toxicity.

Method:
Between 2006 and 2015, 26 patients were treated with RT alone for solitary lung tumors that were postoperative local recurrence, pulmonary metastasis, or multiple primary lung cancer after complete resection of NSCLC. At the time of RT, 22 patients (85%) were medically inoperable. The median age was 79 years (range, 61-88 years). Histological confirmation was obtained in 4 patients (15%). The median maximum diameter of the solitary lung tumors was 15 mm (range, 6-30 mm). None of the patients had regional or extra-pulmonary distant metastasis. SBRT using 48 Gy in 4 fractions at the isocenter was administered to 15 patients with peripheral solitary lung tumors (SBRT group). CFRT using 66-70 Gy in 33-35 fractions was administered to 11 patients with central solitary lung tumors to avoid a risk of severe hilar or mediastinal toxicity with SBRT (CFRT group).

Result:
The median follow-up time was 32 months (range, 9-79 months). Regarding characteristics of the patients, adjuvant chemotherapy after surgery was significantly more often performed in the SBRT group than the CFRT group (p = 0.036; Fisher's exact test). However, adjuvant chemotherapy after surgery was not a significant factor for overall survival and local control rates after RT (p = 0.232 and 0.547, respectively; log-rank test). No other characteristics of the patients differed significantly between the SBRT and CFRT groups. The 3-year overall survival rates in the SBRT and CFRT groups were 81% and 40%, respectively (p = 0.008; log-rank test). The 3-year local control rates in the SBRT and CFRT groups were 83% and 35%, respectively (p = 0.035; log-rank test). Regarding toxicities (CTCAE v4), no significant differences in the occurrences of grade 2 radiation pneumonitis and grade 2-3 dyspnea were found between the SBRT and CFRT groups (p = 1.000 and 1.000, respectively; Fisher's exact test). No other grade 3-5 toxicities were observed.

Conclusion:
SBRT may be more effective compared with CFRT in patients with solitary lung tumors after complete resection of NSCLC.

Background:
Lung stereotactic body radiotherapy (SBRT) for medically inoperable early stage lung cancer involves extremely precise delivery and requires robust systems for patient (pt) immobilization, breathing control, and daily image guidance. Severe cognitive impairments [CIs] in pts may interfere with their suitability for lung SBRT. Herein, we report on the pt/tumor/treatment characteristics of CI cases for which out-pt anesthesia [OPA] was employed to ensure safe and rigorous SBRT delivery.

Method:
A survey of an IRB-approved institutional prospective SBRT registry of 1330 pts for the interval April 2004 to December 2016 revealed 7 pts with medically inoperable early stage T1-T3N0M0 non-small cell lung cancer (NSCLC) requiring OPA. SBRT was delivered by a stereotactic-specific LINAC platform with vacuum-bag based immobilization, and CBCT +/- infrared-based X-ray positioning system for image-guidance. Tumor motion management involved an abdominal compression device in all cases and SBRT dose/fractionation was selected at the discretion of the treating physician.

Result:
Seven OPA cases were treated between March 2006 and July 2016. Pt characteristics included: female sex (71.4%); median age 66 years (range 44-66); median Karnofsky performance status 70 (range 40-80). Four pts completed spirometry: median FEV1 was 1.005 L and 41 % predicted; only 2 were able to do diffusion capacity testing. CI causes were: Alzheimer’s related dementia (n=3); chronic schizophrenia requiring institutionalization (n=3); severe mental disability from birth with tracheostomy (n=1). Tumor characteristics included: median diameter 3.8 cm (range 1.7-10.5); median PET SUVmax 10.5 (range 6.4-25.5); T stage 1a – 2 pts; 1b – 1 pt; 2a – 2 pts, 2b – 1 pt, 4- 1 pt; “central” location (per RTOG 0813): 6 pts. Treatment doses included 50 Gy/5 fractions (fx) in 3 pts, 60 Gy/3 fx in 1 pt, 60 Gy/8 fx in 2 pts and 50 Gy/10 fx for 1 pt. OPA consisted of a propofol 10mg/ml-including IV sedation regimen in all cases and was done at the time of simulation and daily with treatments. All SBRT was completed as planned. There were no complications attributable to OPA and no post-OPA hospitalizations. Median follow up was 17.7 months (range 6.6-105.5). At analysis, 5 pts (71%) were alive. One pt died of a grade 5 tracheo-esophageal fistula in the absence of cancer at 8.2 months after SBRT, otherwise there were no grade 3 or higher toxicities. One pt died from biopsy-proven loco-regional failure 105.7 months after SBRT. Otherwise, there has been no other local, regional nodal or distant failure at the time of analysis.

Conclusion:
OPA facilitated lung SBRT delivery for pts with CIs. SBRT outcomes were in keeping with expected values. CIs should not be considered contraindications to safe lung SBRT delivery in pts otherwise appropriate for this modality.

Background:
To provide a promising option for early stage non-small-cell lung cancer (NSCLC) treatment, a meta-analysis of stereotactic body radiotherapy (SBRT) and surgery in lung cancer was carried out.

Method:
Literatures were retrieved from the databases of PubMed, Embase and the Cochrane library and qualities were assessed by Nine Stars System Scale. All of the statistical analyses were conducted using Stata 11.0. Risk ratios (RRs) with its 95% confidence interval (CI) were set as effective indicators. Heterogeneity was estimated by Q statistics and I[2], and the publication bias was evaluated by Egger test.

Result:
A total of 12 high-quality studies were enrolled in this study (Table 1). No significant difference was identified in 1-year overall survival (OS) rate between SBRT and surgery. An obvious higher 3-year OS rate was detected in surgery compared with SBRT (RR = 0.78, 95% CI: 0.63 - 0.97). Moreover, superior 5-year OS rates were also identified in surgery (RR = 0.69, 95% CI: 0.52 - 0.91) and lobectomy (RR = 0.58, 95% CI: 0.47 - 0.72) compared with SBRT. The 3-year loco-regional recurrence control rate in SBRT was remarkably higher than that in surgery (RR = 1.11, 95% CI: 1.01 - 1.22), but the pooled 5-year distant recurrence control rate of SBRT was markedly lower than that in surgery (RR = 0.87, 95% CI: 0.76 - 0.99). Table 1 Characteristics of the included studies.

Study	Year	Country	Duration	Design	Stage	Follow up time	Treatment	Sample size	Male/Female	Age (years)	Outcomes
Chang	2015	Multi centers	2008- 2014	RCT	I	40.2 months	SBRT	31	14/17	67.3 (9.2)	1y SR; 3y SR; 3y DCR
						35.4 months	Surgery	27	11/16	67.3 (8.2)
Crabtree	2010	USA	2000- 2007	RCS	I	5 years	SBRT	57	NA	71 (50-94)	3y SR
							Surgery	57	NA	73 (47-90)
Crabtree	2014	USA	2004- 2010	RCS	I	5 years	SBRT	56	29/27	70.7 (10.6)	1y SR; 1y DCR; 3y SR; 3y DCR; 5y SR; 5y DCR
							Surgery	56	32/24	70.0 (8.1)
Hamaji	2015	Japan	2003- 2009	RCS	I	40.7 months	SBRT	41	31/10	73 (58-85)	3y SR; 5y SR
						54 months	Lobectomy	41	32/9	74 (61-86)
Matsuo	2014	Japan	2003- 2009	RCS	I	6.7 years	SBRT	53	42/11	76 (58-86)	5y SR; 5y DCR
						5.3 years	SLR	53	37/16	76 (50-88)
Mokhles	2015	the Netherlands	2003- 2012	RCS	I	28 months	SBRT	73	42/31	67 (10)	1y SR; 1y LGR; 1y DCR; 5y SR; 5y LGR; 5y DCR
						49 months	Lobectomy	73	44/29	67 (9)
Palma	2011	the Netherlands	2005- 2007	RCS	I	43 months	SBRT	60	40/20	79 (76–81)	1y SR; 3y SR
							Surgery	60	40/20	79 (76–80)
Paul	2016	USA	2007- 2013	RCS	I	6.25 years	SBRT	201	76/125	76.9 (6.1)	3y SR
							SLR	201	78/123	76.8 (6.0)
Puri	2015	USA	1998- 2010	RCS	I	36.5 months	SBRT	5355	2407/2948	74.3 (8.5)	3y SR
						36.5 months	Surgery	5355	2382/2973	74.2 (8.4)
Varlotto	2013	USA	1999- 2008	RCS	I	25.8 months	SBRT	72	NA	73.3	3y SR; 3y LGR; 5y SR; 5y LGR
							Lobectomy	72	NA	68.6
							SBRT	17	NA	73.3	3y SR; 3y LGR; 5y SR; 5y LGR
							SLR	17	NA	67.5
Verstegen	2013	the Netherlands	2007	RCS	I–II	60 months	SBRT	64	37/27	70.5(9.9)	1y SR; 1y LGR; 1y DCR; 3y SR; 3y LGR; 3y DCR
						48 months	Lobectomy	64	36/28	67.9 (8.8)
Wang	2016	China	2002- 2010	RCS	I	58.7 months	SBRT	35	33/2	77.1 (5.2)	1y SR; 1y LGR; 3y SR; 3y LGR; 5y SR; 5y LGR
							Surgery	35	33/2	74.8 (6.6)

RCT, randomized controlled trial; RCS, Retrospective cohort study; SBRT, Stereotactic body radiotherapy; SR, survival rate; SLR, sublobar resection; DCR, distant control rate.

Conclusion:
SBRT might have a superior loco-regional recurrence control in early stage of NSCLC, but the OS rate was lower than that in surgery. However, well-designed investigation with a larger sample was still need to verify and update this conclusion.

Background:
Recently, stereotactic body radiotherapy (SBRT) has become available for patients who are at high risk for lung resection. Although SBRT for peripheral lung tumors produces excellent outcomes with low toxicity, it is associated with an increased risk of severe toxicity when used to treat central tumors. We hypothesized that using a spacer designed to provide a predetermined distance between the target lesion and mediastinal organs may reduce adjacent organ toxicity, thereby expanding the indication of SBRT for lung cancer.

Method:
We developed a novel silicon-based spacer that imitated the shape of a canine’s left mediastinum. Animal experiments were performed on canine models to evaluate the feasibility, utility, and safety of the spacer. Two adult beagle dogs were used in this study. Video-assisted thoracoscopic surgery (VATS) was performed through two ports to insert the spacer between the lung and mediastinum of the left thoracic cavity. CT examination was performed with the spacer inflated at 1 week and 2 weeks after insertion. Four weeks after insertion, the spacer was removed. We created two virtual tumors that presented a high risk of severe mediastinal organ toxicity from SBRT. Radiation treatment planning of SBRT was conducted in both cases, and the radiation dose for mediastinal organs was compared between the cases with and without the spacer.

Result:
The spacer could be safely inserted between the lung and mediastinum via the VATS procedure. The novel spacer provided a distance of 5-10 mm between the virtual tumor and the mediastinal organs. The reduced radiation dose for risk organs were calculated as 7.0-27.5% in the aorta, 3.0-12.3% in the esophagus, and 7-25% in the spine. The spacer did not adhere to the mediastinal organs, and was removed smoothly. Figure 1



Conclusion:
The novel mediastinal spacer may potentially reduce mediastinal organ toxicity from SBRT when treating centrally located lung tumors.

Background:
Mediastinal and hilar lymph node metastases after definitive treatment for lung cancer is one of the main recurrence. Generally, isolated lymph node metastases without other recurrence are treated with local treatment, such as radiotherapy and surgery. Carbon-ion radiotherapy has a superior dose distribution and higher biological effectiveness compared with photon therapy. We retrospectively evaluated the efficacy and safety of hypofractionated carbon-ion radiotherapy for isolated lymph node metastasis in lung cancer patients.

Method:
Between April 2013 and August 2016, 15 patients were treated with carbon-ion radiotherapy. Median age was 72 years old (range: 51-83), and male patients were 11 (73%). Initial treatments were carbon-ion radiotherapy (n=8) and surgery (n=7). Pathological types were adenocarcinoma (n=9), squamous cell carcinoma (n=4), and others (n=2), respectively. All patients were treated using 12 fractions over 3 weeks. Fourteen patients received 52.8 Gy (relative biological effectiveness [RBE]) in and 1 patients received 48.0 Gy (RBE). Local control, progression free survival, and overall survival rates were statistically calculated by the Kaplan-Meier method. Acute and late adverse events were evaluated according to the Common Terminology Criteria for Adverse Events, version 4.0. This retrospective study was reviewed and approved by our Institutional Review Board.

Result:
The median follow-up time was 14 months. One patient had local lymph node failure, and the 1-year local control rate was 90%. This patient had a primary tumor recurrence, accompanied with lymph node failure at the same time. Three patients died of lung cancer, and the 1-year OS rate was 93%. Distant metastases were observed in 6 patients, and the 1-year PFS were 64%. Acute grade 2 esophagitis and grade 2 cough were observed in 2 (13%) and 2 (13%) patients, respectively. These acute adverse events were immediately improved by conservative therapy. There were no patients with grade ≧2 pneumonitis.

Conclusion:
Although follow-up period was short, hypofractionated carbon-ion radiotherapy showed great local control and overall survival without severe toxicities in lung cancer patients with isolated lymph node metastasis. Carbon-ion radiotherapy is considered an option of salvage treatment for isolated lymph node metastasis. Further follow-up is required to evaluate local control, overall survival, and late adverse events.

Background:
Lung cancer is the leading cause of cancer-related mortality. It remains a challenge to simultaneously detect and treat early lung cancer in vivo. Herein, we report the use of fluorescent magnetic nanoparticles-labeled mouse mesenchymal stem cells to accomplish targeted imaging and hyperthermia therapy of lung cancer in vivo.

Method:
The silica-coated fluorescent supermagnetic nanoparticles (FMNPs) were prepared and characterized, and then were used to label mouse mesenchymal stem cells（MSCs). The FMNPs-labeled MSCs were injected via tail vein into nude mice bearing non-small cell lung cancer A549 cells, which were followed using small animal imaging system and magnetic resonance imaging system. Thesubcutaneous lung cancer tissues in the nude mice models were subsequently treated in external alternating magnetic field.

Result:
.Results showed that FMNPs -labeled MSCs could target and image in vivo lung cancer cells after being intravenously injected for 7 days, and FMNPs-labeled MSCs could inhibit the growth of in vivo lung cancer through hyperthermia effects. The potential mechanism is discussed.

Conclusion:
FMNPs-labeled MSCs may target in vivo lung cancer cells and have great potential in applications such as targeted imaging and hyperthermia therapy of early lung cancer in the near future.

Background:
For inoperable stage III NSCLC, chemoradiotherapy is the standard of care. However, this treatment is associated with significant side effects and only offers a small chance of cure. Having adequate prognostic information at the start of treatment is essential in order to select the most appropriate treatment strategy for each individual patient. This study investigates the prognostic value of pre-treatment platelet (Plt) levels in this treatment setting.

Method:
Data were collected retrospectively from two phase II trials conducted from 2002 to 2007 in Sweden with patients treated with chemoradiotherapy for stage IIIA-IIIB NSCLC. Clinical and laboratory data at enrollment were collected for all patients and studied in relation to overall survival using Kaplan-Meier product-limit estimates and a multivariate Cox regression model. An optimal prognostic cut-off point for Plt was estimated by using a stepwise log-rank testing of survival comparing patients with a Plt count below and above every Plt count in the dataset. The cut-off point was defined as the Plt count that gave the lowest p-value using the log-rank test.

Result:
Patients with thrombocytosis (defined as Plt > 350 x 10[9]/L) had a shorter median overall survival than patients with normal Plt (≤ 350 x 10[9]/L) at baseline (14.5 and 23.7 months, respectively), which was statistically significant (p=0.0025). This significant association was retained in a multivariate model where other laboratory and clinical factors, such as performance status, were included. The optimal prognostic cut-off point for platelet levels in this patient material was estimated at Plt = 610. Figure 1



Conclusion:
In stage III NSCLC treated with curatively intended chemoradiotherapy, elevated platelet levels showed to be an independent prognostic marker for shorter overall survival. Further research is needed to establish the role of platelet levels and appropriate cut-off limits when making treatment decisions in this clinical setting.

Background:
Advances in lung cancer radiotherapy now permits increased accuracy of tumour targeting through image guided radiotherapy (IGRT) and advanced forms of intensity modulated radiotherapy (IMRT) such as volumetric modulated arc radiotherapy (VMAT), which helps minimise toxicity to normal tissues. We conducted a retrospective analysis to assess the impact of these new technologies on our patients.

Method:
We compared 2 radical (chemo)radiotherapy patient cohorts treated in our institution; Group A treated from February 2013 - February 2014 and Group B from September 2015 - September 2016. We analysed radiotherapy planning techniques, dose delivered, normal tissue doses and outcomes.

Result:
In Group B, we treated double the number of patients (26) with radical radiotherapy (64Gy/32# or 55Gy/20#) compared to Group A (13). Baseline characteristics were similar; median age 65yrs (A) and 70yrs (B). Most patients had stage III disease (69%-A, 81%-B). 77% of patients in both groups had concurrent cisplatin and vinorelbine chemotherapy. All patients in Group A had conventional CT planning scans and 3D-conformal planning. In Group B, all had 4D-CT planning scans and 85% (22/26) had VMAT plans. Patients treated with 55Gy/20# increased from 23% (3/13-A) to 46% (12/26-B). The median CTV increased from 64cm[3] (range 45cm[3 ]– 99cm[3] Group A) to 142cm[3] (range 15cm[3] – 656cm[3] Group B), (p-value 0.00005). Despite the increase in CTV, the median PTV remained similar (312cm[3]- A vs 364cm[3]- B). With VMAT plans, the lung doses remained low despite the increase in CTV; lung V20 (22%-A vs 20%-B), lung V5 (49% vs 49%) and mean lung dose (15Gy vs 12Gy). We selected the 5 largest CTVs from group B (CTV range 294 cm[3] – 656 cm[3]) and compared 3D conformal plans with the respective VMAT plans. We found VMAT allowed optimal dose coverage without compromising the PTV. VMAT benefited large midline tumours most where constraints of cord, heart and brachial plexus were met without PTV compromise. All Group A and 25/26 Group B patients completed their planned treatment. Median overall survival in Group A was 20.1 months but not yet reached in Group B.

Conclusion:
Adoption of 4D-CT scanning and VMAT treatment delivery has enabled us to treat larger tumours which seems to be particularly advantageous for large midline tumours. We hypothesise that radiotherapeutic advancements can increase the number of patients treatable to a radical radiotherapy dose without PTV compromise and further work is underway to confirm this and the possible impact it might have on our workload and resources.

Background:
To investigate the relationship between malnutrition and the severity of radiation pneumonitis (RP) in lung cancer patients with normal baseline pulmonary function and lungs’ V20<35% treated by intensity-modulated radiation therapy (IMRT) and concurrent chemotherapy.

Method:
One hundred and fifty patients with lung caner who received definitive IMRT (≥60 Gy) and concurrent chemotherapy were enrolled. In the condition of normal baseline pulmonary function and strict constraints of the irradiation dose to normal lung tissues, we recorded Eastern Cooperative Oncology Group (ECOG) score, concurrent chemotherapy, clinical stage, the level of albumin (ALB), hemoglobin and C-reactive protein (CRP), Subjective Global Assessment (SGA) scores and radiation esophagitis (RE) grade. These factors were correlated with RP using univariate and multivariate regression analyses.

Result:
Of 150 patients, 12 patients (8.0%) developed Grade 3–5 RP, 37 (24.6%) patients developed Grade 3–5 esophageal toxicity. In univariate analysis, ALB level (p = 0.002), RE (p < 0.001) and SGA score (p < 0.001) were significantly associated with RP. Multivariate analysis revealed that SGA (p < 0.001) was the independent predictor of RP.

Conclusion:
SGA could be a predictor for RP in lung cancer patients treated with definitive IMRT and concurrent chemotherapy.

Background:
To investigate the incidence of radiation esophagitis (RE) and tumor local control using esophagus sparing technique in locally advanced non-small cell lung cancer (LANSCLC) treated by simultaneous integrated boost intensity-modulated radiation therapy (SIB-IMRT) and concurrent chemotherapy.

Method:
Ninety-five patients with stage IIIA/B NSCLC who received definitive SIB-IMRT and concurrent chemotherapy had been divided into two groups: 1.with esophagus sparing technique; 2.without esophagus sparing technique. Chi-square test was performed to compare sex, clinical stage, histology, concurrent chemotherapy, RE and nutrition status between two groups. T-test was used to compare the dosimetric parameters. Overall survival (OS) and loco-regional failure free survival (LRFS) were calculated by the Kaplan–Meier method and compared by a log-rank test.

Result:
There were 50 patients in the esophagus sparing group and 45 in the non-sparing group. The incidence of severe RE (Grade 3-5) was significantly lower in patients with esophagus sparing technique (p = 0.000). Patients in esophagus sparing group had better nutrition status (p = 0.029). With a median follow-up of 23 months (range 0-37 months), the 3-year OS of all the patients was 33.4%. OS time was found to be longer in the esophagus-sparing group (32 vs. 27 months, p= 0.010). LRFS was comparable between two groups (29 vs. 24 months, p=0.960).

Conclusion:
Esophagus-sparing technique is an effective and essential method to limit RE in LANSCLC treated by SIB-IMRT and concurrent chemotherapy. Reducing severe RE when escalating radiation fraction size may help to achieve higher local control and better general performance status.

Background:
This study investigated the loco-regional control (LRC) and toxicity of hypofractionated simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) for locally advanced non-small-cell lung cancer (LANSCLC) in the setting of concurrent chemotherapy.

Method:
One hundred and ten LANSCLC patients treated with SIB-IMRT and concurrent chemotherapy were retrospectively analyzed. Radical-intent radiotherapy was delivered at a fraction dose of 2.0~2.2, 2.4~2.6, and 2.9~3.1Gy respectively. Factors potentially predictive of LRC (age, sex, tumor stage, tumor volume, biological effective dose (BED), dose per fraction, overall radiation time (ORT) and concurrent chemotherapy) were assessed in the univariate analysis and Cox multivariate model. Toxicity data was collected and analyzed.

Result:
With a median follow-up of 24.4 months, the median duration of LRC was 21.4 months. LRC was 71.9% at 1 year, 45.9% at 2 years, and 41.8% at 3 years. In univariate analysis, BED (p=0.007), dose per fraction (p=0.002) and ORT (p=0.029) were associated significantly with LRC. In multivariate analysis, RT dose per fraction was independently prognostic of LRC (HR, 0.597; CI, 0.362~0.986). Grade ≥3 pneumonitis, pulmonary fibrosis and esophagitis were observed in 6 (5.5%), 2 (1.8%) and 19 (17.3%) of patients, respectively. There was no significant difference in toxicity among different doses per fraction.

Conclusion:
Our study showed that LRC was improved by the dose per fraction escalation in the setting of concurrent chemotherapy. Hypofractionated SIB-IMRT could be a feasible and effective approach for dose intensification, while maintaining tolerable toxicities.

Background:
Local failure is common after concurrent or sequential chemo-radiation therapy for non-small cell lung cancer (NSCLC). Hypothesizing that a higher dose of radiation to the gross tumor volume (GTV) might increase local control of advanced NSCLC. We investigated whether high-dose radiation improved local control in patients with stage III NSCLC.

Method:
Sixty-four patients with stage III NSCLC were treated with three-dimensional conformal radiation therapy. Clinical target volume (CTV) contains GTV, plus a margin which is determined to consider the anatomic structure. Elective nodal irradiation had not been allowed. Patients with NSCLC were received high dose radiotherapy, 74Gy at CTV. The volume of lung receiving at least 20Gy (V20) is restricted to 25% because of lung toxicity. Acute and late toxicities were scored per the Common Terminology Criteria for Adverse Events version 4.0. The primary endpoint was overall survival (OS) and local progression free survival (LPFS) the length of time during and after the treatment of a disease that a patient lives with the disease but it does not get worse. All analyses were done by intention-to-treat.

Result:
Between Feb. 08, 2011 and Feb. 22, 2016, 64 patients received high dose radiotherapy and/or chemotherapy. 8 patients (12.5%) did not complete full dose radiotherapy. 3 patients stopped treatment voluntarily, 3 patients due to tumor progression during radiotherapy, and 2 patients dropped out of the treatment side effects – 1 neutropenia, 1 general weakness. Median follow-up was 14.6 months (1.2-51.6). Median OS was 20.0 months (1.2-65.6, and 3-year OS was 50.5%. Median LPFS was 15.7 months (1.2-57.0), and 3-year LPFS was 54.5%, retrospectively. Only one patient (1.6%) had grade 5 radiation induced pneumonitis. And other complication rates were tolerable which was compared with historical studies.

Conclusion:
High dose radiation is tolerable and contributes to improve outcomes, especially local progression free survival in patients with inoperable stage III non-small cell lung cancer, if radiation field is restricted to gross tumor only.

Background:
Our aim was comparative dosimetric evaluation of volumetric modulated arc therapy (VMAT) and 3-dimensional conformal radiotherapy (3D-CRT) in patients with locally advanced non-small cell lung cancer (LA-NSCLC) and to confirm whether this dosimetric benefit translates into a radiobiological advantage with respect to tumor control probability (TCP) and normal-tissue complication probability (NTCP) and finally to generate an algorithm and software to integrate the radiobiological component during plan evaluation and quality assurance.

Method:
A total of 25 3D-CRT naïve patients of LA-NSCLC, treated with radical radiotherapy were included in this study. We used copies of the Eclipse plan data, organized in separate study treatment courses. For each course, new VMAT plans were generated using the standard provincial dose-volume constraints. The DVH parameters for PTV (planning target volume), lung-GTV (gross tumor volume subtracted from lung), heart, esophagus and spine were reviewed and then the TCP and NTCP values for these regions of interest (ROI), cardio-pulmonary toxicity index i.e. C.P.T.I (∑~i ~NTCP~i~; i=1-2 representing heart, lung), morbidity index i.e. M.I (∑~i ~NTCP~i~; i=1-4 representing heart, esophagus, lung and spinal cord) and therapeutic gain (defined as the value of TCP when M.I=0; i.e. TG=TCP(1-M.I)) values were generated. The resulting data sets were compared using the Weltch two sample t-test and p < 0.05 was accepted as significant. Parameters were calculated using DVH data exported from the Eclipse and software written in the "R" programming language. The user interface has been developed with the "shiny" “R” web library. Dosimetric parameters included V~98%~ and D~99% ~of PTV, V~50Gy ~of esophagus and mean dose to esophagus, V~45Gy ~of spinal cord, V~30Gy ~and mean dose of heart and V~20Gy, ~V~10Gy ~and V~5Gy ~and mean dose of (lung-GTV). The radiobiological metrics included TCP, NTCP of heart, esophagus, lung and spinal cord,C.P.T.I, M.I and therapeutic gain.

Result:
Dosimetric evaluation did not show any significant difference in V~98% ~(p=0.169) and D~99%~ (p=0.797) of PTV between VMAT and 3D-CRT, however, there was significant improvement in V~50Gy~ of esophagus (p=0.039), V~45Gy~ of spinal cord (p=0.003) and V~30Gy~ of heart (p=0.038) with VMAT. V~10Gy ~of (lung-GTV) was higher with VMAT (p=0.019). Rest of the dosimetric paramters were not significantly different two modalities. TCP was better with 3D-CRT (p<0.0001) while NTCP of heart (p=0.028), esophagus (p=0.053) and spinal cord (p=0.001) was substantially improved with VMAT. There was no difference in NTCP of lung between two modalities. Overall C.P.T.I (p=0.039), M.I (p=0.019) was remarkably lower and therapeutic gain (p=0.005) was significantly better with VMAT.

Conclusion:
The study reveals that although TCP is higher with 3D-CRT, majority of the NTCP parameters including C.P.T.I and M.I are substantially improved with VMAT even in 3D-CRT naïve patients. The overall therapeutic gain is therefore notably higher with VMAT which emphasizes its potential to achieve superior oncologic outcome in patients with LA-NSCLC.

Background:
Local control rate by stereotactic body radiotherapy (SBRT) for stage I non-small cell lung cancer (NSCLC) has been reported to be approximately 90%. But, most studies had relatively short follow-up time, and our group has previously published preliminary report that late local recurrence (LR) might not be negligible. Thus, the aim of this study was to assess LR rate and timing after SBRT, using long-term follow-up data of large cohorts from single institution.

Method:
Eligible patients were those who were treated with SBRT (isocenter prescription of 48Gy/4fr) between April 1998 and August 2014 for primary/recurrent NSCLC < 5cm and with > 6 months follow-up time.

Result:
Figure 1A total of 213 patients (229 tumors) were analyzed. Tumor and treatment characteristics are shown in Table. Median follow-up time was 7 years [95% confidence interval (CI) 6.2–7.8]. 5-year overall survival and progression-free survival rate was 47%[95% CI 40–54] and 32%[95% CI 26–39], respectively. The number of LR was 45, and 5- and 10-year cumulative incidence of LR was 18%[95% CI 13–23] and 26%[95% CI 18–33], respectively. Clinical T stage, histology, tumor location, overall treatment time and use of cone-beam CT for patient set-up did not impact LR rate, as shown in Table. Median time to LR was 1.7 years (range: 0.6–9.5, interquartile range: 1.0–3.2) and time to LR was significantly longer in adenocarcinoma (Adeno) than in squamous cell carcinoma (SqCC) (median: 2.7 vs. 1.1 years, p=0.04). The number of late LR > 5 years after SBRT was six. The histology of tumors with late LR was Adeno/SqCC/unknown=3/1/2 (one of two unknown cases was proven to be Adeno by salvage surgery). Five of six late LRs were isolated LR as the first progression site.



Conclusion:
Late LR was not uncommon. Long-term follow-up after SBRT is needed, especially for adenocarcinoma.

Background:
Distinguishing fibrosis from tumor recurrence following lung SBRT remains a clinical challenge since CT has poor sensitivity and specificity for detecting recurrence. 18F-Fluoro-L-thymidine-PET (FLT-PET) uptake correlates with cell proliferation. The purpose of this study is to investigate the feasibility of FLT-PET as an imaging biomarker for lung SBRT response assessment.

Method:
In this prospective study, three groups were included: 1) newly-diagnosed biopsy-proven NSCLC pre-SBRT, 2) established post-SBRT mass-like fibrosis on serial follow-up CT scans by co-investigators’ consensus, and 3) biopsy-proven locally-recurrent NSCLC after SBRT. Non-gated, helical gated (3D-CT/4D-PET) and phase-matched (4D-CT/4D-PET) FLT-PET images were obtained. Group-1 underwent fluorodeoxyglucose (FDG)-PET scan according to clinical guidelines. FLT uptake was measured by SUV95 and SUV50 (95% and 50% of maximum pixel value plus average background value, respectively), SUV2Dpeak and SUV3Dpeak (1cm diameter circular or spherical around region of interest, respectively), SUVmean and SUVmax. Descriptive statistics were gathered. Kolmogorov–Smirnov test was used to determine normality. Statistical significance was reported using student’s t-test.

Result:
27 patients were included, with 19 primary tumors (group-1), 12 established fibrosis (group-2) and 1 recurrence (group-3). In group-1, 16 tumors were T1. Group-1, mean FDG-PET SUVmax, SUV95, SUV50, SUV2Dpeak, SUV3Dpeak and SUVmean were 7.40, 5.88, 2.39, 5.59, 6.02 and 2.78, respectively. Mean FLT-PET values for group-1 were 3.43, 2.84, 1.71, 2.9, 2.82 and 1.78, respectively. Group-2 SBRT dose was either 48Gy in 4 fractions (83%) or 60Gy in 8 fractions. Median time from radiation to FLT-PET scan in group-2 was 19.5 months (5.8-83.8mos). The patient in group-3 had SUV50, SUV95, SUV2Dpeak, SUV3Dpeak, SUVmean and SUVmax of 2.27, 3.85, 6.37, 6.05, 2.39 and 7.64, respectively. Mean FLT-PET SUVmax for groups 1 and 2 was significantly different (p=0.03) at 3.42(1.14-7.04) and 2.34(1.23-4.35) respectively. Similarly, mean (range) of SUV50, SUV95 and SUVmean for group-1 was 1.8(0.74-3.43), 2.97(1.03-5.83), 1.87(0.73-3.44), and for group-2 was 1.22(0.81-2.26), 1.85(1.13-3.8) and 1.25(0.83-2.39), respectively (p<0.01, <0.01 and <0.01). There was no statistically-significant difference between SUV2Dpeak and SUV3Dpeak between groups 1 and 2, with a mean of 2.97(0.99-6.30) and 2.91(0.90-6.11) for group-1 and 2.10(1.11-3.91) and 2.03(1.00-3.86) for group-2 (p=0.06 and 0.06), respectively. There was no statistically significant difference between the 3D and 4D image acquisition in group-1. There were no FLT-PET-related toxicities.

Conclusion:
FLT-PET is feasible in SBRT patients pre- and post-treatment, and may assist in distinguishing fibrosis from recurrent tumor. Further validation studies are needed.

Background:
Radical radiotherapy often relies solely on radiological imaging to determine treatment volumes. Systematic mediastinal staging with endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) may identify PET-occult sites of mediastinal disease, or demonstrate benign causes for PET-positive LN. This study evaluated 1) Involved nodal coverage 2) Doses to organs-at-risk when planned based on PET-CT and EBUS-TBNA and 3) Incident dose to mediastinal nodes between 3D-CRT and Intensity-Modulated-Radiotherapy (IMRT).

Method:
Radical radiotherapy plans (60Gy/30 fractions) were created for patients with stage change following EBUS-TBNA from a prospective clinical trial. We compared lung Normal-Tissue-Complication-Probability (NTCP, pneumonitis), oesophageal and heart dose for planning to targets based on PET-CT versus PET-CT+EBUS-TBNA. The incidental dose to PET-negative/EBUS-TBNA-positive nodes from 3DCRT and IMRT was evaluated using volume receiving 35Gy as a surrogate for control of sub-clinical disease (Kepka, IJROBP, 73(5) 2009).

Result:
Of 30 patients enrolled, four were upstaged by EBUS-TBNA; these patients had a significant geographic miss of nodal GTV when planned to PET-positive nodes only (Figure 1). When planned based on PET-CT alone, the incidental dose to PET-negative/EBUS-TBNA-positive nodes was higher with IMRT for two patients (v35Gy increased by 17% & 6%; Figure 1a&b) and lower with IMRT (v35Gy reduced by 16% and 6%; Figure 1c&d) for two, dependent on nodal position relative to the primary. Six patients had negative pathology for PET avid nodal stations; Inclusion of EBUS-negative, PET-positive nodes resulted in an average increased lung NTCP of 5% (range 1%-13%), mean oesophagus dose of 13Gy (range 4-23Gy) and mean heart dose of 4Gy (range -0.1-11Gy) over plans based on EBUS-positive nodes alone. Figure 1



Conclusion:
Systematic EBUS-TBNA has the potential to improve loco-regional control and limit the probability of lung and heart toxicity. The incidental dose to adjacent tissue is inherently related to involved node/tumour position and not solely dictated by the radiation delivery technique.

Background:
A Volume Modulated Arc Therapy (VMAT) service for our radical lung patients has been offered since 2011. Attention has now turned towards how this service can be improved further. The RapidPlan[TM] package has already been used to great effect in our Prostate service so was assessed for its potential in radical lung planning.

Method:
RapidPlanTM models were created using the Eclipse Treatment Planning System [Varian Medical Systems] v13.6: consisting of 50 randomly selected radcial right lung patients (M_R), left lung patients (M_L) and a combined model using all 100 of these same patients (M_COM). The models were assessed using the standard RapidPlanTM tools. A retrospective planning study was performed for 10 right lung and 10 left lung patients. Each of the 20 patient treatments were replanned using each model. All plans were normalised to ensure that the target mean was 100% and compared to the manually optimised plan (O_P) The PTV coverage was assessed using dose homogeneity indices. Differences in organ at risk (OAR) dose volume histogram parameters were calculated to assess plan quality. The plans were compared on a variety of criteria including but not limited to whole lung V5 (with tolerance considered 70%) and V20 (with tolerance considered 30%) and the maximum dose to spinal canal (tolerance considered to be 80 %). Significance was assessed by two-tailed t-test (p<0.01).

Result:
Although all models gave a clinically acceptable plan differences in the homogoeneity indices were observed with M_COM values showing an improvement on the other models. M_COM plans had a statistically significant increase in maximum spinal cord dose when compared to the other plans set, however doses were within tolerance. An increase in mean whole lung and whole lung minus PTV V20Gy was also observed. There was no significant difference in contra lateral lung V5Gy or whole lung minus PTV V5Gy. There was no statistical difference observed when comparing right sided tumour patient calculated with M_L and left sided tumour patients planned with M_R.

Conclusion:
M_COM outperformed the other models and O_P in relation to PTV coverage without impacting clinically acceptable OAR constraints. This model demonstrated improvement when compared to M_L and M_R suggesting that 50 plans are insufficient to perfect a lung model and that 100 plans is more effective. When compared with manually optimised plans the M_COM model demonstrates an improved relationship between balancing OAR objectives and PTV conformity.

Background:
Lung stereotactic ablative radiotherapy (SABR) is associated with low morbidity, however there is an increased risk of treatment-related toxicity in tumors directly abutting or invading the proximal bronchial tree, termed ‘ultra-central’ tumors. For such tumors, there is no consensus regarding the most appropriate dose-fractionation scheme. The purpose of this planning study was to evaluate the therapeutic ratio of SABR treatment plans for ultra-central tumours using commonly utilized dose fractionation regimens.

Method:
In this research ethics board approved study, 10 patients with ultra-central lung tumors were identified from our institutional database. New plans were generated for each of the 10 cases using 3 different hypofractionated schedules: 50 Gy in 5 fractions, 60 Gy in 8 fractions and 60 Gy in 15 fractions. For each of the three dose regimens, 2 plans were generated, one prioritizing tumor coverage and the other plan compromising PTV coverage in order to respect the dose constraints for the esophagus, lung and proximal bronchial tree. Using published normal tissue complication probability models, plans were evaluated for likelihood of toxicity to these organs at risk.

Result:
In the scenario where PTV coverage was prioritized, the probabilities of acute esophageal or pulmonary toxicity were low, ranging from 0.9-1.2% and 3.7-4.3%, respectively. In contrast, the estimated risk of grade 4 or 5 toxicity to the proximal bronchial tree varied significantly: 68% for 50 Gy in 5 fractions, 44% for 60 Gy in 8 fractions and 2% for 60 Gy in 15 fractions. When dose to the organs at risk was prioritized, risk of toxicity to the proximal bronchial tree was reduced to <1% for all 3 dose fractionation schemes. This compromise resulted in a reduction in the calculated tumor control probabilities, from 92.9% to 60.3% for 50 Gy in 5 fractions, 92.4% to 65.7% for 60 Gy in 8 fractions and 52% to 47.8% for 60 Gy in 15 fractions.

Conclusion:
With the use of SABR or hypofractionated radiotherapy for ultra-central lung tumors, the competing risks of tumor local control and treatment toxicities need to be considered. Predicted rates of local control are inversely related to the risk of severe pulmonary toxicity due to trade-offs in the radiation planning process. Further prospective research is needed to better assess the optimal dose fractionation schedule for ultra-central lung tumors.

Background:
Cytokines are soluble proteins with a relevant role in immune response that can be modulated by immunotherapy. In this study we aimed to evaluate the serum concentrations of Th1/Th2 and inflammatory cytokines and their changes in SCLC patients treated with ipilimumab and chemotherapy compared to chemotherapy alone.

Method:
We evaluated 2 cohorts (C) of patients with SCLC: in C1, 47 patients were treated with standard platinum/etoposide (PE); in C2, 37 patients with ipilimumab, carboplatin and etoposide (ICE trial). We analyzed serum samples at baseline and subsequent time points with the Cytokine Human Magnetic 10-Plex (GM-CSF, IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10 and TNF-α) plus MIP-1a. Serum samples from 30 healthy volunteers were used as controls. Statistical analysis was carried out with SPSS 22.0 (SPSS Inc.) and Prism 6.0 (GraphPad).

Result:
Patients with SCLC showed significantly lower levels of IL-1b, Mip-1a, IL-5 and IL-10 and higher TNF-a compared to healthy volunteers. Patients treated with chemotherapy alone (C1), showed a decrease of Th1 and inflammatory cytokine median concentrations at tumor response and an increase at progression, while no such pattern was observed in Th2 cytokines and TNF-a. In contrast, patients treated with ipilimumab in addition to chemotherapy (C2), showed a global increase on the level of all cytokines after treatment initiation (Figure 1).Figure 1



Conclusion:
In patients with SCLC, Th1 and inflammatory cytokines (except TNF-a) reflect tumor burden. Chemotherapy reduces these levels targeting cytokine secreting tumor cells. Th2 cytokines may be mainly secreted by immunological cells as they remain unaltered upon chemotherapy treatment. Interestingly, ipilimumab increases globally Th1, Th2 and inflammatory cytokine secretion counteracting the effect of chemotherapy. The correlation of these changes to outcome and toxicity warrants further investigation.

Background:
Amrubicin is one of the most active chemotherapeutic agents for small-cell lung cancer (SCLC). Previous studies reported its effectiveness and severe hematological toxicity. However, the efficacy of amrubicin monotherapy in elderly patients with SCLC has not been described. The objective of this study was to investigate the feasibility of amrubicin monotherapy in elderly patients, and its efficacy for relapsed SCLC.

Method:
A retrospective cohort study design was used. We retrospectively evaluated the clinical effects and adverse events of amrubicin treatment in elderly (≥70 years) SCLC patients with relapsed SCLC at one of four Japanese institutions (Gunma Prefectural Cancer Center, Tochigi Prefectural Cancer Center, Ibaragi Central Hospital, and Fukushima Medical University).

Result:
Between November 2003 and September 2015, 86 patients (aged ≥70 years) received amrubicin monotherapy for relapsed SCLC at four institutions There were 42 cases of sensitive relapse (S) and 44 of refractory relapse (R). S cases with median age of 75 years (range, 70–85 years) and R cases with median age of 74 years (range, 70–84 years) were included in our analysis. The median number of treatment cycles was 3 (range 1–9), and the response rate was 33.7% (40.5% in the S and 27.2% in the R cases). Median progression-free survival time was 4.0 months in the S and 2.7 months in the R patients (p = 0.013). Median survival time from the start of amrubicin therapy was 7.6 months in the S and 5.5 months in the R cases (p = 0.26). The frequencies of grade ≥3 hematological toxicities were as follows: leukopenia, 60.4%; neutropenia, 74.4%; anemia, 11.6%; thrombocytopenia, 16.2%; and febrile neutropenia, 17.4%. Treatment-related death was observed in 1 patient.

Conclusion:
Although hematological toxicities, particularly neutropenia, were severe, amrubicin showed excellent anti-tumor activity, not only in the S, but also in the R cases, as shown in previous studies. Amrubicin could be a preferable standard treatment in elderly patients with relapsed SCLC. These results warrant further evaluation of amrubicin in elderly patients with relapsed SCLC by a prospective trial.

Background:
Patients with extensive disease small cell lung cancer (ED-SCLC) have limited treatment options after recurrence, and their overall survival (OS) remains poor. This study explored the OS benefit of second-line therapy in patients with platinum-refractory versus platinum-sensitive ED-SCLC.

Method:
Linked data from Surveillance, Epidemiology, and End Results program and Medicare claims were used. Eligible patients were ≥66 years of age, and had pathologically confirmed first primary ED-SCLC diagnosis between January 1, 2007 and December 31, 2011 and Medicare Parts A and B coverage. Patients were followed from diagnosis until death, end of follow-up, second primary cancer diagnosis, or switch to managed care coverage. Therapy was determined using Medicare claims for outpatient chemotherapy, and lines of therapy were inferred from changes and gaps in therapy. Platinum-refractory status was defined in 2 ways based on criteria used in clinical trial enrollment and from clinical guidelines: 1) a gap of ≤90 days between the last administration of first-line therapy and the start of second-line therapy and 2) a gap of ≤183 days from start of first-line therapy to the start of second-line therapy. Cox proportional hazards models were used to identify factors associated with OS from the start of second-line therapy.

Result:
In all, 1059 patients with ED-SCLC received first-line platinum-based therapy. At diagnosis, mean age was 73 years, 53% were male, 87% were white, 30% had ≥1 indicator of mobility limitations, and 21% lived in a high-poverty area. Median OS for all patients was 4.3 months. There were 572 patients (54%) classified as platinum-refractory according to ≥1 definition, of whom 402 (70%) were classified as refractory according to both definitions. Based on the 90-day gap and the 183-day gap, respectively, median OS was 3.7 and 3.8 months for platinum-refractory patients, and 5.3 and 5.1 months for platinum-sensitive patients. In adjusted models using both definitions, factors associated with significantly shorter OS included male sex, stage IV disease at diagnosis, and platinum-refractory status.

Conclusion:
Median survival was <6 months for both platinum-refractory and platinum-sensitive patients, with refractory patients faring slightly worse. These findings highlight the need for new treatments for patients with ED-SCLC irrespective of their platinum sensitivity.

Background:
The prognosis of small cell lung cancer (SCLC) remains poor and there is a high unmet need for effective therapies. Poly (ADP-ribose) polymerase (PARP) inhibitors and immunotherapies hold promise due to expression of PARP and high mutational burden in SCLC. PARP inhibition leads to upregulation of anti-programmed cell death ligand-1 (PD-L1) and enhanced cancer immunosuppression. This led us to investigate the combination of olaparib and the PD-L1 inhibitor, durvalumab in SCLC (NCT02734004).

Method:
Individuals with relapsed SCLC at least 12 weeks after platinum-based therapy were eligible. Patients received olaparib tablets 300 mg PO BID for a 4-week run-in, followed by a combination of olaparib 300 mg PO BID and durvalumab 1.5 g IV q 4 weeks. The combination was continued until progressive disease by RECIST 1.1. Tumor assessments were done at baseline, 4 weeks and every 8 weeks thereafter. The primary endpoints were disease control rate (DCR) at 12 weeks, as well as safety and tolerability. The secondary endpoints included DCR at 28 weeks, objective response rate (ORR), duration of response (DoR), progression-free survival (PFS) and overall survival (OS). Biomarker endpoints included PD-L1 expression and evaluation of tumor infiltrating lymphocytes (TILs). A target DCR of 60% was used to calculate the sample size in a Bayesian predictive probability design.

Result:
Among the 38 patients, the median age was 63 years (range 44-76) and median line of prior chemotherapies 1 (range 1-3). At the time of analysis, each patient was followed up for at least 12 weeks. The most common grade 3 or higher AEs included anemia (34.2%), hyponatremia (10.5%), lymphopenia (10.5%), chronic obstructive pulmonary disease (5.3%), increased GGT (5.3%) and increased lipase (5.3%). DCR at 12 weeks was 29%. Confirmed responses included one partial response and one complete response. Three additional patients had unconfirmed responses. The updated primary and secondary endpoints, as well as biomarker and PK data will be presented.

Conclusion:
Although AEs of all grades were seen commonly, the combination of olaparib and durvalumab was relatively well tolerated, as most of the AEs were attributed to underlying disease. While efficacy of the combination in this SCLC population did not reach the target DCR and is below the futility boundary (<40%), a minority of patients obtained significant benefit and will be followed up for further clinical and translational analyses.

Background:
Recently, it has been reported that MYC-driven SCLC cell lines exhibit synthetic lethality with Aurora kinase (AURK) inhibitors. The aims of this study are to evaluate sensitivities to neuroendocrine (NE) lung cancer cell lines with or without any MYC family overexpression and/or amplification using representative AURK inhibitors and to investigate the associations between drug sensitivities, MYC family status and NE differentiation.

Method:
We screened a panel of 62 cell lines including 33 SCLC, 18 other NE, and 11 NSCLC, with various MYC family status for growth inhibition upon AURK inhibitors. MYC family copy number, gene expression, and protein status were examined by quantitative real-time PCR, microarray and Western blotting. Relative cell growth was analyzed by MTS assay, and selective AURK A and B inhibitors, MLN8237 (Alisertib) and AZD1152 (Barasertib), respectively, were used in this study. Cell lines with IC50 values < 0.1 μM were defined as sensitive. Drug effects on cell cycle and morphology were determined by flow cytometry and examination of formalin-fixed paraffin embedded cell pellets.

Result:
Of 31 NE cell lines with MYC family overexpression/amplification, 21 (68%) and 18 (58%) were sensitive to Alisertib and Barasertib, respectively. All 20 NE (and most NSCLC) cell lines lacking MYC family overexpression/amplification were resistant to AURK inhibitors. There was an excellent concordance (86%) between response to the two AURK inhibitors. Both MYC family overexpression and amplification were predictive of sensitivity; however, some overexpressing lines had normal copy number. Cell cycle analysis showed a mitotic arrest in some sensitive cell lines with treatments of these drugs. Representative sensitive cell lines showed cell ballooning and bizarre multinucleated polyploid cells, which indicated cell cycle arrest in G2/M.

Conclusion:
MYC family overexpression/amplification in NE lung cancer cell lines confers sensitivity to AURK inhibitors in approximately 70% of cases. Lack of MYC family overexpression/amplification was always associated with drug resistance. MYC family overexpression may occur in the absence of gene amplification, and, thus, overexpression is a better predictor of sensitivity than amplification. We are currently investigating the mechanism of resistance in overexpressing NE cell lines and determining whether NE differentiation plays a role in drug sensitivity.

Background:
Small cell lung cancer (SCLC) is one of the most lethal malignancies with rapid chemoresistance. Based on our previous study, enriched environment (EE) has a clear effect on improving the mental state of mice and can reduce chemoresistance caused by platinum regimens. In this study we investigated the complex links between benign mental stress (EE) and chemosensitivity of SCLC, and use anti-depressants to improve the mental state of mice to observe its impact on chemosensitivity to platinum regimens, and the underlying mechanism was explored.

Method:
The mental state of mice was evaluation by behavior tests include: elevated plus maze (EPM), open field experiment (OF), forced swimming (FS). Then, the mice were transplanted subcutaneously and treated with cisplatin, carboplatin and oxaliplatin. The tumor was analyzed by gene expression profiling and the differential genes were screened. The expression level of differential genes were examed by real-time PCR, and verified by western bolt and immunohistochemistry, respectively. And then ABCG2 blocker was used for chemosensitivity verification in vivo and in vitro.

Result:
EE significantly increased the movement on openarms in the EPM (35.24 sec V.S. 16.78 sec, P<0.01), increased the center area time in OF test (54.25 sec V.S. 35.24 sec, P<0.05), significantly increased the struggling time in the FS test (46.02 sec V.S. 25.81 sec, P<0.01). Antidepressants can also significantly improve the state of depression of mice, but can not achieve the effect of EE. For platinum chemosensitivity test, the antidepressant drugs (Diazepam, Quetiapine and Clomipramine) have no direct inhibition to tumor cells. A can significantly increased the sensitivity of chemotherapy in mice, but can not achieve the inhibitory effect of EE. Next we found the serum BDNF levels significantly decreased in EE mice. Similarly, antidepressants also significantly reduced serum BDNF levels in mice. Gene expression profiles showed that a variety of genes were downregulated mainly in ABC transporters and drug metabolic pathways by EE and antidepressants. The expression level of ABCB1, ABCC2, ABCG2, ABCC9, PPARa, DPYD, GST-P1 and GSTM1 in SCLC sample were examed by real-time PCR, and verified by western bolt and immunohistochemistry, respectively. ABCG2 expression in tumor of EE and antidepressants mice were even 3 fold higher than control (P<0.001). Nicardipine blocks ABCG2 expression can restore chemosensitivity to platinum based drugs (P<0.001).

Conclusion:
Antidepressants can partially mimic the chemotherapeutic effect of EE and we confirm that the mechanism is partially achieved by increasing BDNF and reducing the expression of ABCG2.

Background:
Hypercoagulation is a hallmark of cancer, and several coagulation factors contribute to tumor development and progression in addition to development of venous thromboembolism (VTE), which is a major cause of morbidity and mortality in lung cancer. Early studies suggested that coagulation inhibition with low molecular weight heparin (LMWH) may improve survival specifically in small cell lung cancer (SCLC) patients, whereas other studies showed contradictory results. The aim of RASTEN was to investigate the survival effect of LMWH enoxaparin in a trial powered to demonstrate a clinically significant difference in a homogenous group of SCLC patients. (ClinicalTrials.gov: NCT00717938)

Method:
We performed a randomized, multicenter, open-label trial to investigate the effect of LMWH enoxaparin administered at a supraprophylactic dose (1 mg/kg) and continuously during standard treatment in patients with newly diagnosed SCLC. The primary outcome was overall survival (OS), and secondary outcomes were progression free survival (PFS), incidence of VTE and hemorrhagic events.

Result:
In RASTEN, 390 patients were randomized over an 8-year period, of which 186 and 191 were included in the final analysis in the LMWH and control arm, respectively. We found no evidence of a difference in OS or PFS by the addition of enoxaparin (HR 1.11; 95% CI: 0.89-1.38, P=0.36, and HR 1.18; 95% CI: 0.95-1.46, P=0.14, respectively). Subgroup analysis of patients with limited and extensive disease did not show any reduction in mortality by enoxaparin. The incidence of VTE events was significantly reduced in the LMWH arm (HR 0.31; 95% CI: 0.11-0.84, P=0.02). Hemorrhagic events were more frequent in the LMWH-treated group but fatal bleedings occurred in both arms.

Conclusion:
Anticoagulants have previously been found to exert impressive tumor inhibiting properties in experimental models; however, results from clinical trials have been conflicting. This may partly be explained by the use of suboptimal, prophylactic LMWH dosages. In the present study, LMWH enoxaparin in addition to standard therapy did not improve OS in SCLC patients despite being administered at a supraprophylactic dose and despite resulting in a significant reduction in VTE incidence. Based on these results, the addition of LMWH cannot be generally recommended in the management of SCLC patients. Further, our data underline that predictive biomarkers of VTE and LMWH-associated bleeding are warranted for individualized anticoagulant therapy of cancer patients.

Background:
Carcinoid tumors of the lung are an uncommon group of pulmonary neoplasms. Carcinoid tumors represent the most indolent form of a spectrum of bronchopulmonary neuroendocrine tumors, however little is known about its molecular features. We analyzed pulmonary carcinoid tumors to identify biologically relevant genomic alterations.

Method:
We reviewed all the patient data from 2006 to 2016 in our hospital and collected 20 cases of lung carcinoid tumors. We summarized their clinical features and imaging data. Among 20 cases of lung carcinoid tumors, quality control was passed for 6 patients. We performed targeted capture sequencing of 56 cancer-related genes. Moreover, we made a literature review of pulmonary carcinoid tumors and summarized the clinical features and gene mutations.

Result:
Among the 20 pulmonary carcinoid tumors cases, which include 9 typical carcinoid and 11 atypical carcinoid tumors, there was a male predominance of this disease (Male vs Female: 15 vs 5). The range of age is 14 to 71 with the median age of 48. For gene mutation profiling on 6 pulmonary carcinoid tumors, we detected 27 mutations in 21 genes, including 22 missense mutations, 2 deletion mutations, 1 frameshift mutation and two others. Among the 21 genes, there are 11 proto-oncogenes and 6 tumor suppressor genes, which were reported to participate in the tumorigenesis, growth, invasion and metastasis of tumor.

Conclusion:
Through the next generation sequencing, we detected 27 mutations in 21 gene on the 6 pulmonary carcinoid tumors. Among these genes, the mutation of gene IGF1R, ERBB4, KIT and TSC2 showed the most frequent. We supposed that these genes might be involved in the tumorigenesis of pulmonary carcinoid tumors and the potential targets of therapy. Further functional studies of these genes are worthy of being explored.

Background:
There is still an unmet need for patients with extensive small cell lung cancer(SCLC) who failed from the previous treatment even though topotecan was approved by Food and Drug Administration as second line setting in this population. Nab-paclitaxel (nab-P) has showed promising efficacy in pancreas cancer, breast cancer and nonsmall cell lung cancer, this phase II trial try to evaluate the safety and efficacy of nab-paclitaxel (nab-P) monotherapy as the secondary or later line therapy in patients with extensive SCLC.

Method:
Main included criteria were performance status 0-2, extensive disease, failed or insensitive relapse from the previous treatment, sufficient myeloid function. Sensitive relapsed from the last line chemotherapy was excluded. Patients who met these criteria received weekly nab-paclitaxel 130mg/m2, d1,8,15, every 4 week or nab-paclitaxel of 230 mg/m2, d1 every 3 weeks. The Primary end point is objective response rate. The secondary end point included progression free survival(PFS), overall survival, and side effects.

Result:
From Sep, 2014 to Mar, 2017, 40 patients were included into this study, included 39 males, 6 never smokers, PS 1/2:27/13 with a median age of 66 years. The median line of nab-P monotherapy is 3(2-5). Among them, 30 patients received weekly nab-P and 10 received nab-P every 3 weeks. 9, 27, 4 patients were resistant, refractory and sensitive relapse to first line chemotherapy respectively. 7 patients got partial response,17 stable diseases and 16 progression disease. The objective response rate was 17.5% and disease control rate(DCR) was 60%. The median PFS was 3 months and the during of response was 5.8 months. Subgroup analysis showed that patients who were refractory or sensitive relapse to first line chemotherapy had a significant higher DCR (67.8% vs 28.5%, p=0.042) and longer PFS(3.3 vs 1.4 months, p=0.04), while similar results were found in different PS, smoking status and lines of therapy. Toxicity was mild and manageable including alopecia, neuritis, neutropenia and anemia, no grade 3/4 adverse event observed.

Conclusion:
Nab-P showed promising efficacy together with acceptable toxicity in patients with extensive SCLC who failed or insensitive relapse from the previous treatment, especially in the subgroup of refractory or sensitive relapse to first line chemotherapy, large cohort study is needed to validate these findings.

Background:
Small cell lung cancer (SCLC) originates from neuroendocrine-cell percursors and is characterized by rapid growth, high response rates and development of treatment resistance in patients with metastatic disease. In the past few years its heterogeneity in form of presentation, behaviour in response to therapy and time to progression has raised several questions.

Method:
Review of clinical files of patients with SCLC diagnosed between may 2012 and may 2017 in our hospital, according to demographic characteristics, risk factors, comorbidities, form of presentation and diagnostic approach, clinical stage, therapy performed and outcome.

Result:
In this period 46 patients were followed, of whom 80% were male, with an average age of 65.5 ± 9.2 years (min 45, max 88). About 96% had active or past smoking habits. Regarding to comorbidities, it was found that 61% had a history of chronic obstructive pulmonary disease, 57% of cardiovascular disease, 17% of type 2 diabetes mellitus and 9% had a history of a second tumor. One patient had a severe usual intersticial pneumonia. The most frequent forms of presentation were pneumonia (28%) followed by constitutional symptoms (15%). Histological diagnosis was achieved in most cases by bronchial biopsy (59%). At the time of diagnosis most of the patients had ECOG performance status 1 (67%) and presented stage IV disease (72%), followed by stage IIIB (13%). In 65% of patients therapy was conducted with palliative intent, 17% with curative intent and the remaining were eligible to Best Supportive Care. Only 1 patient performed surgery with curative intent. In the 30 patients submitted to first line palliative chemotherapy with platinum doublet and etoposide, 13 partial responses and 3 stable disease (according to RECIST 1.2 criteria) were observed. About outcome, there were 35 deaths (76%), 94% of whom were patients whose initial approach was palliative. Median survival was 246 days (CI 95%).

Conclusion:
SCLC comprehends a heterogeneous group of patients. In recent years diferent subtypes of SCLC have been identified and new therapeutic molecules have been tested in order to improve management of these tumors. More studies are necessary.

Background:
SCLC is a devastating cancer with poor overall survival. Mutation profiles and treatment regimens differ significantly from non-small cell lung cancer (NSCLC). Here we demonstrate feasibility of monitoring patients with SCLC by deep sequencing from only 2 ml of plasma, without prior knowledge of the tumor tissue mutations relative to CT imaging.

Method:
Cell free DNA (cfDNA) was isolated from 64 longitudinal plasma samples (2ml) from 23 subjects with advanced SCLC using the cobas® cfDNA Sample Preparation Kit. The AVENIO ctDNA Surveillance kit (RUO, Roche, Pleasanton, CA, USA) with 197 genes detects SNVs, fusions, CNVs and InDels, and was used for sequencing the cfDNAs. Library preparation with 10-50ng cfDNA yielded a mean pre-capture library yield of 1,728ng. Mean % reads on-target was 65% with a mean deduped coverage of 3,397 fold. CT scans were reviewed to assess disease burden.

Result:
47 longitudinal plasma samples from 8 subjects were successfully analyzed without access to matched tumor tissue. Sixteen subjects with only one baseline plasma sample were excluded from further analysis. Subjects had 3-10 longitudinal plasma samples. Somatic variants were detected with allele frequency (AF) of >0.5% to 30% and 60-90% if they were present in cfDNA from at least three different time points. Germline variants were identified and removed if AFs were 40-60%, and >90%. All variants with frequencies >1% in ExAC were removed. Somatic variants were identified in TP53 (5), APC (2), NPAP1 (2), MKRN3 (2), BRAF, NFE2L2, CDKN2A, TIAM1, LRRTM1, NYP2, FAM135B, FAM71B, PIK3CG, KEAP1, DCAF12L1, PCDH15, EGFLAM. Tracking somatic variants in the longitudinal plasma samples allowed monitoring of treatment response at the molecular level for 6 of 8 subjects. In one subject with 10 longitudinal plasma samples mutations in five different genes were tracked at 1-3% AF before rising to 5- 20% at month 8 and 12-55% at month 9. Molecular progression was detected 1 month earlier than clinical progression by CT. Another subject had a TP53 splice mutation over 10 time points and through 3 lines of treatment and AF correlated with clinical response as measured by imaging.

Conclusion:
Subjects with advanced SCLC and mixed SCLC/NSCLC can be monitored at the mutation level using molecular barcoded duplex sequencing in longitudinal plasma samples. 2ml of plasma yielded sufficient cfDNA for testing with the Surveillance kit. Somatic mutation monitoring is possible without matching tumor tissue samples where longitudinal mutation profiles correlate with clinical response by CT imaging.

Background:
SCLC represents 15% of all lung cancers and is one of the most aggressive types with rapid progression. Because of this, two thirds of patients are diagnosed with ED. The ED-SCLC is highly sensitive to chemotherapy. However, many patients are diagnosed in ages 65 and older. This retrospective study was designed to examine factors associated with chemotherapy administration among elderly patients with SCLC and to quantify the survival benefit.

Method:
Between Jan 1995 and Dec 2015, we analyzed 88 cases of elderly patients with ED-SCLC who treated chemotherapy in Korea University Medical Center.

Result:
A total of 88 patients were diagnosed ED- SCLC at the age 65 and older. Median age is 71 years old (range 65-83). Most of cases were male (82%) and 16 patients were female (18%). The most common chemotherapy regimens included etoposide combined with platinum. Median overall survival was 8.65 months. In multivariate analysis, ECOG PS <2, SCS <9, administration > 4 cycles of 1[st] line chemotherapy and treatment-free interval (TFI) > 3 months were defined as a favorable prognostic factors. Figure 1

	Univariate			Multivariate
	HR	95% CI	p value	HR	95% CI	p value
ECOG PS 0,1 ≥2	0.34 1	0.18-0.67	0.002	0.60 1	0.31-1.16	0.13
SCS <9 ≥9	0.42 1	0.26-0.66	< 0.001	0.52 1	0.32-0.82	0.005
1st line chemotheraly ≤4cycles >4cycles	1 0.44	0.28-0.70	0.004	1 0.44	0.27-0.72	0.005
Response to 1st line Tx. CR,PR SD,PD	0.49 1	0.31-0.79	0.003	0.45 1	0.28-0.72	0.001
TFI* (months) ≤3 >3	1 0.36	0.17-0.76	0.007	1 0.37	0.17-0.78	0.01

Conclusion:
Even an elderly patient with ED- SCLC who has lower SCS< 9 and good ECOG PS <2 should consider first line chemotherapy more than 4cycles.

Background:
Small cell lung cancer (SCLC) is the most aggressive histologic type of lung cancer. It consists in approximately 10-15% of all lung cancer cases. There are very few studies on its risk factors besides tobacco, and even less have analyzed the effect of residential radon. We aim to know the risk factors of SCLC.

Method:
We designed a multicentre, hospital-based case-control study with the participation of 11 hospitals in 4 regions of Spain. An interview about personal, family and work history, as well as tobacco and alcohol consumption and diet habits, was made to each case. Also the cases were provide with a radon detector, and a genetic blood test was made.

Result:
.Results of the first 113 included cases, 63 of them with residential radon measurements, were analyzed. Median age at diagnosis was 63 years old and 11% of cases were younger than 50. 22% of cases were women. 57% had extended disease and 95% were smokers or ex-smokers. Median residential radon concentration was 128 Bq/m3. 8% of cases had concentrations higher than 400 Bq/m3. The only remarkable difference by gender was the percentage of never smokers, which was higher in women compared to men (p<0,001). Radon concentration was higher for extended disease (non-significant difference) and was higher for patients diagnosed at 63 or older (p=0,032).

Conclusion:
A high percentage of SCLC cases are diagnosed at an earlier age. There is a predominance of extended disease at diagnosis (57%). Age and stage at diagnosis are similar between men and women, although it appears that men tend to be diagnosed with stage IV cancers more often. Regarding the concentration of radon, it is elevated in SCLC when compared, for example, with data from the general population of Spain. It can be seen that subjects with extended cancer have a slightly higher radon concentration and that older subjects at diagnosis have significantly higher radon concentrations than younger cases.

Background:
Surgical resection can be considered for the treatment option for early-stage small cell lung cancer (SCLC). However, few reports have evaluated the use of limited pulmonary resection for patients with SCLC. This study was undertaken to evaluate the clinical impact of limited resection for SCLC patients with c-stage I.

Method:
We retrospectively analyzed surgically resected 40 SCLC patients with c-stage I from 2006 to 2016. We compared patients who underwent limited resection and those who underwent curative resection. In addition, factors affecting survival and recurrence were evaluated by Kaplan-Meier survival and Cox regression analysis.

Result:
Sixteen patients who underwent limited resection, including 13 wedge resection and 3 segmentectomy, were compared with 24 patients who underwent curative resection, including lobectomy and pneumonectomy. All patients were considered to be treated with standard chemotherapy or chemoradiotherapy. Twenty eight patients with pure SCLC and 12 patients with combed SCLC were identified. Histological examination showed a component of adenocarcinoma in 3 cases, squamous cell carcinoma in 4 cases, large cell neuroendocrine carcinoma in 4 cases and adenosquamouns cell carcinoma in a case. The median age was 73 years old (range, 39 to 90), and six (15.0%) patients were female. Almost all patients (39 out of 40; 97.5%) had a smoking history, and median pack-years was 53.5 (range, 0-150). Mean follow-up for cancer survivors was 33.0 months. In patients who underwent limited resection, significantly worse 5-year overall survival (5-OS) and 5-years disease-free (5-DFS) survival were observed compared to patients who underwent curative resection (5-OS; 20.4 months vs. 27.3%, p-value = 0.03, 5-DFS; 14.8 months vs. 36.5 months, p-value=0.04). Among patients who underwent limited resection, 5 patients experienced intrathoracic recurrence. Limited resection for patients with SCLC is associated with an increased risk of intrathoracic recurrence compared with those who underwent curative resection (hazard ratio 0.136, p=0.075).

Conclusion:
Surgical resection followed by chemotherapy or chemoradiotherapy can be a treatment option for early-stage SCLC, however limited resection increased the risk of recurrence and was associated with poor survival significantly. For patients who can not tolerate curative resection, limited resection may not be an effective therapeutic alternative.

Background:
The aim of this study was to evaluate whether the pretreatment forced expiratory volume 1 (FEV1)/forced volume vital capacity (FVC) ratio could predict survival in patients with limited-stage small cell lung cancer (LS-SCLC).

Method:
We assessed 74 patients with LS-SCLC treated with chemoradiotherapy who were divided into two groups: those with FEV1/FVC <0.74 (n=24) and those with FEV1/FVC ≥0.74 (n=50).

Result:
The 3-year overall survival (OS) and 3-year progression-free survival (PFS) rates were significantly lower in patients with FEV1/FVC ratios <0.74 than in those with ratios ≥0.74 group (35.4% vs. 61.2%, P=0.0033; and 11.7% vs. 51.8%, P=0.0072, respectively). On multivariate analysis, a low FEV1/FVC ratio was independently associated with OS and PFS (hazard ratio [95% confidence interval]: 2.15 [0.99–4.63], P=0.052; and 2.13 [1.04–4.39], P=0.039, respectively).

Conclusion:
The pretreatment FEV1/FVC ratio appears to be a potential prognostic factor for LS-SCLC.

Background:
Elderly patients with SCLC have limited treatment options and poor survival. Lobaplatin(LBP) is a representative of the third-generation platinum compound, which has showed significant efficacy and favorable toxicity for SCLC. Therefore, we adopt population pharmacokinetic methods to explore the pharmacokinetics and its correlation with adverse reactions, and to make individualized dosing regimens of lobaplatin for elderly SCLC patients.(ChiCTR-OPN-15006057)

Method:
SCLC patients aged≥65 years and creatinine clearance(Ccr) ≥60ml/min were divided into two arms, receiving four cycles of lobaplatin regimens according to Ccr. LBP was administrated at dose of 30mg/m[2 ]in Arm A(Ccr≥80ml/min) or 20mg/m[2] in Arm B(60ml/min≤Ccr＜80ml/min). Four blood samples were randomized collected from each patient in the first cycle. For the subsequent cycles, only one blood sample were collected. The primary endpoint was plasma concentrations at different time points after administration of LBP. The secondary endpoints were PFS, OS, ORR, DCR and safety.

Result:
Between January 2014 and July 2016, 100 patients(30 with limited stage and 70 with extensive stage disease) were enrolled into the study at 7 institutions in China. There were 51 patients in Arm A and 49 patients in Arm B. The median PFS and OS for Arm A and B were 155 days vs.170 days, 306 days vs. 272 days, respectively. The ORR and DCR were 50% vs. 51.22%, 88.64% vs. 90.24% respectively. Grade III/IV AEs incidence of Arm A and B were 60.8% vs. 51.0%. In terms of population pharmacokinetic, we can get the following conclusions by computer simulation that if the total doses of LBP are fixed, the exposure levels of lobaplatin in the body have great differences when the body surface areas(BSA) are different. If administrated according to the BSA, the AUC differences of individual with different BSA are little, and there is only about 8% AUC differences between the two arms. As administrated in accordance with the protocol, the AUC of Arm B is about 39% lower than that of Arm A. If dose of LBP in Arm B was increased from 20 mg/m2 to 27 mg/m2, the AUC difference between the two groups was only 3%.

Conclusion:
When Ccr≥60 ml/min, it’s necessary to administration on the basis of BSA. It’s reliable and safe to use LBP-based regimens to treat elderly patients with SCLC. Lobaplatin may offer an alternative choice for Chinese elderly patients with advanced SCLC.

Background:
The survival benefit of prophylactic cranial irradiation (PCI) in extensive stage small cell lung cancer (ES-SCLC) is unclear. This study aimed to determine the use of PCI and the factors associated with its use as well as its impact on overall survival (OS) in the Singapore population.

Method:
We conducted a retrospective cohort study including patients diagnosed with ES-SCLC without brain metastases treated in the only two Singapore national cancer centres from 2003 to 2010. We identified the patients using the institutions’ pathology registries and linked the electronic medical records to the National Death Registry. We used multivariable logistic regression to identify factors associated with the use of PCI and its impact on OS. All analyses were performed using STATA version 11.0.

Result:
We identified 224 eligible patients. 65 of 224 patients did not receive chemotherapy. 71 of 159 patients had at least stable disease (SD) after first line chemotherapy. 16 of these 71 patients received PCI. There was an increase in the use of PCI from the period 2007 to 2010 compared with 2003 to 2006 (13 patients versus 3 patients, chi-square P value = 0.01). The use of consolidation thoracic radiation therapy (TRT) was associated with use of PCI (odds ratio 18.3, 95% confidence interval (CI) 4.70 to 71.96, P value (P) < 0.001). PCI improved OS (adjusted hazard ratio 0.47, 95% CI 0.24 to 0.91, P = 0.02) compared to no PCI use among the 71 patients who had at least SD after first line chemotherapy. Consolidation TRT did not improve OS among this group of patients.

Conclusion:
The utilization rate of PCI remained low in the Singapore population between 2003 to 2010 despite an increase in its use since 2007. Patients who had at least SD after first line chemotherapy or had consolidation thoracic radiation therapy were more likely to receive PCI. Among patients who had at least stable disease after first line chemotherapy, the use of PCI was associated with an improved survival outcome.

Background:
The proportion of younger patients with lung cancer is smaller than the older. But, as with older patients, the number is on the rise and clinical features of younger patients might be different compared to older patients. So we investigated the characteristics of younger patients with resected lung cancer through reviewing medical records.

Method:
From January 2010 to December 2014, 424 patients underwent operation for lung cancer at Pusan national university hospital. Mean age was 63.4±9.8 years old. Of them, 135 were under 60 years old (younger group). Medical records including demographic factors, histological type, surgical factors and outcomes, disease free survival rate (DFS) and overall survival rate (OS) were reviewed retrospectively.

Result:
In younger group, mean age was 52.2±7.6 years old and proportion of female was significantly higher (p value=0.00). Co-morbidity and other combined malignancies were smaller (respectively, p value = 0.00 and 0.007) and proportion of adenocarcinoma were higher than older group (p value = 0.03). Mean operative time was shorter than older group (4.57 versus 4.90 hours, p value= 0.03). There was no significant difference in other factors (postoperative complications, surgical approach, FEV1, hospitalization, and etc.). Mean follow up duration was 34.0±17.7 months, and 3 year DFS and 3 year OS of younger group in stage IA was 97.9% (versus 94.0% in older patients, p value = 0.009) and 96.4% (versus 93.3% in older patients, p value = 0.07). In other stage, there was no significant difference of DFS and OS.

Conclusion:
This study shows that there were significantly different characteristics between younger and older patients group including DFS in pathologic stage IA, sex, and proportion of histological type, and suggests that development and application of more adequate modalities for early diagnosis and treatment in younger patients is needed.

Background:
Segmentectomy is thought to be able to spare lung parenchyma compared with lobectomy. On the other hand it might cause more local recurrences. The management of local recurrence after segmentectomy is thought to be an important issue. The aim of this study is to evaluate the management of local recurrence after segmentectomy.

Method:
From June 2005 to March 2009 we performed segmentectomy for clinical stage IA lung cancer, 88 male and 91 female with mean age of 66 year-old (32-83). The histological types of 179 lung tumors according to WHO histological classification are as follows: atypical adenomatous hyperplasia (2), adenocarcinoma in situ (34), minimally invasive adenocarcinoma (27), invasive adenocarcinoma (96), Squamous cell carcinoma (2), adenosquamous carcinoma (4), and carcinoid (2), respectively. Median follow-up time was 2920 days. During follow up there were 15 recurrences. Of 15 cases with recurrence 6 cases had local recurrences without distant metastasis.

Result:
Figure 1Mean time to local recurrence after segmentectomy was 1595 ± 1027 days (356－2965). Of 6 cases with local recurrence 5 cases had micropapillary component more than 5 %. The initial treatments for local recurrence were as follows: completion lobectomy (4), radiation (1), radiofrequency ablation (1), respectively. Three of 6 cases have been alive without evidence of disease since initial treatment for local recurrence of lung cancer.



Conclusion:
Management of local recurrence after segmentectomy is important. Local treatment, such as, completion lobectomy, radiation, or radio frequency ablation may effective for selected cases.

Background:
Optimal minimally invasive approach in treatment of non-small cell lung cancer (NSCLC) is controversial. Our goals were: 1.To profile the learning curve of adoption of robotic lobectomy by an experienced open thoracic surgeon, novice with VATS-lobectomy techniques; 2. To compare the clinical outcomes of robotic lobectomy vs. historical open lobectomy by the same surgeon (AA).

Method:
We conducted a retrospective review of 157 consecutive patients undergoing lobectomy for clinical stage I and II NSCLC by one surgeon, previously novice in performing minimally invasive lobectomy, at a single facility between 2007 and 2014. Robotic platform was adopted in 2011. 57 patients underwent open thoracotomy (OT), 40 prior to 2011, and 100 patients underwent robotic lobectomy.

Result:
The preoperative characteristics and risk profile of the two groups were similar. Aside from longer operative time (a bimodal learning curve), the robotic group (including 13% of patients with open conversion) had significantly lower intraoperative blood loss and overall morbidity rate, significantly shorter chest tube duration and length of stay, and a statistical trend toward lower 90 day mortality and 30 day readmission rate (Table 1). Median number of lymph node stations dissected and percentage of pathologic nodal upstaging were equivalent between robotic and OT groups (5 vs. 4; 17% vs. 14%, respectively). The conversion rate for the latter half of the robotic group was significantly lower (6% vs. 20%, p<0.05). Figure 1



Conclusion:
Adoption of robotic platform for lobectomy for NSCLC is safe and feasible without significant preceding VATS experience. In our hands, the learning curve entails approximately 50 robotic lobectomies after which the operative times and conversion rates significantly diminish. In comparison to open thoracotomy, robotics, even during the learning phase, result in a significant reduction in perioperative morbidity and permit equivalent nodal sampling in performing lobectomy for clinical stage I and II patients.

Background:
In recent years, non-intubated video-assisted surgery (VATS) is gaining popularity worldwide, especially in elderly lung cancer patients (ELC). The main goal of this surgical practice is to achieve an overall improvement of patients management and outcome thanks to the avoidance of side-effects related to general anesthesia and single-lung ventilation. We compared non-intubated anesthetic technique with intubated general anesthetic technique for VATS. .

Method:
Forty octogenerians (patinets aged 80 years or more) scheduled for VATS lung cancer surgery, were allocated randomly into two groups with 20 patients each. First group received standard general anesthesia with double lumen tube. Second group went under non-intubated anesthetic technique. Heart rate, mean arterial pressure, end-tidal CO2 and the visual analog pain score (VAS) measurements were recorded during the surgery and 24 hours after the surgery. Both group received ultrasound guided paravertebral block before surgery with single injection of 20 ml 0.25% levobupivacaine. VATS lobectomy followed by sample mediastinal lymphadenectomy was performed in all patients. Figure 1



Result:
Time for anesthetic procedure was shorter in the nonintubated group. VATS lobecotomy was performed in usual manner in all patients without any intraoperative complications. VAS score in the first 24 hours was comparable. We found significantlly shorter recovery time, reduced oxygen requirement, shorter chest tube drainage and hospital stay in the non-intubated group. There where no significant differences in intraoperative blood loss, operation time or postoperative complications between the non-intubated group and the intubated group of patients.

Conclusion:
Tthis pilot study has shown that non-intubated VATS is a safe and feasible surgery for elderly lung cancer patients with certain advantages for the patients undergoing VATS.. Our results indicated that we can achieve day surgery for selected patients. Further clinical studies should be carried out in order to improve surgical outcome in elderly lung cancer patients.

Background:
Non-small-cell lung cancer (NSCLC) is a very common disease in the elderly population.Incidence in this particular population is expected to increase further, because of the ageing of the Global population. Numerous studies have shown a benefit of the surgery over medication in octogenrian people.However, limited data are available for the treatment between sublobar vs lobar resection in octagenerian groups. Our object is to compare the overall survival between sublobar vs lobar resection in early stage lung cancer in octogenarian group. Secondary outcome is to demonstrate a disease free survival between sublobar vs lobar resection and Co-morbidity after operation between sublobar vs lobar resection.

Method:
From 2003-2016, a total of 77 patients who age over 80 with stage I non small cell lung cancer and underwent sublobar or lobar resection in Bundang hospital, Seoul university. The clinical data were retrospectively analyzed as regards characteric such as underlying disease, histology, smoking status, pulmonary functiontest, complication and overall survival. Survival was analyzed by the Kaplan-Meier method and log-rank test. Univariate and multivariate logistic regression analyses were performed to identify patient characteristics associated death and recurrence of disease

Result:
Overall survival and overall free disease free survival were similar in both groups.Median follow up time was 24 months However, an incidence of complications after lobar resection was more than sublobar resection with 26.4% and 12.5%, respectively. Patient who recieve sublobar resection had a shorter hospital stay than lobar resection. In multivariate analysis, COPD and family history were a risk factor that associated with recurrence of disease and tumour size, vascular invasion associated with overall mortality.

Conclusion:
Sublobar resection is an alternative treatment for early lung cancer in octogenarians which does not increase risk of recurrence or death after the operation and also could be benefit in shorter period of hospital stay and complication after surgery.

Background:
Video Assisted Thoracic Surgery (VATS) has become the recommended approach for treatment of early stage lung cancer. No large randomized clinical trial has been conducted to formally compare VATS to open thoracotomy (OT).Our study sought to assess differences in recurrence-free survival (RFS),overall survival (OS),positive margins and postoperative length of stay (LOS) between VATS and OT.

Method:
A single institution retrospective charts review was conducted for patients diagnosed with stage I-III lung cancer and treated with VATS or OT from May 2005 - May 2015.Patients and tumor characteristics included age at diagnosis, sex, tobacco use, tumor location, stage,size and receipt of chemotherapy or radiotherapy. Chis-square and Wilcoxon-Mann-Whitney tests were used to compare demographic, tumor characteristics and LOS. Multiple logistic and Cox regressions were used to compute relative risk (RR) for positive margins and mortality hazards ratio along with 95 percent confidence interval limits (95%CI), respectively.

Result:
A total of 235 patients underwent lung resection for cancer diagnosis; VATS n = 101 and OT n = 134. Age at diagnosis, sex, tobacco use, tumor location,and size were comparable for VATS and OT. No significant difference was observed in the risk of positive margins for VATS versus OT [RR= 0.56 (95%CI= 0.26, 1.05)]. However,VATS (4 days) had shorter median LOS compared to OT (6 days), P=0.002.Recurrence [HR= 1.21 (95%CI= 0.74, 2.00)] and mortality hazards [HR= 1.34 (95%CI= 0.88, 2.06)] were comparable for VATS versus OT,with consistent results observed for analysis limited to subjects having negative margins and across tumor stage at diagnosis. Figure 1



Conclusion:
Our results show that compared to OT, VATS leads to shorter LOS while achieving comparable margins status, recurrence-free and overall survival regardless of tumor stage at diagnosis. By reducing LOS, VATS is cost effective while achieving similar outcomes and should be considered as the approach of choice for patients undergoing lung resection for cancer.

Background:
In the thoracic surgery for non-palpable and invisible ground-glass opacity (GGO) lung nodules , various methods have been reported, such as needle sticking or infusion of roentgen non-permeable substances around the tumor under computed tomography (CT) guidance. However, there are serious problems such as air embolism and/or tumor dissemination into the thoracic cavity. Mobile computed tomography, O-arm Surgical Imaging System (Medtronic), can provide an image intraoperatively. In this study, we evaluated the usefulness of mobile computed tomography in thoracic surgery for the GGO lung nodules.

Method:
From December 2016 to May 2017, 3 patients with ground-glass opacity lung nodules were evaluated under video assisted thoracoscopic surgery using O-arm system. Before surgery, the patient was placed in lateral decubitus position in the CT room, and the skin directly above the tumor was marked with a skin marker. In the operation room, a port was made on the marked position, and a Naruke's thoraco cotton dyed with indigo carmine was introduced into the port to mark the visceral pleura just above the lesion. Then, the tumor-side lung was deflated, and the marked visceral pleura was grasped with non-traumatic forceps. Intraoperative CT imaging was reconstructed with O-arm, and the GGO lesion was comfirmed and resected under the guidance of positional relationship between the forceps and the tumor.

Result:
In all 3 patients, the tumor could be seen intraoperatively with computed tomography using the O-arm system, and resected properly. No complications were experienced in this study on the use of the O-arm system.

Conclusion:
The O-arm system could be a new strategy for the surgical treatment of non-palpable lung lesions.

Background:
Near infrared (NIR) fluorescence-guided pulmonary segmentectomy following endobronchial or intravenous indocyanine green (ICG) administration has been developed and reported. The aim of this study is to prospectively validate the feasibility and safety of NIR fluorescence-guided pulmonary segmentectomy following endobrochial ICG injection using navigational bronchoscopy.

Method:
Patients who underwent pulmonary segmentectomy were prospectively enrolled in this study. Using preoperative CT datasets a 3D image of target segments was reconstructed for lung volumetry and a bronchial road map was created to determine the bronchus for ICG injection. The ICG concentration was 0.125 mg/mL. Immediately after intubation the ICG was injected into the target bronchi using an ultrathin bronchoscope followed by air flushing to expedite ICG dispersion to the periphery. A NIR thoracoscope (PINPOINT, Novadaq) was used to detect ICG fluorescence and determine intersegmental plane for pulmonary segmentectomy. Usefulness and safety of this technique were evaluated by 1) whether ICG demarcation lines correspond to intersegmental lines expected from pulmonary veins, 2) whether large bronchi and vessels in adjacent segments emerge when dividing intersegmental planes using electrical cautery. The patients were followed up to 1 month after surgery to see if any complication existed.

Result:
Eight male and 7 female patients with a mean age of 66.5 ± 9.6 years were enrolled. Segmentectomy regions included right S1, S2, S6, S8 and S10 segments, and left S1+2+3, lingular, S6, S8, S9+10, and basilar segments. The average bronchoscopic procedure time was 14.3 ± 8.0 minutes. Vital signs were kept stable before and after the bronchoscopic procedure. The mean injected volume of ICG solution was 21.2 ± 8.8 mL as per a case. In 13 out of 15 cases (86.7%), NIR fluorescence guidance was recognized as effective for pulmonary segmentectomy. Intersegmental plane could not be determined in 2 cases likely due to insufficient air flushing, leading to the failure of ICG dispersion to the periphery. There was no complications developed intraoperatively. The average operation time was 193 ± 41 minutes, with a mean bleeding of 110 ± 101 mL. The average duration of drainage was 3.1 ± 1.0 days. Recurrent air leakage happened on postoperative day 6 in 1 case. Otherwise, no procedure related adverse event was noted.

Conclusion:
NIR fluorescence-guided pulmonary segmentectomy following endobrochial ICG injection using navigational bronchoscopy appeared to be safe and feasible. Sufficient air flushing may be the key for clear ICG demarcation of referred segments.

Background:
Adequacy of lymph node dissection is often used to compare video-assisted thoracoscopic surgery (VATS) with open surgery for lung cancer, but no consensus exists over how best to assess nodal yield (by weighing or counting) and to correlate this with survival. This study uses one of the longest follow-up periods to date to address these unanswered questions.

Method:
From February 2006 to July 2010, 230 consecutive adult patients with non-small cell lung cancer received lobectomy with curative intent. Surgical approach was determined by the surgeon’s discretion: 118 (51%) ultimately received VATS and 112 (49%) received open or ‘hybrid’ surgery.

Result:
A summary of the data is shown in the Table. Mean numbers and weights of lymph nodes dissected in the two study arms were similar overall, but VATS yielded more in stations 3 and 7, and non-VATS in station 10. A change in staging was more frequent after non-VATS, but was due mostly to more downstaging. VATS more frequently fulfilled the European Society of Thoracic Surgeons (ESTS) guidelines for adequacy of nodal dissection. Previous tuberculosis reduced nodal yields with non-VATS (p=0.033) but not VATS. On regression analysis, the counted numbers of nodes dissected correlated well with the measured weights in both VATS and non-VATS groups (F ratios: 26.0, p<0.001 and 58.6, p<0.001 respectively). VATS gave a trend for better 5-year overall survival in stage I disease (p=0.108). No significant correlation was found between nodal dissection, surgical approach and survival after a median postoperative follow up of 111 months (range: 82-136), but 33 (26.4%) of the 125 total deaths occurred after 5 years. Figure 1



Conclusion:
Counting and weighing give similar results for comparing lymph node yields after VATS versus non-VATS. VATS gives non-inferior nodal yields, but follow-up for longer than the conventional 5 years may be potentially important in correlating yields with long-term survival.

Background:
Small lung nodules which appear to be ground glass opacity in peripheral lung are difficult to identify during surgery. In order to identify the site of such lesions, various types of preoperative or intraoperative marking methods have been reported. However all of them have advantages and disadvantages, so there is no definitive way. Therefore, we developed a new safe and reliable intraoperative marking method using a thin laser fiber. This is a method to confirm a low power laser light from lung surface irradiated from a small diameter laser fiber inserted into or close to the lesion transbronchoscopically using a navigation system. In this study, we conducted an animal experiment to confirm whether the laser light can actually be observed safely from lung surface.

Method:
Bronchoscopy was performed to a hybrid dog under general anesthesia. A plastic laser probe was inserted into a peripheral bronchus from the biopsy channel of the bronchoscope. The plastic laser probe was a very thin (0.8 mm diameter) and flexible cylindrical-type probe. Therefore, it can be inserted into the peripheral lung. It was developed jointly with Keio University. The probe was induced just below the pleura and 50 mW low power laser irradiation was performed. We examined whether laser light could be confirmed from lung surface under thoracotomy. We also examined the difference in appearance from direct-type laser irradiation.

Result:
When the probe was guided to just below the pleura, laser light could be clearly observed from the lung surface. After that, the probe was gradually withdrawn. The laser light could be observed until the depth of 2.0 cm from the pleura. Moreover, laser irradiation was able to be performed safely without any damage around the laser irradiated area. The laser light was observed consistent with laser irradiation site by the cylindrical probe. On the other hands, it was observed on the pleura ahead of laser irradiation by the direct-type probe. Therefore, it is suggested that cylindrical probe might indicate the target area more accuracy.

Conclusion:
It might be possible to confirm the localization of small nodules in peripheral lung using low power laser light during surgery.

Background:
Progress in diagnostics and surgery in thoracic oncology is associated with increasing number of patients-candidates for sublobar anatomic pulmonary resection. Vascular variability of pulmonary segments anatomy requires special tools for individual preoperative planning.

Method:
We retrospectively analyzed 114 patients who underwent segmentectomy due to low pulmonary function, severe comorbidity or previous history of lung resection. Indications for surgery were clinical T1aN0M0 peripheral non-small cell lung cancer (NSCLC) ≤2 cm (n=53), resectable pulmonary metastases not suitable for wedge resection due to deep parenchymal location (n=47) and benign lesions (n=14). Segmentectomies were divided into typical (where parenchymal division involves 2 planes) and atypical (more complex and technically demanding, when the segmental excision involves 3 planes). 38 patients underwent VATS segmentectomy. Three-dimensional computed tomography (3D-CT) with bronchovascular separation was used preoperatively in 58 patients from October 2014 to April 2017. Mortality, morbidity, proportion of typical versus atypical and VATS versus open segmentectomies in two groups: with or without 3D-CT bronchovascular reconstruction, were compared.

Result:
There was no mortality in whole group. Morbidity rate was 7,9% not exceeding grade 3a according thoracic mortality and morbidity (TMM) score. The difference in morbidity rate was not statistically significant between two groups (6,9% and 8,9%; p=0,23) The most common complication was prolonged air leak > 7 days (2,6%). 3D-CT powered by separation of arterial, venous and bronchial structures enabled surgeons to perform atypical segmentectomies and use VATS approach more often (31,3% vs 13,5%; p>0,05 and 50,0% vs 11,5%; p<0,05, respectively). 8 atypical segmentectomies were performed by VATS due to 3D-CT reconstruction with bronchovascular separation. 5-year survival was 86% and 21% in NSCLC and pulmonary metastases groups, respectively.

Conclusion:
3D-CT reconstruction with bronchovascular separation provides precise preoperative planning of individual pulmonary segments anatomy and allows to increase the proportion of atypical and VATS sublobar anatomic pulmonary resections.

Background:
This study evaluated the feasibility of pre-operative localization of pulmonary nodule using dual marker composed with indocyanine green (ICG) and lipiodol for minimal and accurate resection in video-assisted thoracoscopic surgery (VATS).

Method:
To minimize separation of two materials, we mixed with different frequency and ratio of ICG and lipiodol using a 3-way stopcock, and investigated their distribution with fluorescent microscope. Three rabbits were undergone thoracotomy after computed-tomography (CT) fluoroscopy-guidance injection of each 0.1 ml emulsions into different lobes of rabbit lung at 6, 12 or 24 hours. The localized lesions were evaluated by near-infrared optical imaging and radiograph. The 0.3 ml of emulsion was pre-operatively injected into 22 patients under CT fluoroscpy-guidance, and the localization was then evaluated during surgery by near-infrared imaging and mobile C-arm fluoroscopic x-ray. All freshly excised specimens were diagnosed by pathologic examination.

Result:
In in vitro, the separation time of ICG and lipiodol emulsion was delayed proportionally to mixing frequency and ratio. The emulsion mixed with 90 passages and 90% lipiodol was the least separated at 24 hours. On the rabbit lung, the optimal emulsion remained stably on injection site until 24 hours after injection. Pulmonary nodule localization using the optimal emulsion was performed successfully on the 22 patients without complications.

Conclusion:
This easy optimal method for pre-operative localization of pulmonary nodule was successfully established. The emulsion can be a useful marker to show the location of lesion to surgeons. However, ICG and lipiodol were not mixed perfectly and evenly. Therefore, there will be needed a future research to stabilize two materials completely.

Background:
Video-assisted thoracoscopic surgery (VATS) has been established as the preferred approach for surgical resection of early-stage non-small cell lung cancers. It is shown to have improved oncological outcomes with lower perioperative complication rates when compared with conventional open lobectomy. However, there is a paucity of high-level evidence supporting its use in locally-advanced lung cancers. Moreover, published results have shown contrasting outcomes. We conducted a meta-analysis to compare oncological outcomes as well as perioperative complications for VATS versus conventional thoracotomy in this population.

Method:
Electronic databases (PubMed MEDLINE, EMBASE and Web of Science) were searched for studies evaluating VATS versus conventional thoracotomy for the resection of locally-advanced lung cancers. Individual outcome data was pooled to investigate the summary effect.

Result:
A total of 5 studies comparing the two approaches were identified. Of these, only 3 studies reported long-term survival data appropriately and were analysed separately. There was no difference in 3-year overall survival (HR 0.67, 95% CI 0.29-1.53) or 3-year disease-free survival (HR 1.09, 95% CI 0.77-1.55) when comparing VATS against open thoracotomy. However, VATS was associated with a shorter length of stay (2.02 days, 95% CI 0.65-3.39 days). There was no difference in blood loss between the two approaches.

Conclusion:
Oncological outcomes of VATS resection appear to be at least equivalent to conventional thoracotomy in locally-advanced lung cancers. Length of stay is shorter for VATS, which has been shown to correlate with better cost-effectiveness. Ideally, randomised controlled trials should be designed to confirm and further investigate these conclusions.

Background:
We adopted the ‘thoracoscopic fissureless technique’ for patients with dense fissure undergoing right upper lobectomy to avoid postoperative air leakage. This technique is considered useful in thoracoscopic approach which has the limited direction in dissection. We investigated the efficacy of thoracoscopic right upper lobectomy using fissureless technique in this study.

Method:
Between April 2012 and March 2017, 77 patients underwent thoracoscopic right upper lobectomy with three or four ports, of whom 23 adopted fissureless lobectomy. We compared the characteristics and perioperative outcomes of the patients undergoing the fissureless technique (fissureless group, n=23) and the traditional fissure dissection technique for pulmonary artery exposure (traditional group, n=54). The details of the fissureless technique is as follows. While the upper lobe is retracted towards the back, the upper lobe vein and the anterior PA trunk to the upper lobe are exposed and divided. After the division of right upper lobe bronchus by a stapler, the ascending artery is divided. However, it is better to dissect and divide the ascending A2 prior to right upper bronchus when the ascending A2 branches from a comparatively proximal portion. The fissure is finally divided.

Result:
The patients’ characteristics and perioperative results in the 2 groups are shown in the table. There was no significant inter-group difference about sex ratio, age, blood loss (p=0.95), intraoperative massive bleeding rate (p=0.66), conversion rate (p=0.55) or morbidity (p=0.13), fissureless group had shorter operation time (p=0.047) or postoperative hospital stay (p=0.0004). Additionally, fissureless group had tendency to reduce the duration of postoperative chest tube drainage (p=0.07).

Variable	Fissureless group, n=23 (%)	Traditional group, n=54 (%)	p-value
Operation tim (min.)	197±45	225±61	0.047
Blood loss (ml)	93±150	95±165	0.95
Intraoperative massive bleeding (n)	1 (4.3)	5 (9.3)	0.66
Conversion to thoracotomy (n)	0 (0)	3 (5.6)	0.55
Duration of chest tube drainage (days)	2.7±1.6	3.9±3.2	0.07
Length of postoperative hospital stay (days)	4.6±1.3	7.5±3.5	0.0004
Morbidity (n)	2 (8.7)	14 (25.9)	0.13

Conclusion:
Thoracoscopic right upper lobectomy using fissureless technique is considered useful because it had a tendency to reduce the duration of postoperative drainage, and significantly reduced operation time and the length of postoperative hospital stay.

Background:
Lung cancer is increasing rapidly in China. More and more aged, sickly weak and/or cardiopulmonary dysfunction patients are found with lung cancer, but even for small lung cancer (≤2cm) patients, surgery was usually denied because they could not tolerate traditional large-incision standard posterolateral thoracotomy (SPLT); video-assisted thoracoscopic surgery (VATS) is expensive not always avalable in all hospitals, let alone most Chinese patients still could not afford VATS. miMRST, minimally invasive small incision, muscle- and rib-sparing thoracotomy, minimally invasive lung cancer radical surgery, was developed to help resolve these problems: resecting the tumor minimally invasively, not cost too much, with improved prognosis, widely accepted by Chinese patients.

Method:
Case 1: man, aged 67 in Aug 2012, left lower lobe 2.0cm tumor, hypertension for years, feard of SPLT large-incision. Case 2: man, aged 64 in Jan 2013, left lower lobe 1.0cm tumor, smoking 44 years, with serious chronic bronchitis 15 years, asthma episodes per year, coronary heart disease 13 years, coronary stenting 10 years, serious gastric ulcers, colorectal polyps 2 years, could not tolerate SPLT. Case 3: woman, aged 70 in Feb 2013, left lower lobe 2.0cm tumor, sickly weak and cardiopulmonary dysfunction for years , feard of and could not tolerate SPLT. miMRST was scheduled.

Result:
About 10cm lateral chest incision, with the latissimus dorsi and serratus anterior muscles protected, no rib cut needed, was enough for most lung cancer resection and mediastinal lymph node dissection, no need for the surgeon’s hands entering into the thoracic cavity, not as large-incision standard posterolateral thoracotomy (SPLT) and modified muscle and rib sparing thoracotomy (MRST) usually do. Left lower lobe lobectomy and mediastinal lymph node desection was performed for all three cases, for Case 1: No.5,6,7,9,10,11,12 group, Case 2: No.3A,4,5,6,7,8,9,10,11,12,12u,13,14 group, Case 3: No.3A,5,6,7,8,9,10,10R,11,12,12u,13,14 group lymph nodes and surrounding adipose tissue were dissected. Post-operative pathological diagnosis was adenocarcinoma, squamous carcinoma and adenocarcinaoma, respectively; all pT1N0M0 Stage IA. All recoverd quickly and no adjuvant tratment was used. Follow-up: all healthy in their 5th year postoperatively, 58, 53, 52 months, respectively. No sign of recurrence and metastasis.

Conclusion:
miMRST, minimally invasive small incision, muscle- and rib-sparing thoracotomy, shows advantage of less damage, quick and better recovery than SPLT, cost less than VATS. miMRST is very suitable for lung cancer surgery in developing countries like China, where most patients could not afford for the expensive VATS. (This study was partly supported by Science Foundation of Shenyang City, China, No. F16-206-9-05)

Background:
Video-assisted thoracic surgery (VATS) is currently performed to diagnose and treat solitary pulmonary nodules (SPN). However, the intra-operative identification of small and/or deep nodules can be challenging with VATS as the lung is difficult to palpate. Single-stage image-guided VATS(iVATS) performed in a hybrid operation room has been introduced in recent years for the simultaneous localization and removal of small SPN. However, its efficacy and safety compared with traditional workflow has not been studied.

Method:
Patients with undiagnosed SPN who required tumor localization prior to surgical resection between 2017/3 to 2017/6 were retrospectively reviewed. Based on the type of tumor localization method , patients were divided into two groups( Group1 : iVATS ; Group 2: preoperative computed tomography guide tumor localization followed by VATS). The efficacy in localizing the tumor, complications, necessity to convert VATS to thoracotomy and radiation dose were compared.

Result:
The cohort comprised 24 patients(12 in each group). The median SPN diameter was 7 mm (range: 3 – 11 mm) and the median distance of the lesion from the pleural surface was 13 mm (range: 0 – 47 mm) with no intergroup difference(P>0.05). Tumor localization procedure was successful in all patients with similar procedure time( group1: 28 mins[range: 16~41 mins] ; group2: 20 mins[range:14-35 mins] , p>0.05). However, the time interval from completion of localization to surgery was significantly longer in group2(median: 159 mins[range:78~313mins]) than in group1(median:10mins[range:3~20 mins], p<0.001). In group 2, migration of the hook wire occurred in 1 patients during the waiting period although it did not affect the success of VATS resection (nodule location guided by the lung puncture site). The mean effective radiation dose for group1 was 11.53 mSv and that for group2 was 13.50 mSv, respectively(P>0.05) .

Conclusion:
Compared with the traditional workflow(based on preoperative CT-guided lesion localization followed by its surgical removal), single-stage iVATS for simultaneous localization and removal of small SPN is equally safe and accurate but more efficient .

Background:
Lung cancer is the leading cause of cancer-related death all over the world. Surgery is the treatment choice for patients with non -small cell lung cancer stage I through IIIA. Dr McKenna first described video-assisted thoracoscopic lobectomy (VATS) in 1994. Thereafter, VATS is like mushrooming rapidly spreading all over the world. During recent two decades, minimal invasive thoracoscopic anatomic lung resection with lymph node dissection is now widely accepted as a safe and oncological sound treatment option. The move forward minimal invasive VATS has driven the development of sophisticated instruments and different concepts to cope with the demanding need of working through smaller and fewer incision wounds. Until recently, single port VATS (SPVATS) is now being used for a growing number of applications, even including major lung resection for lung cancer. However, majority of single port VATS related studies are only related to its perioperative outcomes and feasibility. There are still few studies reporting its oncological results. The objective of this study is not only to evaluate the perioperative outcome but also to discuss the middle term oncological outcome in two medical centers’ experience

Method:
We retrospectively reviewed patients who underwent SPVATS anatomic resections between January 2014 and February 2017 in Coruña University Hospital and Minimally Invasive Thoracic Surgery Unit (Spain) and Chang Gung Memorial Hospital (Taiwan). Survival outcomes were assessed by pathological stage of American Joint Committee on Cancer (AJCC) 7th and 8th classifications

Result:
307 patients were finally enrolled in this study. The 2-year disease free survival and 2-year overall survival of the cohort were 80.6 %and 93.4% for 1A , 68.1 %and 84.3% for 1B , 67.5 % and 72.3% for 2A, 18.4% and %49.6 % for 2B , 52.2 % and 61.6 % for 3A, respectively forAJCC 7th classifications. For AJCC 8th classifications, there were 92.3% and 100% for 1A1, 73.7% and 91.4% for 1A2 , 75.2 % and 93.4% for 1A3, 60.9 %and 85.5% for 1B, 55.6% and 72.7 %for 2A, 60.5%and 84.3 % for 2B, 45.4 % and 62.4% for3A

Conclusion:
Our preliminary results revealed that SPVATS anatomic resection achieves non-compromised middle term survival outcomes for early stage lung cancer. For advanced stage NSCLC patients, further evaluation was warranted

Background:
Near Infrared (NIR) fluorescent (Indocyanine green, ICG)-based EPR (enhanced permeability and retention) effects on identifying surgical margins are being used in lung cancer surgery. However, as ICG is equally likely to accumulate in tumors and inflamed tissue, this can cause false-positive results. In this study, we developed the novel method of Inhaled fluorescent based detection of intraoperative tumor resection margin by distinguishing cancerous tissue from normal tissue in mouse and rabbit lung cancer models.

Method:
ICG (1 mg/kg) was administered to healthy mice and mice with lung cancer via inhalation for 1h, and the lung distribution of ICG was investigated using a fluorescence imaging system. And, we established a computed tomography-guided VX2 lung cancer model in 6 rabbits. ICG was administered to these rabbits and resected tumor from lung cancer patients via nebulizer, and the lung cancer was resected under fluorescence imaging system after 1h. The resected tumor margins were investigated using confocal microscopy.

Result:
In normal mice, the inhaled ICG signal was significantly higher in lung compared to other organs (liver, brain, spleen, and kidneys), and this signal decreased over time. In metastatic lung cancer mouse models, the inhaled ICG was distributed only in normal tissues, except cancer. In the rabbit and resected cancer of human, the margin between cancer and normal tissue were distinguished clearly, and the tumor was successfully resected under ICFIS guidance in all 6 rabbits (Fig 3). Additionally, fluorescence and histological microscopy demonstrated that ICG was localized in normal lung tissue. The difference of fluorescent intensity between normal versus cancer tissue showed significantly higher in inhaled ICG Figure 1



Conclusion:
Fluorescent signal was dominantly observed in normal lung tissue comparing to cancer area after inhalation of ICG. The aerosolized ICG could provide better image information for intraoperative identification of resection margin during lung cancer surgery than the intravenous ICG injection.

Background:
In the field of surgical treatment for lung malignancy, segmentectomy has been accepted as a choice of surgical resection for some of early lung cancer cases, for patients with poor ventilatory function, and for some of metastatic lung tumor cases. Meanwhile, thoracic surgeons are familiar with the variety of branching pattern of pulmonary vessels as well as bronchial tree. Before each surgery, surgeons usually reconstruct the branching image from CT. Recently three dimensional angio-bronchography (3D-CTAB) is easily retrieved from the DICOM data of Dynamic CT. Reconstructed 3D-CTangiography has been shown its contribution to the enhancement of the safety of various field of surgery. We conducted a retrospective research whether 3D-CTAB can shorten operation time in segmentectomy cases with lung tumor.

Method:
During May 2012 through May 2017, we conducted lung resection for 272 cases. Among them 39 procedures are segmentectomy that consist of 35 lung neoplasm cases and 4 inflammatory cases. We analyze 35 lung neoplasm cases. Demography of patients are as follows, Male/Female 20/15, Age range 44-87y/o (mean 68.5), operation time was distributed 131-281 minutes (mean 182); blood loss was 1-252ml (mean 37ml). 17 cases underwent surgery without 3DCTAB and remaining 18 cases underwent surgery after 3DCTAB image reconstruction.

Result:
Operation time was 196+/-40min in non 3DCTAB group 173+/-35min in 3DCTAB group. Blood loss was 43.2+/-59.3ml in non-3DCTAB group and 31.2+/-19.8ml in 3DCTAB group. Statistically there are no significant differences between non3DCTAB group and 3DCTAB group in regards to operation time and blood loss. We conducted subgroup analysis. When S6 segmentectomy and lingulectomy were defined as basic procedures (n=17) and remaining segmentectomy procedures as complex procedures (n=18) and analyze the effect of 3DCTAB. There are still no significant differences between non3DCTAB group and 3DCTAB group in regards to operation time and blood loss.

Conclusion:
It seemed that 3DCTAB didn’t contribute to the shortening of the operation time and decrease of blood loss during surgery. However, surgeons perceive that 3DCTAB enhances the safety of surgery and leads to precision medicine.

Background:
Proper management for pulmonary metastasis (PM) after control of primary hepatocellular carcinoma (HCC) has not been established and chemoradiation therapy has been largely ineffective. We investigated clinical outcomes of pulmonary metastasectomy and risk factors for survival rates, and disease-free survival rates in HCC with PM. With propensity score matching analysis, we compared the results according to surgical approach: video-assisted thoracic surgery (VATS) versus open (thoracotomy or sternotomy) method.

Method:
136 patients (112 men) underwent pulmonary metastasectomy for isolated PM of HCC from October 1998 to December 2010 at Seoul Asan Medical Center. 86 patients were operated by VATS (VATS group) and the other 50 patients were operated by thoracotomy or sternotomy (Open group). Propensity score analysis between VATS group and Open group was utilized and matched the groups by age, sex, level of preoperative AFP, treatment method for primary HCC, and PM characteristics (number, size, location, time to interval and range of resection).

Result:
There was no operative mortality and minor complication in 10 patients (7.3%) including prolonged air-leak. During 36 month-follow-up period, 112 patients (82.4%) experienced recurrence and 102 patients (75%) died of disease progression. Matching based on propensity scores produced 50 patients in each group for analysis of survival and disease-free survival. There were no survival and disease-free survival differences between matching VATS group and Open group. Multivariate analysis revealed hepatic recurrence, preoperative level of alpha-fetoprotein, liver cirrhosis to be an independent prognostic factor for survival and disease-free survival.

Conclusion:
Pulmonary metastasectomy may prolong survival in selected patients with HCC. VATS metastasectomy provided comparable outcomes to open metastasectomy in regard to survival rate and disease-free survival rate. Liver recurrence, preoperative level of alpha-fetoprotein, liver cirrhosis were independent prognostic factors for survival and disease-free survival.

Background:
Current evidence is still weak to establish the oncologic equivalence of single port thoracoscopic approach compared to conventional multiport thoracoscopic surgery as one of minimally invasive approach for lung cancer surgery. The purpose of this study is to evaluate the midterm surgical outcomes of single port approach compared to conventional multiport approach in thoracoscopic lobectomy for lung cancer.

Method:
A total of 228 patients in propensity matched group (both 114 patients with pathologic stage I who underwent lobectomy by conventional multiport or single port VATS) were compared the operative outcomes and we analyzed midterm survival and recurrence to evaluate the feasibility of single port VATS lobectomy for lung cancer.

Result:
Both propensity matched groups showed comparable preoperative variables (age, gender, FEV~1~, and tumor size) (Table 1). The mean operation time, the number of resected lymph node, and conversion to open thoracotomy or multiport VATS in both group did not show differences (respectively, P=0.076, P=0.291, P=0.253). There was no difference in postoperative major morbidity (P=0.807) and 30-day mortality (p=0.247). The duration of chest drain was shorter in single port VATS group (p<0.001) (Table 2). The survival (P=0.258) and freedom from intrathoracic recurrence (p=0.797) for mean 32 (6-62) months follow up in patients with pathological stage I were not statistically different between groups (Fig). Figure 1



Conclusion:
Single port thoracoscopic lobectomy in lung cancer showed acceptable oncologic outcomes for midterm follow ups with oncologic equivalence compared to conventional multiport thoracoscopic lobectomy.

Background:
Video-assisted thoracoscopic surgery (VATS) is a well-recognized oncologically sound and safe surgical modality to treat appropriately selected thoracic neoplasms. It is, however, limited by 2D imaging and rigid instrumentations. Such restrictions are addressed by robotic platform offering high-definition 3D optics and angulated instrumentations with multiple degrees of movements. We incorporated this novel technology to our thoracic surgical armamentarium in June 2012 to augment our minimally invasive thoracic surgery (MITS) capability. Between 6/1/2012 and 5/30/2017, we have performed 566 robotic video-assisted thoracic surgical (R-VATS) procedures

Method:
The objective of this retrospective analysis of our prospectively maintained database is to appraise our short-term outcomes and to perform comparative analysis of our data with published results.

Result:
We performed 231 anatomic lung resections (lobectomy/segmentectomy; 98% for lung cancers) and 256 wedge lung resections (196 therapeutic/137 for lung cancers), 60 mediastinal procedures (50% for neoplasm) and 9 esophageal procedures (all benign). Regarding R-VATS anatomic lung resection, there were 8 conversions to open thoracotomy (3.4%); the 30-day morbidity and mortality for the remaining 231 cases are 25% (3% potentially life-threatening) and 0.4% (1/231). The postoperative hospital length of stay (LOS) is 3.46±2.48 (median 3.00) days. 25% patients undergoing R-VATS lobectomy/segmentectomy were ≥75 years old (79.78±3.64 (median 79.00), n=53). Comparing to those ≤75 years old (67.19±10.21 (median 68.00), n=170), older patients had a slight increase in LOS (4.46 ±3.75 (median 3.00) versus 3.15±1.83 (median 3.00), p<0.001) but similar morbidity (34% versus 24%, p=0.16). Our single institution short-term surgical outcomes including LOS, number of intrathoracic lymph node harvested, incidence of nodal upstaging (cN0 to pN1/2), 30-day perioperative mortality and morbidity compare very favorable to data reported by individual academic centers or by databases. The learning curve for robotic anatomic lung resection as judged by the duration of time spent at the console performing the complete procedure is long as it would take about 100 cases to achieve a steady-state average of 150 minutes per case.

Conclusion:
We successfully incorporate this novel technology to our current thoracic surgery practice without adversely affecting surgical outcomes of lung resections for malignancies as exempified by our short-term outcomes of R-VATS anatomic lung resections. Our own results are very comparable to those reported by other single instituitons or better than those reported by large multi-institutional database analysis. Long-term oncologic outcomes and financial impacts of adopting R-VATS are being evaluated.

Background:
Percutaneous computed tomography(CT)-guided marking is a useful method of intraoperative localization of small-sized peripheral pulmonary lesions. However, severe complications may be caused by visceral pleura puncture. Therefore, we report the safe method without visceral pleura puncture.

Method:
The subjects were from November 2016 to May 2017, 6 males and 5 females, average age 70.7 years (59-86 years), total 11 cases of 12 lesions; 6 cases on the right (1 case: 2 lesions in the same lobe) · 5 cases on the left. Before the operation, with the CT-guided , marking on the body surface near the lesion was performed. In cases where ports can be inserted at the marking section, we inserted the ports with both lung ventilation and marked directly on the lung surface. On the other hand, in case of difficult to insert, first we punctured a venous indwelling needle from the marking point and indwelled the outer tube. Second, with both lung ventilation, we inserted a infant nutrition catheter with crystal violet on the tip, and marked the lung surface. Third, we localized the lesion by palpation using marking as an index with partial lung ventilation. And finally, lung partial resection was performed.

Result:
We were able to localize the lesions in all cases, the average operation time was 80 minutes (37 to 147 minutes), and there were no complications during the perioperative period. The resected lesion had an average diameter of 8.8 mm (3 to 16 mm).

Conclusion:
Our method is considered to be quite useful and safe in intraoperative localization of small-sized peripheral pulmonary lesions.

Background:
Bronchial Atresia is a congenital anomaly of the tracheobronchial tree and often pointed out as an incidental finding on routine examinations. Bronchial atresia often complicates tumor at abnormal lung segment. However it is very difficult to obtain a diagnosis of such a tumor. Because there are no bronchi into the tumor and lung tissue occurs emphysematous changes around the tumor, we can not perform bronchoscopy and computed tomography (CT) guided lung biopsy. Thus, it is important to resect abnormal lung segment clearly. Although there are several reports about imaging findings and treatment for bronchial atresia, they often do not mention about detail surgical procedure. Here we report the case of a 24 year old man with bronchial atresia successfully treated with anatomical pulmonary resection using fluorescence navigation with indocyanine green (ICG) by video-assisted thoracic surgery (VATS).

Method:
Case: A 24 year man pointed out abnormal shadow by chest X-ray in health check. A CT scan of the chest was performed and revealed limited emphysematous changes and tumor at right lower lobe superior segment (S6). According to the previous reports, our preoperative diagnosis was bronchial atresia and proposed operation was right S6 segmentectomy. Methods: The initial part of the procedure, we confirmed pulmonary artery, vein and bronchus of S6 and cut off. ICG was then injected into the peripheral vein catheter by anesthesiologist and the thoracoscope visual system changed to fluorescence mode. Tissue with blood flow appeared green within 30 to 40 seconds after ICG injection. Although perfused lung parenchyma appeared green, the isolated segment remained uncolored.

Result:
We could remove this segment with endoscopic staplers. Pathological diagnosis of removal tumor was granuloma and not cause of obstruction. After 6 months from the operation, CT scan shows no emphysematous changes lesion in right lung.

Conclusion:
Segmentectomy using fluorescence navigation with ICG is useful procedure to resect congenital bronchial atresia.

Background:
Combined resection of lung cancer and aortic wall for T4 lung cancer is highly invasive and is a challenging procedure for thoracic surgeon. With the advent of minimally invasive endovascular therapy with thoracic endovascular stent (TEVAR) in recent years, there is a possibility that resection of the aorta may be undergone with minimally invasive approach. The aim of this study is to report the safety of simultaneous TEVAR and combined resection of aortic wall on the same day at the time of lung resection.

Method:
We started this minimal invasive procedure form 2013 with the approval of the ethics committee, treatment using TEVAR in cooperation with cardiovascular surgery upon resection of the aorta. Four cases of primary lung cancer with aortic invasion, one case of recurrent lung cancer with aortic invasion after SBRT for second primary lung cancer after left upper lobectomy. Thoracic surgeon and cardiovascular surgeon discussed on predicted tumor invasion range and resection site, stent placement position and stent length, size, surgical procedure considering safe margin. TEVAR was performed on the same day as open chest surgery in all cases. At first aortic invasion was confirmed by thoracotomy in right lateral decubitus position and, then TEVAR was performed in supine position. After TEVAR, the patient was positioned in the right lateral decubitus position again and lung resection combined aortic resection was completed.

Result:
The site of endovascular stent insertion was the aortic arch and descending aorta in two (the subclavian artery occlusion in one, the fenestration for SCA in one), the distal arch just beneath the subclavian artery in two, and descending aorta in one case. The time required to place the stent was 49 to 149 minutes, and in all cases the stent could be placed at the target position. Procedure of lung resection was upper lobectomy in two, pneumonectomy in two, completion pneumonectomy in one. The depth of aortic wall resection was adventitia in three and adventitia + media in two. TEVAR-related complication was observed in one case; external iliac artery intimal damage requiring vessel repair. There were no complications associated with aortic resection. Two postoperative complications of atrial fibrillation and chylothorax were observed but there was no surgery related death.

Conclusion:
Simultaneous TEVAR and combined resection of aortic wall on the same day at the time of lung resection is feasible. Prior to surgery, thoracic surgeon should share information with cardiovascular surgeon to make this procedure safe.

Background:
Small-sized pulmonary nodules such as ground grass nodule and metastatic nodules are difficult to identify the localization during video-assisted thoracic surgery (VATS). The authors have developed the bronchoscopic indocyanine green fluorescence (ICG-FL) marking of small-sized pulmonary nodules to localize them durging VATS. The ICG-FL marking have some advantages. Near infra-red (NIR) light has excellent tissue penetrating property so that the ICG-FL marked in the lung parenchyma can be detected from the surface of lung with ICG-FL detecting thoracoscope. Also, NIR fluorescence spectrum can be isolated from the visible color spectrum so that ICG-FL can be detected with high sensitivity regardless of the color tone of the background lung. In the current study, taking advantage of the hybrid operating room (Hybrid OR), all procedures such as navigation bronchoscopic injection of ICG, real-time image-guidance by cone beam CT, intraoperative detection of ICG-FL and VATS wedge resection were performed all at one time under general anesthesia. The purpose of the current study was the validation of the presenting procedure in terms of the accuracy of localization, the surgical invasiveness, and operation time.

Method:
The patients with sub-centimeter pulmonary nodules which were diagnosed as the indication of video-assisted wedge pulmonary resection were enrolled in the study (n=5). At Hybrid OR under general anesthesia, thin bronchoscope was inserted into the peripheral bronchus which lead to the pulmonary nodule. Virtual bronchoscopy navigation was utilized to increase the accuracy of bronchoscopy. Transbronchial aspiration cytology (TBAC) needle was inserted to peripheral bronchus adjucent to the pulmonary nodule. After confirming the location of TBAC needle by Cone beam CT, the 0.05mL of 0.025mg/mL of ICG mixed with iopamidol was injected into lung parenchyma. During VATS resection, the infra-red fluorescence spot of ICG adjucent to the pulmonary nodules were visualized by ICG-FL thoracoscopy (Pin-point, Novadaq. Canada). The successful pulmonary resection was confirmed with macro- and microscopic examination during surgery.

Result:
ICG-FL marking was successful in all 5 cases 8 lesions without any complication. All tumors were successfully excised with the sufficient surgical safety margin. No adverse events were experienced throughout the entire study.

Conclusion:
Cone-beam CT in Hybrid OR can increase the accuracy of bronchoscopic ICG-FL marking. Multimodal cone-beam CT-guided bronchoscopic ICG-FL marking is a precise method to excise the multiple, small-sized pulmonary noddules by minimally invasive thoracic surgery.

Background:
Robotic surgery is increasingly used to resect lung cancer. However costs are high. We compared costs and outcomes for robotic surgery, video-assisted thoracic surgery (VATS), and open surgery, to treat non-small-cell lung cancer (NSCLC).

Method:
We retrospectively assessed 103 consecutive patients given lobectomy or segmentectomy for clinical stage I or II NSCLC. Three surgeons could choose VATS or open, the fourth could choose between all three techniques. Between-group differences were assessed by Fisher’s exact, two-way analysis of variance, and Wilcoxon-Mann-Whitney test. P values <0.05 were considered significant.

Result:
Twenty-three patients were treated by robot, 41 by VATS, and 39 by open surgery. Age, physical status, pulmonary function, comorbidities, stage, and perioperative complications did not differ between the groups. Pathological tumor size was greater in the open than VATS and robotic groups (P=0.025). Duration of surgery was 150, 191 and 116 minutes, by robotic, VATS and open approaches, respectively (p<0001). Significantly more lymph node stations were removed (p<0.001), and median length of stay was shorter (4, 5 and 6 days, respectively; p<0.001) in the robotic than VATS and open groups. Estimated costs were 82%, 69% and 68%, respectively, of the regional health service reimbursement for robotic, VATS and open approaches.

Conclusion:
Robotic surgery for early lung cancer was associated with shorter stay and more extensive lymph node dissection than VATS and open surgery. Duration of surgery was shorter for robotic than VATS. Although the cost of robotic thoracic surgery is high, the hospital makes a profit.

Background:
Video-assisted anatomical lung resections(VATS) have been increasingly performed worldwide for lung cancer with excellent results. Nonetheless, no comparative analysis has been done in Latin America where we find a different mix of cases when compared to the US or Europe. The purpose of this study was to compare the outcomes of VATS versus open thoracotomy (OT) for anatomical lung resection in patients from the Brazilian Society of Thoracic Surgery (BSTS) database.

Method:
This study was a propensity score analysis of 728 lung cancer patients who underwent anatomic lung resections (358 thoracotomies and 370 VATS) registered in the BSTS database from its inception in August 2015 until May 2017. Pneumonectomies were excluded for analisis purposis A propensity-score model was built using the following baseline characteristics: age at surgery, gender, BMI, comorbidities, type of resection, staging. The main outcomes were mortality, complications and major cardiopulmonary complications.

Result:
Overall in hospital mortality was significant higher in OT(3.6%) in comparison to VATS(0.8%) (OD=4.75, 95%CI=1.28-17.62). Major cardiopulmonary complications were more frequent in patients who underwent OT (17.3%) in comparison to VATS (13%) (OR=1.32; 95%CI:0.85-2.05), but not significant. When analyzing all complications, both technics were similar (OD=1.08, 95%CI0.77-1.51). Figure 1



Conclusion:
In Brazil, minimally invasive surgery (VATS) for anatomic lung resections is associated with a significantly lower rate of mortality when compared to conventional thoracotomy.

Background:
Thymic carcinomas (TC) are remarkably rare aggressive tumors. Due to this, the optimal first-line regimen in patients with advanced TC has not been clarified since the previous studies included a relatively small number of TC patients. The purpose of this study was to evaluate the optimal first-line regimen in patients with advanced TC.

Method:
We conducted a retrospective study in patients with advanced TC from 2006 to 2015. The primary end point of this study was to evaluate the objective response rate (ORR) and progression free survival (PFS) of different chemotherapy regimens. Age, gender, stage (IVa or IVb), radiation therapy after chemotherapy, resection of primary lesion, different chemotherapy regimens and cycles of chemotherapy were analyzed for significance on PFS. Multivariate Cox model was used to identify significant factors.

Result:
Sixty-seven patients with stage IV (Masaoka stage) TC were enrolled. Thirty-six patients were treated with paclitaxel-platinum regimen every 3 weeks for a maximum of six cycles. Thirty-one patients were treated with gemcitabine-platinum regimen every 3 weeks for a maximum of six cycles. Resections of primary lesion were performed in fourteen patients before chemotherapy. Thirty-three out of 67 patients were given radiation therapy after chemotherapy. Multivariate analysis demonstrated that different stages (HR = 2.47, P = 0.003), surgical resection (HR = 0.32, P= 0.0049) and radiation therapy after chemotherapy (HR = 0.32, P= 0.0001) were significantly associated with PFS. The ORR were 31% (11/36) and 29% (9/31) in paclitaxel-platinum regimen group and gemcitabine-platinum regimen group (P=0.89), respectively. The median PFS, 1-/2-year PFS rates in paclitaxel-platinum regimen group were 7.0 (95% CI 4.0–8.0) months, 26%/6% respectively compared to 12 months (95% CI 11.2–24.0), 48%/24% in gemcitabine-platinum regimen group (P=0.03). The median PFS, 1-/2-year PFS rates were 18.0 (95% CI 12.0–36.0) months/7.3(95% CI 5.0–11.3) months, 57%/31% and 33%/7% for patients with and without resection of primary lesion (P = 0.0302). The median PFS, 1-/2-year PFS rates were 13.0 (95% CI 11.3–17.0) months/4.3(95% CI 3.0–7.3)months, 52%/22% and 20%/7% for patients with and without radiation after chemotherapy (P = 0.0013). Major adverse event was grade 3–4 neutropenia in both paclitaxel-platinum regimen (27.7%) and gemcitabine-platinum regimen group (12.9%). Grade 1-2 sensory neuropathy and/or muscle pain were seen in 25.0% of patients treated with paclitaxel-platinum regimen.

Conclusion:
Both gemcitabine-platinum and paclitaxel-platinum regimen showed promising efficacy in advanced TC. Resections of primary lesion and radiation after chemotherapy might be an option for selected patients.

Background:
The epithelial to mesenchymal transition (EMT) is a fundamental biological process during which epithelial cells change to a mesenchymal phenotype which has a profound impact on cancer progression. It has been proposed that increased expressions of EMT markers, loss of epithelial markers such as E-cadherin, and altered expressions of mesenchymal markers such as N-cadherin are called as cadherin switching and associated with poor prognosis in cancer case. We analyzed the expression of E-cadherin and N-cadherin in thymic cancer to determine the relationship to clinicopthological factors and prognosis.

Method:
We collected the data of 31 patients with thymic cancer from our institution between 2000 and 2014. Immunohistochemistry was used to examine the expression of EMT markers, E-cadherin and N-cadherin in tumor specimens. We evaluated the correlation between EMT and prognosis in patients with thymic cancer. We also compared expressions of the cadherins in tumor specimens obtained both before and after preoperative chemoradiotherapy or chemotherapy from 14 patients with thymic cancer who underwent preoperative biopsy in our hospital.

Result:
Eighteen patients underwent preoperative treatment. The resection was extended to the surrounding organs in addition to thymectomy including thymic tumor and anterior mediastinal lymphadenectomy. Twenty-six patients had a R0 resection. Pathological findings revealed that one patient had Masaoka stage I disease, one had II, 20 had III, one had IVa, and 8 had IVb. The histological diagnosis was squamous cell carcinoma in 24, undifferentiated carcinoma in 4, and others in 3 patients. Immunohistochemically, decreased expression of E-cadherin or upregulation of N-cadherin was detected in surgically resected specimens in 15 patients whose tumor was classified as EMT marker-positive. According to a clinicopathological comparison of these groups, EMT status was not related to preoperative therapy, Masaoka staging, or histology. The 5-year survival rate for all patients was 86 %, 63 % for EMT marker-positive, and 100 % for EMT marker-negative. The survival rate of patients with EMT marker-positive tumors was significantly lower than that of those with EMT marker-negative tumors. Decreased expression of E-cadherin or upregulation of N-cadheirn was detected in surgically resected specimens after preopetative treatment compared with biopsy specimens obtained before treatment in 10 of 14 patients.

Conclusion:
EMT marker expression such as cadherin switching was detected in thymic cancer tumor and was more often detected after preoperative treatment, indicating that EMT may affect the degree of malignant potential in thymic cancer and make them insensitive to treatment.

Background:
Our study tries to demonstrate the underlying genetic mechanisms of tumorigenesis of thymoma and understand the related features: association with myasthenia gravis, and histologic variability.

Method:
This study uses CapitalBio mRNA microarray analysis of 31 cases of thymoma (including 5 cases of type AB, 6 B1-type cases, 12 B2-type cases, 5 B2B3-type cases, 3 type- B3 cases of; only 6 cases of thymoma were not associated with myasthenia gravis, 25 cases with myasthenia gravis).

Result:
Some differentially expressed genes after comparisons between thymoma and the thymus tissue around tumor were identified preliminarily. Among them, 292 genes increased more than 2-fold, 2 genes more than 5-fold; on the other hand, 596 genes were decreased more than 2-fold, 115 genes more than 5-fold, 21 genes more than 10-fold, 6 genes more than 20-fold. Among these genes upregulated or downregulated, 6 driver genes, such as FANCI、NCAPD3、NCAPG、OXCT1、EPHA1 and MCM2, were identified. We selected 2-fold upregulated and 2-fold downregulated genes to generate a supervised clustering heat map. 6 distinct clusters were identified. In cluster 1, two were type B2 tumors; in cluster 6, three were type B2/B3 tumors. KEGG database analysis, utilized for research and education, found that the pathogenesis of thymoma might be associated with several signaling pathways, which provides important information for revealing genetic mechanisms of thymoma; By comparing with genetic differences of thymoma with myasthenia gravis and without, 4 genes （PNISR，NBPF14，PIK3IP1和RTCA）were upregulated more than 2-fold, more than 30 genes were downregulated more than 2-fold, and 2 signaling pathways with more than 2-fold upregulated genes (TGF- beta signaling pathway and HTLV-I signaling pathway)were found.Figure 1



Conclusion:
The study would be shed light on the molecular bases for selecting appropriate oncological management, predict prognosis and provide important information on the genetic background of thymoma. But Confirmation of the data will be performed using immunohistochemical and multiplex quantitative RT-PCR methods.

Background:
The optimal treatment method for thymoma with pleural dissemination remains controversial. We have performed a multimodality treatment including extrapleural pneumonectomy (EPP) for patients with stage IVa thymoma and pleural dissemination. There are few literatures investigating malignant behavior of disseminated nodules at the parietal and visceral pleura. Therefore, whether complete resection can be accomplished by EPP is not known.

Method:
Our treatment strategy for those patients was induction chemotherapy with cisplatin, doxorubicin, and methylprednisolone (CAMP therapy), followed by thymectomy combined with EPP. We pathologically investigated parietal and visceral pleural nodules obtained by EPP in 8 patients with thymoma and pleural dissemination.

Result:
The median age was 49 (31 to 60) years old. Seven patients had stage IVa disease and 1 had recurrent disease. Preoperative CAMP therapy was performed in 5 patients. Macroscopic complete resection was archived in all patients. Parietal pleural invasions by disseminated nodules were found in 6 patients, invasions to the diaphragm in 6 and visceral pleural invasions in 7. Invasions into the muscle layer of the diaphragm were discovered in 4 patients. Pathological complete resection (R0) was archived in all patients, and the 5-year recurrence free survival rate was 80.0%.

Conclusion:
EPP could be a successful complete resection and might be beneficial for patients with stage IVa thymoma and pleural dissemination. In those some patients, resection of the muscle layer of the diaphragm is needed to obtain R0.

Background:
Acquired pure red cell aplasia (PRCA) associated with thymoma is relatively rare and relevant reports are limited. The optimal treatment and expected clinical outcomes are not yet standardized.

Method:
We have experienced 8 patients with PRCA in 146 patients who underwent surgical resection of thymoma at Nagoya City University Hospital between 2004 and 2015. These patients were retrospectively reviewed.

Result:
There were 5 males and 3 females, with a mean age at PRCA diagnosis of 61 years old (range 49-80 years). One patient had a complication of myasthenia gravis. Extended thymectomy (n=4) and thymectomy (n=4) was undergone in 8 patients with thymoma. In WHO classification of thymoma, subtypes were diagnosed as A (n=1), B2 (n=5), and B3 (n=2). According to the Masaoka’s classification, stages were classified into II (n=1), III (n=2), IVa (n=3), and IVb (n=2). Complete resection was achieved macroscopically in only 4 patients. Five patients received preoperative chemotherapy using cytotoxic agents (n=1) and high-dosed steroid (n=4). Postoperative radiotherapy was given in 6 patients. Recurrence of thymoma occurred in 3 patients who underwent complete resection. Six patients were diagnosed with PRCA after surgical resection of thymoma (range 1-88 months, median 56.5 months), 2 patients before 60 months and 1month of surgical resection. Ciclosporin was used for PRCA in 6 patients with or without corticosteroid and immunosuppressive agents were not used in the other 2 patients only with occasional transfusion. As treatment-related complications of ciclosporin, pneumonia was seen in 5 patients and renal insufficiency in 1 patient of 6 patients who received it. Follow-up period ranged 9-137 months (median 49.5 months) after PRCA diagnosis. Two patients obtained complete remission of anemia by ciclosporin with and without corticosteroid. Two patients remained transfusion-dependent. Four patients have died. In one patient, ciclosporin could be stopped because of complete remission of anemia. However, re-administration of ciclosporin was needed following 6 years interruption. Main causes of the death were diagnosed as pneumonia (n=2), thymoma (n=1), and cardiac failure (n=1).

Conclusion:
PRCA associated with thymoma was diagnosed postoperatively in three quarter patients. We should pay attention to the occurrence of PRCA even after the resection of thymoma especially in patients with incomplete resection or advanced disease. Ciclosporin was effective for PRCA, but treatment-related complications occurred, particularly as pneumonia. As treatment for PRCA associated with thymoma and its complications were combined complexly, it is not easy to treat PRCA associated with thymoma.

Background:
Pleural metastases of thymic carcinoma are relatively common, and their unique growth pattern makes accurate and consistent tumor measurement difficult. To minimize intra-observer variability, The ITMIG proposed modified criteria for measurement of tumor response to nonsurgical therapies for thymic carcinoma.

Method:
We conducted a retrospective review of the medical record of advanced or recurrent thymic carcinoma patients treated with chemotherapy between 1980 and 2016 in our institution. The best objective responses were assessed and concorded using the Response Evaluation Criteria in Solid Tumor version 1.1 (RECIST 1.1) and the ITMIG modified criteria.

Result:
27 patients ----. All of 6 patients showing PR assessed by the RECIST criteria remained PR using the ITMIG criteria. Of 19 patients showing SD assessed by RECIST, 18 remained SD and 1 reclassified as PR using the ITMIG criteria. Both of 2 patients showing PD assessed by the RECIST criteria remained PD using the ITMIG criteria. The overall response rate assessed by the two methods did not differ significantly, with kappa value of 0.996.

Conclusion:
ITMIG modified criteria showed a high concordance rate with RECIST 1.1 criteria in response assessment of thymic carcinoma.

Background:
Thymic carcinoma is a rare malignant tumor. At present, cisplatin based doublet or triplet antitumor drugs are used in neo-adjuvant setting for advanced thymic carcinomas. However, no optimal chemotherapeutic regimen is well established and recent small case studies with carboplatin and paclitaxel doublet demonstrates the similar efficacy with less toxicity. We retrospectively evaluated effectiveness and toxicity of platinum based doublet chemotherapy for patients with advanced thymic carcinoma.

Method:
Between 2013 and 2016, we retrospectively identified 21 patients from hospital information system with pathologically confirmed advanced thymic carcinoma, who were treated with platinum based doublet chemotherapy followed by surgical resection. The most commonly used regimen being carboplatin plus docetaxel in 75% of the patients. Other regimens included cisplatin plus gemcitabine, carboplatin plus gemcitabine and cisplatin plus doxorubicin plus cyclophosphamide.

Result:
The clinical response rate was achieved in 61.5 % of the patients. The disease control rate was achieved in 92% of the patients. The median progression-free survival was 7.9 months (95% CI 1.3–10.0) and median overall survival was 33.8 months (95% CI 8.3–45.9). The toxicity profiles of platinum doublets demonstrated grade 3-4 hematological and non-hematological toxicities in 18% and 24% of the patients respectively. No febrile neutropenia and toxic death was recorded.

Conclusion:
We concluded that platinum doublet chemotherapy is active and tolerable for advanced thymic carcinoma in the front-line setting with regard to efficacy, toxicity, and usage in clinical setting.

Background:
Despite the fact that Thymic tumors are considered as an orphan disease, they represent the most common adult tumor in the anterior mediastinum. Most of evidence in this neoplasm comes from small, single institution reports. Moreover, the low incidence and a wide spectrum of clinical and morphological characteristics are well-known factors that difficult treatment decisions.

Method:
Single Institution, retrospective chart review of patients with resected thymoma, from January 2005 to December 2016.

Result:
We found 25 patients, with complete clinical data available for review, who underwent thymectomy for epithelial thymic neoplasm. There were 14 females (56%) and 11 males (44%), mean age 56.6 years (27 to 82 years). A total of 22 patients underwent up-front surgery and only 3 patients required neo-adjuvant treatment due to advanced disease. Trans-esternal thymectomy was the most common approach with 18 cases (72%), lateral thoracotomy in 4 cases (16%) and VATS in 3 cases (12%). A complete resection was achieved in 92% of patients. Most of cases, 15 (60%) required an extended thymectomy due to their extension, in 7 (28%) a standard thymectomy was performed,1 case (4%) required a maximal thymectomy and in 2 cases (8%) only a biopsy was performed. R0 resection was achieved in 88% (22 cases) and one patient (4%) was reported as R1 and 2 cases were R2 resections (8%). Distribution according to WHO classification was: A 12%, AB 36%, B1 8%, B2 28%, B3 8% and C 8%. Staging according to Masaoka-Koga Classification was: I 28%, IIA 16%, IIB 24%, III 8%, IVA 12% and IVB 8% Median size of thymomas was 82mm (47-140mm). Mean operative time was 194 minutes (88 – 480), mean blood loss was 362 ml (15 – 2000). Chest tube mean duration was 5.4 days, with a mean hospital stay of 6.2 days (3-18) Morbidity was 24%, but none of patients required re-intervention. Only 2 patients die in the 90 days after surgery for an 8% mortality. In 12 patients (48%) adjuvant treatment was required. Median follow-up was 11.03 months (1.8-108.5) and Median OS was 12.4 months. To date, 21 patients (84%) still alive and only 2 relapses were documented.

Conclusion:
Surgical resection stills the mainstay of treatment for thymomas. Our series comprises mostly large size thymomas requiring extended thymectomy for complete resection. Despite this fact, our perioperative and oncological results and are encouraging

Background:
Preoperative neutrophil-lymphocyte ratio (NLR), which is an inflammatory marker, has been reportedly associated with a poor prognosis in patients with various cancers. This study aimed to investigate the clinical significance of preoperative NLR in patients with surgically resected thymic epithelial tumor.

Method:
A retrospective review was conducted of 64 patients who underwent surgical resection for thymic epithelial tumor between January 2000 and April 2017. Preoperative NLR was calculated as peripheral blood neutrophil (cells/m[3]) divided by lymphocyte (cells/m[3]). Receiver operating characteristic (ROC) curve analysis was performed to identify the optimal value for NLR predicting recurrence. Univariate analysis was performed to assess the association between preoperative NLR and relevant clinicopathological variables. Recurrence-free survival (RFS) after first surgery was calculated using the Kaplan-Meier method.

Result:
The median follow-up period was 66 months. The patients were 32 men and 32 women with a median age of 60 years. The WHO classification was type A (n=10), AB (n=20), B1 (n=9), B2 (n=12), B3 (n=8), and thymic carcinoma (n=5). The patients were classified into two groups according to preoperative NLR: high NLR (≥2.1, n=29) and low NLR (<2.1, n=35) group. Univariate analysis showed that aggressive histology (B2/B3 and thymic carcinoma) and a lower incidence of myasthenia gravis were significantly correlated with high NLR. The RFS rate of the high NLR group was significantly poorer than that of the low NLR group (5- and 10-year RFS rates: 82.6% vs 93.2% and 48.3% vs 93.2%, p=0.034).Figure 1



Conclusion:
Preoperative high NLR value was significantly associated with aggressive histology (type B2/B3 thymoma and thymic carcinoma) and a lower incidence of myasthenia gravis. Preoperative high NLR could be a predictorof poor outcome in patients undergoing surgical resection of thymic epithelial tumor.

Background:
Preoperative diagnosis of anterior mediastinal tumor has been depending on the radiographic findings and clinical findings. We investigated the diagnostic value of serum tumor markers in patients with anterior mediastinal tumor.

Method:
Consecutive anterior mediastinal tumor patients referred to our hospital who had examined either of the serum tumor markers (CEA, SCC, CYFRA 21-1) preoperatively and underwent radical surgery or surgical biopsy between January 1999 and February 2016 were retrospectively reviewed.

Result:
One hundred eighteen patients were eligible, including 16 thymic carcinomas, 48 thymomas, 11 lymphomas, 13 mature teratomas, 7 other malignant tumors, 23 other benign legions. Preoperative serum CYFRA 21-1 was significantly higher in thymic carcinoma group (median = 2.4 ng/ml) than other anterior mediastinal tumor group (median = 1.1 ng/ml, p = 0.0005), whereas CEA (median 2.0 vs 2.1) and SCC (median 0.7 vs 0.8) showed no significant difference. The ROC curves identified an optimal serum CYFRA 21-1 cut off value of 1.65 ng/ml for predicting the diagnosis of thymic carcinoma (AUC = 0.80; sensitivity = 76.9%, specificity = 79.3%; P = 0.046). Pre- and post operative serum CYFRA 21-1 were measured in 6 patients who underwent radical resection. All those patients showed decrease of serum CYFRA 21-1 after resection.

Conclusion:
To measure serum CYFRA 21-1 may help the diagnosis of thymic carcinoma. The level of CYFRA 21-1 reflected the condition of the tumor in each patients. The optimal serum CYFRA 21-1 cut off value for predicting the diagnosis of thymic carcinoma was 1.65 ng/ml.

Background:
Thymoma and thymic carcinoma are rare thymic epithelial tumours. This study investigated the efficacy of first-line gemcitabine and cisplatin combination chemotherapy in advanced thymoma and thymic carcinoma.

Method:
Retrospective review of patients with histologically-confirmed invasive, metastatic thymoma or thymic carcinoma treated with gemcitabine plus cisplatin as a first-line therapy between August 2008 and July 2016 at the Department of Respiratory Medicine II Peking University Cancer Hospital and Institute. The objective response rate was the primary end point.

Result:
Forty patients, 14 with thymoma and 26 with thymic carcinoma, were identified. 19 received gemcitabine and cisplatin combined with Endostar (injectable recombinant human Endostatin); 21 received gemcitabine and cisplatin only. Of the 14 patients with thymoma, five (35.7%) achieved a partial response (PR) and nine (64.3%) had stable disease (SD); no patients had a complete response (CR) or progressive disease (PD). Among the 26 patients with thymic carcinoma, 14 (53.8%) achieved a PR, 12 (46.2%) had SD; no patients had a CR or PD. In thymic carcinoma, median progression free survival (PFS) was 16 months and median survival (OS) was 41 months; in thymoma, median PFS was 29 months and median OS was 68 months. In chemotherapy combined Endostar group, median PFS was 25 months and median OS was 68 months. In chemotherapy only group, median PFS was 18 months and median OS was 31 months. But PFS and OS were not significantly different between chemotherapy combined Endostar and chemotherapy only (P = 0.931, P = 0.184; respectively).Figure 1



Conclusion:
This retrospective analysis indicates gemcitabine plus cisplatin has moderate efficacy and could represent a suitable first-line therapy for thymic carcinoma and thymoma, especially for patents who cannot tolerate anthracyclines.Chemotherapy combined with anti-vascular drug Endostar may improve the OS of patients with thymic carcinoma or thymoma, but more patients need to be included in the study.

Background:
Thymic epithelial neoplasms (TN), thymoma and thymic carcinoma are a rare heterogeneous category of lesions with a broad spectrum of pathologic characteristics and clinical presentations. The histologic classification and staging are complex and controversial; however they remain the most important prognostic factors to consider. Complete radical surgical resection remains the gold standard of therapy. Radiation and chemotherapy are important elements of the multimodality approach. The objective of this study is to describe demographic variables, staging, performed treatment and overall survival (OS) of patients diagnosed with TN followed in our institution, in the last 13 years.

Method:
Retrospective analysis of medical records of patients diagnosed with TN, followed in our cancer Institute from January 2004 to February 2017.

Result:
We followed 43 patients (22 female, and 21 male) with TN diagnose, 3 thymic carcinoma (1 squamous cell carcinoma) and 40 thymoma. The average age at diagnose was 52 years (min 22, max 84). 79% were symptomatic at diagnosis (45% with respiratory symptoms, no differences found for early and advanced stage). In 18,6%, the TN was associated with paraneoplastic autoimmune syndrome (7 pts Miastenia Gravis, 1 pt pure red cell aplasia). The most frequent performance status (ECOG scale) at diagnosis was 0 (41,8%) and 1 (48,8%). The majority of pts (60.4%) were at Masaoka stage I and II (13 pts each group). 6.9% stage III, 11.6% ( 5 pts) stage IVA and 20.9% (9 pts) stage IVB. Regarding to the OMS Classification, 27.9% were type AB, 16.3% type B1 and 11.6% type B2/B3. 81.4% of the patients were treated with surgery. 23.3% (10 pts) received chemotherapy (3 pts preoperative). 39.5% (17 pts) received adjuvant radiotherapy, and 7% pts received palliative radiotherapy. Overall survival (OS) at 5 years is 81%; at 10 years is 66%. The median survival time was 16,36 years (IC95%: 8,716 - 24,007). Disease progression was documented in 8 pts, with a median time to progression of 5,8 months. Median survival wasn’t reached for stage I, and for stage II, III, IVa, IVb was, respectively: 9,9 years, 5,76 years, 0,9 years and 6,4 years.

Conclusion:
In this retrospective study, we found an important percentage of pts symptomatic at diagnose, almost 20% with paraneoplastic syndromes, but with a good performance status. As expected most (86%) were treated with surgery, but many with a multimodal approach (46,5%). Prognosis is good even in stage IV disease.

Background:
Thymic cancer is one of the aggressive thoracic malignancies. Chemotherapy, radiation therapy, and surgery are the main therapeutic options. However, no standard therapy has not been established because of the rarity, and the mortality rate remains high. Therefore, additional therapeutic options are needed. Recently, cancer immunotherapy has been developed and shown promising results against some malignancies in clinical trials. One of the immuno-check point proteins; the programmed cell death 1/ Programmed cell death 1-Ligand 1 (PD-1/PD-L1) pathways play one of the main role in cancer immunology. The expression of PD-L1 in cancer cells and PD-1 positive tumor infiltrating lymphocytes (TIL) are reportedly one of the useful prognostic and predictive factor for the therapeutic effect of anti-PD-1 or anti-PD-L1 immunotherapies in several malignancies. However, clinical significance of PD-1 and PD-L1 in thymic cancer remains unclear. In this present study, we retrospectively investigated the relationships between the expression of PD/1PD-L1 and clinical backgrounds in thymic cancer.

Method:
A total of 30 patients of thymic cancer surgically resected from 1998 to 2016 in our institutes were retrospectively analyzed. Median follow up periods was 4.2 years. The expression of PD-L1 and PD-1positve TIL was evaluated by immunohistochemical staining using formalin-fixed paraffin embedded surgically resected tissues and analyzed the relationships between those expressions and clinical backgrounds. A Pearson's chi-square test was used to compare the variances. Disease-free survival (DFS) were analyzed by using the Kaplan–Meier method, and the Log-rank test was used to compare the survival distributions of subgroup.

Result:
14 cases were positive in immunohistochemistry staining of PD-L1 (47%). While, 16 cases were positive in PD-1 TIL staining (55%). There were no significant relationships between PD-1/PD-L1 positive staining and Masaoka-Koga stage. In tumor size, age and gender, there were also no significant difference among IHC results of PD-1/PD-L1. While, in disease free survival rate (DFS), the PD-1 and PD-L1-positive cases were significantly worse as compared to negative cases (PD-1; P=0.001, PD-L1; P=0.03). Uni- and multivariant analysis showed the PD-1 and PD-L1 expression were independent prognostic factors (P < 0.05).

Conclusion:
Our results suggested that the high PD-L1 expression and the PD-1 positive TIL are indicators of poor prognosis, and anti PD-1/PD-L1 immunotherapy may be reliable option to treatment in thymic cancer.

Background:
Advanced unresectable thymic epithelial tumors (TETs) are usually treated with platinum-based chemotherapy, although no randomized trials have been conducted and no clear recommendation on the regimens choice are available. Actually, the modern scenario of TETs treatment has become more complex after the introduction of biological agents, but no clear evidences on the more effective sequence treatment between chemotherapy and target therapy have been stated. Here we investigate the effectiveness of platinum rechallenge in advanced TETs.

Method:
All the clinical data of patients with advanced/unresectable or metastatic TETs, treated with first line platinum-based chemotherapy at our institution during a 10-year period were retrospectively reviewed, and those who received platinum rechallenge from the third line and beyond, were included in this study. Patients characteristics, disease control rate (DCR), overall survival (OS), progression free survival (PFS) and post-rechallenge (P-Re) OS and PFS were analysed.

Result:
Platinum rechallenge was administered in 22 patients, of whom 17 had thymoma and 5 thymic carcinoma. A DCR of 95.4% (stable disease (SD) 63.6%, partial response (PR) 31.8%) was achieved after the first line platinum-based chemotherapy according to RECIST criteria, while a DCR of 81.8% (SD 63.6%, PR 18.1%) was registered after platinum rechallenge. All the responders to first line, were confirmed as responders also to rechallenge, only 3 patients with stable disease to first line, had a progressive disease after rechallenge. The median OS of 122 months was statistically correlated with histotype (p=0.015) and with the median treatment free interval (TFI) of 18 months (p=0.019). No statistical correlation has been found between the median P-Re OS of 27 months, the histotype and the TFI. To point out that a statistical correlation between the P-Re PFS of 7 months and the administration of target therapy before rechallenge, has been observed (p=0.04).

Conclusion:
Our retrospective analysis showed that platinum rechallenge may be considered a suitable treatment for advanced, heavily pretreated TETs, especially in case of previous response and longer TFI. Moreover, in the light of our results, we assume, as already stated for other solid tumors, that the chemo-resistant clones can be re-sensitized to platinum by target agents. Prospective trials are needed.

Background:
The effectiveness of long acting octreotide and prednisone has been already observed in some cases of advanced, heavily pretreated thymic epithelial tumors (TETs) and confirmed in small phase II study with an overall response rate of about 30-38%. Based on these reports, here we investigate the outcome of patients treated with LAR octreotide and prednisone in a real life clinical experience.

Method:
All the patients with advanced and heavily pretreated TETs, who received LAR octreotide and prednisone from January 2007 to January 2017, were included in this monocentric, retrospective analysis. As for local practice, all the patients performed OctreoScan and the treatment schedule consisted of administration of LAR octreotide (30 mg/every 28 days intramuscularly) plus prednisone 0.2 mg/kg/day until documented progressive disease. Patients characteristics, survival outcome, overall response rate and toxicity were evaluated.

Result:
26 patients (12 males and 14 females) were included in the study. The median overall survival was 88 months, which statistically correlates with histotype (thymoma vs thymic carcinoma) (p=0.0006), but no with stage disease (Masaoka-Koga IVA vs IVB) (p=0.21). The median progression free survival of 21 months, statistically correlates with stage disease (p=0.008); age at diagnosis (p=0.04) and previous surgery (p=0.04). No correlation has been found with histotype (p=0.12) and line of therapy (third vs beyond) (p=0.50). In the whole population, an overall response rate of 42% was achieved and only 2 patients, both with thymic carcinoma, showed a progressive disease. Treatment was safe and no severe side effects were registered.

Conclusion:
Our clinical real life data confirm that somatostatin analogs plus prednisone is an effective and safe treatment in advanced, heavily pretreated TETs and, despite the new available therapy options, it may be still considered in the therapeutic algorithm for obtaining a prolonged control disease.

Background:
Thymic epithelial tumors (TET) are rare neoplasms with inconsistent treatment strategies. When researching for molecular pathways to find new therapies, the correlation between specific molecular markers and outcome has been rarely investigated. The aim of this study was to investigate the correlation between survival, metastatic potential and invasiveness of aggressive subtypes of TET and immunohistochemical markers.

Method:
We performed retrospective analysis on patients with WHO type B2/B3 mixed type thymoma (MT), thymoma type B3 (B3) and thymic carcinoma (TC) who underwent surgery from 1998 to 2013. Overall survival (OS), disease-free survival (DFS), progression-free survival (PFS) and metastasis-free survival (MFS) were examined. Tumor specimens were stained using a tissue microarray (TMA) (CD117, CD5, p63, p40, p21, p27, p53, Bcl-2, Ki67, podoplanin, synaptophysin, PTEN and Pax8). Invasive behavior of primary tumors and the presence of extrathoracic metastases were assessed.

Result:
In 23 patients included into this study (four MT, ten B3, nine TC), we found (I) p21 expression in the cytoplasm significantly correlated with a decrease of OS (P=0.016), PFS (P=0.034) and MFS (P=0.005); (II) MFS was significantly shorter when the combination of p21-low p27-low p53-high was present (P=0.029); and (III) nuclear p27 (P=0.042), Ki-67 (P=0.024) and podoplanin (P=0.05) expression correlated with the presence of extrathoracic metastases.

Conclusion:
The main finding of this study is that cytoplasmic p21 expression negatively influences the outcome of malignant TETs and correlates with metastatic activity. Additionally, selected immunohistochemical markers correlate with the distant metastatic potential of TETs. These results may contribute to the stratification of diagnosis and improvement of treatment strategies for thymic malignancies. ​

Background:
It is difficult to diagnose the tumor in the anterior mediastinum by computed tomography. Distinguishing between thymic epithelial tumors and malignant lymphoma is important, because therapeutic strategy is difficult in each disease. The objective of this study was to clarify the usefulness of positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) for distinguishing thymic epithelial tumors and malignant lymphoma.

Method:
We retrospectively reviewed FDG PET-CT scans of 62 patients pathologically diagnosed by surgery or biopsy as thymic epithelial tumors or malignant lymphoma. FDG uptake was measured as the maximum standard uptake value (SUVmax). Student t tests were used to assess association between SUVmax and pathological diagnosis.

Result:
Among the 62 patients, 36 patients had a pathological diagnosis of thymoma: WHO classification type A in 3 patients (11%), type AB in 9 patients (19%), type B1 in 6 patients (19%), type B2 in 15 patients (42%), and type B3 in 3 patients (7%). Eleven patients had the thymic carcinoma. Fifteen patients had the malignant lymphoma. The SUVmax in malignant lymphoma (14.9 ± 6.4) was significantly higher than that in the thymic epithelial tumors (5.1 ± 2.5) (p＜0.001). The SUVmax in thymic carcinoma (7.8 ± 　3.2) was higher than that in the thymoma (4.0 ± 1.5) (p=0.002). The ROC curve of SUVmax for predicting malignant lymphoma indicated that the optimal cutoff value　was 7.3. This value had a sensitivity of 0.89 and a specificity of 0.87

Conclusion:
FDG PET-CT is helpful for distinguishing malignant lymphoma from thymic epithelial tumors with cut off value of 7.3.

Background:
Thymectomy has been a mainstay in the treatment of myasthenia gravis. However, the situation of ectopic thymic tissues remains unknown .The aim of this study was to investigate the distribution of ectopic thymic tissue in Chinese patients using flow cytometry (FCM).

Method:
The resected tissues from 54 patients with MG was divided and classified into: right pericardiacophrenic angle (Number 1), left pericardiacophrenic angle (2), peritracheal (3), right phrenic nerve (4), left phrenic nerve (5), superficial cervical (6) and deep cervical (7). Cells were then stained with anti-CD4, anti-CD8, anti-CD3, anti-TCRvβ, anti-CD56, anti-CD20, anti-CD14,anti-CD11b and labelled with live/dead for analyzing by BD LSRFortessa.

Result:
Ectopic thymic tissue incidence in individual locations was as follows: 47.8% (22 in 46)right pericardiacophrenic angle, 39.5% (15 in 38) left pericardiacophrenic angle, 57.6% (19 out of 33) peritracheal, 83.3% (5 in 6) right phrenic nerve, 57.1% (4 out of 7) left phrenic nerve, 100% (4 specimens) superficial adipose and 100% (8 specimens) deep neck adipose (Fig 2). Figure 1Figure 2





Conclusion:
Our study indicated that the incidence of ectopic thymic tissues was more frequently than former acknowledge by HE staining test.

Background:
B7-H3 (CD276) belongs to the B7 immunoregulatory family that includes PD-L1. Its expression is associated with poor overall survival (OS) in a range of solid tumours but its expression in TETs is unknown. Phase II clinical trials with anti-PD-1 inhibitors are on-going and exhibit good efficacy although they are often complicated by severe autoimmune toxicities. We measured the levels of B7-H3 in TETs and associated them with PD-L1 levels, OS and GTF2I status.

Method:
TMA sections from each of 125 TET FFPEs and 18 thymic hyperplasias were stained separately with antibodies to PD-L1 (clone 28-8, Abcam) and B7-H3/ CD276 (clone 6A1, Abcam). CD45 and cytokeratin (MF116) stains were used to differentiate epithelia and lymphocytes. All sections were scored with an H-score, giving a final score range of 0-300. For each antibody scores for each TET subtype were compared to each other with the Mann-Whitney test. Positive staining was defined as any staining above 0. Associations between the antibody scores and clinicopathological variables were determined.

Result:
The histological breakdown of analyzed samples was 17 A, 4 MNT LS, 30 AB, 25 B1, 26 B2, 5 B3, 10 CA, 8 NETT and 18 hyperplasias. B7-H3 protein was detected in the epithelia of 110 of 125 TETs (88%) and in 15 of 17 hyperplasias (88%) (Subtype breakdown in Diagram 1). No link between OS and GTF2I mutations status (previously described) was found. B7-H3 and PD-L1 were co-expressed in 94 of 125 TETs (75%). Only 2 B1 TETs were negative for both. Figure 1



Conclusion:
B7-H3 protein is expressed in the large majority of TETs, being highest in A and AB thymomas followed by squamous and neuroendocrine carcinomas. Trials with anti-B7-H3 monoclonal antibodies are already underway and given these findings, patients with TETs are likely to be good subjects for these trials.

Background:
Thymic malignancies are rare thoracic tumors for which pathological diagnosis is complex due to multiple subtypes and variations in interobserver reproducibility. In this study, we aimed at analysing the consistency between initial diagnosis in the largest thoracic oncology center in Estonia, and one of the expert center for thymic pathology in France.

Method:
Hospital electronic database and pathology databases from the Tallinn North Estonia Medical Centre were searched for thymic and mediastinal tumors from 2010 to 2017. Pathology specimens were referred to the Pathology Department of the Lyon University hospital.

Result:
Figure 1 55 tissue specimens from 49 patients were included (Table 1). The quality of pathology reports was assessed, with tumor size, diagnosis, and invasion mentioned in ≥80% of cases, while resection status and staging were assessed in 52% and 31% of cases, respectively. The initial diagnosis was consistent with that of the review in 60% of cases. Minor discrepancies - regarding thymoma subtype - were observed in 20% of cases. Three patients had normal thymus according to the reference centre, whereas thymoma B1 or B2 had been diagnosed locally, including one patient with severe myasthenia gravis. Three patients had implications for treatment due to the major differences in pathohistological diagnoses.



Conclusion:
Implementing structured pathology reports may help to decrease discrepancies in the diagnosis of thymic malignancies. The development of expert networks is an opportunity in this setting.

Background:
Malignant thymomas are uncommon tumours. The optimal therapy after subtotal resection is controversial. Adjuvant therapy using chemotherapy and/or radiotherapy brings contradictory results and this treatment can be limited by escalation of acute and late toxicity.

Method:
Between 1994 and 2016 we assessed a total of 39 patients. All patients underwent subtotal resection. Sixteen patients (41%) were treated with the standard adjuvant radiotherapy (RT) only (group A). Twenty-three patients (59%) were treated with the sequence of chemotherapy (CT) and conformal radiotherapy (3D-CRT), (group B). The CT regimens consisted of doxorubicin + cisplatin + cyclophosphamide ± vincristine. The doses of 3D-CRT ranged 50 - 60 Gy. Acute toxicities (acute eosophagitis-AE, radiation pneumonitis-RP) and late toxicities (lung fibrosis-LF, heart failure-HF) were classified according to CTC v 3.0. The manifestations of RP were softened by oxygenotherapy, antibiotics, corticosteroids and pentoxifylline (PTX). Pentoxifylline (400 mg) was administered orally tid in patients with severe manifestation of RP grade 3/4.

Result:
The median age at the time of diagnosis was 54 (38–75) years. By Masaoka staging system, 9 patients were stage II (23%) and 30 stage III (77%). The number of CT regimens ranged 4 - 8 cycles. The median 3D-CRT dose was 57.6 Gy (43.2–66.6 Gy). AE grade 1/2 was observed in 1 (6%) and 5 (21%) patients and grade 3/4 in 2 (13%) and 7 (30%) patients in groups A vs B. RP grade 1/2 was observed in 5 (31%) and 11 (48%) patients in groups A and B, respectively. RP of grade 3/4 was observed in 2 (13%) and 10 (43%) patients in groups A vs B. Median time to recover RP grade 3/4 was 4.9 months in patients without PTX vs 2.7 months in patients using PTX. Radiographic changes of partial LF were observed in 3 (19%) and 10 (43%) patients in groups A and B, respectively. HF was diagnosed only in one patient (4%) in group B. The median time to tumor progression was 51 months in group B vs 21 months in group A (p=0.0001). Five-year survival rates were 43.7% (7/16) and 78.2% (18/23) in group A vs group B, respectively (p=0.0001).

Conclusion:
Intensive adjuvant chemotherapy and radioterapy after subtotal resection leads to an improvement of the local control of this disease. Acute eosophagitis and radiation pneumonitis were not too serious. Radiation pneumonitis could be beneficially reduced by application of pentoxifylline. Manifestation of late toxicities, predominantly lung fibrosis and heart failure, was acceptable.

Abstract:
Introduction The new tumor, node and metastasis (TNM) classification of lung cancer –the 8[th] edition– has already been discussed in the two previous World Conferences of Lung Cancer. (J Thorac Oncol 2015; 10 (Supp 2): s69; J Thorac Oncol 2017; 12 (Supp 1): s2-s3.) The purpose of this educational session is to revise the innovations of the 8[th] edition, to point out its lights and shadows, and to highlight how they can affect our clinical practice. The innovations introduced in the 8[th] edition were based on sound statistical analyses of 70,189 patients with non-small cell lung cancer and 6,189 with small cell lung cancer diagnosed from 1999 to 2010. (1) Although a large number of patients was registered in the International Association for the Study of Lung Cancer database, data originated mainly from Asia and Europe and the other geographic regions of the world were scarcely represented. The innovations are applicable to both types of carcinomas (2) and also to bronchopulmonary carcinoids. (3) Rules to classify lung cancers with multiple lesions were provided based on data where data were available or on multidisciplinary consensus. (4) Primary tumor (T component) New T categories were introduced based on tumor size: T1a 1-2cm, T1c >2-3cm, T2a >3-4cm, T2b >4-5cm, T3 >5-7cm and T4 >7cm. In addition, endobronchial location less than 2 cm from the carina and total atelectasis /pneumonitis were reclassified as T2, while invasion of the diaphragm was reclassified as T4 and invasion of the mediastinal pleural was deleted as a T descriptor. The definition of visceral pleural invasion proposed for the 7[th] edition, i.e., the invasion of its elastic layer, was confirmed for the 8[th] edition and the recommendation to use elastic stains was reinforced. (5, 6) Codes for adenocarcinoma in situ –Tis(AIS) – and minimally invasive adenocarcinoma –T1mi– were defined, too. (7) Because tumor size has more prognostic relevance, its measurement must be as accurate as possible. The recommendation is to measure it on computed tomography with the lung window, because the mediastinal window may underestimate it. The registered size should be the greatest dimension in any of the available projections: axial, coronal or saggital. For part-solid non-mucinous adenocarcinomas, only does the size of the solid part on computed tomography at clinical staging or the size of the invasive part at pathologic examination count to assign a T category based on tumor size. (7) Nodal involvement (N component) The present N categories (NX, N0, N1, N2 and N3) and their descriptors remain unchanged. An important confirmation in the analyses of survival was that quantification of nodal disease at pathologic staging impacts prognosis: the more involved nodal stations, the worse the prognosis. (8) Therefore, identifying the number of involved nodal stations is important both at clinical and pathologic staging, although it is difficult to determine them accurately at clinical staging unless a lymphadenectomy is performed at the time of mediastinoscopy. The proposed subclassification of the N categories for prospective testing are: N1a – involvement of a single N1 station; N1b – involvement of multiple N1 stations; N2a1 – involvement of a single N2 station without N1; N2a2 – involvement of a single N2 station with N1; and N2b – involvement of multiple N2 stations. N1b and N2a1 have similar prognosis. Metastatic disease (M component) Intrathoracic metastases (M1a: malignant pleural and pericardial effusions and/or nodules, and contralateral separate tumor nodules) remain the same. Extrathoracic metastases were divided into single extrathoracic metastasis (the redefined M1b category) and multiple extrathoracic metastases in one or in several organs (the new M1c category). (9) These innovations imply that counting the number of metastases is important, at least from the prognostic point of view, but also from the therapeutic, because single extrathoracic metastasis can be the base to define oligometastatic disease, the treatment of which is aimed to be radical, with whatever therapeutic means are available, instead of palliative, as it usually is the case with polymetastatic disease. Stage grouping More stages have been created to accommodate the new T1 (T1a N0 M0 is stage IA1, T1b N0 M0 is stage IA2 and T1c N0 M0 is stage IA3) categories; to isolate locally advanced tumors (T3-T4 N3 M0 are now stage IIIC); or to separate metastatic disease (M1a and M1b are stage IVA and M1c is stage IVB). (10) Some tumors have shifted their positions. Tumors that are stage shifters should be treated according to evidence and not according to the treatment for those stages in which they now are based on prognosis, because a mere change in taxonomy does not imply a change in treatment. Clinical judgment in the multidisciplinary team discussions should led to the best therapeutic option for these patients whose tumors have moved from one stage to another. Conclusion The 8[th] edition facilitates the indication of prognosis and the stratification of tumors in future clinical trial, but requires more discipline from us when measuring tumor size, quantifying nodal disease and determining the number of extrathoracic metastasis. References 1. Rami-Porta R, Bolejack V, Giroux DJ et al. J Thorac Oncol 2014; 9: 1618-1624. 2. Nicholson AG, Chansky K, Crowley J et al. J Thorac Oncol 2016; 11: 300-311. 3. Travis WD, Giroux DJ, Chansky K, et al. J Thorac Oncol 2008; 3: 1213-1223. 4. Detterbeck FC, Nicholson AG, Franklin WA et al. J Thorac Oncol 2016; 11: 539-650. 5.Travis WD, Brombilla E, Rami-Porta R et al. J Thorac Oncol 2008; 3: 1384-1390. 6. Rami-Porta R, Bolejack V, Crowley J et al. J Thorac Oncol 2015; 10: 990-1003. 7. Travis WD, Asamura H, Bankier A et al. J Thorac Oncol 2016; 11: 1204-1223. 8. Asamura H, Chansky K, Crowley J et al. J Thorac Oncol 2015; 10: 1675-1684. 9. Eberhardt WEE, Mitchell A, Crowley J et al. J Thorac Oncol 2015; 10: 1515-1522. 10. Goldstraw P, Chansky K, Crowley J et al. J Thorac Oncol 2016; 11: 39-51.

Abstract:
The 2015 WHO Classification had a major impact on the new 8[th] Edition TNM Classification. Compared to the 2004 Classification, major changes include: 1) use of immunohistochemistry throughout; 2) New emphasis on genetic studies and personalized therapeutic strategies; 3) A new classification of lung cancer in small biopsy and cytology samples; 4) adoption of the 2011 IASLC/ATS/ERS lung adenocarcinoma classification; 5) reclassification of large cell carcinoma based upon immunohistochemistry and genetics. Since publication of the 2015 WHO Classification new advances include recognition of ciliated muconodular papillary tumors, SMARCA4 and SMARCB1 deficient neoplasms and digital image analysis as a novel way to assess lung cancer morphology. This presentation will primarily focus on the impact of the new WHO Classification on the 8[th] Edition TNM classification. First the new TNM classification incorporates the introduction of the concepts of adenocarcinoma in situ (AIS) which should be staged as Tis (AIS) and minimally invasive adenocarcinoma (MIA) which should be staged as T1mi. AIS is defined as a lung adenocarcinoma with pure lepidic growth measuring ≤3 cm. MIA is defined as a ≤3 cm lepidic predominant adenocarcinoma with an invasive component measuring 0.5 cm or less. Both AIS and MIA should lack stromal, vascular, or pleural invasion and spread through alveolar space invasion (STAS). Lepidic predominant adenocarcinomas are lung adenocarcinomas with a predominant lepidic component that measure > 3 cm in total size or that have an invasive component measuring >0.5 cm. It is recommended to use invasive size for T-descriptor size in nonmucinous adenocarcinomas with a lepidic component. This is in keeping with a recommendation made in three editions of the UICC TNM Supplement since 2003. It is also supported by a growing amount of evidence showing that invasive size is a better predictor of survival than total size in nonmucinous adenocarcinomas with a lepidic component. Both radiologists and pathologists should report the greatest dimension for tumor size for both clinical and pathologic staging. In addition for nonmucinous lung adenocarcinomas, both the total size and invasive size should be reported with invasive size used for T-factor size determination. By computed tomography (CT) in nonmucinous lung adenocarcinomas, the presence of ground glass versus solid opacities generally correspond to lepidic versus invasive patterns respectively seen pathologically. Since, this is not an absolute correlation, when CT features suggest nonmucinous AIS, MIA and LPA, reporting of the suspected diagnosis and clinical staging, should be made as a preliminary assessment that may need to be revised after evaluation of resected specimens pathologically. Since the mucinous variants of AIS, MIA and invasive mucinous adenocarcinomas usually present by CT as a solid or consolidated nodule, and due to the lack of proven correlation between ground glass/solid CT appearance with lepidic/invasive growth pathologically it is not recommended to apply the total vs solid size assessment by CT in suspected invasive mucinous adenocarcinomas. Furthermore there is insufficient data in invasive mucinous adenocarcinomas that invasive size is a better predictor of survival than total size. Pathologic assessment of total vs invasive tumor size in resected nonmucinous lung adenocarcinomas with a lepidic component can be improved by reviewing CT scans because the lepidic component is often poorly appreciated pathologically on gross exam and size is underestimated. In addition, tumor size can be more accurately assessed after radiologic pathologic correlation in the following settings: 1) Lepidic nonmucinous adenocarcinomas that do not fit onto a single slide, 2) Sausage or bilobed shaped tumors where the maximum single diameter may be better assessed using all three CT views (axial, coronal and sagittal) rather than just axial alone, 3) Tumors removed in multiple parts, 4) Intraoperative defects in tumors, 5) Marked non-neoplastic reactions, 6) Mistaken pathologic assessment. In neoadjuvant tumors, it can be difficult to measure tumor size because tumors that show considerable treatment effect often do not have a uniform response allowing a single focus of viable tumor to be measured. It has been shown that 90% or more treatment effect is the most important prognostic finding instead of tumor size in surgically resected nonsmall cell lung cancer patients following induction therapy. One way to estimate viable tumor size is to multiply the percent of viable tumor cells times the size of the total tumor bed. This can be utilized in the setting of a single focus or multiple foci of viable tumor. Recording the percentage of treatment effect is important in addition to estimating tumor size for T-factor determination. REFERENCES 1. Travis WD, et al The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification. JThoracic Oncol 2011;6:244-85. 2. Travis WD, et al WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: International Agency for Research on Cancer; 2015. 3. Travis WD, 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 Thorac Oncol 2016;11:1204-23. 4. Tsutani Y, et al Prognostic significance of using solid versus whole tumor size on high-resolution computed tomography for predicting pathologic malignant grade of tumors in clinical stage IA lung adenocarcinoma. JThoracCardiovascSurg 2012;143:607-12. 5. Maeyashiki T, et al The size of consolidation on thin-section computed tomography is a better predictor of survival than the maximum tumour dimension in resectable lung cancer. Eur J Cardiothorac Surg 2013;43:915-8. 6. Yoshida A, et al Clinicopathological and molecular characterization of SMARCA4-deficient thoracic sarcomas with comparison to potentially related entities. Modern pathology : 2017;30:797-809. 7. Luo X, et al Comprehensive Computational Pathological Image Analysis Predicts Lung Cancer Prognosis. J Thorac Oncol 2016;12:501-9. 8. Kamata T, et al . Ciliated Muconodular Papillary Tumors of the Lung: A Clinicopathologic Analysis of 10 Cases. The American journal of surgical pathology 2015;39:753-60. 9. MacMahon H, et al Guidelines for Management of Incidental Pulmonary Nodules Detected on CT Images: From the Fleischner Society 2017. Radiology 2017;284:228-43. 10. Kamata T, et al. Frequent BRAF or EGFR Mutations in Ciliated Muconodular Papillary Tumors of the Lung. J Thorac Oncol 2016;11:261-5.

Abstract not provided

Abstract:
Multiple tumor nodules arising in the lungs can be due either to separate primary lung cancers (SPLCs) or intrapulmonary metastases (IPM) (separate tumor nodules). The recently revised Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC) staging manuals (8th editions), based on proposals from work undertaken by the IASLC Staging and Prognostic Factors Committee (SPFC), include updates in T, N and M components, that reflect increased interest in staging of patients with multiple tumor nodules (1-4) due to increased frequency of presentation (1) and advances in classification of tumor subtypes (5). T categories for multiple tumor nodules are unchanged when compared to the 7[th] edition, with SPLCs continuing to be staged individually, with the recommendation that multiple lesions be grouped with the number of lesions in brackets (e.g. (2)), or (m) for multiple. Patients with IPM are staged as T3 (same lobe), T4 (different lobe in ipsilateral lung) and M1a (contralateral lung). However, although unchanged, these categories have been impacted by changes in the histologic classification of lung cancer (6), in particular adenocarcinomas (7). For the current edition, those tumors that present with multiple areas of pneumonic consolidation, these frequently corresponding to invasive mucinous adenocarcinomas, are viewed as a potential subgroup of IPM. There is also increased interest in those patients who present with multiple ground glass lesions, these typically corresponding to patients with non-mucinous adenocarcinomas with a lepidic component. These types of multiple tumor nodules are currently viewed as a potential subgroup of SPLCs. It is hoped that the next decade will see further research from within the lung cancer community that informs the 9[th] edition in relation to the staging of these types of tumor (3). In relation to pathologic staging, from 1975 until recently, distinction between SPLC and IPM was undertaken using criteria proposed by Martini and Melamed: tumors occurring in different lobes, having different major histologic types or being separated by a time interval of more than two years were to be classified as SPLCs (8). Recently, these criteria have been supplanted by the process of comprehensive histologic assessment (CHA) (9). CHA involves determination of major histologic type, assessment of predominant and minor histologic patterns according to histologic subtyping and evaluation of cytological features. CHA has been shown to significantly improve the pathologic distinction between SPLC and IPM to a level comparable to molecular analysis (9). Recent work undertaken by the IASLC Pathology Committee has also shown that usage of this methodology has good reproducibility amongst diagnostic pathologists. Furthermore, p staging status strongly correlated with nuclear pleomorphism, cell size, acinar formation, nucleolar size, and mitotic rate. In addition to the above, immunohistochemistry already has a role in refining the distinction between SPLC and IPM, and molecular techniques are also likely to be used increasingly in the situation. Studies have been published showing that comprehensive genotypic and morphological assessment is feasible, though they are not yet sufficient to establish clonal relationships between multiple tumour nodules (10). Ultimately, a multidisciplinary approach is likely to be the best methodology for distinction between SPLC and IPM, in particular the assessment of imaging data alongside histologic, immunohistochemical and molecular profiles, both in the context of biopsies and resections. 1. Detterbeck FC, Franklin WA, Nicholson AG, Girard N, Arenberg DA, Travis WD, et al. The IASLC Lung Cancer Staging Project: Background Data and Proposed Criteria to Distinguish Separate Primary Lung Cancers from Metastatic Foci in Patients with Two Lung Tumors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2016. 2. Detterbeck FC, Bolejack V, Arenberg DA, Crowley J, Donington JS, Franklin WA, et al. The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Classification of Lung Cancer with Separate Tumor Nodules in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2016. 3. Detterbeck FC, Nicholson AG, Franklin WA, Marom EM, Travis WD, Girard N, et al. The IASLC Lung Cancer Staging Project: Summary of Proposals for Revisions of the Classification of Lung Cancers with Multiple Pulmonary Sites of Involvement in the Forthcoming Eighth Edition of the TNM Classification. J Thorac Oncol. 2016. 4. Detterbeck FC, Marom EM, Arenberg DA, Franklin WA, Nicholson AG, Travis WD, et al. The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Application of TNM Staging Rules to Lung Cancer Presenting as Multiple Nodules with Ground Glass or Lepidic Features or a Pneumonic-Type of Involvement in the Forthcoming Eighth Edition of the TNM Classification. J Thorac Oncol. 2016. 5. Travis WD, Asamura H, Bankier AA, Beasley MB, Detterbeck F, Flieder DB, 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 Thorac Oncol. 2016;11(8):1204-23. 6. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson, AG WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. IARC Press, 2015. 7. Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, 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(2):244-85. 8. Martini N, Melamed MR. Multiple primary lung cancers. J Thorac Cardiovasc Surg. 1975;60:606-12. 9. Girard N, Deshpande C, Lau C, Finley D, Rusch V, Pao W, et al. Comprehensive histologic assessment helps to differentiate multiple lung primary nonsmall cell carcinomas from metastases. Am J Surg Pathol. 2009;33(12):1752-64. 10. Schneider F, Derrick V, Davison JM, Strollo D, Incharoen P, Dacic S. Morphological and molecular approach to synchronous non-small cell lung carcinomas: impact on staging. Mod Pathol. 2016;29(7):735-42.

Abstract:
Background Lung cancer is the most important tobacco-related health problem worldwide, accounting for an estimated 1.3 million deaths each year, representing 28% of all deaths from cancer. Lung cancer screening aims to reduce lung cancer-related mortality with relatively limited harm through early detection and treatment. The US National Lung Screening Trial showed that individuals randomly assigned to screening with low-dose CT scans had 20% lower lung cancer mortality than did those screened with conventional chest radiography. On the basis of a review of the literature and a modelling study, the US Preventive Services Task Force (USPSTF) recommends annual screening for lung cancer for high-risk individuals. However, the balance between benefits and harms of lung cancer screening is still greatly debated. Some investigators suggest the ratio between benefits and harms could be improved through various means. Nevertheless, many questions remain with regard to the implementation of lung cancer screening. Whether nationally implemented programmes can provide similar levels of quality as achieved in these trials remains unclear. The NELSON trial is Europe’s largest running lung cancer screening trial. The main purposes of this trial are; (1) to see if screening for lung cancer by multi-slice low-dose CT in high risk subjects will lead to a 25% decrease in lung cancer mortality or more; (2) to estimate the impact of lung cancer screening on health related quality of life and smoking cessation; (3) to estimate cost-effectiveness of lung cancer screening. The NELSON trial was set up in 2003 in which subjects with high risk for lung cancer were selected from the general population. After informed consent, 15,792 participants were randomised (1:1) to the screen arm (n=7,900) or the control arm (n=7,892). Screen arm participants received CT-screening at baseline, after 1 year, after 2 years and after 2,5 years. Control arm participants received usual care (no screening). In the NELSON trial a unique nodule management protocol was used. According to the size and volume doubling time of the nodules, initially three screen results were possible: negative (an invitation for the next round), indeterminate (an invitation for a follow-up scan) or positive (referred to the pulmonologist because of suspected lung cancer). Those with an indeterminate scan result received a follow-up scan in order to classify the final result as positive or negative. All scans were accomplished at the end of 2012. The lung cancer detection rate across the four rounds were, respectively: 0.9%, 0.8%, 1.1% and 0.8%. The cumulative lung cancer detection rate is 3.2% which is comparable with the Danish Lung Cancer Screening Trial (DLCST). Relative to the National Lung Screening Trial (NLST), more lung cancers were found in the NELSON: 3.2% vs. 2.4%. However, the NLST had less screening rounds and a different nodule management protocol and a different study population. False-positive rate after a positive screen result of the NELSON is 59.4%. The overall false-positive (over four rounds) is 1.2% in the NELSON study, which is lower compared to other lung cancer screening studies. A 2-year interval did not lead to significantly more advanced stage lung cancers compared with a 1-year interval (p=0.09). However, a 2.5-year interval led to a stage shift in screening-detected cancers that was significantly less favourable than after a 1-year screening interval (e.g. more stage IIIb/IV cancers). It also led to significantly higher proportions of squamous-cell carcinoma, boncho-alveolar carcinoma, and small-cell carcinoma (p<0.001). Compared with a 2-year screening interval, there was a similar tendency towards unfavourable change in stage distribution for a 2.5-year screening interval although this did not reach statistical significance. Also, the interval cancer rate was 1.47(28/19) times higher in the 2.5-year interval compared with the 2-year interval. Moreover, in the last six months before the final fourth screening round the interval rate was 1.3(16/12) times higher than in the first 24 months after the third round, suggesting that a 2.5-year interval may be too long. On average, 69.4% of the screening-detected lung cancers across the four screening rounds in the NELSON trial were diagnosed in stage I and 9.8% in stage IIIb/IV. This cumulative stage distribution of the screening-detected lung cancers in the NELSON trial appears to be favourable compared to those of the DLCST and the NLST (68.1% and 61.6% of cancers at stage I, and 15.9% and 20.0% at stage IIIb/IV, respectively).However, this finding should be interpreted with caution because 1) the NLST used the 6th edition of the TNM staging system, while the NELSON trial used the 7th edition, 2) the NLST and DLCST applied different eligibility criteria than the NELSON trial, and 3) the proportion of over-diagnosed lung cancers in the screening group is yet unknown. The lung cancers found in the NELSON control group have yet to be investigated.

Abstract:
The Fleischner Society guidelines (most recently revised in 2017) [1,2] are the most referenced guidelines for management of pulmonary nodules detected incidentally on CT images. In 2014, the American College of Radiology produced the Lung-RADS assessment categories specifically to guide management of nodules detected by Low Dose CT screening for lung cancer [3]. Nodule management guidelines have also been published by the American College of Chest Physicians (ACCP) in 2013 [4] and the British Thoracic Society (BTS) in 2015 [5]. Whilst the Fleisher guidelines and Lung-RADS predominantly offer specific recommendations for interpretation of CT images and guidance for surveillance imaging, the ACCP and BTS guidelines in addition offer more proscriptive recommendations for ongoing investigation or treatment of larger nodules with PET-CT, biopsy techniques, and surgical/non-surgical treatment. There is much common ground between the four proposals. Most of the high quality evidence for nodule management comes from screening studies that only included patients at high risk of lung cancer, and there is an acknowledged paucity of evidence for guiding nodule management in patients with a lower background risk of cancer. There is agreement about the need to minimise radiation dose for CT surveillance for nodules, and an acknowledgement of the low likelihood of malignancy in small nodules detected through any route. All guidelines recognise that sub-solid nodules require a different management algorithm which incorporates a less interventional approach (acknowledging the more indolent nature of the tumours that these may represent) but by implication the need for longer follow-up before nodules can be deemed benign or harmless. Differences between the recommendations are summarised in Table 1. The size below which nodules can be ignored differs slightly between the guidelines. Lung-RADS recommends no intervention for nodules <6mm (or <4mm for new nodules) on the assumption that the patient continues with annual LDCT screening. Determining a threshold for discharge of small nodules detected out a screening program is of potentially greater significance, as a patient with a small malignant nodule discharged in this context is likely to have a poor outcome if that nodule subsequently presents as a symptomatic lung cancer. The Fleischner Society guidelines select a threshold of 1% lung cancer risk (roughly equating to 6mm diameter) below which surveillance is not routinely recommended (although is an option if the patient is high risk). The BTS guidelines base their discharge threshold of 80mm­[3] (5mm) on data from the NELSON screening trial which demonstrated this to be the threshold below which the presence of a nodule did not appear to increase the likelihood of subsequently diagnosed lung cancer above that seen in screening participants with no nodules [6]. More recent data from NELSON has suggested a different size threshold for nodules newly appearing during the screening process. New incident nodules above 27mm[3] appeared to confer an increased risk of cancer [7], and this is reflected in the Lung-RADS category 3 which suggests a 6 month surveillance scan for new incident nodules ≥4mm. When an incidentally detected nodule can be shown to be new compared to recent CT imaging, a lower threshold for ongoing surveillance is probably merited, although not currently recommended in the three relevant guidelines. The use of composite risk-prediction scores in guiding nodule management differs between the various guidelines. The Fleischner guidelines highlight the various risk factors to be considered when deciding management but do not recommend use of a risk prediction score. The ACCP guidelines recommend either qualitative assessment of the probability of malignancy, or quantitative assessment using a validated model (referencing the Mayo model [8]). The BTS guideline recommend use of the Pancan lung cancer risk calculator [9] to decide which nodules should be evaluated with PET-CT on the basis of a validation study in a UK population [10]. Subsequent studies from Australia and Denmark have also demonstrated the utility of the Pancan model in screening studies. The guidelines also differ in the extent to which they promote use of semi-automated volumetry. No reference to volumetry is made in Lung-RADS assessment categories. Both the Fleischner and BTS guidelines acknowledge the better reproducibility of volumetry over diameter measurements and the superior sensitivity in detecting growth. Both however highlight the need to use identical software versions if comparing nodule volumes between scans due to clearly demonstrated variability between different software programs/versions. The Fleischner guidelines comment that robust validated volumetry is not currently widely used hence continuing to base recommendations predominantly on caliper long and short-axis diameter measurements, whereas the BTS guidelines have strongly recommended volumetry in an attempt to drive uptake of this technology. The definition of what constitutes nodule growth also differs between the guidelines. Lung-RADS and the Fleischner guidelines define growth as an increase is diameter of >1.5mm and ≥2mm respectively, reflecting possible inaccuracy in smaller increments in size according to caliper measurements. The threshold of 25% change in volume recommended in the BTS guideline is based on the nodule management stategy used in both NELSON and UKLS. By way of comparison, nodule growth from 7mm to 9mm represents a 113% increase in volume (from 180mm[3] to 381mm[3]). All four guidelines/assessment categories have been published within the last 5 years, and there have been few validation studies published to date. Lung-RADS was compared to the National Comprehensive Care Network guidelines for lung cancer screening and was shown to increase the positive predictive value without increasing false-negative results. Prospective comparisons between these guidelines/approaches are needed to guide future practice.

	Fleischner [1,2]	Lung-RADS [3]	BTS [4]	ACCP [5]
Remit	Incidentally detected nodules	Screen-detected nodules	Incidentally and screen-detected nodules	Incidentally and screen-detected nodules
Assessment of size	Average of long & short axis diameter	Average diameter	Semi-automated volumetry	As per Fleischner guidelines
Threshold for discharge	<6mm - optional follow-up below this size if high risk	<6mm (revert to annual screen)	<80mm[3]	<5mm - optional follow-up below this size if high risk
Selection of further investigation for larger nodules	>8mm consider PET, PET-CT or biopsy	≥8mm PET-CT, biopsy or assess with Brock/Pancan score	≥8mm Brock/ Pancan score to guide PET-CT/other tests	≥8mm clinical judge-ment or validated model (e.g. Mayo)
Assessment of growth	Increase in size of ≥2mm	Increase in size of >1.5mm	Increase in volume of >25%	Not specified
Pure Ground Glass Nodules	Surveillance only for 5 years duration	Revert to annual screen (unless >20mm)	Risk assess, but surveillance pref-erred (for 4 years)	CT surveillance for 3 years

Table 1: Summary of significant differences between nodule management strategies recommended by various guidelines/assessment categories Fleischner [1,2] Lung-RADS [3] BTS [4] ACCP [5] Remit Incidentally detected nodules Screen-detected nodules Incidentally and screen-detected nodules Incidentally and screen-detected nodules Assessment of size Average of long & short axis diameter Average diameter Semi-automated volumetry where possible As per Fleischner guidelines Threshold for discharge <6mm - optional follow-up below this size if high risk <6mm (revert to annual screen) <80mm3 <5mm - optional follow-up below this size if high risk Selection of further investigation for larger nodules >8mm - consider PET, PET-CT or biopsy ≥8mm - PET-CT, biopsy or assess with Brock/ Pancan score ≥8mm - Brock/ Pancan score to guide PET-CT/other tests ≥8mm - clinical judgement or validated model (e.g. Mayo) Assessment of growth Increase in size of ≥2mm Increase in size of >1.5mm Increase in volume of >25% Not specified Pure Ground Glass Nodules Surveillance only for 5 years duration Revert to annual screen (unless >20mm) Risk assess, but surveillance preferred (for 4 years) CT surveillance for 3 years References [1] MacMahon H, Naidich DP, 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 [2] Bankier AA, MacMahon H, Goo JM, et al. Recommendations for measuring pulmonary nodules at CT: a statement from the Fleischner Society. Radiology 2017, epub ahead of print. [3] American College of Radiology. Lung CT Screening Reporting and Data System (Lung-RADS). Available at : https://www.acr.org/Quality-Safety/Resources/LungRADS . Release date April 28, 2014, Accessed August 1, 2017. [4] Gould MK, Donington J, Lynch WR, et al. Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143:e93s-e120S. [5] Callister ME, Baldwin DR, Akram AR, et al. British Thoracic Society guidelines for the investigation and management of pulmonary nodules. Thorax 2015;70:ii1-ii54 [6] Horeweg N, van Rosmalen J, Heuvelmans MA, et al. Lung cancer probability in patients with CT-detected pulmonary nodules: a pre-specified analysis of data from the NELSON trial of low-dose CT screening. Lancet Oncol. 2014;15:1332–41. [7] Walter JE, Heuvelmans MA, de Jong PA, et al. Occurrence and lung cancer probability of new solid nodules at incidence screening with low-dose CT: analysis of data from the randomised, controlled NELSON trial. Lancet Oncol. 2016;17:907-16. [8] Swensen SJ, Silverstein MD, Ilstrup DM, et al. The probability of malignancy in solitary pulmonary nodules. Application to small radiologically indeterminate nodules. Arch Intern Med 1997;157:849–55. [9] McWilliams A, Tammemagi MC, Mayo JR, et al. Probability of cancer in pulmonary nodules detected on first screening CT. N Engl J Med 2013;369:910–9. [10] Al-Ameri AMP, Malhotra P, Thygesen H, et al. Risk of malignancy in pulmonary nodules: a validation study of four prediction models. Lung Cancer 2015;89:27-30

Abstract:
Marked heterogeneity exists in clinical, radiologic, molecular, and pathologic features among adenocarcinoma cases. Therefore, a new Classification of Lung Adenocarcinoma was proposed by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society in 2011 (1). The 2011 classification addressed three important weaknesses in the previous classification. First, it eliminated the term bronchioloalveolar carcinoma (BAC). Second, it added new terminologies of carcinoma-in-situ (CIS), and minimally invasive adenocarcinoma (MIA) to recognize that minimal invasion (< 5mm) had nearly similar clinical outcome as noninvasive nodules. Third, it replaced the terminology of mixed subtype of adenocarcinoma. In this revised classification, invasive lung ADCs were divided into the five subtypes; lepidic, acinar, solid, papillary, and micropapillary patterns primarily based on histologic features. The term predominant is appended to all categories of invasive ADC, as most of these tumors consist of mixtures of the subtypes (1). The widespread availability of MDCT and abundance of new information obtained especially from low-dose CT lung cancer screening programs, have increased our understanding of the types and management of small peripheral lung nodules encountered in daily clinical practice, in particular, the importance and prevalence of subsolid pulmonary nodules (atypical adenomatous hyperplasia (AAH), ground glass nodules (GGN) and part-solid nodules). Thin-section CT has emerged as a new biomarker for lung adenocarcinoma subtypes. The approval of CT as a screening tool for lung cancer was based primarily on National Lung Screening Trial (NLST) results. The NLST recently found that Low Dose Helical Computed Tomography (LDCT) reduces lung cancer specific mortality by 20% relative to chest x-ray screening in a cohort at high risk of lung cancer (2). However, significant concerns remain regarding its high false positive rate, overdiagnosis, cost effectiveness and concerns related to radiation burden from repeat CT screens. There is a trade-of between early detection of lung cancer vs unnecessary work-up of indeterminate nodules resulting in many side effects including anxiety, radiation exposure from CT follow-up to assess for growth, cost and morbidity and mortality related to biopsy or resection of a benign nodule. It is expected that false positive rate would decrease by 50% using more accurate phenotyping of a nodule using the lung CT reporting and data system (Lung-RADS) appropriately (3). One of the major changes proposed in Lung-RADS is the size threshold for positive screen, from 4 mm in NLST to 6 mm for solid nodules and 20 mm for nonsolid nodules. Tissue sampling would be used primarily for larger than 15 mm solid nodules or PET positive nodules with larger than 8 mm solid component. False positive rate would still be likely not acceptable for an individual using this approach. There is need for more accurate nodule assessment and risk stratification as given our current understanding that genetic make-up of a nodule is the ultimate determinant of clinical outcome (4). Further improvements in stage discrimination and management of lung nodules could be expected in the future, as more robust data related to texture analyses of tumors, their genetic profiles and impact of those on clinical outcome becomes available (5-8). Simple measuring the tumor size with one-dimentional (Response Evaluation Criteria in Solid Tumors (or RECIST) long-axis measurements do not reflect the complexity of tumor morphology or behavior. Also, it may not be predictive of therapeutic benefit. In contrast, the emerging field of radiomics is a high-throughput process in which a large number of shape, edge, and texture imaging features are extracted, quantified, and stored in databases in an objective, reproducible, and mineable form. Once transformed into a quantifiable form, radiologic tumor properties can be linked to underlying genetic alterations and to medical outcomes. Marked heterogeneity in genetic properties of different cells in the same tumor is typical and reflects ongoing intratumoral evolution. Clinical imaging is well suited to measure temporal and spatial heterogeneity. Subjective imaging descriptors of cancers are inadequate to capture this heterogeneity and must be replaced by quantitative metrics that enable statistical comparisons between features describing intratumoral heterogeneity and clinical outcomes and molecular properties. A recent study adds further support toward taking a conservative approach in the management and treatment of patients with part-solid nodules especially when the solid component is small. This strategy is already reflected in the Lung-RADS guidelines, which recommend focusing on the size of the solid component in the part-solid nodule instead of on the overall nodule size. For the future, the critical issue will be further refinements for the follow-up of nonsolid and part-solid nodules based on the size or volume that allow a process of shared decision making in selecting appropriate management and treatment (9-10). This lecture will address the radiologic implications of this new lung adenocarcinoma classification. References: 1. Travis W, Brambilla E, Noguchi M, et al. IASLC/ATS/ERS International multidisciplinary classification of lung adenocarcinoma. J Thoracic Oncol 2011;6:244-285 2. Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395-409 3. American College of Radiology: Lung-RADS Version 1.0 Assessment Categories Release date: April 28, 2014. Accessed on 17 March, 2015 4. McWilliams, A. et al. Probability of cancer in pulmonary nodules detected on first screening CT. The New England journal of medicine 2013;369: 910-919, doi:10.1056/NEJMoa1214726 5. Lambin P, et al. Radiomics: extracting more information from medical images using advanced feature analysis. Eur J Cancer 2012;48 (4):441-446 6. Gatenby RA, Grove O, Gillies RJ. Radiology 2013;269:8-15 7. Bartholmai BJ, Koo CW, Johnson GB, et al. Pulmonary nodule characterization including computer analysis and quantitative features. J Thorac Imaging 2015;30 (2) 139-156 8. Song SH, Park H, Lee G, et al. Imaging phenotyping using Radiomics to predict micropapillary pattern within lung adenocarcinoma. JTO 2017;12:624-632 9. Rowena Yip, Henschke CI, Xu DM, et al. Lung cancers manifesting as part-solid nodules in the National Lung Screening Trial. AJR 2017;208:1011-1021 10. American College of Radiology website. Lung CT Screening Reporting and Data System (Lung-RADS). Accessed January 11, 2016 11. MacMahon H, Naidich DP, 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

Abstract:
Recent advances molecular target therapies have provided a remarkable benefit to patients harboring specific genetic alterations. Most patients treated against molecular targets eventually develop resistance even after initial dramatic response. T790M mutation is a major mechanism for clinical failure in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. Osimertinib has been recently approved and demonstrated dramatic response in NSCLC patients with T790M mutation. In tumors with anaplastic lymphoma kinase (ALK) or ROS-1 rearrangement, cereitinib has been approved and recommended in case of crizotinib resistance. Therefore, clinical demand for rebiopsy to identify these druggable mutations has been increasing, and rebiopsy plays an important role in clinical application for exploring resistant mechanisms and determining further therapeutic strategies. This session will focus on rebiopsy issues in relapsed NSCLCs. We will describe the growing need for rebiopsy and review the current data about rebiopsy, both published and unpublished. We will discuss the technical aspects of interventional radiology-guided rebiopsy; patient selection, guiding-modalities, lesion targeting, and tissue sampling. Hurdles and solutions for rebiopsy will be discussed with appropriate examples. Current role of liquid biopsy in comparison with conventional tissue biopsy will be briefly covered. Finally, we will discuss how to collaborate more effectively as a lung cancer multidisciplinary team from radiologists’ perspective.

Abstract:
Since magnetic resonance imaging (MRI) was introduced for the assessment of thoracic and lung diseases, various limitations. However, from 2000, various techniques have been demonstrated their utility for lung cancer evaluations, and is now covered by health insurance in many countries including North America, Eastern Asia and Europe. In this lecture, I will show you these recent advances in lung MRI focusing on its application in lung cancer evaluation, especially with regard to 1) pulmonary nodule detection, 2) pulmonary nodule and mass assessment, and 3) lung cancer stage and recurrence evaluations.

Abstract not provided

Abstract not provided

Abstract:
Lung cancer is still the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) remains the predominant form of the disease, with majority of patients being diagnosed at advanced stages. The survival benefit offered by chemotherapy regimens has reached a therapeutic plateau. Fortunately, mutation-specific targeted therapies directed against “actionable” genetic alterations have significantly improved the prognosis of advanced NSCLC. Epidermal growth factor receptor (EGFR) mutation is the most common targetable genetic alteration in NSCLC. The prevalence of EGFR mutations range from 10% in Caucasians, to 60% in never-smoking, Asian, adenocarcinoma patients. This presentation will focus on the first-line management of EGFR mutant NSCLC. Overview of EGFR-TKIs Nine large randomised controlled studies have established the superiority of EGFR tyrosine kinase inhibitors (EGFR-TKIs) against chemotherapy as first-line treatment in NSCLC harboring EGFR mutations in terms of progression-free survival (PFS), objective response rate (ORR) and quality of life (QoL) (Table 1). Several studies suggest there is no significant difference in efficacy between gefitinib and erlotinib. LUX-lung 7 (afatinib) and ACHER 1050 (dacomitinib) are two randomised head-to head trials comparing second-generation EGFR-TKIs to gefitinib, respectively. Although PFS is significantly improved with second-generation TKIs, the increased rates of grade 3 or higher adverse events such as rash and diarrhea result in more dose modification with second-generation TKIs. FLAURA study, which assesses the efficacy of third-generation EGFR-TKI osimertinib versus first-generation EGFR-TKIs as first-line treatment, has been accomplished recently. This trial may establish the role of osimertinib as first-line treatment for EGFR mutant NSCLC. Management of uncommon mutations Exon 19 deletion and L858R mutation account for about 90% of all EGFR mutations. The remaining 10% of EGFR mutations (uncommon mutations) are a heterogeneous group of molecular alterations. Results of retrospective studies and case reports of first-generation EGFR-TKIs show inconsistent responses in this population. According to the post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6, objective responses to afatinib are observed in certain types of uncommon mutations such as G719X (77.8%), L861Q (56.3%), and S768I (100%). However, Patients with de-novo Thr790Met and exon 20 insertion mutations are insensitive to afatinib. Jonathan Riess and colleagues report that osimertinib has in vivo activity across multiple exon 20 insertion mutations in preclinical study. Thus osimertinib warrants further study in patients with exon 20 insertion mutations. Combination treatment strategies Combinations of EGFR-TKIs with chemotherapy, anti-angiogenetic therapy, and immunotherapy have been explored in clinical trials. JMIT study is a randomized phase II trial comparing addition of pemetrexed to gefitinib with gefitinib alone as first-line therapy in EGFR mutant NSCLC. PFS was significantly longer with pemetrexed+gefitinib than with gefitinib (15.8 months vs 10.9 months; hazard ratio [HR], 0.68; 95% CI, 0.48 to 0.96; P = 0.029). According to JO25567 study, combination of erlotinib with bevacizumab also significantly prolongs PFS than erlotinib. Several phase III trials evaluating combination of EGFR-TKIs with anti-angiogenetic therapy are ongoing. Attention should be paid to adverse events such as interstitial lung disease when EGFR-TKIs are used with immunotherapy. Management of brain metastases Brain metastases is a major challenge when managing EGFR mutant NSCLC as up to 40% of patients would develop central nervous system (CNS) metastases during the course of their disease. Novel EGFR-TKIs provide new strategies for brain metastases treatment. AZD3759 is a CNS penetrable and reversible EGFR-TKI. The phase I study (BLOOM) of AZD3759 in TKI naïve EGFR mutant NSCLC with CNS metastases is reported in 2017 ASCO annual meeting. Intracranial response is observed in 83% of patients with measurable brain metastases lesions at baseline. The extracranial anti-tumor efficacy of AZD3759 is also promising. 13 out of 18 patients with extracranial lesions have confirmed objective response. CNS response to osimertinib in patients with T790M-positive advanced NSCLC from AURA3 study is also presented in 2017 ASCO annual meeting. In 30 patients with more than one measurable CNS metastases, the intracranial response is 70%. The median CNS PFS with osimertinib is 11.7 months. Furthermore, osimertinib shows encouraging activity in patients with leptomeningeal metastases. Table 1. First-line treatment of EGFR mutant NSCLC: EGFR-TKIs vs. Chemotherapy

Trial	TKI	PFS (month)			OS
		TKI	Chemo	HR (95%CI)	HR (95%CI)
IPASS	Gefitinib	9.5	6.3	0.48 (0.36-0.64)	0.78 (0.50-1.20)
First Signal	Gefitinib	8.4	6.7	0.61 (0.31-1.22)	0.82 (0.352-1.922)
NEJ002	Gefitinib	10.8	5.4	0.322 (0.236-0.438)	0.88 (0.634-1.241)
WJTOG3405	Gefitinib	9.6	6.6	0.52 (0.378-0.715)	1.185 (0.767-1.829)
OPTIMAL	Erlotinib	13.1	4.6	0.16 (0.10-0.26)	1.19 （0.83-1.71）
ENSURE	Erlotinib	11.0	5.5	0.34 (0.22-0.51)	0.91 （0.63-1.31）
EURTAC	Erlotinib	9.7	5.2	0.37 (0.25-0.54)	0.80 (0.47-1.37)
Lux-lung 3	Afatinib	11.1	6.9	0.58 (0.43-0.78)	0.88 （0.66-1.17）
Lux-lung 6	Afatinib	11.0	5.6	0.29 (0.20-0.33)	0.93 （0.72-1.22）

Abstract not provided

Abstract:
The identification of anaplastic lymphoma kinase (ALK) gene rearrangements as an oncogenic driver in NSCLC has radically changed the treatment of a subset of patients harboring this molecular alteration. [1] ALK mutations occur in 3-7% of NSCLCs and are more frequently associated with never/light smoker, younger age and adenocarcinoma histology. Crizotinib, an oral small-molecule multitargeted ALK/c-MET /ROS1 tyrosine kinase inhibitors, was the first-in-class agent approved from FDA for advanced, ALK-rearranged NSCLC. The accelerated approval in 2011 was granted on the basis of pronounced activity observed in early phase I and II clinical studies, coupled with a favorable toxicity-profile and concurrent development of a diagnostic test for ALK rearrangement. [2] More recently, the results from a front-line phase III trial in ALK-positive NSCLC, PROFILE 1014, revealed the superiority, in terms of progression free survival (PFS) and overall response rate (ORR), of crizotinib versus standard pemetrexed-platinum chemotherapy.[3] Based on these data, crizotinib represents standard fist- line therapy in patients with advanced ALK mutant NSCLC. [4] Despite marked and durable initial responses to crizotinib, most patients develop progressive disease after a median of 11 months, with the brain as a common site of relapse. This can be explained by pharmacokinetic limitations rather than a biologic resistance. Several acquired resistance mechanisms have been characterized, including secondary mutations in the ALK kinase domain and/or ALK copy number alterations. ALK-independent resistance mechanisms can also occur through activation of alternative bypass signaling pathways, such as EGFR activation, KIT amplification, KRAS mutation and IGF-R1 activation.[5] This evidence has prompted the development of increasingly potent, selective and brain-penetrant ALK inhibitors, with differential spectrum of activity against the most common resistance mutations. [6] Several next-generation ALK inhibitors, such as ceritinib, alectinib, brigatinib have demonstrated clinical benefit in patients with crizotinib-refractory NSCLC patients also at the central nervous system (CNS) level. This observation has supported the assessment of these drugs as frontline therapy in patients crizotinb-naïve with advanced ALK+ NSCLC.[7] Soria and colleagues have published the results of the ASCEND-4 trial, randomizing ALK+ treatment naïve patients to ceritinib or chemotherapy. Ceritinib treatment significantly has improved median PFS compared to chemotherapy (16.6 vs 8.1 months; hazard ratio [HR] 0.55,P<0.00001). This molecule was also associated with a better control of the disease in the brain (PFS 10.7 vs 6.7 months, HR 0.70, 95% CI: 0.44–1.12). Dose-limiting gastrointestinal adverse events were common with ceritinib at the starting dose of 750 mg daily and 80% of cases required dose reduction or interruption. Although ceritinib has not been compared head-to-head with crizotinib, data confirm ALK inhibitor superior efficacy compared to standard chemotherapy in the ALK-rearranged NSCLC and suggest ceritinib as another option for the front line management. [8] First Line Head to Head trials are ongoing or recently completed. Findings from J-ALEX trial, involving untreated Japanese patients with ALK-rearranged advanced NSCLC, have shown that alectinib induces longer durations of response compared to crizotinib. Median PFS exceeded 2 years in the alectinib group, compared with just over 10 months in the crizotinib group. [9] Recently, Peters et al. have presented the results of global ALEX study. Data are consistent with previous Japanese analysis: PFS was significantly improved with alectinib as compared to crizotinib (25,7 5% vs 10,4%, HR 0.5, p<0.0001). In addition, 12% of patients in alectinib arm vs 45% in crizotinib arm has experienced brain progression (cause specific HR 0.16; 95% CI, 0.10 to 0.28; P<0.001). Alectinib appeared to be better tolerated than crizotinib with grade 3 to 5 adverse events occurring in 41% vs 50% of patients, respectively.[10] Other studies with next-generation ALK inhibitors versus crizotinib—such as lorlatinib, brigatinib, are ongoing and they will help define optimal sequencing therapy for patients with ALK-rearranged NSCLC. To improve outcomes in this patient population, some studies are also currently investigating several combination strategies, including immunotherapy, anti-angiogenetic agents or radiotherapy approach in association with ALK inhibitors as shown in Table 1. Table 1

DRUGS (dose)	Clinical trial (phase)	Patient Number	Comparator	ORR (%)	PFS (mo)
Crizotinib (250 mg twice/day)	PROFILE 1014 (III)	343	Pemetrexed+platinum	74 vs45	10.9 vs 7.0
Ceritinib (750 mg/die)	ASCEND 4 (III)	376	Pemetrexed+platinum pemetrexed±maintenance	72.7vs27.3	16.6 vs 8.1*
Alectinib (300 mg twice/day)	J-ALEX (III)	207	crizotinib (250 mg twice/day)	85vs70	NEvs10.2
Alectinib (600 mg twice/day)	ALEX (III)	303	crizotinib (250 mg twice/day)	82.9vs75.5	25.7vs10.4*
Brigatinib (90 mg/die for 7 days, 180 mg/die)	ALTA 1L (III)	ongoing	Crizotinib (250 mg twice/day)	-
Lorlatinib (150 mg/die)	NCT03052608 (III)	ongoing	Crizotinib (250 mg twice/day)	-
Crizotinib+Bevacizumab (250 mg twice/day; 7.5 mg/kg every 3 wks)	CAMAR01 (II)	ongoing	_	_	_
Crizotinib+Pembrolizumab	NCT02511184 (I)	ongoing	_	_	_
ORR: overall response Rate, PFS Progression free survival, NE not evaluable, *independent review committee

Treatment paradigms continue to evolve for patients with advanced ALK-positive NSCLC subsequently to rapid development of ALK inhibitors history. It is expected that one of the next generation of ALK inhibitors will be used as first-line. In this landscape it is necessary to define the impact of first-line choice on patterns of progression and mechanisms of resistance. [11] It is uncertain if a specific sequence of therapeutic agents influences the biology of the cancer and therefore the clinical course of the patient. The spectrum of ALK resistance mutations varies according to ALK inhibitor and it is unclear if the mechanisms of resistance to these agents as the first ALK inhibitor will be similar to the mechanisms of resistance identified when they are used after crizotinib. Future efforts should be focused on determining the best treatment sequence to maximize clinical outcomes. Key factors to guide the selection of therapies could be include: molecular characteristics of the patient's tumor, different toxicity profile of different ALK inhibitors, availability of combinations/ multimodal therapy. References 1. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Soda M et al. Nature 2007; 448:561–567 2. The continuum of care for ALK-positive NSCLC: from diagnosis to new treatment options-an overview Solomon & Soria, Ann Oncol Vol 27 Supp 3 2016 3. First-line crizotinib versus chemotherapy in ALK-positive lung cancer Solomon et al N Engl J Med 2014 Dec 4;371(23):2167-77 4. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Novello S et al. Annals of Oncology 27 (Supplement 5): v1–v27, 2016 5. Crizotinib resistance: implications for therapeutic strategies. Dagogo-Jack & Shaw Ann Oncol Supp 3 2016 6. Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged LungCancer. Gainor et al Cancer Discov2016Oct;6(10): 1118-1133. 7. Ascending role of next-generation ALK inhibitors. Costa. Lancet Oncol.2017 Jul; 18(7):837-839. 8. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomized, open-label, phase 3 study. Soria et al Lancet 2017; 389: 917–29 9. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomized phase 3 trial Hida et al. Lancet 2017; 390: 29–39 10. Alectinib versus Crizotinib in Untreated ALK-Positive Non–Small-Cell Lung Cancer Peters et al for for the ALEX Trial Investigators NEJM N Engl J Med. 2017 Jun 6. 11. First-line treatment options for ALK-rearranged lung cancer. Solomon. Lancet Oncology 2017 Mar 4; 389(10072): 884-886

Abstract not provided

Background:
The new 2015 WHO classification broadly divided pulmonary neuroendocrine tumor (NET) of the lung in low-grade typical carcinoid (TC) and atypical carcinoid (AC), to the high-grade large-cell neuroendocrine carcinoma (LCNEC) and the small-cell carcinoma (SCLC). The molecular alterations underlying the pathogenesis of these tumors have been studied showing two blocks of entities with independent cellular mechanisms. Many of the differences between the two NETs blocks can be ascribed to tobacco consumption, which induces epithelial to mesenchymal transition activation, responsible for invasive and metastatic behavior. These correlations further highlight the difference in OS for patients with low and high grade metastatic NETs. Therefore, epithelial to mesenchymal transition (EMT) genes profile emerge promise as indicator of invasion and metastasis in NETs.

Method:
Fresh frozen tissue from SCLC (n = 10), LCNEC (n = 4), AC (n = 5), TC (n = 5) and matched normal tissue samples were collected for qRT-PCR analysis carried out on StepOnePlus™ Real-Time PCR System (Applied Biosystems) with RT[2] Profiler PCR Array System for the EMT pathway with 84 target genes (Qiagen, Dusseldorf, Germany). Linear regression was done to evaluate association between gene expressions. Clinical variable such as age, gender, tobacco history, lymph node metastasis and histologic types were associated with gene expression. Differences were regarded as statistically significant at P < 0.05.

Result:
High expression of membrane receptor EGFR (p = 0.003), protein of the matrix metalloproteinase MMP3 (p = 0.044), transcriptional factor TCF3 (p = 0.022) and signaling pathway factor WNT5A (p = 0.013) were observed in patients with tobacco history. Metastatic LCNEC and SCLC presented significant lower expression of JAG1 gene and higher level of EGFR (p<0.01), transmembrane protein DSP (p = 0.03), TCF3 (p = 0.01), TGF-B3 (p = 0.04) and WNT5A (p = 0.01) compared to TC and AC. In addition to these genes, AKT1 and MAP1B were equally high expressed in metastatic NE carcinomas. Importantly, increased expression of these genes added of MMP2 gene was significantly associated with poor OS of the patients.

Conclusion:
A panel of 84 EMT genes was tested and the best biomarkers included EGFR, MMP2, MMP3, TCF3, WNT5A, JAG1, TGFB3, AKT1 and MAP1B with impact on unfavorable prognostic and overall survival of patients, highlight that EMT play a fundamental role in pathogenetic pathway of metastasis in NETs. Supported by CNPq project 301411/2016-6; FAPESP 2013/10113-7.

Background:
Small-cell lung cancer (SCLC) has been occasionally detected in never-smokers as smoking rates decrease worldwide. We investigated the clinical and genetic characteristics of SCLC in never-smokers (Geno1.3-CLICaP)

Method:
A cohort of patients diagnosed with SCLC were grouped into smokers (n=10) and ever/never-smokers (n=10). For both groups, somatic mutation profiling was carried out using a comprehensive NGS assay (TruSight Tumor 170) targeting the full coding regions of 170 cancer-related genes. Epidermal growth factor receptor (EGFR) mutation was confirmed by RT-PCR (Cobas[TM]). The clinical outcomes of the two groups were compared using Kaplan-Meier and Cox proportional models.

Result:
Median age was 58 years (r, 46-81), 55% (n = 11) were men, most patients had extended disease (85%) and the dominant tumor involvement site was pleura and lungs (65%). No significant differences were found in age, disease distribution, baseline performance status and cerebral metastases in relation to tobacco exposure. The ORR to first-line therapy were 50% and 90% between smokers and ever/never-smokers, respectively (p=0.032). The median overall survival (OS) was 29.1 months in ever/never-smokers (95%CI 23.5-34.6) versus 17.3 months in smokers (95%CI 4.8-29.7; p=0.0054). Never-smoking history (HR 0.543, 95%CI 0.41-0.80), limited stage disease (HR 0.56, 95%CI 0.40-0.91) and response to first line platinum based chemotherapy (HR 0.63, 95%CI 0.60-0.92) were independently related with good prognosis. Among ever/never smokers main genetic mutations were TP53 (80%), RB1 (40%), CYLD (30%), EGFR (30%), MET (20%), SMAD4 (20%) and BRIP1 (20%). None of the smokers had mutations in EGFR, MET or SMAD4, but there was a greater involvement in RB1 (80%, p=0.04), CDKN2A (30%, p=0.05), CEBPA (30%, p=0.05), FANCG (20%), GATA2 (20%), and PTEN (20%).

Conclusion:
Never-smokers with SCLC are increasingly prevalent and have a better prognosis than their smoker counterpart. EGFR, MET and SMAD4 are frequent mutations among SCLCs of ever/never smokers, and RB1, CDKN2A and CEBPA among smokers. Figure 1

Background:
Although small cell lung cancer (SCLC) is sensitive to initial therapy, almost all patients relapse and survival remains poor. Outgrowth of treatment-resistant subclones could be responsible for recurrence. However, genomic evolution of SCLC after treatment hasn’t been well investigated, partially due to the challenge of obtaining longitudinal samples. CT is the standard modality for response assessment and disease monitoring. But it doesn’t always accurately assess the disease status. SCLC is characterized by early hemagenous spread, which makes circulating tumor DNA (ctDNA) analysis a promising modality for genomic profiling and disease monitoring of SCLC.

Method:
Targeted-capture deep sequencing (mean target coverage 538x-1866x) of 545 cancer genes was performed to 44 ctDNA samples collected before therapy as baseline and at different timepoints during treatment from 23 SCLC patients. Pretreatment tumor biopsies from 8 patients were also sequenced (mean target coverage 348x-1281x) of the same gene panel. DNA from peripheral blood mononuclear cells was served as the germline control.

Result:
Mutations were identified in all 44 ctDNA samples with a median of 16 mutations per sample (average mutation burden of 6.6/Mb). TP53 and RB1 were the most frequently mutated genes, detected in 91% (21/23) and 65% (15/23) patients, respectively. 74 mutations were identified from the 8 tumor biopsies, among which, 69 (93.2%) were detected in matched ctDNA. We inferred subclonal architecture of each ctDNA sample based on cancer cell fraction derived using PyClone. A median of 10 (ranging 2-26) subclones was inferred from each ctDNA sample and only 17% (2% to 60.%) of mutations were clonal mutations suggesting substantial genomic heterogeneity. Single gene mutations were not associated with survival. However, mean variant allele frequency of clonal mutations (clonal-VAF) at baseline was associated with progression-free survival (PFS) and overall survival (OS) independent of stage, age, or platinum sensitivity. The median PFS of patients with higher versus lower than median clonal-VAF was 5.2 months (95% CI, 4.6 to 5.8 months) versus 10.0 months (95% CI, 9.3 to 10.7 months), p=0.002. The median OS was 8.1 months (95% CI, 5.5 to 10.7 months) versus 24.9 months (95% CI, 0.0 to 51.2 months) in patients with higher versus lower than median clonal-VAF, respectively, p=0.004. Analysis of serial ctDNA before and during treatment showed that clonal-VAF closely tracked closely with treatment responses.

Conclusion:
ctDNA sequencing is a promising modality for genomic profiling and disease monitoring for SCLC patients. Clonal VAF may be a better ctDNA metric than single gene mutations.

Abstract not provided

Background:
Lurbinectedin (PM01183) is a new anticancer drug that binds to DNA, inhibits transactivated transcription and modulates tumor microenvironment. Preclinical evidence of synergism was observed for PM01183 in combination with doxorubicin (DOX).

Method:
Multicenter, phase I clinical trial to determine the recommended dose (RD) of the combination of PM01183 and DOX. An expansion cohort was recruited after finding striking activity in second-line small cell lung cancer (SCLC) patients. Due to hematological toxicity, the trial was amended to use a lower DOX dose and thus improve safety of the combination in selected indications. SCLC patients <75 years with ECOG performance status (PS) 0-1 and pretreated with no more than one chemotherapy line were included. Stable brain metastases were allowed. DOX was interrupted after 10 cycles and PM01183 could be continued as single-agent. Primary G-CSF prophylaxis was not mandatory.

Result:
48 patients were treated: 21 in Cohort A (PM01183 3-5 mg flat dose [FD] Day (D)1 + DOX 50 mg/m2 D1 every 21 days [q21d]), and 27 in Cohort B (PM01183 2 mg/m2 D1 + DOX 40 mg/m2 D1 q21d). Males: 74%; median age: 64 (48-77) years, ECOG 0-1: 37%-63%; known central nervous system (CNS) involvement: 10%; bulky disease (>50 mm): 67%. 85% responded to first line, including 4% with complete response (CR). Median chemotherapy free interval (CTFI): 3.4 months. Refractory (CTFI<30 days) 23%; resistant (CTFI 30-90 days) 34%; sensitive (CTFI>90 days) 43%. RD: PM01183 4 mg FD (or 2 mg/m2) + DOX 50 mg/m2 D1 q21d. Confirmed ORR: 50% (95CI: 35-65%) with 6% CR in both cohorts; ORR=69% (95CI: 49-85%) with 10% CR in sensitive patients. Cohort A: ORR=67% (95%CI: 43-85%) with 10% CR; ORR=92% (95%CI: 62-100%) in sensitive patients. Cohort B: ORR=37% (95%CI: 19-58%) with 4% CR; ORR=53% (95%CI: 28-77%) in sensitive patients. Median PFS (mPFS) 4.6 months (95%CI: 3.1-5.8), with mPFS 1.5 months (95%CI: 1.2-3.8) in resistant patients and 5.8 months (95%CI: 3.6-7.9) in sensitive patients. In both cohorts, grade 4 neutropenia/anemia/thrombocytopenia appeared in 73%/4%/15% of patients and febrile neutropenia in 21% (11% at RD). Non-hematological toxicity was mainly fatigue (G3=14%) and nausea (G3=5%).

Conclusion:
PM01183/DOX combination showed remarkable activity as second line in SCLC, especially in patients with CTFI>90 days, regardless of dose. Activity is higher than reported for CAV or topotecan in this setting. Reversible myelosuppression was the most frequent and expected side effect. A phase III trial with this combination in relapsed SCLC is ongoing.

Background:
Small cell lung cancer (SCLC) has poor prognosis and systemic chemotherapy is the standard treatment. Irinotecan is a topoisomerase-I inhibitor that has been used in treating SCLC. Etirinotecan pegol (NKTR-102) is a polyethylene glycol conjugate of irinotecan uniquely designed for prolonged tumor cell exposure by using the polymer conjugate technology. This is a single arm phase II study to evaluate single agent etirinotecan pegol in patients with relapsed SCLC (NCT01876446). In WCLC 2016 we reported its promising activity with an acceptable toxicity profile in treatment of chemotherapy-sensitive SCLC. Here we report the results in chemotherapy-resistant SCLC.

Method:
A total of 38 patients who have received only one prior systemic therapy for SCLC were enrolled. There were 2 patient cohorts: those progressing on first-line chemotherapy <3 months after completion of treatment (Group A: chemotherapy-resistant, N=20) and those progressing on first-line chemotherapy ≥3 months after completion of treatment (Group B: chemotherapy-sensitive, N=18). Etirinotecan pegol was administered at 145 mg/m[2] IV once every 3 weeks. Cycles were repeated every 21 days until disease progression, unacceptable toxicity, or withdrawal from study. The primary endpoint was the 18-week progression free survival (PFS) rate. The secondary endpoints were objective response rate (ORR), duration of response (DOR), overall survival (OS) and toxicity. A single-stage design was used to assess the primary endpoint separately for each patient group.

Result:
Group A has completed targeted enrollment of 20 patients and the results are presented here. Median age was 60.4 (46.1-74.8) years, with 50% male and ECOG PS 0 (9/20) or 1 (11/20). Prior chemotherapy included cisplatin/etoposide (25%) or carboplatin/etoposide (70%). Patients received a median of 2 (1-10) cycles of etirinotecan pegol, with dose reduction in 15%. PFS rate at week 18 was 35% (7/20, 95% Confidence Interval (CI): 16-55%). ORR was 20% (4/20), all of which were partial response. Another 30% (6/20) of patients had stable disease. Median DOR was 4.8 (1.6-10.5) months. Median PFS was 9.4 (95% CI: 5.8, 21.6) weeks, and OS was 8.1 (95% CI: 2.9, 11.9) months. The most common treatment-related adverse events (AEs) of any grade were diarrhea (50%), fatigue (35%), weight loss (35%), nausea (30%), and vomiting (30%). The most common AEs ≥grade 3 were diarrhea, leukopenia and neutropenia (2 cases each, all grade 3).

Conclusion:
Etirinotecan pegol has demonstrated promising activity with an acceptable toxicity profile and a convenient schedule in treatment of patients with chemotherapy-resistant relapsed SCLC and therefore warrants further investigation.

Background:
SCLC is featured by both a rapid response and progression during/after standard upfront therapy. Thus, maintenance strategies emerged as potential treatment opportunities, although to date all drugs failed to significantly improve prognosis. SCLC cells harbor a neuroendocrine phenotype, frequently expressing somatostatine (SST) receptors. This study aimed to investigate the efficacy of somatostatine (SST) analogue Lanreotide (LAN) as a maintenance strategy for SCLC patients (pts) after response to standard upfront treatment.

Method:
A multicentre, randomized, open-label, no-profit national trial was conducted, randomizing (1:1) SCLC (limited/extended disease, L/ED) pts expressing SST receptors (by SST receptor scintigraphy) with objective response (CR or PR) after upfront platinum-based chemotherapy plus/minus radiotherapy to receive maintenance LAN 120 mg subcutaneously every 28 days, up to progressive disease (PD) for 1 year (Arm A), versus observation (Arm B). Primary end-point was 1-year Progression-Free Survival (PFS). Primary intention-to-treat (ITT) analysis was planned (power: 80%; 2-tailed alpha-error: 5%) after 47 PFS events.

Result:
Seventy-one pts (median age 66 [37-82]; male/female 72/28%; L/ED 39/61%; ECOG-PS 0-1/2 97/3%; previous best response CR/PR 6/94%) were randomized in 9 Italian centers. Median time from diagnosis and end-of-1[st] line to inclusion was 5.7 months (3-160) and 30 days (0-119), respectively. Median number of LAN doses and treatment duration (Arm A) was 4 (1-12) and 83 days (1-392), respectively. With a median follow-up of 9.4 months and 62 events, median PFS was 3.6 (95% CI 3.2-3.9) versus 2.3 months (95% CI 1.7-2.9), for Arm A and B (log-rank p=0.11; HR 1.51, 95% CI 0.90-2.50), with a 1-year PFS of 10.3% versus 7.3%, respectively. At the cox-proportional multivariate modelling, stage (ED versus LD, HR 2.88 [95% CI 1.64-5.04, p<0.0001) and treatment arm (B versus A, HR 1.63 [95% CI 0.97-2.72], p=0.06) were independent predictors for PFS. Median PFS of arm A and B was 7.0 [95% CI <1-13.5] and 3.8 months [95% CI <1-8.6] in LD pts (p=0.21), and 3.0 (95% CI 2.2-3.8) and 2.2 (95% 1.7-2.7) in ED pts (p=0.19). Median OS was 9.5 (95% CI 4.8-14.3) and 4.7 months (95% CI 1.7-16.6), for Arm A and B (log-rank p=0.47), respectively. LAN was well-tolerated: serious treatment-related adverse events were grade 3 abdominal pain and electrolyte disorder in overall 2 pts.

Conclusion:
Although the primary end-point was not met, the overall efficacy of LAN as a maintenance strategy after response to standard upfront treatment for SCLC deserves future investigations, particularly in pts with LD.

Abstract not provided

Background:
Small cell lung cancer (SCLC) comprises ~10-15% of lung cancers. The majority of patients with SCLC present with extensive disease (ED) and have extremely poor outcomes; <5% survive 2 years. Although first-line (1L) treatment is typically platinum-based, many patients are platinum-resistant with few effective options after relapse. The study objective was to compare treatment patterns across regions and by platinum resistance/sensitivity.

Method:
This study used data from the Oncology Monitor (Ipsos Healthcare), a global clinical database of oncology patients collected through retrospective medical chart reviews. Treating physicians were invited to submit information on their patients with SCLC treated from January 2014 through December 2016 in the United States (US), the European Union 5 (EU5; France, Germany, Italy, Spain, and the United Kingdom), or Japan.

Result:
A total of 5849 patients with SCLC were included (2605 in the US, 2203 in the EU5, and 1041 in Japan). Mean age was 65.6 years (standard deviation: 8.8); 66.3% were male and 94.0% diagnosed with ED. In all, 73.4% of patients were receiving 1L, 19.8% second-line (2L), and 6.8% third-or-later-line therapy. Platinum/etoposide was the most frequently prescribed 1L therapy, although it was significantly more common in the US (87.0%) than the EU5 (82.1%) or Japan (73.3%) (P<0.05). Cisplatin/etoposide was prescribed more often in 1L in the EU5 (40.8%) than in the US (26.6%) or Japan (23.7%) (P<0.0001). Platinum/irinotecan was an uncommon 1L treatment in the US (2.0%) and EU5 (0.5%) but common in Japan (22.7%; P<0.0001). Platinum-resistance (relapse within ≤3 months of 1L treatment completion) was observed in >40% of patients (US: 45.4%, EU5: 40.9%, Japan: 56.1%). Regardless of platinum-resistance versus sensitivity, the most common 2L treatment in the US and EU5 was topotecan (42.3% vs 47.6%) and (59.5% vs 56.1%), and amrubicin in Japan (52.1% vs 53.1%). Among platinum-resistant patients in the US, EU5, and Japan, 27.3%, 10.8%, and 36.4% received a platinum-based 2L therapy. Additionally, 52.3%, 66.7%, and 44.9% of platinum-sensitive patients did not receive 2L platinum re-challenge.

Conclusion:
Current NCCN and ESMO guidelines (endorsed by JSMO) recommend platinum-resistant patients receive non–platinum-based 2L therapies. The guidelines also recommend that platinum-sensitive patients (relapse >6 months) receive the original 1L regimen as a 2L re-challenge. However, this real-world study found that a significant proportion of platinum-resistant patients were re-challenged with a 2L platinum-based therapy. Conversely, in patients where platinum re-challenge is recommended, a large proportion did not receive platinum-based therapies in 2L.

Background:
The prognosis for patients with extensive stage small-cell lung cancer (ES-SCLC) is dismal. Immune suppression and systemic inflammation have been linked with outcomes for patients with a variety of malignancies, including lung cancer. The purpose of this study was to investigate the impact of baseline immune suppression and systemic inflammation as assessed with hematologic markers such as total lymphocyte count (TLC) and neutrophil-to-lymphocyte ratio (NLR) on overall survival (OS) in patients with ES-SCLC.

Method:
We retrospectively investigated 253 consecutive patients with pathologically and radiographically proven ES-SCLC treated at a single tertiary cancer center from 1998 through 2015. Potential correlations between initial complete blood counts & differential and other clinicopathologic characteristics were sought. Hematologic markers such as pretreatment TLC, NLR, platelet count, and platelet-to-lymphocyte ratio and other clinical characteristics including age, sex, performance status, race, TNM stage (M1a vs. M1b), weight loss, smoking status, number of initial chemotherapy cycles (<4 vs. ≥4 cycles), thoracic radiation therapy (TRT) dose (<45 Gy vs. ≥45 Gy), and receipt of prophylactic cranial irradiation (PCI) were evaluated for correlation with OS. Median values for each hematologic marker were used as cutoffs. Factors identified as important by univariate analysis were selected as covariates to construct a multivariate Cox model for OS.

Result:
Pretreatment TLC was below the lower limit of normal (i.e., <1.0×10[3]/µL) in 58 patients (23%). Median OS was 11.0 months for the entire cohort. Median OS time was significantly worse in patients with lower pretreatment TLC (TLC ≤1.5×10[3]/µL: 9.8 months, 95% confidence interval [CI] 8.9‒10.7 vs. TLC >1.5×10[3]/µL: 11.6 months, 95% CI 9.3‒13.9) and higher pretreatment NLR (NLR >4.0: 9.3 months, 95% CI 8.8‒9.8 vs. NLR ≤4.0: 13.9 months, 95% CI 11.2‒16.6). Multivariate analysis identified lower pretreatment TLC (hazard ratio [HR] 0.735, 95% CI 0.561‒0.962, P=0.025) and elevated pretreatment NLR (HR 1.534, 95% CI 1.182‒1.991, P=0.001) as being independent predictors of inferior survival. Six other clinicopathologic factors (age >63 years, being male, performance status score ≥2, having <4 initial chemotherapy cycles, TRT <45 Gy, and no PCI) were also shown to be independent predictors of worse OS in multivariate analysis (P<0.05).

Conclusion:
Pretreatment TLC and NLR are useful prognostic markers for OS in patients with ES-SCLC. These findings have important implications for stratifying patients with ES-SCLC for various treatment approaches, possibly including immune modulation.

Background:
The optimal thoracic radiation dose/fraction for limited-stage small cell lung cancer (SCLC) is still in debate. This study mainly aims to retrospectively compare the impact on local/regional progression-free survival (LRPFS) of different thoracic radiation dose/fraction schedules from two prospective trials.

Method:
Patients in the hyperfractionated arm received thoracic radiotherapy consisted of 1.5 Gy twice a day in 30 fractions to 45 Gy. Patients in the hypofractionated arm received 2.5 Gy daily in 22 fractions to 55 Gy. Kaplan-Meier method was used to estimate survival data. Multivariate prognosis analysis was made by Cox proportional hazard regression analysis.

Result:
Nighty-two and 96 patients were accrued into to the hyperfractionated and hypofractionated arm respectively. The 1-year, 2-year LRPFS rates of the two arms were 82.1%, 60.7% and 84.9%, 68.8% respectively (P=0.27). The median OS time (months) of the two arms were 28.3 and 22.0 respectively, while 1-year, 3-year, 5-year OS rates were 85.2%, 40.8%, 27.1% and 76.9%, 34.3%, 26.8% respectively (P=0.37). On multivariate Cox regression study, the time (days) from the initiation of chemotherapy to thoracic radiotherapy (TCT) ≤ 43 (HR: 0.397, 95%CI: 0.207-0.762, P=0.005) was independently associate with improved LRPFS. The time (days) from the start of chemotherapy to end of thoracic radiotherapy (SER) ≤ 63 (HR: 0.508, 95%CI: 0.322-0.762, P=0.044) and PCI (HR: 0.433, 95%CI: 0.298-0.630, P=0.000) were favorably related to OS. Grade 2 and 3 acute radiation esophagitis were observed in 28.3%, 8.7% and 15.5%, 2.1% of patients in hyper- and hypofractionated arm respectively (P=0.009). Figure 1



Conclusion:
Both hyperfractionated and hypofractionated radiotherapy had achieved good LRPFS and OS in this study, although there was no statistical significance between the two arms. Keep TCT ≤ 43, SER ≤ 63 resulted in better LRPFS and OS. However, the incidence of acute radiation induced esophagitis was significantly more common in the hyperfractionated arm than in hypofractionated arm.

Abstract not provided

Background:
Combination therapy with agents that target the molecular and cellular mechanisms of resistance to checkpoint inhibitor therapy (CIT) is a rational approach to restoring or improving the efficacy of CIT in patients with immunotherapy resistant NSCLC. Sitravatinib is a spectrum-selective TKI which targets TAM receptors (Axl, MER), split family receptors (VEGFR2 and KIT), and MET. Inhibition of these target classes by sitravatinib may enhance anti-tumor activity through targeted depletion of immunosuppressive Type 2 tumor associated macrophages, regulatory T cells and myeloid-derived suppressor cells (MDSCs) and increasing antigen presentation capacity of dendritic cells in the tumor microenvironment (TME) thereby enhancing anti-tumor T effector and NK cell responses. Given these pleiotropic immune activating effects, the combination of sitravatinib with nivolumab is a rational approach to restoring or enhancing the clinical activity of CIT in patients with immunotherapy resistant NSCLC.

Method:
MRTX-500 is a Phase 2 Study of sitravatinib in combination with nivolumab in non-squamous NSCLC patients who have experienced progression of disease on or after treatment with CIT. The primary objective is to assess the clinical activity of the combination using ORR by RECIST 1.1. Enrollment into the Phase 2 treatment arm is stratified by prior outcome of CIT (e.g., clinical benefit versus progression of disease in ≤12 weeks). The investigational agent sitravatinib is administered orally in continuous regimen; nivolumab is administered intravenously, 240 mg every 2 weeks. The sample sizes for the treatment arms are based on two-stage Simon Optimal Design.

Result:
The recommended phase 2 dose of the combination is 120 mg of sitravatinib orally, once daily with nivolumab given at a flat dose of 240 mg IV Q 2 weeks. As of June 20, 2017, the study has enrolled 11 patients and 6/11 patients have had at least one on-study tumor assessment. Two patients out of 6 have achieved PR by RECIST. The first patient is a 72 yo female with pan-wild type metastatic NSCLC with history of treated brain metastases with multiple prior therapies who previously received pembrolizumab (stable disease for 14 months) and obtained confirmed PR at first disease evaluation. The second patient is a 71 yo female with pan-wild type metastatic NSCLC with multiple prior therapies who previously received nivolumab (progressive disease as best overall response) but who obtained unconfirmed PR at first disease evaluation. Treatment has been associated with manageable side effects to date.

Conclusion:
This study is ongoing and actively accruing patients.

Background:
Studies have demonstrated that epigenetic modifiers, such as azacitidine, may sensitize tumor cells to treatment with checkpoint inhibitors, such as pembrolizumab (pembro). Efficacy and safety results from a phase 2, randomized, double-blind study of pembro in combination with CC-486, an oral formulation of azacitidine, vs pembro+placebo (PBO) for 2L treatment of advanced NSCLC are reported.

Method:
Patients aged ≥ 18 years with stage IIIB/IV NSCLC with only 1 prior platinum-based chemotherapy were randomized 1:1 (stratified by histology) to pembro 200 mg day 1 plus either CC-486 300 mg or placebo days 1-14 of a 21-day cycle. Primary endpoint was PFS. Key secondary endpoints included OS, ORR and safety.

Result:
51 and 49 patients were randomized to the pembro+CC-486 and pembro+PBO arms. Baseline characteristics were generally balanced between treatment groups. Efficacy results are shown in Table 1. Median duration of treatment for pembro+CC-486 vs pembro+PBO was 14 vs 24 weeks, and median number of cycles was 5 vs 7. The most common grade 3/4 TEAEs associated with pembro+CC-486 were nausea (14%), vomiting (12%), asthenia (10%), and diarrhea (8%), vs diarrhea (6%), asthenia (6%) and pneumonia (6%) with pembro+PBO. Patients treated with pembro+CC-486 vs pembro+PBO experienced a higher rate of pembro dose interruptions (29% vs 16%) and discontinuations (20% vs 10%), and a higher rate of CC-486 or PBO dose interruptions (61% vs 24%) and discontinuations (33% vs 12%). Gastrointestinal events, asthenia/fatigue, and elevated transaminase levels were the most common TEAEs leading to discontinuations.

Conclusion:
The addition of CC-486 to pembro did not improve the primary endpoint of PFS compared with pembro+PBO. PD-L1 expression did not appear to be predictive of CC-486 treatment efficacy. The increase in TEAEs in the combination arm, particularly gastrointestinal (nausea and vomiting), which are known to be associated with CC-486, may have influenced treatment exposure.

Efficacy Endpoints	Pembro + CC-486 n = 51	Pembro + PBO n = 49
Overall
PFS, median, months	3.1	4.0
ORR, n (%)	10 (19.6)	7 (14.3)
By PD-L1 Level at Baseline	n = 45	n = 44
PFS, median, months ≥ 50% ≥ 1%-49% 0%	5.5 1.6 3.6	8.0 1.4 3.9
ORR, % ≥ 50% ≥ 1%-49% 0%	37.5 20.0 18.5	37.5 0.0 7.1

Background:
ACY-241, an oral inhibitor of histone deacetylase 6, has demonstrated activity in preclinical NSCLC models in combination with immunotherapy. The objectives of this study are to evaluate safety, dose-limiting toxicities (DLTs), the maximum-tolerated dose (MTD), and preliminary antitumor activity of ACY-241 in combination with the immune checkpoint inhibitor nivolumab.

Method:
In the 3+3 dose-escalation design, previously treated patients with advanced NSCLC and ECOG PS of 0 or 1 will receive ACY-241 on days 1 to 28 of each 28-day cycle at 3 dose levels (180, 360, and 480 mg) in combination with nivolumab 240 mg on day 15 of cycle 1 and days 1 and 15 of each subsequent cycle. Antitumor activity will be assessed per RECIST v1.1 and immune-related response criteria (irRC).

Result:
As of 16 June 2017, 13 patients have been treated in the 3 dose-escalation cohorts. All patients had received first-line treatment with platinum-based chemotherapy. The median age of all patients was 66 years, 62% were male, 54% had an ECOG PS of 0, 54% had stage IV disease, and 85% had adenocarcinoma (15% had squamous histology). No DLTs were observed in the 180- or 360-mg ACY-241 cohorts. The 480-mg cohort is currently under investigation. The most common all-grade adverse events (AEs) in all cohorts were cough (15%), arthralgia (15%), and fatigue (15%, including grade 3 in 1 patient). One patient experienced a grade 3 cerebrovascular accident related to a brain metastasis but unrelated to study drug. No immune-related AEs have been observed. Six patients were evaluable for response: 2 experienced objective responses (1 complete and 1 partial); 2 patients had stable disease; 2 patients had disease progression. Two patients were not evaluable for efficacy, and 5 patients have not yet undergone a response assessment.

Conclusion:
No DLTs have been observed with ACY-241 at 180 or 360 mg. Preliminary antitumor activity has been observed with the combination treatment. Updated pharmacokinetic data will be presented at the meeting. NCT02635061

Abstract not provided

Background:
Nivolumab significantly improved overall survival (OS) versus docetaxel in patients (pts) with previously treated non-squamous non small cell lung cancer (non-Sq-NSCLC) in the Checkmate 057 study. In a pre-specified subgroup analysis of this trial, this advantage was confirmed also in patients (pts) with KRAS-mutation (KRAS+). However, since the number of KRAS+ pts enrolled in the trial was too small to draw definitive conclusions, the Italian nivolumab expanded access program (EAP) for non-Sq-NSCLC might represent an important source of information about this subpopulation. Here we report the results of the use of nivolumab in pts with KRAS mutation treated in the Italian EAP.

Method:
Nivolumab was provided upon physicians’ request for pts aged ≥18 years who had relapsed after a minimum of one prior systemic treatment for stage IIIB/stage IV non-Sq-NSCLC. Nivolumab 3 mg/kg was administered intravenously every 2 weeks for <24 months. Pts included in the analysis received ≥1 dose of nivolumab and were monitored for adverse events (AEs) using Common Terminology Criteria for Adverse Events.

Result:
Overall, 1588 pts with advanced non-Sq-NSCLC, enrolled in 168 sites, received at least one dose of nivolumab in the Italian EAP. Among 532 pts evaluated for KRAS mutation, 206 (39%) resulted positive. In this subgroup of pts, the best overall response rate (BORR) was 20%, including 2 pts with complete response and 39 pts with partial response. The median OS was 10.7 months (8.6-12.8), with a median follow-up of 7.7 months (0.1-21.2) and a median number of 8 doses (1-45). These results were in line with those ones showed in the overall population (18% BORR and 11 months median OS, respectively). Overall, among pts with KRAS mutation, 166 discontinued treatment for any reason, with only 14 (8%) pts who discontinued treatment due to adverse events, in line with what observed in the general population and in previous studies.

Conclusion:
To date, no direct targeted therapy is available for pts with KRAS mutation. This analysis seems to confirm, in a real word setting and in a larger number of pts, the results obtained with nivolumab in KRAS-positive pts in CheckMate 057, thus representing a potentially effective therapeutic option for this subpopulation.

Background:
The efficacy of immune check-point inhibitors (ICPi) in BRAF mutant non-small cell lung cancer (NSCLC) is largely unknown. The correlation with different parameters predicting efficacy of ICPi (e.g., PD-L1 expression, tumor mutational burden (TMB) and microsatellite instability status (MSI) in these tumors needs further evaluation.

Method:
A retrospective analysis of 30 patients with BRAF mutant advanced NSCLC treated between Aug 2013 and May 2017 was performed. The patients were divided into 2 groups: BRAF V600 E (Group A, N=16), non-V600E BRAF (Group B, N=14). PD-L1 was assessed by immunohistochemistry using 22C3 Dako antibody clone on Dako or Ventana's platform in 16 patients. TMB and MSI were assessed in 9 and 11 patients, respectively. Median progression-free survival (mPFS) with ICPi and targeted agents as well as median overall survival (mOS) were assessed in each group by Kaplan-Meier method.

Result:
Baseline characteristics of the cohort: median age 66y (range 39-98); males 53%; current/past smokers/never smokers/NA 13%/44%/40%/3%; adenocarcinoma/other histology 80%/20%; ECOG PS 0/1/2/3/4/NA 27%/33%/10%/13%/0%/17%. The distribution of TMB, PD-L1 expression and MSI status between the 2 groups is presented in Table 1. Ten patients received ICPi (nivolumab-8, pembrolizumab-2), and thirteen patients received anti-BRAF therapy (dabrafenib+trametinib-6, dabrafenib-4, vemurafenib-3). mOS and mPFS with ICPi and anti-BRAF therapy are summarized in Table 1. Four patients with BRAF V600 E PD-L1 ≥ 50% tumors were included in the series; one patients responded to dabrafenib+trametinib combination (response ongoing, 7.1months+); in two patients ICPi were initiated, response assessment pending. One patient with a non-V600E BRAF mutant NSCLC responded to dabrafenib for 6.7 months.Figure 1



Conclusion:
BRAF mutant NSCLC tumors are associated with high level of PD-L1 expression, low/intermediate TMB and MSI stable status. ICPi may induce prolonged responses both in BRAF V600E and non-V600E BRAF mutant NSCLC. Some non-V600E BRAF mutant NSCLC may benefit from anti-BRAF targeted therapy.

Background:
Pembrolizumab, a humanized monoclonal antibody that inhibits the interaction between programmed cell death 1 (PD-1) and programmed death-ligand 1 (PD-L1) has demonstrated significant antitumor activity and produced durable responses in non-small cell lung cancer (NSCLC). However, data to date suggests that responses are less frequent in patients whose tumors harbor mutations in the epidermal growth factor receptor (EGFR) gene. Our single center experience with the KEYNOTE-001 trial suggested that EGFR mutation positive NSCLC patients with a history of prior tyrosine kinase inhibitor (TKI) therapy had worse clinical outcomes than those who were TKI naïve. However, that analysis was limited by small sample size. As a result of this observation, we are currently enrolling an open-label, phase II trial, of front-line pembrolizumab in EGFR mutation positive NSCLC patients that are PD-L1+.

Method:
This is an open-label, phase II trial of pembrolizumab in patients with EGFR mutation positive NSCLC whose tumors are PD-L1 positive [>1% tumor membranous staining by immunohistochemistry (IHC), 22C3 pharmDx test in a CLIA certified laboratory]. Patients receive pembrolizumab 200mg by IV infusion every three weeks and are evaluated every 9 weeks +/- 1 week with radiographic imaging to assess response to treatment for a maximum of 35 trial treatments of pembrolizumab. After progression on pembrolizumab, patients are followed for evaluation of EGFR TKI efficacy. The primary end point of the study is objective response rate (ORR) to pembrolizumab, per RECIST 1.1. Secondary endpoints include safety and efficacy [progression-free survival (PFS), overall survival (OS)] of front-line pembrolizumab in this population, as well as efficacy [PFS, OS, ORR] of subsequent EGFR TKI after progression on pembrolizumab. Correlative analyses include whole exome sequencing and IHC of patient specimens. To date, 8 out of the 25 planned patients have been enrolled.

Result:
Section not applicable

Conclusion:
Section not applicable