Virtual Library

Background:
Mutant neoantigens generated from genetic alterations that are exclusively present in tumors represent highly promising cancer vaccine targets. However, publically available neoantigen prediction algorithms only identify and utilize single nucleotide mutations (SNVs) but not short insertion and deletions (INDELs). Short INDELs can lead to the generation of novel junctional or frameshift neoantigens which may be more immunogenic than neoantigens that result from single nucleotide missense mutations.

Method:
We developed a bioinformatics pipeline for neoantigen prediction using paired normal tissue and tumor exome sequencing, RNA sequencing and HLA binding prediction. 536 lung adenocarcinoma (LUAD) and 466 lung squamous cell carcinoma (LUSC) cases were analyzed using our bioinformatics pipeline. The non-synonymous somatic SNVs and short INDELs mutations were identified to generate a list of mutation neoantigen-derived and, when possible, their corresponding wild-type epitopes. Binding affinities of the paired wild-type and mutant peptides to HLA class I were then predicted and compared.

Result:
On average, 8.65 (range1-158) mutant neoantigen peptides per sample were identified in 395 out of 536 (73.6%) LUAD samples. Among them, 63.7% were SNVs and 36.3% were INDELs. On average, 8.54 (range 1-504) mutant neoantigen peptides per sample were identified in 360 out of 466 LUSC samples. Among those, 67% were SNVs and 33% were INDELs. Most neoantigen peptides are private in both LUAD and LUSC. The mutant neoantigen peptides identified from INDELs were predicted to have 3.9 (p = 2.42E-74) and 1.14 (p = 5.44E-67) fold higher HLA class I binding affinity than wild type peptide compared to those from SNVs in LUAD and LUSC respectively.

Conclusion:
Tumor INDELs may be a rich source of neoantigens with a higher predicted high HLA binding affinity in lung cancers that warrant consideration in development of a personalized cancer vaccine.

Background:
The genomic landscape of primary resistance to PD-1 blockade in lung adenocarcinoma (LUAD) is largely unknown. We previously reported that co-mutations in STK11/LKB1 (KL) or TP53 (KP) define subgroups of KRAS-mutant LUAD with distinct therapeutic vulnerabilities and immune profiles. Here, we present updated data on the clinical efficacy of PD-1/PD-L1 inhibitors in co-mutation defined KRAS mutant and wild-type LUAD patients and examine the relationship between genetic alterations in individual genes, tumor cell PD-L1 expression and tumor mutational burden (TMB) using cohorts form the SU2C/ACS Lung Cancer Dream Team and Foundation Medicine (FM).

Method:
The cohorts included 924 LUAD with NGS (FM cohort) and 188 patients with KRAS non-squamous NSCLC (SU2C cohort) who received at least one cycle of PD-1/PD-L1 inhibitor therapy and had available molecular profiling. Tumor cell PD-L1 expression was tested using E1L3N IHC (SU2C) and the VENTANA PD-L1 (SP142) assay (FM). TMB was defined as previously described and was classified as high (TMB-H), intermediate (TMB-I) or low (TMB-L).

Result:
188 immunotherapy-treated (83.5% nivolumab, 11.7% pembrolizumab, 4.8% anti-PD1/PD-L1 plus anti-CTLA-4) pts with KRAS-mutant NSCLC were included in the efficacy analysis. The ORR differed significantly between the KL (8.8%), KP (35.9%) and K-only sub-groups (27.3%) (P=0.0011, Fisher’s exact test). KL LUAC exhibited significantly shorter PFS (mPFS 1.8m vs 2.7m, HR=0.53, 95% CI 0.34-0.84, P<0.001, log-rank test) and OS (mOS 6.8m vs 15.6m, HR 0.53, 95% CI 0.34 to 0.84, P=0.0072, log rank test) compared to KRAS-mutant NSCLC with wild-type STK11. Loss-of function (LOF) genetic alterations in STK11 were the only significantly enriched event in PD-L1 negative, TMB-I/H compared to PD-L1 high positive (TPS≥50%), TMB-I/H tumors in the overall FMI cohort (Bonferroni adjusted P=2.38x10[-4], Fisher’s exact test) and among KRAS-mutant tumors (adjusted P=0.05, Fisher’s exact test) . Notably, PD-1 blockade demonstrated activity among 10 PD-L1-negative KP tumors, with 3 PRs and 4SDs recorded. In syngeneic isogenic murine models PD-1 blockade significantly inhibited the growth of Kras mutant tumors with wild-type LKB1 (K), but not those with LKB1 loss (KL), providing evidence that LKB1 loss can play a causative role in promoting PD-1 inhibitor resistance.

Conclusion:
Loss of function genomic alterations in STK11 represent a dominant driver of de novo resistance to PD-1/PD-L1 blockade in KRAS-mutant NSCLC. In addition to tumor PD-L1 status and tumor mutational burden precision immunotherapy approaches should take into consideration the STK11 status of individual tumors.

Background:
Baseline high derived NLR (dNLR>3, neutrophils/(leucocytes-neutrophils) ratio) has recently correlated with no benefit to immune checkpoint inhibitors (ICI) in advanced NSCLC, but the dynamic monitoring of dNLR has not been assessed in this population.

Method:
dNLR at baseline, at 2[nd] cycle and at progressive disease were retrospectively collected in advanced NSCLC patients treated with ICI from November 2012 to April 2017, in a multicentric cohort (N= 292) from 4 European centers. The primary endpoint was overall survival (OS), and secondary endpoints were progression free survival (PFS), response rate (RR) and disease control rate (DCR).

Result:
Out of 292 patients (67%) were males, 264 (92%) smokers and 239 (83%) with PS ≤1, with median age 64 years; 153 (52%) had adenocarcinoma and 114 (30%) squamous; 44 (15%) were KRASmut, 11 (4%) EGFRmut and 3 (1%) ALK positive. PDL1 was ≥ 1% by immunohistochemistry in 67 (76%), negative in 21 (24%) and unknown in 204 patients. The median of prior lines was 1 (0-10). The median follow-up was 12 months (m) [11-14]. The median PFS and OS were 4m [3-5] and 11m [9-15]. Baseline dNLR was>3 in 106 patients (36%) and at 2[nd] cycle in 90 patients (32%). dNLR>3 at baseline and at 2[nd] cycle were associated with poor PFS (p<0.0001 and p=0.0008, respectively), poor OS (both p<0.0001) and progressive disease (p=0.002 and p=0.005, respectively). At 2[nd] cycle of ICI, the dNLR status (> high or ≤ 3 low) changed in 63 patients: in 38 (14%) dNLR decreased; in 25 (9%) dNLR increased. According to the dNLR monitoring (combining dNLR at baseline et at 2[nd] cycle), the median OS was 17m (95%CI 13-NA) when dNLR remained low (n=153), 10m (95%CI 7-NA) when dNLR changed (n=64) and 4m (95%CI 3-7) when dNLR remained high (dNLR>3, n=64, p<0.0001).The dNLR monitoring was also associated with PFS (p=0.002), RR and DCR (p=0.003 and p=0.013, respectively).

Conclusion:
Monitoring dNLR at baseline and at 2[nd] cycle could be a routinely tool to early assess benefit to ICI in NSCLC patients on treatment. The dNLR monitoring showed a strong correlation with OS and PFS. Modification of dNLR between baseline and 2[nd] cycle impacts outcomes in NSCLC patients treated with ICI.

Background:
Recent clinical trials have demonstrated the efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer (NSCLC). However, not all the patients receive survival benefit from these immunotherapies. In an attempt to refine the current strategy of cancer immunotherapy to treat NSCLC, we examined the influence of tumor-infiltrating lymphocytes (TILs) on postoperative survival.

Method:
We evaluated the prognostic significance of TILs (CD4[+], CD8[+], and FOXP3[+]) comprehensively by immunohistochemical (n = 234) and immune-related gene expression analysis (n = 58), and explored the relationship between immune features and clinical characteristics including histological types, smoking habit, epidermal growth factor receptor mutation, and postoperative survival.

Result:
Compared with non-adenocarcinoma (non-AD) patients, adenocarcinoma (AD) tumors had significantly higher number of tumor-infiltrating CD4[+] T cells (P < 0.05) but lower CD8[+] T cells and FOXP3[+] T cells (P < 0.01). We found higher accumulation of CD8[+] T cells in non-AD patients was correlated with longer survival, indicating it is a better prognostic factor (P < 0.02). On the contrary, high accumulation of CD8[+] T cells and FOXP3[+] T cells were identified as unfavorable prognostic factors (P < 0.05) in AD patients, particularly in AD nonsmokers (P < 0.02). The expression of activated T cell-related genes including interferon gamma and granzyme was associated with CD8[+] T-cell accumulation in non-AD patients, but not in AD patients, especially in AD nonsmokers. Infiltrating CD8[+] T cells were significantly less activated in immunosuppressive microenvironment with high expression of immunoregulation related genes including GATA3, IL13, CCR4 and CCL17 in AD nonsmokers (P < 0.05). In AD nonsmokers, there are possibly immunodysfunctional CD8[+] GATA3[+] T cells (P < 0.01) and immunoregulatory CD8[+] FOXP3[+] T cells (P < 0.01), accompanied by immunoregulatory CD4[+] FOXP3[+] CCR4[+] T cells (P < 0.01) that may be recruited by CCL17 produced by tumor-associated CD163[+] macrophages (P < 0.05) in IL13-associated tumor microenvironments (P < 0.05).

Conclusion:
In contrast to presence of activated CD8[+] T cells in non-AD, CD8[+] T cells are not activated, and may include dysfunctional and immunoregulatory T cells, accompanied by FOXP3[+] regulatory T cells and M2-like macrophages in IL13-associated tumor microenvironment of AD nonsmokers. Our study suggests that modulation of such immunosuppressive condition may be an attractive strategy for treatment of AD nonsmokers including immune-checkpoint blockade.

Abstract not provided

Background:
The checkpoint inhibitors programmed cell death and its ligand (PD-L1) antibodies are promising treatment agents for patients with advanced non-small cell lung cancer (NSCLC). Their clinical efficacy is predicted by drug-tailored PD-L1 immunohistochemistry (IHC) assays. We aimed to identify the similarity and distinction of 22C3 and 28-8 IHC tests.

Method:
Three hundred and ninety consecutive cases of completely resected NSCLC between January 2009 and September 2014 that had adequate tissue samples were investigated. From the archived samples, 5-μm thick sections were cut and stained with PD-L1 IHC 22C3 PharmDx and 28-8 PharmDx (Dako, Santa Clara, CA). The staining and evaluation in 22C3 and 28-8 test were performed by two separate laboratories. PD-L1 expression and high PD-L1 expression were defined as ≥1% and ≥50% of tumor cells stained, respectively. Statistical significance was defined as a p-value of <0.05.

Result:
The study population included 288 patients with adenocarcinomas, 70 with squamous cell carcinomas, 18 with large cell carcinomas, 9 with adenosquamous carcinoma and 5 with pleomorphic carcinoma. Two hundred and ninety-three patients had pStage I; 47, pStage II; and 46, p Stage IIIA tumors. Two hundred and twenty-nine specimens showed no PD-L1 expression with either 22C3 or 28-8. The detection rate of PD-L1 expression was 36.9% (144 cases) with 22C3 and 35.6% (139 cases) with 28-8, respectively (p= 0.710). The detection rate of high PD-L1 expression was 16.9% (66 cases) with 22C3 and 9.0% (35 cases) with 28-8 (p= 0.0013). The Spearman correlation coefficient was 0.866 (95% confidence interval, 0.838–0.890; p< 0.0001). Figure 1



Conclusion:
22C3 IHC assay may be more sensitive to detect high PD-L1 expression in NSCLC compard to 28-8 IHC assay, whereas 22C3 and 28-8 showed no significant difference to detect PD-L1 expression. Further investigation is necessary to reveal clinical, pathological and molecular background. This approach will help better interpretation of PD-L1 IHC results.

Background:
Tumor PD-L1 IHC relates moderately with treatment outcome following anti-PD1 therapy in pts with NSCLC and single biopsies do not account for tumor heterogeneity. Aim: 1. Assess safety of the PET procedures. 2. Quantify [89]Zirconium-labeled nivolumab ([89]Zr-nivo) and [18]F-labeled BMS-986192 ([18]F-PD-L1) uptake. 3. Assess tracer uptake heterogeneity. 4. Correlate tracer uptake with PD-1/PD-L1 IHC in tumor, stroma and with treatment outcome.

Method:
NSCLC pts eligible for treatment with nivolumab were included. Pts received whole body [18]F-PD-L1 and [89]Zr-nivo PET scans. Baseline tumor biopsy was required to assess PD-(L)1 IHC status (28.8 assay). SUV~peak~ was calculated for delineable lesions and correlated to PD-(L)1 IHC and response after 12 wks of nivolumab treatment.

Result:
10 pts (3 ≥50%, 5 ≥1%, 5 negative by PD-L1 IHC) were enrolled and 37 lesions analysed. No toxicity related to radiotracer was observed. Tumor uptake of both tracers was visualized in all pts, but not in all lesions. Tracer uptake varied among pts with mean [18]F-PD-L1 SUV~peak~ 4.6, range 0.5 - 14.4 and mean [89]Zr-nivo SUV~peak~ 5.0, range 1.6 – 11 (p=0.03) and within pts with mean SUV~peak~ difference 3.6-fold (±2.1) and 2.4-fold (±0.77) between lesions for [18]F-PD-L1 and [89]Zr-nivo, respectively. For lesions with ≥50% PD-L1 IHC, mean [18]F-PD-L1 SUV~peak~ was 8.0 (±4.7) as compared to 3.5 (±1.6) for lesions with <50% PD-L1 IHC (p=0.03). For tumors with high TIL/ stromal PD-1 expression, mean [89]Zr-nivo SUV~peak~ was 8.6 (±2.4) as compared to 6.1 (±2.1) for lesions with low PD-1 expression (p=0.1). Mean SUV~peak ~for [18]F-PD-L1 was 8.4 (±5.4) for pts with PR and 4.5 (±2.9) for pts with PD/SD (p=0.3). Mean SUV~peak~ for [89]Zr-nivo was 7.8 (±1.8) for pts with PR and 5.4 (±2.2) for pts with PD/SD (p=0.2).

Conclusion:
1. PET-imaging with both tracers is safe and feasible, with good tumor-to-normal tissue contrast. 2. Tumor uptake showed heterogeneity among pts and among tumors within pts. 3. Pts with ≥50% tumor PD-L1 expression showed higher [18]F-PD-L1 uptake. 4. Pts with high PD-1 expression showed higher [89]Zr-nivo uptake, and pts with PR demonstrated higher [18]F-PD-L1 and [89]Zr-nivo tracer uptake than pts with PD/SD, although these are without statistical significance which may be due to the small dataset.

Background:
Immunotherapy has become one of the options among the treatments of lung cancer. Nivolumab was first proven to have the utility as a second line treatment for non-small cell lung cancer. However, predictive factor of its efficacy is unknown. In recent years, studies have evolved on circulating tumor DNA (ctDNA). Clinical applications expanded and included prediction of prognosis, monitoring treatment effects and acquired resistance of driver genes, and assessment of residual tumor burden of resected cancer. In this study, we took cases in which tumor tissue was surgically resected or obtained by biopsy and the corresponding somatic mutations in plasma were studied. Then, we used these somatic mutations presumably derived from original tumor tissue as “tumor markers”. We took serial blood samples before and after starting nivolumab and examined to see whether early change of the level of ctDNA can predict long term treatment outcomes.

Method:
Fourteen patients who were treated by nivolumab from February 1st to September 30th in 2016 were studied. Peripheral blood samples were collected from the patients before, 1, 2, 4, 6 and 8 weeks after the initiation of nivolumab treatment. To identify somatic mutations in tissue and total plasma DNA, we performed targeted sequencing using “lung cancer panel” spanning whole exons of these 53 genes, and next generation sequencing was performed. Gene mutations detected in both tumor tissue and plasma were defined here as circulating tumor DNA (ctDNA). Early response of the level of ctDNA after starting nivolumab was evaluated to see whether it could predict treatment outcome.

Result:
Of 14 cases, 6 cases were Responders, and 8 Non-responders. ctDNA was detected more often in the serial plasma samples of patients carrying high tumor burden (p=0.02). In addition, basal and serial ctDNA analysis revealed that decrease of allelic frequency (AF) level within 2 weeks correlated with the good durable response, and on the contrary, the increase with no or poor response.

Conclusion:
In patients carrying high tumor burden, plasma analysis of ctDNA which was validated by tumor tissue, revealed the durable good response of nivolumab could be predicted within 2 weeks.

Background:
Association between T-effector (Teff) gene expression (GE), a marker of pre-existing immunity, and OS benefit with atezolizumab (anti–PD-L1) was demonstrated in the Phase II study POPLAR of atezolizumab vs docetaxel in 2L+ NSCLC. We analyzed Teff GE association with atezolizumab efficacy in a larger Phase III study, OAK.

Method:
Patients with 2L+ NSCLC were randomized to receive atezolizumab or docetaxel. Teff signature was defined by 3 genes (PD-L1, CXCL9, and IFNγ), and Teff GE was measured by averaging the normalized expression of each gene. Teff GE subgroups were defined by quartiles. PD-L1 expression was assessed using the SP142 IHC assay; the TC1/2/3 or IC1/2/3 subgroup had ≥ 1% PD-L1 expression on tumor cells (TC) or tumor-infiltrating immune cells (IC).

Result:
753 of 850 patients from the OAK primary analysis constituted the biomarker evaluable population (BEP) for Teff GE. Expression of the Teff signature was associated with PD-L1 expression by IHC (P = 7.3×10[−45]). Although no significant PFS benefit with atezolizumab vs docetaxel was observed in the BEP (HR, 0.94 [95% CI: 0.81, 1.10]) or the TC1/2/3 or IC1/2/3 subgroup (HR, 0.93 [95% CI: 0.76, 1.15]), a gradient of improved PFS benefit with atezolizumab was observed with increasing Teff GE. Significant PFS benefit occurred with ≥ median Teff GE cutoff (HR, 0.73 [95% CI: 0.58, 0.91]; Table). Teff GE also enriched for improved OS; however, a trend toward OS benefit was still observed in patients with low Teff GE (Table).

Table. PFS and OS with atezolizumab vs docetaxel by PD-L1 IHC and Teff GE subgroups
	PFS, HR (95% CI)	OS, HR (95% CI)
OAK primary population (N = 850)[a]
ITT[a]	0.95 (0.82, 1.10)	0.73 (0.62, 0.87)
TC1/2/3 or IC1/2/3[a ](n = 463)	0.91 (0.74, 1.12)	0.74 (0.58, 0.93)
TC2/3 or IC2/3[a] (n = 265)	0.76 (0.58, 0.99)	0.67 (0.49, 0.90)
OAK BEP for Teff GE (N = 753)
BEP	0.94 (0.81, 1.10)	0.71 (0.59, 0.85)
TC1/2/3 or IC1/2/3 (n = 420)	0.93 (0.76, 1.15)	0.74 (0.58, 0.95)
Teff GE subgroups
≥ 25% (n = 570)	0.91 (0.76, 1.09)	0.67 (0.54, 0.83)
< 25% (n = 183)	1.11 (0.82, 1.49)	0.87 (0.63, 1.21)
≥ 50% (n = 379)	0.73 (0.58, 0.91)	0.59 (0.46, 0.76)
< 50% (n = 374)	1.30 (1.05, 1.61)	0.87 (0.68, 1.11)
≥ 75% (n = 190)	0.66 (0.48, 0.91)	0.60 (0.42, 0.87)
< 75% (n = 563)	1.10 (0.92, 1.31)	0.76 (0.62, 0.92)
[a]Rittmeyer A. et al. Lancet, 2017;389:255-265. NCT02008227.

Conclusion:
This is the first demonstration of the association between markers of Teff biology and clinical outcomes with cancer immunotherapy in a randomized Phase III trial. Teff GE may reflect pre-existing immunity and be a more sensitive biomarker compared with PD-L1 IHC, identifying more patients (50% prevalence) likely to experience PFS benefit with atezolizumab.

Abstract not provided

Background:
Immunotherapy has become a promising recourse for lung cancer therapy. The endothelium separates circulating immune cells and the tumor microenvironment, and it is necessary for immune cells to penetrate this barrier to accost the tumor. This requires cell-matrix interactions via endothelial adhesion molecules(EAM) such as selectin and integrin. While it is expected that higher expression of EAM is linked to greater immune cell infiltration in general, little is known as to its actual effect on various types of immune cells in human lung cancer.

Method:
Based on the TCGA database, mRNA-seq values of genes related to the leukocyte recruitment cascade were analyzed in 504 patient samples with lung squamous cell carcinoma(SCC) and 522 patient samples with lung adenocarcinoma. The genes were divided into 3 sets: rolling, firm adhesion, and transmigration. Immune cell infiltration of each set was analyzed using Gene Set Enrichment Analysis(GSEA), and p values were derived from Fisher’s exact and Chi-squared tests.

Result:
In lung SCC, overexpression(z score>2.0) of the above genes was statistically significantly correlated with decreased infiltration of activated CD4/CD8 T cells, but increased infiltration of activated B/Treg cells (Figure1). Similar trend was also observed in lung adenocarcinoma. Macrophage, dendritic cells, and natural killer cells showed increased infiltration in the EAM overexpression groups of both SCC and adenocarcinoma. Overall survival showed no significant difference in all three EAM gene overexpression groups in both types of lung cancer.Figure 1



Conclusion:
We demonstrate for the first time that overexpression of EAM genes is linked to differential infiltration of various immune cells (including decreased CD4/CD8 T cells and increased activated B/Treg cells) in human lung cancer tissue. Recruitment of B/Treg cells by EAM may have an impact on inactivation of infiltrated T cells in the tumor microenvironment. This suggests that EAM status may serve as a predictive biomarker for T cell-mediated immunotherapy.

Background:
Lung cancer development is driven by the expression of mutant oncogenes, with EGFR and KRAS the most frequent in lung adenocarcinoma. However, these mutations alone are not sufficient for tumorigenesis suggesting additional factors influence tumour development and progression, including the balance of anti-tumour immune effector cells and pro-tumorigenic immune suppressor cells. Tumour cells can evade immune surveillance by producing cytokines to recruit immune modulatory cells that promote an immune suppressive environment, such as regulatory T cells (Tregs). We hypothesized that oncogene signaling regulates the production of cytokines by tumour cells in order to recruit immune suppressive cells and promote lung tumour development.

Method:
We used CIBERSORT to quantify 22 immune cell types in over 300 human lung adenocarcinoma and 100 matched normal lung tissues, and validated findings with immunohistochemistry. Cells expressing doxycycline inducible EGFR[L858R] and KRAS[G12V]were analyzed for cytokine production using a multiplex assay (LUMINEX). EGFR (Afatinib) and MEK (Trametinib) inhibitors were used in lung cancer cell lines harbouring EGFR or KRAS mutations and cytokine production was quantified using ELISA. Conditioned media from EGFR[L858R] and KRAS[G12V] expressing cells were used in a trans-well assay to determine if secreted cytokines could induce Treg migration. Transgenic mouse models of lung adenocarcinoma and bronchoalveolar lavage (BAL) from patients with and without lung cancer were used to assess CCL5 and Tregs in vivo.

Result:
Treg cells were significantly enriched in lung tumours and not normal tissue. CCL5 production is increased rapidly upon oncogene induction and subsequent transformation of normal cells and is dependent on sustained ERK signaling for continued expression. Conditioned medium from EGFR[L858R] expressing cells increased Treg migration, which was mitigated by an anti-CCL5 antibody. Transgenic mice expressing EGFR[L858R ]or KRAS[G12D] in the lung epithelium recruited Tregs to the lung upon tumor induction. Assessment of CCL5 in BAL from patients with and without lung cancer is currently in progress.

Conclusion:
Oncogene driven ERK signaling may regulate expression of CCL5 from lung tumour cells, and oncogene induced CCL5 production stimulates Treg migration ex vivo. These data suggest CCL5-mediated Treg recruitment to lung tumours may occur in early stages of lung tumour development and that targeted inhibition of CCL5 or ERK signaling may represent therapeutic strategies to block recruitment of immunosuppressive Tregs by lung tumours.

Background:
Tumor-associated macrophages (TAMs) with immunosuppressive and tumor promoting features are attractive targets for immunotherapy. MARCO is a scavenger receptor expressed on a subpopulation of macrophages in secondary lymphoid organs. A recent study performed in animal models concluded that treatment with an anti-MARCO antibody results in reprogramming of the TAMs and inhibition of tumor growth and metastatic spread. The expression and function of MARCO in lung cancer TAMs is not known.

Method:
The infiltration of TAMs expressing MARCO, CD68, CD163 and MSR1, in the tumor and stromal compartments, was analyzed by immunohistochemistry in a non-small cell lung cancer (NSCLC) cohort (n=352). In addition, PD-L1 expression was assessed on tumor cells. Immunofluorescence was performed on selected cases to evaluate marker co-expression. Associations to immune cells and regulatory inflammatory pathways were studied in a subset of cases (n=174) with available RNA-seq data.

Result:
A large variance in TAM density could be observed between cases as well as a strong correlation between CD68 and CD163, indicating a pro-tumor phenotype of infiltrating macrophages. Correlation to clinical data showed a trend towards worse survival for patients with high macrophage infiltration. TAM expression of MARCO was seen on a subpopulation of pro-tumor macrophages. The majority of MARCO expressing TAMs were found to be located within tumor cell nests. Interestingly, stromal macrophages expressing MARCO tended to aggregate in close proximity to the tumor nests. On the transcriptomic level, increased MARCO gene expression correlated to genes linked to immunosuppressive TAMs, T-cell infiltration and immune checkpoint molecules like PD-L1 and CTLA-4. The association between macrophage infiltration and tumor cell PD-L1 expression was confirmed by immunohistochemistry. Also, co-expression of PD-L1 and MARCO could be detected on certain macrophages within the tumor cell nests.

Conclusion:
MARCO expression characterizes a specific subpopulation of pro-tumor macrophages that are enriched in PD-L1 positive NSCLC cases. Patients with significant infiltration of MARCO positive TAMs could benefit from treatment with anti-MARCO antibodies, possibly in combination with available immune checkpoint inhibitors.

Background:
STING is a protein that promotes type I IFN production (IFNα/β) essential for activation of dendritic cells and antigen presentation and priming of T-cells. The cytoplasmic DNA sensor cGAS (cGAMP Synthase) is able to detect tumor DNA, and in response will synthesize cGAMP. cGAMP binds STING specifically, resulting in production of type I IFN. STING is therefore referred to as an adaptor protein essential for immune signaling following detection of tumor DNA. Analysis of the TCGA database indicates decreased survival in lung adenocarcinoma patients lacking STING expression. STING expression is decreased in tumor tissues and can be lost as the tumor progresses. One reported mechanism of loss of STING or cGAS in tumors is due to hypermethylation, a common occurrence in lung cancer. Agonists of STING show potent immune response and are currently in clinical trials. Importantly, recent studies show that expression of STING and cGAS proteins are essential for response to PD-1:PD-L1 blockade.

Method:
Section not applicable

Result:
We analyzed 55 NSCLC and 39 SCLC cell lines, and 317 NSCLC and 78 SCLC tissues for STING and cGAS expression using immunohistochemistry. 14/55 (25.45%) NSCLC cell lines and 25/39 (64.10%) SCLC cell lines showed no STING expression. Separated in to adenocarcinoma (AC) and squamous cell carcinoma (SCC) subsets, STING expression in AC shows loss of STING as tumor stage increases (Positive: 70% Stage I, 65% Stage II, 52% Stage III, 40% Stage IV, 71% total; n=156) while STING expression is low at all stages of SCC (Positive: 29% Stage I, 18% Stage II, 36% Stage III, 13% Stage IV, 27% total; n=161). SCLC tissues stained showed widespread loss of STING (Positive: 40% Stage I, 27% Stage II, 31% Stage III, 100% Stage IV, 37.18% total, n=78). Expression of cGAS was higher in AC (94%) than SCC (75%) and showed no correlation with stage. TCGA analysis of STING methylation shows hypermethylation in AC (0.15- ± 0.13 tumor vs 0.05 ± 0.02 normal, n=422) and SCC (0.23 ± 0.16 tumor vs 0.04 ± 0.03 normal, n=359). cGAS shows slight methylation in AC (0.05 ± 0.07 tumor vs 0.05 ± 0.01 normal, n=422) but a large increase in SCC (0.19 ± 0.24 tumor vs 0.04 ± 0.01 normal, n=359).

Conclusion:
This study indicates drastic differences in STING and cGAS expression in AC, SCC, and SCLC. Differential expression of these proteins could impact the efficacy of STING agonists, radiation therapy, and immunotherapy in lung cancer.

Abstract not provided

Background:
The avoidance of immune surveillance by tumor cells is an accepted hallmark of cancer. The aim of this study was to describe the natural immune landscape of NSCLC tissue, to identify important regulatory associations and potential targets of immune response. This includes mutational load and cancer testis antigen (CTA) expression, and the comprehensive analysis of tumor infiltrating immune cells in connection with immune signaling and clinical information.

Method:
Tissue microarrays including duplicate cancer samples of 357 NSCLC patients were stained with antibodies against CD3, CD4, CD8, CD45RO, FoxP3, CD20, CD138, and CD44 to analyze the protein expression in the stroma and tumor compartment. For 197 of these cases, corresponding RNA-seq data were available. The immunological data were correlated to the transcriptomic data and to patients’ clinical outcome. The mutation status and the mutational load was based on a targeted next-generation sequencing panel of 82 genes (HaloPlex).

Result:
The immune cell infiltration was predominantly in the stroma, although CD8 and FoxP3 cells also showed relevant infiltration of the tumor cell compartment. The amount of T-cells of different subsets and CD20-positive B-cells correlated positively to each other. A higher mutational load was associated with higher CD8 T-cell infiltrates, CD45RO cells, FoxP3 regulatory cells as well as CD20-positive B-cells in the tumor compartment. In contrast, the number of expressed CTAs were associated with an abundance of CD45RO-positive cells in the stromal compartment. Only CD44-positivity (HR = 0.61, p< 0.01) as well as high CD20 positive B-cells (HR = 0.34, p< 0.01) and plasma cell (CD138, HR = 0.71, p< 0.05) counts in the tumor, and for plasma cells also the stromal (HR = 0.61, p< 0.01), compartment were associated with longer overall survival.

Conclusion:
Here we describe natural immune profiles in a large clinical NSCLC patient cohort. Interestingly both mutational load and CTA expression is associated with the abundance of distinct immune cell infiltrates. We could not confirm the impact of tumor infiltrating T-cells on survival. However, the consistent prognostic impact of both B-cell markers indicates a major role of the humoral immune response in lung cancer.

Background:
Immunohistochemical (IHC) testing for programmed death ligand 1 (PD-L1) expression by non-small cell lung cancer (NSCLC) specimens has become standard of care to help select immune checkpoint inhibitor therapy. The companion IHC assay for pembrolizumab has been validated and approved for use on surgical pathology specimens; however, the performance of this assay when applied to cytology specimens is not well characterized.

Method:
Following IRB approval, all NSCLC cytology or surgical pathology specimens obtained from 11/2015 to 5/2017 at our institution that were tested for PD-L1 expression by a commercial vendor (Integrated Oncology/LabCorp, NY) using the FDA-approved companion diagnostic PD-L1 clone 22C3 pharmDx kit on the Dako Automated Link 48 platform (Dako, Carpenteria, CA) were identified. Patient cohorts where testing was performed on diagnostic cytology vs. surgical pathology specimens were compared. Tumor PD-L1 expression was stratified by clinically relevant groups: <1%, 1-49%, and ≥50%. Tumor genotyping results for EGFR, KRAS, ALK, and ROS1 were also collected.

Result:
Cytology formalin-fixed paraffin-embedded (FFPE) cell blocks included endobronchial ultrasound transbronchial needle aspirates (57%), pleural/pericardial fluids (28%), fine needle aspirates (13%), and bronchial washings/lavages (2%). Surgical FFPE specimens included small core/incisional biopsies (60%), bronchial biopsies (12%), and large resections (28%). PD-L1 testing was successful for over 96% (223/232) of specimens (Table). Overall, EGFR mutations were more frequent with no/low PD-L1 expression, ALK rearrangements with high PD-L1 expression, but no relationship between KRAS mutations and PD-L1 expression.

PD-L1 Tumor Proportion Score Stratified by Specimen Type

	Cytology Cell Block	Surgical Pathology
<1% PD-L1 TPS	35 (37.2%)	52 (37.7%)
1-49% PD-L1 TPS	20 (21.3%)	35 (25.4%)
≥50% PD-L1 TPS	33 (35.1%)	48 (34.8%)
Failed Analysis	6 (6.4%)	3 (2.2%)
Total	94 (100%)	138 (100%)

Chi-squared value=2.95, p>0.39 (not significant); TPS=tumor proportion score

Conclusion:
For NSCLC, no statistically significant differences in PD-L1 expression patterns were observed between cytology cell block and surgical pathology specimens, implying that in clinical practice any adequate cytology cell block or surgical pathology specimen could be utilized for testing. Importantly, analysis of clinical outcomes with use of first line pembrolizumab based on cytology vs surgical pathology specimen PD-L1 ≥50% expression is currently ongoing.

Background:
Advances in understanding of immune checkpoint inhibitors, have resulted in FDA approvals of anti-PD-1/PD-L1 inhibitor therapies for clinical use in nonsmall cell lung cancer (NSCLC). Detecting PD-L1 expression, as a predictive biomarker using companion diagnostic test (PD-L1 IHC 22C3 pharmDx), helps us identify NSCLC patients eligible for anti-PD-1 therapy (Pembrolizumab). Tumor Proportion Score (TPS) >50% and TPS >1% qualitatively estimated, by PD-L1 IHC 22C3 pharmDx test, are cut-offs which indicate use of Pembrolizumab as monotherapy in first line (TPS >50%) or second line (TPS >1%) settings for NSCLC. Intratumoral heterogeneity of PD-L1 expression in NSCLC is known. Approximately 60% of NSCLC present with advanced stage of disease. Tissue sampling of metastatic sites for initial diagnosis using core needle biopsy or fine needle aspiration techniques is common clinical practice. Significant body of literature is not available to address the issue of PD-L1 expression at metastatic sites and its concordance/discordance with primary lung tumor. We decided to look at cases with repeat request for PD-L1 testing at alternate sites or on subsequent tumor resections.

Method:
Our departmental anatomic pathology database was queried to search for NSCLC cases wherein PD-L1 immunohistochemistry was performed in our laboratory using companion diagnostic test (PD-L1 IHC 22C3 pharmDx) on AutoLink 48 autostainer as per protocol, and reported by one of our pathologists. Analysis was performed to determine additional PD-L1 IHC test requests for same patient and subsequent subgroup analysis to determine test results and other parameters such as type of specimens, tumor sites, and concordant/discordant results.

Result:
PD-L1 IHC 22C3 pharmDx test request was received on 460 NSCLC patient specimens in last six months. Of these, in twenty-five patients testing was attempted/performed on two tissue specimens, with final results reported in eighteen patients. Discordant results are noted in four patients (22.22%). In an additional patient, reported level of PD-L1 expression (low) was concordant; however reported TPS (5% & 45%) was different.

Conclusion:
Currently, in routine clinical practice, PD-L1 IHC test results are usually reported on a single tissue specimen. However, when tested on separate site/s or specimen type/s, our results suggest, that one can observe discordant results. At the lower end of results (PD-L1 negative or low expression), this can impact therapeutic decisions. Though a larger study is necessary to address this issue, one can suggest, that PD-L1 IHC testing should be performed on multiple site specimens, especially when temporally separated, in best interests of patient care.

Background:
To search actionable driver mutations, various cancer panels using next-generation target sequencing technologies are rapidly developed and adopted in the treatment of lung cancer. We developed a new cancer panel to detect 313 coding gene mutations, 30 fusion and 3 exon-skipping genes including either known or potential target genes. Performance of the panel was tested on our archived lung cancer tissue bank samples.

Method:
Two hundreds and two samples were tested (male 118, female 84, median age 63 (30-84) years). Histologic cell types were mainly adenocarcinoma (adenocarcinoma 158, squamous cell 25, large cell 6, sarcomatous 3, small cell 1, and mixed cell types 9).

Result:
With our cancer panel, 139 samples (68.8%) were identified to have mutations including 88 EGFR, 23 KRAS, 8 MET mutations, 7 ALK, 6 RET, 3 ROS1, 6 rare fusions (PTEN, BRAF, MET, CBFB, EWSR1, BCR), and 18 CNV alterations. Medical records revealed that traditional single-site tests including Sanger sequencing of EGFR, KRAS mutations and either immunohistochemical stain or FISH test for ALK or RET fusion had been performed in 191 patients. Among those patients, we identified 102 pathogenic mutations (53.4%) including 80 EGFR, 14 KRAS mutations, 6 ALK, and 2 RET fusions. Conventional single-site test results matched with that of cancer panel in 139 samples (72.8%). Cancer panel detected additional mutations in 48 samples (25.1%; 38 from the single-site test negative and 10 from positive samples). In two samples, the results showed discrepancy while in the other two, mutations were detected only in single-site test. However additional tests revealed cancer panel results to be correct. Excluding 4 patients with M1 stage, 198 patients’ long-term survival were analyzed according to the mutational status. In Cox’s proportional hazard model, presence of EGFR mutation was the only prognostic marker that predicted long-term survival along with clinical variables such as age, pT-stage, and pN-stage.

Conclusion:
In our results, we confirmed superior accuracy of our cancer panel compared to the traditional single-site tests. Furthermore, the new cancer panel discovered novel mutations, of which significance requires future functional investigation and potential development of new target agents.

Abstract not provided

Background:
Receptor Activator of Nuclear Factor κappa-B (RANK) is a pathway involved in bone homeostasis. Recent evidence suggests that RANK signalling may also play a role in bone metastasis, and primary breast and lung cancers. The European Thoracic Oncology Platform (ETOP) Lungscape project allows evaluation of the prevalence of RANK expression and its clinical significance in a cohort of surgically-resected NSCLCs.

Method:
RANK expression was assessed on tissue microarrays (TMAs) using immunohistochemistry. Up to 4 cores per patient were analysed based on sample acceptance criteria. An H-Score (staining intensity + % cells stained) was used to assess RANK expression (positivity), as defined by at least 1 core with any degree of positive staining. Prevalence of RANK positivity and its association with clinicopathological characteristics, other cancer-related biomarkers (IHC ALK/MET/PTEN/PD-L1 expression and EGFR/KRAS/PIK3CA mutations) and patient outcome [Relapse-free Survival (RFS), Time-to-Relapse (TTR), Overall Survival (OS)] was explored in a subset of the ETOP Lungscape cohort. The prevalence of RANK overexpression (proportion of positive cancer cells ≥50%) was also investigated.

Result:
RANK expression was assessed in patients from 3 centers, a total of 402 from the 2709 patients of the Lungscape cohort, with median follow-up 44 months; 32.6% female, 40.8/54.2/5.0% adenocarcinomas (AC)/squamous cell carcinomas (SCC)/other, 44.8/28.4/26.9% with stage I/II/III, 20.6/57.7/18.9% current/former/never smokers (and 2.7% with unknown smoking status). Median was 74 months for both RFS and OS, while median TTR was not reached. Prevalence of RANK positivity was 26.6% (107 of the 402 cases), with 95% confidence interval (95%CI):22.4%-31.2%; significantly higher in AC: 48.2% (79 of 164 cases), 95%CI:40.3%-56.1%; vs SCC: 9.2% (20 of 218 cases), 95%CI:5.7%-13.8%; (p<0.001). RANK positivity was more frequent in females (38.9% vs 20.7% in males, p<0.001) and tumors≤4cm (30.7% vs 21.1% in tumors>4cm, p=0.031). Significant associations were also detected between RANK and PTEN expression in AC (RANK positivity 57.4% in PTEN expression vs 30.5% in PTEN loss; p=0.0011) and with MET status in SCC (RANK positivity 27.8% in MET+ vs 7.6% in MET-; p=0.016). No association with outcome was found. RANK overexpression was identified in 43 (10.7%; 95%CI: 7.9%-14.1%) cases.

Conclusion:
In this early-stage NSCLC cohort, RANK positivity (26.6% overall) is found to be significantly more common in adenocarcinomas (48.2%), females, patients with tumors of smaller size, with PTEN expression (in SCC) and MET positivity (in AC). No prognostic significance of RANK expression was found. Analysis of additional cases is ongoing and results will be presented.

Background:
Non-receptor tyrosine kinase (nRTK) pathways are aberrantly activated in cancer, and mutations in nRTKs have potential therapeutic and prognostic importance. Tumor profiling with next-generation sequencing (NGS)enables a gene’s entire coding sequence to be evaluated, facilitating the identification of novel non-synonymous single nucleotide polymorphisms (nsSNPs) in nRTKs.

Method:
We searched nsSNPs in 14 nRTKs in the tumors of advanced NSCLC patients (pts) at our institution that received NGS with Caris from 2013-2015. All mutations test-defined as pathogenic (PATH) or nsSNPs labelled variants of undetermined significance (VUS) were included. To classify VUS, nsSNPs underwent PolyPhen-2’s in silico analysis to predict pathogenicity. Any VUS predicted-damaging with PolyPhen-2 we denote pnsSNP. nsSNPs were then classified as occurring within or outside of the tyrosine kinase domain (TKD); JAK1-3 pseudokinase domain (PSKD) lesions were also described.

Result:
157 NSCLC pts were identified with median age 65 (range 26-85); 51% were male; 65% Caucasian, 35% African-American. 98 nRTK variants were found (93 nsSNPs and 5 PATHs). 5/5 PATHS were PIK3CA. 31/93 (33%) nsSNPs were pnsSNPs and spread among 30 pts. pnsSNPs were found in 12/14 nRTKs with median 2 (range 0-6). The most frequent were JAK3 (6/20 nsSNPs were pnsSNPs), BTK (5/8), ABL1 (3/12), JAK2 (3/11), CDK12 (3/9) and JAK1 (3/3). 66% were extra-TKD (28% were pnsSNP), 23% TKD-restricted (44%) and 11% PSKD of JAK1-3 (100%). There were 6 N-lobe PSKD, 3 C-lobe PSKD and 1 C-lobe TKD JAK1-3 pnsSNPs (Table 1) at PSKD-TKD contact sites known to harbor the majority of activating JAK mutations. 6/12 JAK pnsSNPs were in pts whose tumors were EGFR-/KRAS-/ALK-/ROS-/PDL1-. Table 1: JAK1-3 pnsSNPs in NSCLC patients.

JAK	VUS; allele frequency	Location	Accession Number; Minor allele frequency (ExAC)	Histology	Age, race, gender	Genomics (EGFR, KRAS, ALK or ROS1-rearranged, PDL1 (%))
JAK1	D660N; 66%	PSKD; N-lobe	rs368904859; T=2.0e-5	Adeno-carcinoma	66, C, M	Negative
	P674S; 9%	PSKD; N-lobe	None	Squamous	76, C, M	PDL1+ (5%)
	D739N; 47%	PSKD; N-lobe	rs759709239; T=3.3e-5	Large cell	43, C, M	KRAS+
JAK2	E621D; 30%	PSKD; N-lobe	None	Unspecified	65, AA, M	Negative
	D686H; 13%	PSKD; N-lobe	None	Adeno-carcinoma	55, C, M	Negative
	C1105F; 41%	TKD; C-lobe	None	Adeno-carcinoma	73, C, F	KRAS+, ROS1-rearranged
JAK3	V55E; 13%	FERM	None	Adeno-carcinoma	74, C, F	Negative
	Y105H; 21%	FERM	None	Squamous	68, C, F	PDL1+ (20%)
	R537Q; 47%	PSKD; N-lobe	rs587778413; T=4.1e-5	Adeno-carcinoma	60, C, F	PDL1+ (65%)
	L702P; 53%	PSKD; C-lobe	rs772117537; G=1.7e-5	Squamous	80, C, M	Negative
	P745L; 50%	PSKD; C-lobe	rs776106625; A=8.3e-6	Adeno-carcinoma	68, C, M	EGFR+ (E746_A750del)
	L788I; 7%	PSKD; C-lobe	None	Squamous	68, AA, M	Negative

Conclusion:
>19% NSCLC pts held a pnsSNP with 77% occurring outside of the TKD-proper. The majority of JAK1-3 pnsSNPs localized to the PSKD; their frequency and functional impact should be examined on a larger scale.

Background:
Genetic testing for alterations of oncogenic driver genes has become essential and standard in clinical practice. Germline mutations predisposing to lung cancer are rare, but there have been reports regarding germline mutations in EGFR, HER2, BRCA2, CDKN2A, BAP1, SFTPA2, and PARK2. Next generation sequencing is being introduced to clinical practice of lung cancer, enabling investigation of multiple oncogenic driver genes simultaneously. In addition, liquid biopsy, which analyzes cell free DNA in blood, increases the opportunity to detect germline mutations in lung cancer patients. We examined the frequency and characteristics of lung cancer patients with germline mutations.

Method:
Between February 2012 and January 2017, 3,869 patients with a diagnosis of lung cancer were seen by Division of Medical Oncology in Ohio State University. Of these, seven were found to have germline mutations. The patient characteristics and treatment outcomes were retrospectively investigated.

Result:
Table 1 shows characteristics and treatment outcomes of the seven lung cancer patients with germline mutations. Median age was 50 (range, 34-72). Three had BRCA2 germline mutations, two had germline TP53 mutations(of which one patient also had a PARK2 mutation), one had a BRCA1 mutation, and one had an EGFR mutation. Testing for other oncogenic drivers were done in five patients, and interestingly, four patients had oncogenic driver mutations. The frequency of detecting germline mutations in lung cancer patients has been increasing in recent years, but is often unrecognized by providers. In our series, one patient was found to have a germline mutation by Foundation ONE, and another was found to have a germline mutation by Foundation ACT.

Year	Age	Sex	Histology	Stage	Smoking hisory	Other cancer	Germline mutation	Other somatic gene alteration	Targeted therapy	Respnse
2014	37	F	Ad	IA	former smoker (2py)	No	BRCA2	not evaluated	－	－
2014	72	F	Ad	IV	former smoker	breast cancer, lung cancer	EGFR T790M	EGFR G719S	rociletinib	SD
2015	69	F	Ad	IIIA	former smoker	breast cancer, uterine cancer	BRCA2	EGFR L858R	－	－
2015	50	F	SCLC	IA	never smoker	breast cancer	TP53 Y236*, PARK2 Q347*	FGFR2 amplification	－	－
2016	34	F	Ad	IV	former smoker	No	BRCA2 L3061*	MET 3028+2T>C	crizotinib	PR
2016	44	F	Ad	IV	never smoker	orbital rhabdomyosarcoma	TP53	ALK fusion	crizotinib	PR
2017	62	F	SCLC	IV	former smoker	breast cancer	BRCA1	not evaluated	－	－

Conclusion:
Introduction of next generation sequencing technology and liquid biopsies to clinical practice can raise the probability of detecting germline mutations in lung cancer patients. Clinicians should be alert to the potential existence and importance of germline mutations in their lung cancer patients.

Background:
Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) targeting sensitizing mutations and T790M mutation, which causes ~60% of acquired resistance after first-line TKI treatment. T790M testing provides guidance for second-line treatment decisions. This study evaluated four T790M detection platforms using plasma circulating tumor DNA (ctDNA).

Method:
ADELOS is a multicentre, open-label, single-arm study (NCT 02997501) of Chinese patients with advanced non-small cell lung cancer (NSCLC) and progression on previous EGFR-TKI treatment. Plasma ctDNA testing for T790M was performed by Cobas[®] real-time polymerase chain reaction (PCR), super amplification refractory mutation system (Super-ARMS) PCR, capture-based next-generation sequencing (NGS, 168 gene panel), and QuantStudio3D digital PCR (3D dPCR). T790M-positive patients detected by these platforms received osimertinib 80 mg/day orally until progression. Matched tissue re-biopsy samples were also tested by Cobas[®] or NGS. The primary objectives were to evaluate concordance between the Cobas[®] test and the other three platforms and to assess the efficacy of osimertinib in ctDNA T790M-positive patients.

Result:
Of 256 patients enrolled, 181 were ctDNA T790M-positive, among which 167 received osimertinib monotherapy. T790M plasma positive rate was from 37.4% to 63.5% (Cobas[®]< Super-ARMS90% for all three platforms. Specificity was between 53% (3D dPCR) and 89% (Super-ARMS). Compared with paired tissue testing results (n=73), NGS showed the highest concordance and sensitivity, while Cobas[® ]showed the highest specificity (Table 1). Table 1. Comparison of different platforms for T790M detection

	Cobas[®] PCR n=254	Super-ARMS PCR n=256	NGS n=256	3D dPCR n=255
T790M detected, n (%)	95 (37.4)	108 (42.2)	138 (53.9)	162 (63.5)
Comparison vs Cobas plasma test (n=254)
Concordance %, (95% CI)	--	91.3 (87.2, 94.5)	82.7 (77.5, 87.1)	66.8 (60.6, 72.6)
Sensitivity %, (95% CI)	--	94.7 (88.1, 98.3)	98.9 (94.3, 100.0)	90.5 (82.8, 95.6)
Specificity %, (95% CI)	--	89.3 (83.4, 93.6)	73.0 (65.3, 79.7)	52.5 (44.4, 60.5)
Comparison vs Tissue (n=73)
Concordance %, (95% CI)	67.1 (55.1, 77.7)	64.4 (52.3, 75.3)	69.9 (58.0, 80.1)	61.6 (49.5, 72.8)
Sensitivity %, (95% CI)	57.1 (42.2, 71.2)	61.2 (46.2, 74.8)	71.4 (56.7, 83.4)	69.4 (54.6, 81.7)
Specificity %, (95% CI)	87.5 (67.6, 97.3)	70.8 (48.9, 87.4)	66.7 (44.7, 84.4)	45.8 (25.6, 67.2)

Conclusion:
Super-ARMS showed highest concordance and NGS showed highest sensitivity compared with Cobas® plasma T790M testing. Concordance and specificity of 3D dPCR was lower using other ctDNA tests or tissue as reference. Subsequent osimertinib treatment in these patients will justify the effectiveness of T790M testing by different technologies.

Abstract not provided

Background:
Distant metastases confer mainly resistance to improving the long-term survival of patients with lung cancer. The major reason was that the genetic heterogeneity and evolutionary patterns between primary tumor and their distant metastases or among distinct metastatic sites remains poorly understood. The current study aimed to depict the distinct mutational landscape of primary lung adenocarcinoma and their distant metastases (brain or liver) and reconstruct the evolutionary history of metastases.

Method:
Seventeen patients with primary lung adenocarcinoma and distant metastases [5 with primary lesion and matched brain metastases (BM), 6 with primary lesion and matched liver metastases (LM), 6 with sole BM] were included. All tissues (by either biopsy or surgical resection) and matched peripheral blood samples were collected before systemic treatment. We performed whole-exome (150×) and targeted 416-gene panel sequencing for these samples.

Result:
In the matched cases, the mutational landscape of primary lesions for BM was distinctly different from those for LM. Compared to the primary lesions, BM had the significantly different patterns of somatic genome alterations while LM had the similar ones. In six cases with sole BM, both intratumoral and intertumoral genetic homogeneity of BM were observed. By using a set of genes which were frequently found in the primary lesions, we can clearly segregate the copy number variations (CNV) pattern of patients with BM from those with LM. Moreover, when we performed the hierarchical clustering based on these genes, we saw clear segregation between BM and LM. Patients with BM had dramatically higher tumor mutational burden (TMB) than those with LM in both primary (P < 0.01) and metastatic lesions (P < 0.001). Significant differences in TMB were also observed between primary and metastatic lesions in patients with BM (P < 0.001) instead of LM (P > 0.05). Phylogenetic analysis showed that LM followed the liner progression whereas BM followed the parallel progression. In patients with sole BM, both intratumoral and intertumoral lesions have a monoclonal origin and descend from a common ‘metastatic precursor’.

Conclusion:
The current evidence suggested that BM had distinctly different mutational landscape from LM in lung adenocarcinoma. Patients with BM had higher TMB than those with LM. BM followed the parallel progression whereas LM followed the liner progression. Intratumoral and intertumoral lesions of BM had genetic homogeneity and originated from the same precursor. These results had profound clinical implications for application of immunotherapy and improvement of prognosis in patients with lung adenocarcinoma and distant metastases.

Background:
A subset of lung adenocarcinoma is transformed by fusion genes, i..e. EML4-ALK, KIF5B-RET. Practically, fusion genes are detected using PCR, FISH and/or RNAseq. Although TCGA project sequenced many lung cancer genomes, little is known about the genomic landscape of driver-fusion positive lung adenocarcinoma. In particular, we wondered the frequency and impact of complex genomic rearrangements, such as chromothripsis, chromoplexy, and chromoanasynthesis, in the pathogenesis of lung adenocarcinomas.

Method:
We performed whole-genome sequencing analyses for 38 pairs of driver-fusion-positive lung adenocarcinoma and its normal counterpart samples. These 38 tumors harbored one driver fusion genes such as EML4-ALK, KIF5B-RET, and CD74-ROS1. We mapped reads using Burrows-Wheeler Aligner, and processed aligned reads with Picard and Genome Analysis Toolkit. We analyzed tumor purity, ploidy and copy number variations using Sequenza. We called point mutations and indels using Mutect and Strelka. And we also called structural variations using Delly.

Result:
The number of somatic point mutations of these samples was lower than general lung adenocarcinomas. Mutational signature analysis revealed that signature 1 and 5 are major factors in these samples. More than 70% of driver fusion genes were established by complex genomic rearrangements rather than simple events. Based on the copy number change and the microhomology, replication-based mechanism is presumed to be a main cause of these complex events. Somatic mutation on TP53 was rare in these samples.

Conclusion:
Much of driver fusion genes in lung adenocarcinomas are made by complex genomic rearrangements. TP53-independent replication-based mechanism is critical to these phenomena.

Background:
Lung cancers rely on metabolites to fuel growth and to signal to surrounding tissues. Systematic study of these molecules may identify biomarkers for early diagnosis and novel pathways tractable to therapy. Previous studies of the metabolome in lung cancer have been confined to the serum and to sputum. We have therefore interrogated biochemical profiles in human lung cancers and matched adjacent normal tissues with the aim of identifying metabolites and metabolic signatures associated with lung cancer.

Method:
Global biochemical profiles were determined in human lung tumour and adjacent normal tissue. 12 tumours and 12 matched normal samples were tested from adenocarcinoma (ADC) patients, and 12 tumour/normal pairs were similarly tested from squamous cell carcinoma (SCC) patients. Samples were analysed on the Metabolon GC/MS and LC/MS/MS platforms, with the inclusion of technical replicates.

Result:
Application of PCA as a function of the tissue metabolome demonstrated that the normal, ADC and SCC groups were clearly distinguishable. We observed general metabolic changes associated with tumour tissue (q<0.10 throughout), with reductions in glucose and concomitant elevations in sorbitol and lactate indicative of Warburg metabolism in both ADC and SCC. Levels of reduced glutathione (GSH) were higher in SCC compared to ADC and normal tissue, indicating elevated antioxidant capacity in SCC. Conversely, alternative antioxidants including taurine, biliverdin, ascorbate, alpha- and gamma-tocopherol, and ergothioneine were higher in ADC than SCC. The neurotransmitters serine, NAA, GABA, and NAAG were also significantly elevated in ADC but not SCC. Finally, elevations in prostaglandin D2 and 6-keto prostaglandin F1alpha were confined to SCC and prostaglandin E2 was elevated to a much greater extent (8-fold versus 3-fold) in SCC vs. ADC, as compared respectively to normal lung tissue.

Conclusion:
Results from this pilot global profiling study confirm greater glucose utilization and lactate production, increased fatty acid synthesis, and changes in membrane biology in ADC and SCC. However, changes in glutathione metabolism, antioxidant capacity, neuroactive metabolites, and inflammation appear to vary according to tumour type. A larger scale study may identify differential therapeutic avenues and response to therapy. Profiling of matched serum/plasma from lung cancer patients may allow for identification of disease-specific biomarkers to supplement histological-based diagnostic techniques.

Background:
Lung adenocarcinomas are characterized by genetic alterations along receptor tyrosine kinase pathways. Around 50% of lung adenocarcinomas contain alterations in KRAS and EGFR alone. Nonetheless, genetic drivers in a large proportion of other cases remain to be determined. Recent exome sequencing analysis of lung adenocarcinomas in our lab has identified SOS1, a guanine nucleotide exchange factor, as being significantly mutated in lung cancers lacking canonical oncogenic mutations. However, the functional significance of the mutations is unclear.

Method:
In vitro cellular assays as well as in vivo transplatation experiments were performed to determine the phenotype of SOS1 mutants. Biochemical approaches were used to determine the mechanism by which SOS1 mutants confer an oncogenic phenotype. RNA sequencing of SOS1 mutant cells was performed to transcriptionally profile the cells, and inhibitors of the RTK/Ras/MAPK pathway were tested for their efficacy against SOS1 mutants.

Result:
We demonstrate that ectopic expression of mutated SOS1 induces anchorage-independent cell growth in vitro and tumor formation in vivo. Biochemical experiments suggest mutant SOS1 drives over-activation of the Ras pathway, and through RNA sequencing, we identify an upregulation of MYC targets in cells expressing mutant SOS1. Furthermore, we demonstrate that cancer cells with mutant SOS1 are dependent on SOS1 for survival and are also sensitive to inhibitors of the MAPK pathway.

Conclusion:
Our work provides experimental evidence for the role of SOS1 as a novel oncogene and suggests possible therapeutic mechanisms to target SOS1-mutated cancers.

Abstract not provided

Abstract not provided

Abstract:
Lung cancer is the leading cause of cancer-related deaths in other Western countries, with more than 1.8 million new cases and 1.5 million deaths worldwide in 2012 (Globocan, 2012). Recent advances in the management of NSCLC have included use of therapies targeting oncogenes (EGFR, BRAF or HER2 mutations, ALK or ROS1 rearrangements) but molecular alteration is currently detected in only the half of the patients with non-squamous NSCLC (Barlesi et al., 2016). Immune check point inhibitors (ICI), the first of which targeted the lymphocyte cell surface inhibitory receptor PD-1 or its ligand PD-L1, have recently become available and have been shown to provide an overall survival advantage over standard second-line chemotherapy (Borghaei et al., 2015; Brahmer et al., 2015; Herbst R et al, Lancet 2016; Rittmeyer et al, 2016), and more recently over first-line standard chemotherapy in monotherapy for a small subgroup driven by PD-L1 expression (Reck et al., 2016) or in combination regardless of PD-L1 expression (Langer et al, Lancet Oncol 2016), for both squamous and non-squamous NSCLC. Unfortunately, the long-term overall survival benefit is driven by only about 20-25% of the patients. PD-L1 tumor expression has been proposed to guide the patients’ selection but remains controversial (Kerr K, 2016). However, PD-L1 tumor expression of more than 1% and 50% is mandatory for the use of pembrolizumab monotherapy in second and first-line, respectively. Therefore, how to choose the best way to use ICIs for advanced NSCLC patients? Many aspects may be considered and will be discussed during the session including the PD-L1 expression and other potential predictive biomarkers (as tumor mutational burden), the current contra-indications to ICIs, the potential suspected factors predicting a higher risk of rapid progression on ICIs, the potential synergy for the concomitant combination of ICIs with chemotherapy or conversely a sequential use, the side effects for monotherapies and combinations, and the recent data on ICIs combinations versus standard chemotherapy. In summary, the attendees will have the arguments to globally assess the risk/benefit balance in using ICIs first or at resistance to chemotherapy and discuss the chosen strategies with their patients.

Abstract not provided

Abstract:
Combination of chemotherapy with immune-check point inhibitor is considered to be one of the most promising strategy to improve efficacy of immune-check point inhibitors. Several clinical trials of chemotherapy with immune-check point inhibitor are conducted and the results have been reported. KEYNOTE-021 cohort G is a randomised, open-label, phase 2 cohort of a multicohort study assessed whether the addition of pembrolizumab to carboplatin and pemetrexed improves efficacy in patients with advanced non-squamous NSCLC. Thirty-three (55%; 95% CI 42–68) of 60 patients in the pembrolizumab plus chemotherapy group achieved an objective response compared with 18 (29%; 18–41) of 63 patients in the chemotherapy alone group (p=0·0016). Progression-free survival (PFS) was significantly longer with pembrolizumab plus chemotherapy compared with chemotherapy alone (HR 0·53 [95% CI 0·31–0·91]; p=0·010). Median PFS was 13·0 months for pembrolizumab plus chemotherapy and 8·9 months for chemotherapy alone. The FDA has granted an accelerated approval to pembrolizumab for use in combination with pemetrexed plus carboplatin as a frontline treatment for patients with metastatic or advanced non-squamous NSCLC, regardless of PD-L1 expression. Antiangiogenic monoclonal antibodies, bevacizumab and ramucirumab that are currently approved for use in the treatment of NSCLC. Bevacizumab, in addition to platinum-based chemotherapy is widely used for the first-line treatment of advanced, metastatic, or recurrent NSCLC, excluding squamous cell carcinoma. VEGF influences lymphocyte trafficking across endothelia to the tumor by inhibiting lymphocyte adhesion and VEGF has a systemic effect on immune-regulatory cell function through multiple mechanisms, such as Tregulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs); suppression of dendritic cell maturation; and inhibition of T-cell development from hematopoietic progenitor cells. Thus, combination of antiangiogenic monoclonal antibody and immune-check point inhibitor is potentially synergistic. National Cancer Center Hospital conducted a single-center phase Ib study investigated the tolerability, safety, and pharmacokinetics of nivolumab combined with standard chemotherapy in patients with advanced NSCLC. In this trial, nivolumab with gemcitabine/cisplatin, pemetrexed/cisplatin, paclitaxel/carboplatin/bevacizumab, or docetaxel were evaluated for six patients each arm. Combination of nivolumab and chemotherapy showed an acceptable toxicity profile and encouraging antitumor activity in patients with advanced NSCLC. Although small number of patients, nivolumab with paclitaxel/carboplatin/bevacizumab seems to be most promising with higher response rate and longer PFS. Based on these data, phase III study of paclitaxel/carboplatin/bevacizumab with/without nivolumab for advanced non-squamous NSCLC is ongoing.

Abstract not provided

Abstract:
The development of metastases from a primary tumor is the ultimate cause of death in most of patients with cancer. In a non-small cell lung cancer (NSCLC) series of 236 patients with advanced disease, brain metastasis appeared to be the second leading site of metastasis after bone (1). In fact, 31.8% of the patients presented brain metastasis at onset and a total of 42.8% of all patients included developed brain metastasis at any time point (1). Despite recent advances in the treatment of patients with NSCLC, CNS infiltration remains a frequent complication leading to impaired quality of life and shortened survival among NSCLC patients. In the era of personalized medicine for patients harboring oncogenic driver mutations, CNS infiltration has become an especially relevant clinical issue. In fact, an apparent higher incidence of brain metastasis at onset, among patients with molecular alterations, in particular for ALK + tumors has been reported (2). In addition, a higher cumulative incidence of CNS involvement overtime during treatment with targeted agents has been shown and CNS may be the only site of progression to first or second-line tailored therapies. Unfortunately however, most patients with advanced NSCLC present tumors lacking druggable oncogenic driver aberrations. In 2011, the tumors’ capacity of avoiding immune destruction was recognized as a new emerging hallmark of cancer. More recently, the constellation of interactions between tumor cells and the immune environment around them has definitely emerged as a potential and valuable source of innumerable novel anti-cancer targets. From the clinical perspective, treatment with immune checkpoint inhibitors targeting programmed-cell death 1 (PD-1) and its ligand (PDL-1) represent the best treatment option for many patients with advanced NSCLC in first-line (3) and most of them in second-line (4-6) due to an improved quality of life and a significant survival benefit. Unfortunately, most phase II randomized/phase III clinical trials assessing the efficacy of monoclonal antibodies against PD-1 (3,4,6) and PDL-1 (5) immune checkpoints in second or first-line settings excluded patients with active or untreated brain metastasis. Additionally, no data on the evolution of previously locally treated CNS lesions during immunotherapy have been provided, nor information revealing the sites of distant progression in patients on the study arm experiencing progression disease to the treatment. The only available results in this regard are reflected in KEYNOTE-024 trial in which the subgroup analysis showed a statistically significant benefit in terms of progression-free survival for patients without baseline brain metastasis on pembrolizumab compared to non-significant differences among patients with brain involvement receiving the PD-1 blocker (3). More interestingly, Goldberg et al. reported the only direct evidence on the potential activity of an immune checkpoint inhibitor against brain metastasis from NSCLC in a non-randomized, open label, phase II clinical trial (7). The study enrolled 36 patients with untreated brain metastases from melanoma (18 patients) or NSCLC (18 patients) receiving pembrolizumab monotherapy. Patients were given 10 mg/kg pembrolizumab every 2 weeks until progression and the primary endpoint was brain metastasis response assessed in all treated patients. In the preliminary results reported, a brain metastasis response was achieved in four (22%; 95% CI 7–48) of 18 patients with melanoma and six (33%; 14–59) of 18 patients with NSCLC. Despite the low number of patients included, this remarkable activity shown by pembrolizumab among brain metastases in patients with NSCLC warrants further investigation in larger series and prompt the analysis of the anatomic, molecular and immune factors involved in those responses. Other studies have focused their attention in the immune microenvironment of the brain in an attempt to unravel the theoretical activity of an immune-directed therapeutic approach. Berghoff at al. investigated tumor-infiltrating lymphocytes (TIL) subsets and their prognostic impact in 116 brain metastases (BM) from different tumor type’s specimens using immunohistochemistry for CD3, CD8, CD45RO, FOXP3, PD1 and PD-L1 (8). Interestingly enough, they found TIL infiltration in 115/116 (99.1%) BM specimens. PD-L1 expression was evident in 19/67 (28.4%) BM specimens and showed no correlation with TIL density (p > 0.05). High infiltration was most frequently observed for CD3+ TILs (95/116; 81.9%) and least frequently for PD1+ TILs (18/116; 15.5%; p < 0.001). Highest TIL density was observed in melanoma, followed by renal cell cancer and lung cancer BM (p < 0.001). More importantly, the density of CD3+, CD8+, and CD45RO+ TILs showed a positive and significant correlation with favorable median overall survival (OS) times. The same group has found TIL infiltration and PD-L1 expression as a common feature in Small-cell Lung Cancer (SCLC) BM. In addition, the presence of CD45RO+ memory T-cells and PD-L1+ TILs in SCLC BM seemed to be associated with favorable survival times suggesting an active immune microenvironment in SCLC BM (9). Takamori et al., evaluated the discordance in PD-L1 expression between primary and metastatic lesions and analyzed the association between the discordance and other clinical factors in 21 NSCLC patients (10). Remarkably, among the 16 patients with brain metastases, in three of them there was a good correlation in PDL-1 expression between the primary tumor and the brain metastasis. In other two patients however, positive PDL-1 primary lesions produced PDL-1 brain metastases. Interestingly enough, in two patients with PDL-1 negative NSCLC undergoing radiation therapy for brain metastases followed by surgical resection of BM, irradiated lesions turned to be positive for PDL-1 expression suggesting a potential capacity of radiotherapy to induce PDL-1 expression in BM (10). In fact, these observations along with several preclinical findings have paved the way for the design of clinical trials combining radiation therapy and immune checkpoint inhibitors against brain metastases. In summary, here we present and discuss the most relevant evidences about the particular immune microenvironment of the brain, the clinical activity of immune checkpoint inhibitors against NSCLC brain metastasis as well as their potential combination with local radiation therapy and the hypothetical use of TIL infiltrates and PDL-1 expression as predictive biomarkers for response of brain metastases to immunotherapy. Several clinical cases illustrating these evidences will be also presented and discussed. References 1. Castanon E, Rolfo C, Vinal D, Lopez I, Fusco JP, Santisteban M, et al. Impact of epidermal growth factor receptor (EGFR) activating mutations and their targeted treatment in the prognosis of stage IV non-small cell lung cancer (NSCLC) patients harboring liver metastasis. J Transl Med. 2015;13:257. 2. Kang HJ, Lim HJ, Park JS, Cho YJ, Yoon HI, Chung JH, et al. Comparison of clinical characteristics between patients with ALK-positive and EGFR-positive lung adenocarcinoma. Respir Med. 2014;108(2):388-94. 3. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016;375(19):1823-33. 4. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373(17):1627-39. 5. Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016;387(10030):1837-46. 6. Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540-50. 7. Goldberg SB, Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M, et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol. 2016;17(7):976-83. 8. Berghoff AS, Fuchs E, Ricken G, Mlecnik B, Bindea G, Spanberger T, et al. Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases. Oncoimmunology. 2016;5(1):e1057388. 9. Berghoff AS, Ricken G, Wilhelm D, Rajky O, Widhalm G, Dieckmann K, et al. Tumor infiltrating lymphocytes and PD-L1 expression in brain metastases of small cell lung cancer (SCLC). J Neurooncol. 2016;130(1):19-29. 10. Takamori S, Toyokawa G, Okamoto I, Takada K, Kozuma Y, Matsubara T, et al. Discrepancy in Programmed Cell Death-Ligand 1 Between Primary and Metastatic Non-small Cell Lung Cancer. Anticancer Res. 2017;37(8):4223-8.

Abstract:
Although Masaoka clinic-pathological staging system has been accepted as the global standard staging system for thymic epithelial tumors, several problems of this staging system have been pointed out because clinical practices in diagnosis, medical treatment and surgical procedure has enormously advanced during more than 30 years. Furthermore, there has not been a TNM classification system approved by UICC to describe a tumor’s clinical status adequately. To overcome these situations, International Thymic Malignancy Interest Group (ITMIG) established global database and proposed a novel staging system based on TNM definition in collaboration with IASLC staging committee in 2016. This is a great progress in clinical medicine in the field of thymic epithelial tumor, but as a matter of fact, stage grouping according to this novel TNM classification is mostly defined by tumor invasion to adjacent organs similarly to Masaoka staging system. Japanese Association for Research of the Thymus (JART) established by Akira Masaoka and colleagues contributed to the ITMIG project of global database, and several studies using JART database were performed and reported from Japanese researchers. Novel findings in the JART database study are reviewed and new insights in further modification in TNM staging system are addressed in the present article. The significance of involved organs as a prognostic factor has been a great interest, because some structures are easily resected while others are difficult to be completely resected. Actually, some previous studies showed prognostic significance of involvement of the great vessels. Based on the ITMIG database, involvement of the pericardium alone is defined as T2 in the UICC TNM classification while involvement of SVC and brachiocephalic vein is defined as T3 and involvement of the aorta, aortic branches and intrapericardial vessels is defined as T4. One of the JART database study focusing on the involved organs in Masaoka stage III tumors showed that invasion to the chest wall is an independent prognostic factor by multivariate analysis while involvement of the great vessels is not. The hazard ratio of involvement of the chest wall is 4.07. Invasion to the chest wall is defined as T3, but when invasion to the sternum is extended, resection of the chest wall including sternum is sometimes a difficult procedure, and complete resection is hard to be achieved. Lymphatic channels are distributed in the chest wall, of which involvement by the tumor can result in nodal metastasis. Thus, invasion to the chest wall might be considered as an important factor to determine the tumor spread, and therefore, as one factor in T definition. Involvement of SVC and brachiocephalic vein is defined as T3, but is heterogenous variable because some tumors invade to the outer surface of the vessel but others enter the lumen of the vessel, which can result in pulmonary metastasis. The extent in involvement of the great vessels could be a significant factor in T definition. Tumor size could reflect the time from initiation of the tumor and the larger tumor is more likely to be in an advanced status. Actually, tumor size is a critical factor in T definition in lung cancers. In thymic epithelial tumors, however, T definition does not reflect the tumor size. Using JART database, oncological significance of the tumor size was examined in thymoma and thymic carcinoma, separately. In thymoma, the rate of R0 resection in the tumors less than 5.0 cm, 5.1 to 10 cm, and more than 10.1 cm was 94.4%, 91.3%, and 84.0%, respectively. Recurrence rate after R0 resection in the tumors less than 5.0 cm, 5.1 to 10 cm, and more than 10.1 cm was 3.0%, 8.9% and 27.2%, respectively. In thymic carcinoma, the rate of R0 resection in the tumors less than 5.0 cm, 5.1 to 10 cm, and more than 10.1 cm was 80.2%, 63.2%, and 62.5%, respectively. Recurrence rate after R0 resection in the tumors less than 5.0 cm, 5.1 to 10 cm, and more than 10.1 cm was 28.2%, 53.7% and 62.5%, respectively. Thus, there was apparent difference in oncological behavior between tumors less than 5.0 cm and those more than 5.1 cm both in thymoma and thymic carcinoma. These observations suggest that tumors size also should be included in T definition in thymic epithelial tumors. Finally, the category of Masaoka stage IVA disease includes pleural dissemination, but the situation of pleural dissemination varies greatly from a single lesion to numerous lesions. Furthermore, some disseminations are resectable while others are not. JART study revealed that the number of disseminated lesions on the pleura In conclusion, T definition remains to be further evaluated in reference to tumor size, chest wall invasion and extent of involvement of the great vessels. M definition also remains to be further discussed in terms of extent of the pleural dissemination.

Abstract:
Background: Thymectomy via median sternotomy has been the standard surgical approach for patients with thymic malignancies. However, the last decade has seen an increasing interest in minimally invasive thymectomy for early stage tumors. By avoiding sternal split, video-assisted thoracoscopic surgery (VATS) has been reported to be associated with similar operating time but less blood loss during operation, shorter length of intensive care unit and hospital stays, diminished postoperative pain, and improved postoperative pulmonary function. A recent propensity-score matched study by the Chinese Alliance of Research for Thymomas (ChART) reported 100% complete resection rate in both VATS and open thymectomies for UICC stage I (T1N0M0). Both overall and disease-free survivals, as well as cumulative incidence of recurrence were similar between the matched groups. The role of minimally invasive surgery has thus been well established in early stage thymic tumors. Using the International Thymic Malignancy Interest Group (ITMIG) global database, a recent propensity-score matched study found that complete resection rate was comparable between minimally invasive and open approaches (96% vs. 96%, P=0.7), including 33 and 10 patients with Masaoka stage III and IV diseases. And surgical approach was not a predictor of R0 resection in that study. The results suggested that minimally invasive surgery may also have a role in some patients with locally invasive tumors. To prove this, it is necessary to show that VATS is associated with improved peri-operative results, while maintaining similar resection rate and oncologic outcomes as open surgery. We therefore carried out a propensity-score matched study comparing the results of VATS and median sternotmy in UICC T2-3 thymic tumors to see whether minimally invasive surgery might be an acceptable approach. Patients and Methods: Surgical patients with UICC stage pT2-3 thymic tumors were retrospectively retrieved from a prospectively maintained database at the Shanghai Chest Hospital. Those who undergone VATS resection were compared with patients receiving median sternotomy (Open). A propensity-score matched study was then carried out to compare resection rate, peri-operative outcomes, and follow-up results between the two matched groups. Results: During 2007-2017, 115 patients who undergone surgical resection of thymic malignancies turned out to have UICC pT2-3 tumors upon histological examination. In 29 patients, video-assisted thoracoscopic surgery (VATS) was attempted and completed in 26 cases. In 89 patients (including the 3 conversion cases due to extensive tumor invasion) the lesion was resected via Open median sternotomy. Comparing with the VATS group, the Open group has larger tumor size, higher T stage, and received more induction therapies. A propensity-score match was carried out according to concomitant autoimmune disease, co-morbidity, induction therapy, tumor size, and UICC pTNM stage in 1:2 ratio. This leaves 26 patients in the VATS group and 52 patients in the Open group (Table 1). Induction therapies were given in 7.7% and 9.6% patients in the two groups (p=0.779). The two groups were comparable in patients’ age, gender, tumor histology, as well as all the matching factors. Complete resection (R0) rate was comparable (76.9% in both groups), with higher primary tumor resection rate in the VATS group (96.2% vs. 86.7%, p=0.151). Because of local tumor invasion, pericardium, lung (wedge resection), phrenic nerve, and left innominate vein were resected together with the tumor in 21, 17, 3, and 3 patients, respectively. Postoperative morbidity rate was also similar between the two groups (15.4% vs. 17.3%, p=0.830). Comparing to the Open group, VATS patients had less intraopertaive blood loss (127 ml vs. 219 ml, p=0.005), shorter duration of chest drainage (3±1.2 day vs. 5±4.7 day, p=o.oo5) and length of hospital stay (5.9±3.1 vs. 9.6±5.1, p<0.001). During a median follow-up of 35 months, overall survival was 100% in the VATS group and 95.2% in the Open group (Figure 1, p=0.664), and 3-year recurrence rates were 0.052 and 0.167, respectively (Figure 2, p=0.554). Conclusions: In addition to UICC stage I thymic malignancy, VATS may also be an acceptable approach for locally advanced thymic tumors. Complete resection rate and follow-up results are comparable to open surgery in well selected cases. And better peri-operative results can be expected via VATS approach as compared to median sternotomy. Based on these results, VATS should be attempted in those patients with potentially resectable thymic tumors. And long-term follow-up is still necessary to confirm its oncological effectiveness. Table 1. Comparison of patient demographics, tumor characteristics, and peri-operative results between the VATS and Open groups.

VATS N=26 Open N=52 P Value Gender male 17 (65.4) 34 (65.4) 1.0 Age year 58.5±13.0 57.7±10.1 0.781 Autoimmune diseases yes 5 (19.2) 8 (15.4) 0.667 Co-morbidity yes 8 (30.8) 14 (26.9) 0.722 Tumor size cm 5.7±2.0 6.4±1.7 0.161 Histology Thymoma 15 (57.7) 29 (55.8) 0.889 Thymic Carcinoma 11 (42.3) 23 (44.2) pT T2 8 (30.8) 14 (26.9) 0.722 T3 18 (69.2) 38 (73.1) pN N0 25 (96.2) 51 (98.1) 1.0 N1 1 (3.8) 1 (1.9) pM M0 21 (80.8) 45 (86.5) 0.506 M1a 5 (19.2) 7 (13.5) Operation time min 136±50 134±47 0.85 Blood lose ml 127±90 219±150 0.005 Chest tube drainage day 3±1.2 5±4.7 0.005 Length of hospital stay day 5.9±3.1 9.6±5.1 0.000 Morbidity yes 4 (15.4) 9 (17.3) 0.830

Figure 1. Overall survivals between the VATS and the Open groups after propensity-score matching. Figure 1 Figure 2. Cumulative incidences of recurrence after propensity-score matching in completely resected patients in the VATS and the Open groups. Figure 2

Abstract:
The argument for cytoreduction The argument in favor of cytoreduction is supported by several observations: First, several randomized trials support this procedure for other disease sites including advanced ovarian, colorectal and renal cell cancer. Second, most long-term survivors of MPM have had surgery as a component of their therapy, whereas there are very few long-term survivors who have been treated with non-operative strategies. Analyses of both the Surveillance Epidemiology and End Results (SEER) and the National Cancer Database have show longer survival of patients who have had ‘cancer-directed’ surgery compared to those whose treatment did not include surgery. Third, the median survival of patients in most recent phase III trials of chemotherapy is between 10 to 13 months, whereas in three multicenter trimodality phase II surgical studies median survival is significantly longer ranging 17 to 20 months. Nevertheless, the quality of evidence supporting a role for cytoreductive surgery for mesothelioma is low, and the only randomized study to performed date, the small, underpowered and highly controversial MARS 1 trial, failed to show benefit of extrapleural pneumonectomy compared to chemotherapy and supportive care. Cytoreductive surgical options There are two approaches to cytoreductive surgery for pleural mesothelioma: extrapleural pneumonectomy (EPP) and pleurectomy/decortication (PD). The pendulum has swung back and forth over the last 40 years regarding the best operative approach and decisions are influenced by factors including tumor biology, patient physiology, surgical philosophy and availability of adjuvant therapies. A goal common to both EPP and extended PD/PD is macroscopic complete resection (MCR) of tumor, which is generally interpreted as <1cm residual tumor remaining after resection. The argument for EPP Extrapleural pneumonectomy (EPP) involves the en-bloc resection of the parietal and visceral pleura, lung, ipsilateral pericardium and diaphragm. The latter structures are usually reconstructed with prosthetic mesh, often polytetrafluoroethylene (Goretex), though use of polyglycolic acid (Vicryl), polypropylene and various biologic meshes has also been described. The procedure is associated with an operative mortality of 2 to 8% in experienced centers, however, a recent review of the Society of Thoracic Surgeon’s database reported a 30-day mortality rate of nearly 11%. 90-day mortality as high as 17% has been reported. Postoperative morbidity ranges from 30% to 80%, and major complications include bronchopleural fistula, empyema, hemorrhage, pulmonary embolus and ARDS/pneumonia. The potential value of EPP over PD is that it may offer a more complete cytoreduction in that tumor cells involving the lung and visceral pleura are completely removed. Indeed, most retrospective series show much lower rates of local failure after EPP (13%-35%) than PD (36%-100%). However, distant recurrence (most commonly in the contralateral chest or abdomen) are frequent (~50%). Median survival reported in 3 phase II trials that included EPP in the setting of neoadjuvant chemotherapy ranged between 17 to 20 months from initiation of treatment. Use of intrapleural adjuncts including photodynamic therapy (PDT), heated chemotherapy and other cytotoxic agents is controversial and has yielded varying results. Adjuvant radiation therapy is relatively easy to administer as there is no risk of ipsilateral lung toxicity (lung is removed) and though excellent local control has been reported in several phase II single arm studies, a recent randomized phase III trial showed no benefit to either disease free or overall survival. The argument for PD Pleurectomy decortication involves the resection of parietal and visceral pleura, and localized resection of any tumor involving the lung, diaphragm or pericardium. If the latter two structures are resected the term ‘extended’ PD (EPD) is applied. Several retrospective series have shown improved DFS and OS in patients undergoing either PD or EPD compared to partial pleurectomy (PP) although selection bias is likely to have influenced outcomes to some extent. Perioperative mortality rates following PD averages 3% and major morbidity ranges between 13% to 60%. A common complication after the procedure is prolonged air leak (14% - 58%). Rates of local recurrence after PD are higher than EPP most likely related to the larger surface area at risk for harboring residual microscopic tumor, however this does not appear to influence overall survival. Analysis of retrospective series reveals a median survival of approximately 20 months, similar to EPP, thought there have been notable recent reports of median survival as high as 36 months in patients who have received EPD with intrapleural therapies. Compared to EPP, adjuvant radiation therapy is more difficult to safely administer after PD, and though technically feasible, the benefit in terms of effect on local control (48% - 64%) is questionable. Comparisons of EPP and PD PD/EPD is associated with lower mortality and fewer and less severe postoperative complications than EPP. Additionally, retrospective comparisons of quality of life metrics tend to favor PD/EPD regarding global health, physical and social function and dyspnea[9]. Analysis of 9 retrospective series that have compared cancer related outcomes of EPP and PD/EPD reveals similar or improved survival in most cases with PD/EPD (Table). Differences in patient selection and prognostic factors such as tumor stage, volume and epithelioid histology make direct comparisons difficult, however. Nonetheless, there does not appear to be a survival benefit to performing EPP, and since the procedure is associated with greater risk of operative mortality, morbidity and functional deficit, it seems justified to recommend PD/EPD as the cytoreductive procedure of choice, where technically feasible[10]. The ongoing prospective, randomized MARS-2 trial currently accruing in the United Kingdom will better define the true role of cytoreductive surgery (PD) in the treatment of malignant pleural mesothelioma.

Author	Group	n	Epithelioid (%)	Node +ve (%)	T3 or T4 (%)	Stage III or IV (%)	Median survival (mo)	Median follow-up (mo)	Local failure (%)	Distant failure (%)
Flores, 2008	EPP	385	70%	nr	75%	75%	12	17 (all)	19%	38%
	PD	278	64%	nr	65%	65%	16*		31%	17%
Lang-Lazdunski, 2012	EPP	22	64%	46%	nr	87%	13	13	52%	56%
	PD	61	67%	30%	nr	63%	23*	16	nr	nr
Rena,2012	EPP	40	86%	0%	0%	0%	20	nr	47%	53%
	PD	37	84%	0%	0%	0%	25	nr	100%	44%
Nakas, 2012	EPP	98	78% (all)	nr	100%	100%	15	21	60%	40%
	PD	67		nr	100%	100%	13	16	56%	18%
Batirel, 2016	EPP	42	75% (all)	49% (all)	52% (all)	nr	18	23	68% (all)	21% (all)
	PD	66				nr	15	16
Infante, 2016	EPP	91	89%	44%	nr	80%	19	17	45%	50%
	PD	47	98%	30%	nr	62%	30	11	26%	24%
Sharkey, 2016	EPP	229	72%	53%	76%	86%	13	nr	43%	57%
	PD	133	76%	56%*	69%	80%*	12	nr	53%	41%
Korston, 2017	EPP	52	94%	nr	nr	65%	23	nr	nr	nr
	PD	26	94%	nr	nr	65%	32*	nr	nr	nr
Verma, 2017	EPP	271	34%	27%	43%	51%	19	15 (all)	nr	nr
	PD	1036	26%	20%	37%	47%	16		nr	nr

Table: Comparative studies of EPP and PD References 1. Nelson DB, Rice DC, Niu J, et al. Long-Term Survival Outcomes of Cancer-Directed Surgery for Malignant Pleural Mesothelioma: Propensity Score Matching Analysis. J Clin Oncol. 2017:JCO2017738401. 2. Flores RM, Riedel E, Donington JS, et al. Frequency of use and predictors of cancer-directed surgery in the management of malignant pleural mesothelioma in a community-based (Surveillance, Epidemiology, and End Results [SEER]) population. J Thorac Oncol. 2010;5(10):1649-1654. 3. Burt BM, Cameron RB, Mollberg NM, et al. Malignant pleural mesothelioma and the Society of Thoracic Surgeons Database: an analysis of surgical morbidity and mortality. J Thorac Cardiovasc Surg. 2014;148(1):30-35. 4. Stahel RA, Riesterer O, Xyrafas A, et al. Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial. Lancet Oncol. 2015;16(16):1651-1658. 5. Lang-Lazdunski L, Bille A, Papa S, et al. Pleurectomy/decortication, hyperthermic pleural lavage with povidone-iodine, prophylactic radiotherapy, and systemic chemotherapy in patients with malignant pleural mesothelioma: a 10-year experience. J Thorac Cardiovasc Surg. 2015;149(2):558-565; discussion 565-556. 6. Marulli G, Breda C, Fontana P, et al. Pleurectomy-decortication in malignant pleural mesothelioma: are different surgical techniques associated with different outcomes? Results from a multicentre studydagger. Eur J Cardiothorac Surg. 2017. 7. Friedberg JS, Simone CB, 2nd, Culligan MJ, et al. Extended Pleurectomy-Decortication-Based Treatment for Advanced Stage Epithelial Mesothelioma Yielding a Median Survival of Nearly Three Years. Ann Thorac Surg. 2017;103(3):912-919. 8. Rimner A, Zauderer MG, Gomez DR, et al. Phase II Study of Hemithoracic Intensity-Modulated Pleural Radiation Therapy (IMPRINT) As Part of Lung-Sparing Multimodality Therapy in Patients With Malignant Pleural Mesothelioma. J Clin Oncol. 2016;34(23):2761-2768. 9. Rena O, Casadio C. Extrapleural pneumonectomy for early stage malignant pleural mesothelioma: a harmful procedure. Lung Cancer. 2012;77(1):151-155. 10. Waller DA, Tenconi S. Surgery as part of radical treatment for malignant pleural mesothelioma. Curr Opin Pulm Med. 2017;23(4):334-338.

Abstract:
Multimodality therapy for malignant pleural mesothelioma (MPM) including radical surgery has been associated with prolonged survival and in selected patients, but the evidence for a long term survival benefit is inconsistent [1,2]. There is little evidence regarding the optimal timing of additional chemotherapy, with some advocating induction treatment or in the immediate post operative setting, and others choosing to delay until progression. We have analysed our experience of the effect of the timing of chemotherapy on the outcome of extrapleural pneumonectomy (EPP) or pleurectomy/decortication (PD) [3] . Induction chemotherapy The use of a standardized neo-adjuvant chemotherapy regimen has been reported to be feasible in patients treated by EPP and adjuvant hemithoracic radiotherapy [4] . This regime requires high levels of patient fitness and is associated with a median survival of 16.8-25.5 months. However, this decreases dramatically if patients are unable to complete the entire trimodality therapy protocol (9-14 months) [5]. This may select those who will not have a prolonged survival, thus avoiding futile but morbid therapy. There is also the potential for tolerance of an increased number of cycles prior to surgery than in the adjuvant setting. The drawbacks include the risk of progression during chemotherapy, or severe toxicity, leaving the patient unsuitable for radical surgery. It is possible that neoadjuvant chemotherapy may select out chemoresistant cells, and lead to more aggressive disease progression following the inevitable R1 resection. There is currently no evidence to show that there is any long-term benefit to a response to chemotherapy prior to radical surgery. In fact, a true, significant, pathological response to chemotherapy is very rare [5]. Adjuvant chemotherapy The apparent benefit with adjuvant chemotherapy may be due to selection bias; only the fittest can receive the full regime, and will therefore have a survival benefit independent of therapy. Nevertheless, the IASLC staging committee found that the provision of adjuvant therapy was an independent prognostic factor for survival in patients with MPM [6]. Adjuvant chemotherapy may be contraindicated due to low compliance as a consequence of the morbidity of surgery In the case of EPP, many patients are not able to tolerate adjuvant chemotherapy, however in the case of EPD, most patients recover from surgery and are able to commence therapy within 8 weeks [7]. There has been a change in practice over time with regards the number of cycles given in the adjuvant setting, from 4 to 6. Delayed (expectant) chemotherapy Oncologists may wish to reserve an active agent, pemetrexed, until assessable disease or symptom-related progression. It may be beneficial as treatment of low volume residual disease following R1 resection may select out clones with resistance to platinum therapy thus reducing the efficacy at re-challenge during relapse. We found no difference in overall survival when chemotherapy was given in the immediate adjuvant setting or only at progression. However, subgroup analysis revealed that in non-epithelioid MPM delayed therapy was an independent predictive factor for poor survival/progression free survival. This could be explained in part by the continued presence of a subpopulation of aggressive and chemo-resistant stem cells in the sarcomatoid element of biphasic disease following an R1 resection. These more aggressive cells are then able to proliferate, as compared with a more indolent group of stem cells in epithelioid disease, leading to a shorter time to relapse and a more aggressive tumour type if no chemotherapy is given in the adjuvant setting. This is often seen after chemotherapy treatment alone, where these aggressive resistant cells are selected for, giving rise to rapid progression, even after an initial response [8]. Similarly, in those with nodal disease delaying chemotherapy was also found to be detrimental. In these patients tumour cells have already developed the ability to metastasise and it is likely that systemic micrometastases are present following local resection. Intra operative chemotherapy Intraoperative instillation of platinum based chemotherapy into the pleural cavity after resection has been shown to be safe in selected experienced institutions, where favourable median overall and progression free survival outcomes have been reported [9]. We did not include this modality in our protocol but one such study showed an increase in time to progression from 12.8 to 27.1 months, and overall survival from 22.8 to 35.5 months in clinically matched patients [10]. Conclusion Our retrospective study [3] showed no significant overall survival benefit from any particular timing of chemotherapy with either neo-adjuvant, adjuvant, or expectant management. Interestingly, we found no benefit in giving neo-adjuvant chemotherapy, despite the intrinsic bias within this group of patients, as only those who did not progress proceeded to surgery. We suggest that it may be important to tailor chemotherapy in 4 clinical sub-groups. In the poorer prognosis groups, non-epithelioid cell type and/or with pathological lymph node disease, giving chemotherapy in the immediate adjuvant setting (within 3 months of surgery) rather than delaying it until progression gave a survival advantage. Conversely, there was no benefit found in giving therapy in the immediate adjuvant setting in better prognosis patients with epithelioid cell type and with no evidence of lymph node metastases at operation. It may therefore be preferable to reserve first line chemotherapy until there is radiological evidence of disease progression in these patients. Future results from the EORTC NCT02436733 trial : a randomized phase II study of pleurectomy/ decortication (P/D) preceded or followed by chemotherapy in patients with early stage malignant pleural mesothelioma [11] will inform this debate. We suggest that the randomization in the trial is stratified in to epithelioid versus non-epithelioid and clinical node positive versus negative. References 1.C. Cao, D. Tian, C. Manganas, P. Matthews, T.D. Yan, Systematic review of trimodality therapy for patients with malignant pleural mesothelioma., Ann Cardiothorac Surg. 2012; 1: 428–37. 2.Nakas A, Waller D. Predictors of long-term survival following radical surgery for malignant pleural mesothelioma .Eur J Cardiothorac Surg. 2014;46:380-5. 3.Sharkey AJ, O'Byrne KJ, Nakas A, Tenconi S, Fennell DA, Waller DA. How does the timing of chemotherapy affect outcome following radical surgery for malignant pleural mesothelioma? Lung Cancer. 2016 Oct;100:5-13 4.Stahel RA, Riesterer O, Xyrafas A, et al. Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial. Lancet Oncol 2015;16:1651-8. 5. L. Donahoe, J. Cho, M. De Perrot, Novel Induction Therapies for Pleural Mesothelioma, Semin Thorac Cardiovasc. Surg. 2014;26:192–200. 6.Pass HI, Giroux D, Kennedy C, Ruffini E, Cangir AK, Rice D, Asamura H, Waller D, Edwards J, Weder W, Hoffmann H, van Meerbeeck JP, Rusch VW; IASLC Staging Committee and Participating Institutions. Supplementary prognostic variables for pleural mesothelioma: a report from the IASLC staging committee. J Thorac Oncol. 2014 Jun;9(6):856-64 7.S. Bölükbas, C. Manegold, M. Eberlein, T. Bergmann, A. Fisseler-Eckhoff, J.Schirren, Survival after trimodality therapy for malignant pleural mesothelioma:Radical Pleurectomy, chemotherapy with Cisplatin/Pemetrexed and radiotherapy, Lung Cancer. 71 (2011) 75–81 8.L. Cortes-Dericks, G.L. Carboni, R.A. Schmid, G. Karoubi, Putative cancer stem cells in malignant pleural mesothelioma show resistance to cisplatin and pemetrexed, Int. J. Oncol. 37 (2010) 437–444. 9.M. Ried, T. Potzger, N. Braune, R. Neu, Y. Zausig, B. Schalke, et al., Cytoreductive surgery and hyperthermic intrathoracic chemotherapy perfusion for malignant pleural tumours: Perioperative management and clinical experience, Eur. J.Cardio-Thoracic Surg. 43 (2013) 801–807. 10.D.J. Sugarbaker, R.R. Gill, B.Y. Yeap, A.S. Wolf, M.C. Dasilva, E.H. Baldini, et al.,Hyperthermic intraoperative pleural cisplatin chemotherapy extends interval to recurrence and survival among low-risk patients with malignant pleural mesothelioma undergoing surgical macroscopic complete resection, J. Thorac.Cardiovasc. Surg. 145 (2013) 955–963. 11. EORTC NCT02436733 trial : a randomized phase II study of pleurectomy/ decortication (P/D) preceded or followed by chemotherapy in patients with early stage malignant pleural mesothelioma. https://clinicaltrials.gov/ct/show/NCT02436733

Abstract:
Intensity-modulated radiation therapy (IMRT) is a highly conformal radiation technique that allows more effective sparing of normal tissues, providing an opportunity for safer, less toxic treatments and increased efficacy by enabling higher radiation doses to the tumor target. It comes with a much higher level of dosimetric control and certainty leading to better target coverage than conventional OR 3D conformal radiation techniques.[1] The higher precision of IMRT delivery when used in the adjuvant setting requires detailed knowledge of the intrathoracic anatomy, incorporation of all diagnostic imaging tools available, incorporation of the pathologic findings at the time of surgery, assessment of the respiratory tumor motion using a 4D scan, and image-guided treatment delivery. IMRT with integration of a boost to areas of gross disease is technically feasible but has not yet been tested in a larger series. The use of 18-fluorodeoxyglucose positron emission tomography (PET) for RT planning purposes may reduce the likelihood of geographic misses and detect radiographically occult lymph node involvement. Small series have suggested that PET may guide the delineation of an integrated boost volume or improve local control.[2] The recent decline in extrapleural pneumonectomies (EPP) in the surgical management of malignant pleural mesothelioma (MPM) due to reports suggesting a lack of survival benefit compared with lung-sparing pleurectomy/decortication (P/D) has posed a particular challenge for adjuvant radiation treatments: how to safely treat the pleural space for microscopic residual disease without exceeding the radiation tolerance of the underlying sensitive normal lung tissue. Older radiation techniques result in unacceptable toxicity and insufficient local control.[3] Thus, an IMRT technique targeting the hemithoracic pleural space including the diaphragm that simultaneously spared the ipsilateral lung, heart, liver, kidneys and abdominal contents was developed (Figure 1).[4] Typically these patients are treated with six to nine coplanar 6 MV beams equispaced over 200-240 degrees around the ipsilateral hemithorax were used. More recently, rotational techniques such as volumetric arc therapy or tomotherapy have been shown to allow for even more effective sparing of organs at risk.[5,6] The first report in 36 MPM patients with 2 intact lungs showed that hemithoracic adjuvant pleural IMRT (50.4 Gy in 28 fractions) could be delivered with a 20% (n=7) ≥ grade 3 pneumonitis risk; 1 patient had grade 5 pneumonitis.[4] The median survival in resectable patients was 26 months. A tomotherapy technique was published with similar toxicity outcomes (20% ≥ grade 2 pneumonitis, one fatal case of pneumonitis).[6] The radiation dose delivered was slightly higher with 50 Gy delivered in 25 fractions including a simultaneous boost to 60 Gy for areas of concern for residual disease based on FDG-PET. A matched analysis of P/D, chemotherapy, and IMRT vs. EPP, chemotherapy and IMRT found favorable median overall (28.4 vs. 14.2 months) and progression-free survival (16.4 vs. 8.2 months) with trimodality therapy involving P/D compared with EPP.[7] Local failure rates vary significantly among studies, ranging from 40 to 68% at 2 years. A systematic review of 67 patients still found a significant risk of local failures in the radiation field, mostly in unresectable patients and sites of gross residual disease, emphasizing the importance of a macroscopic complete resection, need for optimization of radiation targeting and experience with this complex radiation technique.[8] Increasing experience over time led to fewer marginal failures and decreased toxicity, suggesting the improvement in target delineation and RT planning. Most recently an association of radiation dose to the heart and overall survival was reported,[9] similar to observations in locally-advanced non-small cell lung cancer. These encouraging results have led to a 2-institution phase II trial of trimodality therapy using induction chemotherapy with cisplatin and pemetrexed, P/D, and adjuvant hemithoracic intensity-modulated pleural radiation therapy (IMPRINT).[10] Twenty-seven patients were treated and 29.6% developed radiation pneumonitis (6 grade 2; 2 grade 3). Median progression-free and overall survival was 12.4 and 23.7 months, respectively. In resectable MPM patients who received chemotherapy and IMPRINT, 2-year OS was 59%. Based on these findings a multi-institutional phase II study was initiated to demonstrate the safety and exportability of this complex IMPRINT technique in a multicenter setting involving institutions without prior experience of IMPRINT (clinicaltrials.gov: NCT00715611). All patients’ treatment contours and plans are centrally reviewed and revised for uniformity. The goal is to accrue 36 patients from 5 institutions. Given the promising outcomes this study may be succeeded by a randomized trial testing the effect of adjuvant IMPRINT vs no additional treatment after lung-sparing P/D and chemotherapy. Figure 1: Figure 1 1. Krayenbuehl J, Dimmerling P, Ciernik IF, et al: Clinical outcome of postoperative highly conformal versus 3D conformal radiotherapy in patients with malignant pleural mesothelioma. Radiat Oncol 9:32, 2014 2. Fodor A, Fiorino C, Dell'Oca I, et al: PET-guided dose escalation tomotherapy in malignant pleural mesothelioma. Strahlentherapie und Onkologie 187:736-743, 2011 3. Gupta V, Mychalczak B, Krug L, et al: Hemithoracic radiation therapy after pleurectomy/decortication for malignant pleural mesothelioma. International Journal of Radiation Oncology Biology Physics 63:1045-1052, 2005 4. Rosenzweig KE, Zauderer MG, Laser B, et al: Pleural intensity-modulated radiotherapy for malignant pleural mesothelioma. International Journal of Radiation Oncology Biology Physics 83:1278-1283, 2012 5. Dumane V, Rimner A, Yorke ED, et al: Volumetric-modulated arc therapy for malignant pleural mesothelioma after pleurectomy/decortication. Applied Radiation Oncology 5:24-33, 2016 6. Minatel E, Trovo M, Bearz A, et al: Radical Radiation Therapy After Lung-Sparing Surgery for Malignant Pleural Mesothelioma: Survival, Pattern of Failure, and Prognostic Factors. Int J Radiat Oncol Biol Phys 93:606-13, 2015 7. Chance WW, Rice DC, Allen PK, et al: Hemithoracic intensity modulated radiation therapy after pleurectomy/decortication for malignant pleural mesothelioma: toxicity, patterns of failure, and a matched survival analysis. Int J Radiat Oncol Biol Phys 91:149-56, 2015 8. Rimner A, Spratt DE, Zauderer MG, et al: Failure patterns after hemithoracic pleural intensity modulated radiation therapy for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 90:394-401, 2014 9. Yorke ED, Jackson A, Kuo LC, et al: Heart Dosimetry is Correlated with Risk of Radiation Pneumonitis after Lung-Sparing Hemithoracic Pleural IMRT for Malignant Pleural Mesothelioma. Int J Radiat Oncol Biol Phys, 2017 10. Rimner A, Zauderer MG, Gomez DR, et al: Phase II Study of Hemithoracic Intensity-Modulated Pleural Radiation Therapy (IMPRINT) As Part of Lung-Sparing Multimodality Therapy in Patients With Malignant Pleural Mesothelioma. J Clin Oncol 34:2761-8, 2016

Abstract:
Thymic and Mesothelial Tumors are relatively rare. There are few therapies that have been established in prospective studies, so the conditions have poor prognoses. Cisplatin+pemetrexed is the gold standard for unresectable malignant pleural mesothelioma in that it has shown a significantly longer survival than cisplatin in a controlled Phase III clinical study. Moreover, adding on bevacizumab to this combination therapy can extend survival, and these two therapies are recommended as 1L by the NCCN guideline. There have recently been promising results reported with anti-PD-1 antibody and anti-PD-L1 antibody single agent therapies as well as combination therapies with anti-CTLA-4 antibody, and there are many ongoing prospective clinical studies on these now. There are not very many therapies for Thymic malignancies that have already been examined in prospective studies. Carboplatin + paclitaxel, ADOC (cisplatin + doxorubicine + vibncristine + cyclophasphamide) therapy, CAP(Cisplatin + doxorubicine + cyclophosphamide) therapy, and the like are currently used as a result of outcomes in Phase II studies and retrospective studies. Furthermore, there have been reports of responses with molecular targeting therapies such as Sunitinib that target Kit. It has been reported that Thymic tumors express PD-L1, and there are currently several ongoing studies examining the relatively frequency and effect of anti-PD-1 antibody on such. My presentation will provide an overview of the current gold standards, recent clinical study outcomes, and promising pipeline therapies for Thymic and Mesothelial Tumors.

Abstract:
Neuroendocrine tumors (NET) of the lung comprise approximately 20% of all primary lung carcinomas overall and consist primarily of four malignancies: Typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma(SCLC) using 2015 World Health Organization (WHO) nomenclature. The four tumors have historically been regarded as a spectrum; however, there are significant differences between TC/AC and LCNEC/SCLC on many levels. Additionally, while most TC and AC arise de novo, a small percentage of cases with arise in the setting of diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH), a rare pre-neoplastic condition. DIPNECH has not been associated with the development of LCNEC or SCLC. TC and AC, comprise 1-2% of primary lung cancers with the vast majority being TC. Both TC and AC may occur in either a central or peripheral location, with central tumors resulting in symptoms related to obstruction while peripheral tumors are often asymptomatic and discovered incidentally. TC is considered a “low grade” or “well-differentiated” tumor; however, 5-20% of TC are associated with regional lymph node or distant metastases. AC, considered an “intermediate grade” or “moderately-differentiated” tumor, is associated with metastases in up to 40% of cases. The five and 10 year survival for TC is approximately 90% whereas it drops to 70% and 50% for AC. By current WHO criteria, TC is defined as a neuroendocrine tumor greater than 5mm in size with fewer than 2 mitoses per 2mm[2] and lacking necrosis, whereas AC is defined as a neuroendocrine tumor with 2-10 mitoses per 2mm[2] or necrosis. As mitotic activity and necrosis may be focal, the distinction between TC and AC can generally not be made on a small sample. Both tumors classically show an organoid or trabecular pattern of growth and are composed of a relatively uniform population of round to oval cells with granular nuclear chromatin, but may show a wide range of histologic growth patterns, particularly in TC. Given that the main feature distinguishing AC from TC is mitotic activity, one would expect that proliferation markers such as Ki-67 would be of potential value in discriminating these two tumors. Numerous studies have attempted to evaluate this parameter with various cut offs being proposed; however, ultimately there is too much overlap between the Ki-67 scores of TC and AC for it to be reliably useful in discriminating between the two tumors. The Ki-67 score can be useful in separating high-grade from low-grade tumors on small distorted biopsies, and some studies have shown it to have utility as a prognostic marker in TC/AC. As such it may be used to potentially guide treatment and is included as a parameter in the European Neuroendocrine Tumor Society (ENETS) guidelines. Surgery remains the only curative treatment option for TC/AC but there is a lack of consensus in regard to treatment of un-resectable or metastatic disease. Results of the RADIANT-4 trial have led to the approval of everolimus for advanced TC/AC. There is additional evidence that somatostain analogs may be useful in selected patients. Molecular analysis of TC and AC demonstrate distinctly different molecular profiles compared to the high grade NET’s, with MEN1 alterations found essentially exclusively in carcinoids whereas alteration of RB1 cell cycle regulation genes and the PI3K/AKT/mTOR pathway were found less frequently in TC/AC and enriched in the higher grade tumors. TC/AC also tend to show frequent mutations of chromatin remodeling genes, as well as mutations of PSIP1 and ARID1A. Actionable mutations such as EGFR mutations and ALK rearrangements are not found in TC/AC and thus far evaluation of PD-L1 in carcinoids has been negative, suggesting a lack of a role for current targeted therapy or immunotherapeutic agents used in non-small cell lung carcinomas (NSCLC). Several clinical trials are either ongoing or currently recruiting to evaluate the efficacy of several small molecular inhibitors. LCNEC was originally described in 1991 and was initially included as a subtype of large cell carcinoma in subsequent WHO classification, but in the current WHO it is classified as a type of neuroendocrine carcinoma. The tumor is defined as a tumor with neuroendocrine morphology with large cell morphology and greater than 10 mitoses/2mm[2], although most cases have substantially higher mitotic rates. By definition, tumors must show evidence of neuroendocrine differentiation, usually identified by immunohistochemical methods. While distinction of LCNEC from SCLC may appear straightforward on the surface, in reality LCNEC can be heterogeneous and the distinction is not always clear cut. Currently, there is no immunostain or other definitive test to discriminate between the two and distinction ultimately rests of subjective evaluation of the tumor morphology. The extreme rarity of this tumor, combined with the tumor heterogeneity and resultant subjectivity inherent in classification has likely contributed to conflicting reports in the literature regarding prognosis, although it is generally agreed that LCNEC is a high-grade tumor with a poor prognosis. Similarly, variable results have been reported in regard to the responsiveness of LCNEC to treatment regimens typically used for SCLC leading to a lack of consensus regarding whether LCNEC should be managed similar to SCLC or similar to other non-small cell carcinomas. Molecular studies have additionally shown variable results. The majority of studies have shown overlapping features with SCLC. Some studies, however, have shown alterations characteristic of other tumor types, most notably occasional EGFR, ALK and KRAS mutations even in the absence of an overt mixed adenocarcinoma component, which have not been found in SCLC. Interestingly, in 2016, Rekhtman, et al, evaluated 45 LCNEC and pared normal tissue by NGS with 241 cancer gene analysis. This study demonstrated that LCNEC, while having some commonly altered genes, largely fell into two major and one minor subset (SCLC-like, NSCLC-like and a small number of “carcinoid like” tumors). These findings may explain the variability of results in treatment trials and may indicate that more comprehensive analysis of this rare groups of tumors may yield more optimal treatment strategies.

Abstract:
Given that large cell neuroendocrine carcinoma (LCNEC) of the lung is rare and histological diagnosis from small samples is difficult, no large-scale clinical trials has yet evaluated the optimal chemotherapy for LCNEC. In a retrospective study of 45 consecutive patients with advanced LCNEC, response rates for small cell lung cancer (SCLC; n=11) and non-small cell lung cancer (NSCLC; n=34) regimen groups receiving first-line chemotherapy were 73% and 50% (P=0.19), median progression-free survival (PFS) was 6.1 and 4.9 months (P=0.41), and median overall survival (OS) was 16.5 and 9.2 months (P=0.19), respectively. SCLC regimens included platinum plus paclitaxel (PTX) and irinotecan plus platinum, while NSCLC regimens included pemetrexed, erlotinib, and gemcitabine[1]. A second retrospective study of the efficacy of first-line chemotherapies in 22 consecutive patients with advanced LCNEC reported an objective response in five of nine patients receiving CDDP+irinotecan (56%) and in three of five receiving carboplatin (CBDCA)+PTX (60%) [2]. Of the two prospective phase II studies of platinum-based chemotherapies for LCNEC (Table), a French study (GFPC 0302) used a chemotherapy regimen comprising CDDP+etoposide (ETP), while a Japanese study used CDDP+irinotecan. Objective response rate (ORR) was about 40% and median PFS was 5 to 6 months in both studies. Central pathological reviews in both studies demonstrated that about a quarter of patients had SCLC or undifferentiated NSCLC [3, 4]. Everolimus is an oral mTOR inhibitor that has been approved for the treatment of well-differentiated neuroendocrine tumors of the lung. A recent phase II study of CBDCA+PTX+everolimus as first-line chemotherapy for advanced LCNEC was discontinued prematurely due to low recruitment after enrolling only 49 patients versus a planned sample size of 71. Among them, ORR was 45%, disease control rate was 74%, median PFS was 4.4 months, and median OS was 9.9 months [5]. Ongoing studies include a randomized phase II study comparing CBDCA+ETP and CBDCA+PTX for advanced LCNEC and a randomized phase II/III study of CDDP+ETP with or without veliparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, in patients with extensive stage SCLC or metastatic LCNEC.

Study	GFPC 0302	Japanese study	German study
Regimen	CDDP+ETP	CDDP+Irinotecan	CBDCA+PTX+Everolimus
N	42	44	49
ORR (%) (95%CI)	38	55 (39-70)	45 (31-60)
Median PFS (months) (95%CI)	5.2 (3.1-6.6)	5.9 (5.5-6.3)	4.4 (3.2-6.0)
Median OS (months) (95%CI)	7.7 (6.0-9.6)	15.1 (11.2-19.0)	9.9 (6.9-11.7)

Reference 1. Sun JM, Ahn MJ, Ahn JS, et al. Chemotherapy for pulmonary large cell neuroendocrine carcinoma: similar to that for small cell lung cancer or non-small cell lung cancer? Lung Cancer 2012;77:365-370. 2. Fujiwara Y, Sekine I, Tsuta K, et al. Effect of platinum combined with irinotecan or paclitaxel against large cell neuroendocrine carcinoma of the lung. Jpn J Clin Oncol 2007;37:482-486. 3. Niho S, Kenmotsu H, Sekine I, et al. Combination chemotherapy with irinotecan and cisplatin for large-cell neuroendocrine carcinoma of the lung: a multicenter phase II study. J Thorac Oncol 2013;8:980-984. 4. Le Treut J, Sault MC, Lena H, et al. Multicentre phase II study of cisplatin-etoposide chemotherapy for advanced large-cell neuroendocrine lung carcinoma: the GFPC 0302 study. Ann Oncol 2013;24:1548-1552. 5. Christopoulos P, Engel-Riedel W, Grohe C, et al. Everolimus with paclitaxel and carboplatin as first-line treatment for metastatic large-cell neuroendocrine lung carcinoma: a multicenter phase II trial. Ann Oncol 2017.

Abstract:
Carcinoid tumors of the lung belong to a broad group of neoplasms called neuroendocrine tumors (NETs). These tumors are highly heterogeneous and represent a broad spectrum of phenotypes and clinical behavior. Often, the clinical behavior of these tumors corresponds with their underlying pathologic features. For example, in those tumors deemed as “typical carcinoid/NETs”, clinical behavior is often very indolent. At the other end of the spectrum, NETs can present as small cell lung cancer (SCLC) which is characterized by virulent and highly metastatic behavior. Those tumors deemed as “atypical carcinoid/NETs” usually have an intermediate clinical phenotype. Lung NETs are rare: the annual incidence rate is estimated to be approximately 1 in 100,000. In those patients whose lung NETs are no longer surgically resectable and/or have metastasized distantly, the treatment goals are principally disease control and symptom palliation. Because of their rarity, there are very limited prospective Level 1 data to guide optimal management of lung NETs. Treatment recommendations are often based on extrapolation from clinical experience in gastrointestinal NETs (specially pancreatic NET), subset analyses from other NET trials, anecdotal reports (case series), and expert opinion (e.g., consensus panels). Thus, the optimal management strategy for Lung NETs is not yet fully defined. Systemic therapy options range from somatostatin analog therapy, mTOR inhibitor therapy, and cytotoxic chemotherapy. Somatostatin analog therapy is offered in selected patient subsets that have slowly progressing disease and whose tumors express somatostatin receptors as detected by nuclear medicine scanning (Octreoscan). Somatostatin analog therapy is only modestly efficacious, with disease stabilization as the expected clinical benefit. Inhibition of the mTOR with everolimus has demonstrated efficacy in randomized trials. In the RADIANT-2 trial of everolimus+octreotide vs. placebo+octreotide in NETs, a small subset of patients with lung NETs (n=44) was analyzed. This showed an improvement in progression free survival with everolimus+octreotide vs. the control arm (median PFS 8.8 months vs 2.8; Hazard Ratio (HR) = 0.62; p=0.1). Subsequently, the phase III RADIANT-4 trial of everolimus vs placebo in non-functional lung and GI NETs was conducted. In this trial, approximately 30% of the 302 randomized patients had lung NETs. RADIANT-4 showed a PFS and overall survival (OS) benefit in favor of everolimus (PFS HR=0.39, p<0.0001; OS HR=0.64, p=0.037). More recently, a randomized phase II trial (LUNA) of pasitreotide alone, everolimus alone, or the combination showed a trend for improved PFS for the combination arm (PFS at 9 months was 39.0% for pasitreotide alone, 33.3% for everolimus alone, and 58.5% for the combination). In patients who are not candidates for somatostatin analog therapy or everolimus, or have failed these therapies, cytotoxic chemotherapy is often considered. The most commonly used regimens include platinum-etoposide (similar to that employed for SCLC) and temozolomide. Response rates to chemotherapy are reportedly much lower in lung NETs (vs SCLC) in retrospective studies; for example, platinum-etoposide is reported to yield response rates of 20-30% in lung NETs compared to rates greater than 50% in SCLC. It is thought that tumor responses are possibly influenced by the degree of tumor de-differentiation. Other agents with anecdotal activity include 5FU, capecitabine, oxaliplatin, and anthracyclines. Prospective trials of systemic therapy in lung NETs are essential to define the optimal standards of care. Selected References: 1. Hendifar, AE et al. J Thor Oncol 2016; 12(3):425-436 2. Yao, J. et al. Lancet 2016; 387: 968-77 3. Fazio N, et al. Chest 2013; 143(4):955-962

Abstract:
In the 1970s, pulmonary neuroendocrine tumors were classified into three histologically defined categories: typical carcinoid (TC), atypical carcinoid (AC) and small cell lung carcinoma (SCLC) [1]. In 1999, the World Health Organization (WHO) classified large cell neuroendocrine carcinoma (LCNEC) as a fourth neuroendocrine tumor of the lung. Although LCNEC was classified as a variant of large cell carcinoma in 1999 [2], it was classified as a neuroendocrine tumor in 2015. To date, for neuroendocrine tumors of the lung, the major categories of morphologically identifiable neuroendocrine tumors are TC, AC, LCNEC, and SCLC. Analyses of molecular markers revealed that low-grade TC and intermediate-grade AC exhibit a low proliferative rate compared with high-grade LCNEC and SCLC [3], and TC and AC have different genetic alterations from high-grade LCNEC and SCLC [4]. Analyses of their genetic alterations show that neuroendocrine lung tumors may represent a spectrum ranging from low-grade TC and intermediate-grade AC to highly malignant LCNEC and SCLC tumors [4]. TC is classified as a malignant epithelial tumor of the lung [2, 5]. However, the overall survival rate is better for TC than for AC [5, 6], and the frequency of lymph node metastases in TC is lower than in high-grade LCNEC and SCLC [6]. Therefore, some investigators have advocated limited resection in patients with TC [7]. Some reports revealed that sublobar resection was noninferior to lobectomy for survival in patients with TC tumor [7]. However, other reports advised that radical oncologic surgery with radical node dissection was needed, and segmental and other limited procedures had to be avoided because of the high frequency of lymph node involvement and multicentric forms [8]. Moreover, preoperative diagnoses and/or diagnoses from intraoperative frozen sections are often difficult for differentiating AC from TC, because small amounts of necrosis or few mitoses are sometimes unclear in those specimens. A randomized controlled trial is the best method to compare surgical efficacy. However, it may be impractical due to the rarity of carcinoid tumors. Moreover, AC has a poorer prognosis and a higher frequency of lymph node metastases than TC. Therefore, sublobar resection for TC might be the optimal surgical method because of lung preservation and lower mortality than lobectomy; however, limited resection for TC remains an area of controversy. Several reports [9] revealed that the clinical behavior, morphology, and prognosis of LCNEC were similar to those of SCLC, even though there might be several clinicopathological differences between SCLC and LCNEC in peripheral, small-sized, and high-grade neuroendocrine tumors [10]. Because it is difficult to diagnose patients with LCNEC pre-operatively, and most cases have been diagnosed postoperatively from surgically resected specimens, many reports on LCNEC have referred to surgical cases, of which the majority [9] revealed that patients with LCNEC had poor prognoses. Even patients with pathological stage I LCNEC have had poor prognoses, with five-year survival rates of 27-67% [9]. In patients with LCNEC who underwent radical surgery and complete resection, many recurrent tumors were observed as distant metastases [10]. Therefore, surgery alone is not sufficient to treat patients with LCNEC, and subsequent adjuvant therapy may be necessary [10]. Although there were high response rates with platinum-based and SCLC-based chemotherapies in patients with LCNEC, almost all patients had only partial responses [9, 10]. Patients with LCNEC may not be able to expect complete responses with platinum-based and SCLC-based chemotherapies compared with patients with SCLC, even though these chemotherapies are as effective as adjuvant treatment. Therefore, patients with advanced-stage LCNEC had a poor prognosis because they could not always achieve a complete response. Although the indication for surgery is limited to stage I in patients with SCLC, surgery and adjuvant chemotherapy may achieve satisfactory results in terms of survival for patients with LCNEC with not only stage I but also stage II/III [10]. Therefore, surgical indications for patients with LCNEC may not be limited to clinical stage I cases, and surgery with adjuvant chemotherapy should be attempted for resectable LCNEC. References [1] Arrigoni MG, Woolner LB, Bernatz PE. Atypical carcinoid tumors of the lung. J Thorac Cardiovasc Surg. 1972;64:413-21. [2] Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E, editors. Histological Typing of Lung and Pleural Tumours. World Health Organization International Histological Classification of Tumors, XIII, 3rd ed. Berlin/Heidelberg: Springer-Verlag; 1999. [3] Rusch VW, Klimstra DS, Venkatraman ES. Molecular markers help characterize neuroendocrine lung tumors. Ann Thorac Surg. 1996;62:798-810. [4] Onuki N, Wistuba II, Travis WD, Virmani AK, Yashima K, Brambilla E, Hasleton P, Gazdar AF. Genetic changes in the spectrum of neuroendocrine lung tumors. Cancer. 1999;85:600-7. [5] Travis W.D, Brambilla E, Müller-Hermelink H.K, Harris C.C (Eds.): World Health Organization Classification of Tumours. Pathology and Genetics of Tumors of the Lung, Pleura, Thymus and Heart. IARC Press:Lyon 2004. [6] Iyoda A, Hiroshima K, Baba M, Saitoh Y, Ohwada H, Fujisawa T. Pulmonary large cell carcinomas with neuroendocrine features are high grade neuroendocrine tumors. Ann Thorac Surg. 2002;73:1049-54. [7] Fox M, Van Berkel V, Bousamra M II, Sloan S, Martin RC II. Surgical management of pulmonary carcinoid tumors: sublobar resection versus lobectomy. Am J Surg. 2013;205:200-8. [8] Daddi N, Ferolla P, Urbani M, Semeraro A, Avenia N, Ribacchi R, Puma F, Daddi G. Surgical treatment of neuroendocrine tumors of the lung. Eur J Cardiothorac Surg. 2004;26:813-7. [9] Iyoda A, Hiroshima K, Nakatani Y, Fujisawa T. Pulmonary large cell neuroendocrine carcinoma- its place in the spectrum of pulmonary carcinoma. Ann Thorac Surg. 2007;84:702-7. [10] Iyoda A, Makino T, Koezuka S, Otsuka H, Hata Y. Treatment options for patients with large cell neuroendocrine carcinoma of the lung. Gen Thorac Cardiovasc Surg. 2014;62:351-6.

Abstract:
Lung Neuroendocrine Tumors (NETs) are rare neoplasms derived from the neuroendocrine cells of the bronchopulmonary epithelium. They represent about 25% of all the neuroendocrine tumors, and no more than 2%-3% of all the primary tumors of the lung. Their incidence has recently increased by approximately 6% per year, probably due to the improved awareness as well as for the diffusion of lung cancer screening programs worldwide. NETs’ incidence now ranges from 0.2 to 2 per 100,000 individuals per year in the United States. Their rarity, along with the lack of randomized clinical trials, make lung NETs’ global management still questioned, especially in case of advanced diseases, and only few clinical recommendations currently exist. In 2012, during the Annual Meeting in Essen (Germany), the European Society for Thoracic Surgeons (ESTS) created a new Working Group (WG) specifically dedicated to the Lung NETs. The Steering Committees was composed by the following Thoracic Surgeons: Pier Luigi Filosso (Torino, Italy-Chair), Pascal Alexandre Thomas (Marseille, France), Mariano Garcia-Yuste (Valladolid, Spain), Eric Lim (London, UK), Federico Venuta (Rome, Italy), Alessandro Brunelli and Konstantinos Papagiannopoulos (Leeds, UK), Hisao Asamura (Tokyo, Japan). The aim of this WG was to create a group of physicians expert on Lung NETs in order to improve scientific knowledge on such rare neoplasms, and disseminate it among the scientific community. A specific database was rapidly designed, to retrospectively collect data of patients operated for lung NETs, and it was sent to all the ESTS Members who expressed their interest to this project. Moreover, a survey concerning lung NETs’clinical management was prepared and its results were recently published (Future Oncol. 2016;12:1985-1999). Up to now, 2040 operated NETs patients have been collected amongst 17 high-volume International Thoracic Surgery Institution worldwide. This retrospective database was used for several studies about lung NETs clinical behavior and outcome. In particular, the outcome and prognostic factors of two aggressive lung NETs: atypical carcinoids (ACs) and large-cell neuroendocrine carcinomas (LCNCs) were the object of the first publication (Eur.J.Cardiothorac Surg. 2015;48:55-64). For ACs, age (P<0.001), tumour size (P=.015) and sub-lobar resections (P=0.005) were independent negative prognostic factors; for LCNCs, only pTNM stage III tumors (P=0.016) negatively affected outcome in the multivariate analysis. Local recurrences and distant metastases were statistically more frequent in LCNCs (P=0.02), as expected. A prognostic model of survival for typical carcinoids (TCs) was the matter of the second publication (Eur.J.Cardiothorac Surg. 2015;48:441-447): an analysis of 1109 TC patients was performed. A prediction model for mortality, evaluating age, gender, previous malignancies, peripheral tumour location, TNM stage and ECOG PS was elaborated, and the final model showed a good discrimination ability with a C-statistic equal to 0.836 (bootstrap optimism-corrected 0.806). Moreover, this model has been recently validated by Cattoni and Coll. The treatment of biologically aggressive/advanced lung NETs was recently investigated in a paper published by the Journal of Thoracic Disease (J.Thorac. Dis. 2015;7:S163-S171). Surgery, whenever feasible, remains the mainstay of treatment, and chemo/radiotherapy should be reserved to progressive diseases. In case of resected N1-N2 carcinoids, a "watch and see" policy and a close clinical/radiological follow-up is also recommended. Surgery alone is not sufficient to treat high-grade NETs (e.g.: LCNC): adjuvant CT is suggested even in early stages. Platinum-Etoposide regimen demonstrated to be the most effective; Irinotecan and other biological drugs are also regarded to be very promising. The management of advanced lung NETs should be tailored by multidisciplinary teams including Medical and Radiation Oncologists, Surgeons, Pathologists, Pulmonologists, Endocrinologists, Interventional Radiologists; patients’ prognosis is mainly dependent on tumor grade and its anatomical extent. Large-cell neuroendocrine carcinoma (LCNC) is a rare tumor characterized by an aggressive biological behaviour and poor prognosis; its optimal treatment is still under debate. Some recent reports indicate that adjuvant chemotherapy (CT) may have a beneficial effect on survival. Data from 400 patients with resected LCNC were analyzed. The 3- and 5-year survival rates were 54.1% and 45%, respectively. With the multivariable model, increasing age, ECOG ≥2 and advanced TNM stage were indicators of poor prognosis. Weak evidence of a higher overall survival in patients receiving adjuvant CT (adjusted hazard ratio 0.73; 95% confidence interval: 0.56-0.96, P  = 0.022) was also observed (Eur.J.Cardio-Thorac.Surg. 2017;52:339-345). In Stage I TCs (SITCs) non-anatomical resections (wedge) are sometimes advocated because of their indolent behavior. An analysis on effect of surgical procedure on SITC patients’ survival was therefore done (Eur.J.Cardiothorac.Surg. 2017 submitted paper). Eight-hundred seventy-six SITC patients (569 females,65%) were included in this study; the 5-year OS rate was 94.3% (95%CI:92.2 –95.9). At univariable analysis, wedge resection resulted to be associated with a poor prognosis (5-year OS 82%,95%CI:0.71-0.89,P<.001) compared to other anatomical resections. At multivariable score-adjusted analysis, wedge resection confirmed to be an independent predictor of poor prognosis (HR2.17,95%CI: 1.19-3.96,P=.012). Since 2106, a lung NETs prospective database is active through the official ESTS European Database, and up to now, more than 150 new cases have been collected. Through this new platform, very easy to be used, we are confident to collect, in few years, more data especially on possible tumor recurrences and their treatment, as well as on the role of emerging biological drugs used in the adjuvant setting in advanced diseases. An active participation of Medical/Radiation Oncologists to this scientific project would be also desirable. The active role of the most important Scientific Societies could strongly support the success of this scientific project.

Abstract:
Staging of large cell neuroendocrine carcinoma (LCNEC) was classified based on non-small cell type (TNM stage). The treatment of early stage (I, II) was mainly surgery; the use of neo - adjuvant and adjuvant chemotherapy are in consideration but there's not a standard approach; for stage III which limited to the thoracic area, the role of concurrent chemotherapy and radiotherapy is one of the options. Whether the regimen of chemotherapy should be similar to small cell lung cancer (SCLC) or the regimen of non -small cell lung cancer (NSCLC) is not clear. Most of the data are in favor of SCLC regimen which is Cisplatin plus etoposide; however the data came from retrospective and small numbers of patients, thus there's an unmet need to improve the treatment of LCNEC. Large Cell Neuroendocrine Carcinoma and Small Cell Lung Cancer are both consider high grade neuroendocrine carcinoma of the lung. Small cell is the most frequent type of lung neuroendocrine tumor, occurs around 15% of lung cancer while Large Cell neuroendocrine carcinoma was only about 3% of lung cancer. According to WHO classification in 2004 LCNEC was classified as a variant of large-cell carcinoma; however in 2015 WHO classification LCNEC was classified into a group of neuroendocrine tumor which includes SCLC, typical carcinoid, atypical carcinoid and LCNEC. According to genomic analysis, LCNEC was separated into two groups. Some have genomic characteristic of SCLC and some have genomic characteristic of NSCLC. The new modalities such as anti-angiogenesis and in the case of EGFR mutation the treatment with EGFR inhibitor should be considered. The role of met inhibitors in LCNEC should be explored. Thus there is a long way to go in order to improve the outcome of this rare lung cancer type.

Abstract not provided

Abstract:
Local therapy as the primary treatment modality of early malignant pleural mesothelioma (MPM) remains highly controversial due to lack of clear benefit in comparative clinical trials. In specialized experienced centers, the initial approach is usually surgical resection - extrapleural pneumonectomy (EPP) or pleurectomy/decortication (P/D). No consensus exists with regard to the optimal use of radiotherapy (RT) in MPM. At the present time, there is no evidence to support the use of radical RT as a single modality in MPM, because of the inability to deliver a therapeutic high dose of radiation (e.g. 60Gy in 30 fractions) to the entire pleura without overdosing the surrounding organs at risk. However, RT has been used in the management of MPM in three indications: as prophylaxis to reduce the incidence of recurrence and pain at sites of diagnostic or therapeutic instrument insertion, as part of multimodal definitive treatment (following induction chemotherapy and surgical resection) to improve locoregional control in early-stage disease and for palliation of symptoms (mainly chest wall pain) in patients with advanced disease. During thoracoscopy, thoracocentesis or needle biopsy in patients with MPM, the seeding of tumor cells along the needle tract may occur, leading to painful metastases at the intervention sites in 20-50% of cases [1]. Prophylactic radiotherapy to chest wall sites of invasive procedures has previously been recommended. However, recent randomized studies (e.g. SMART trial) have shown that prophylactic RT should not be routinely used to prevent procedure tract metastases (PTMs) in MPM, as it confers no benefits in terms of chest pain control, analgesia use, survival, QoL and the data on the potential effect on PTMs' incidence reduction are discrepant [1]. Instead patients should undergo careful clinical follow-up allowing the immediate detection and treatment of PTMs. Surgical resection alone in early MPM is associated with high local recurrence rates (69% after P/D and 38% after EPP) [2]. Therefore, to reduce local failure rate conventional RT has been used as a component of potentially curative trimodality treatment. Adjuvant RT was first used in patients after EPP and was delivered with anterior posterior photon fields matched with electron boost fields. A similar hemithoracic RT technique was explored after P/D, but additional block for central part of the lungs was required. The population based studies data on the potential role of adjuvant RT in improving overall survival (OS) are conflicting [3]. However, a subsequent analysis utilizing the National Cancer Database (NCDB) revealed the improvement of the 2-year rate of OS from 20% to 34% in patients with MPM receiving conventional RT after surgery [3]. Without significant improvement in local control and overall survival after P/D, conventional RT has been shown to decrease local recurrence after EPP to 13% and result in a median survival of 17 months [3]. The benefit in local control was strongly dose-dependent and obtained with a median dose of ≥54Gy [3]. Subsequently, the IMRT technique was implemented to improve adjuvant RT outcomes after P/D (IMPRINT approach). This novel method offers better coverage of the extensive, irregularly shaped target, safer dose escalation in the target volume and optimal sparing of OARs, but results in more heterogenous dose distribution, with a larger volume of normal tissue receiving low-dose radiation than in conventional techniques. IMRT was shown to be associated with a lower incidence of local recurrence (14% vs 42%), improved overall survival (median 20 vs 12 months) and lower rates of grade ≥2 esophagitis (23% vs 47%) when compared with conventional techniques [4]. A potential disadvantage of IMRT is the dose delivered to the contralateral lung that is associated with higher risk of pneumonitis (up to 46% of fatal pneumonitis in early series) [5]. Mean contralateral lung dose >8,5Gy and higher percentage (>80%) of the contralateral lung receiving dose >5Gy were significantly associated with higher risk of pulmonary toxicity. Strict dosimetric constraints, particularly on the contralateral lung (MLD<8,5Gy, V20<10%, V5<60%) and optimal algorithms in treatment planning (e.g. accurate measurement of volumes receiving low radiation doses on the basis of Monte-Carlo algorithm), are critical for radiotherapy planning [4]. Another novel approach employs the combination of IMRT and electrons, that offers better sparing of heart, liver and kidneys [6]. The technical aspects of adjuvant IMRT for MPM can further be improved. When compared to step-and-shoot linac-based IMRT, the use of helical tomotherapy significantly improved target coverage, homogeneity index, lowered average V5<40% and MLD<5Gy for the contralateral lung [7]. Intensity-modulated arc therapy also demonstrated superior V20 and better target coverage in addition to shorter treatment delivery time [8]. Proton therapy was also evaluated in the mentioned setting, offering better sparing of OARs and possibility of further dose escalation to improve target coverage [9]. Whether these dosimetric advantages will translate into clinical benefit, should be assessed in future prospective studies. The trimodality treatment of MPM consisting of induction chemotherapy (pemetrexed+cisplatin), surgical resection and adjuvant radiation has resulted in the best survival outcome thus far in non-randomized cohorts. Accelerated hemithoracic radiation (25Gy in 5 daily fractions), followed by EPP, was evaluated as an alternative. This approach is feasible and associated with encouraging overall survival (median of 51 months) and disease-free survival (47 months) in patients with epithelial cT1-3N0M0 MPM [10]. These promising results should support further studies to clarify the role of hypofractionated pre-operative RT in the management of MPM. Radiotherapy can provide palliation of chest pain in the course of MPM in 50-60% of cases, although the duration of response is often disappointing (2-3 months) [11]. An effective palliation was observed after the dose ≥40Gy and a higher local response rate for patients treated with a 4Gy per fraction regimen compared with those receiving fractions lower than 4Gy was reported (50% vs 39%) [11]. Many aspects of RT for patients with MPM are still not standardized and warrant further investigations. Clinical trials designs will require integration of new systemic therapies, immune modulation and novel technology advances in RT, with the guidance of predictive and prognostic biomarkers, as well as genetic profiling. MPM patients with resectable disease should be encouraged to participate in clinical trials. Bibliography: 1. Arnold DT, Clive AO: Prophylactic radiotherapy for procedure tract metastases in mesothelioma: a review. Curr Opin Pulm Med 2017, 23(4):357-364. 2. Pass HI, Kranda K, Temeck BK, Feuerstein I, Steinberg SM: Surgically debulked malignant pleural mesothelioma: results and prognostic factors. Ann Surg Oncol 1997, 4(3):215-222. 3. Rosenzweig KE: Malignant pleural mesothelioma: adjuvant therapy with radiation therapy. Ann Transl Med 2017, 5(11):242. 4. Shaikh F, Zauderer MG, von Reibnitz D, Wu AJ, Yorke ED, Foster A, Shi W, Zhang Z, Adusumilli PS, Rosenzweig KE et al: Improved Outcomes with Modern Lung-Sparing Trimodality Therapy in Patients with Malignant Pleural Mesothelioma. J Thorac Oncol 2017, 12(6):993-1000. 5. Allen AM, Czerminska M, Janne PA, Sugarbaker DJ, Bueno R, Harris JR, Court L, Baldini EH: Fatal pneumonitis associated with intensity-modulated radiation therapy for mesothelioma. Int J Radiat Oncol Biol Phys 2006, 65(3):640-645. 6. Chan MF, Chui CS, Song Y, Burman C, Yorke E, Della-Biancia C, Rosenzweig KE, Schupak K: A novel radiation therapy technique for malignant pleural mesothelioma combining electrons with intensity-modulated photons. Radiother Oncol 2006, 79(2):218-223. 7. Sterzing F, Sroka-Perez G, Schubert K, Munter MW, Thieke C, Huber P, Debus J, Herfarth KK: Evaluating target coverage and normal tissue sparing in the adjuvant radiotherapy of malignant pleural mesothelioma: helical tomotherapy compared with step-and-shoot IMRT. Radiother Oncol 2008, 86(2):251-257. 8. Scorsetti M, Bignardi M, Clivio A, Cozzi L, Fogliata A, Lattuada P, Mancosu P, Navarria P, Nicolini G, Urso G et al: Volumetric modulation arc radiotherapy compared with static gantry intensity-modulated radiotherapy for malignant pleural mesothelioma tumor: a feasibility study. Int J Radiat Oncol Biol Phys 2010, 77(3):942-949. 9. Krayenbuehl J, Hartmann M, Lomax AJ, Kloeck S, Hug EB, Ciernik IF: Proton therapy for malignant pleural mesothelioma after extrapleural pleuropneumonectomy. Int J Radiat Oncol Biol Phys 2010, 78(2):628-634. 10. de Perrot M, Feld R, Leighl NB, Hope A, Waddell TK, Keshavjee S, Cho BC: Accelerated hemithoracic radiation followed by extrapleural pneumonectomy for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2016, 151(2):468-473. 11. Davis SR, Tan L, Ball DL: Radiotherapy in the treatment of malignant mesothelioma of the pleura, with special reference to its use in palliation. Australas Radiol 1994, 38(3):212-214.

Abstract not provided

Abstract:
The recent success of checkpoint blockade in other malignancies has led a resurgence of interest in this modality for mesothelioma. Historically, occasional responses were seen with cytokine therapy, immunomodulatory gene therapy, and vaccination incorporating suicide genes or immunological adjuvants. However, the availability of checkpoint blockade and identification of mesothelioma tumour antigens has opened the field to a plethora of multicentre clinical trials and to interest in developing immunotherapy for this indication. The cytotoxic T-lymphocyte Antigen 4 (CTLA-4) blocking antibody tremelimumab was the first checkpoint blockade treatment trialled in mesothelioma, with two single arm phase II clinical trials reporting modest objective responses and encouraging stable disease(1, 2). Unfortunately, the subsequent randomised phase IIb study of tremelimumab versus placebo as second-line treatment for pleural mesothelioma, the DETERMINE trial, did not reach its primary endpoint (Kindler et al. in press). The next reported trials examined the efficacy of PD pathway blockade. Results from the phase I KEYNOTE 028 study mesothelioma cohort of 25 pre-treated patients were recently published. Using single agent pembrolizumab, the partial response (PR) rate of 20% was lower than originally reported, although a 72% disease control rate (DCR) was observed(3). All patients were selected for >1% tumour PD-L1 expression. The median duration of response was 12.0 months, with no new safety concerns. Three other trials of single-agent PD-pathway inhibition have been reported subsequently. Preliminary results have been reported from a second study of pembrolizumab as second line therapy, with PR of 21%, DCR of 80%, and median progression free survival (PFS) of 6.2 months(4). The NivoMes study of second-line single agent nivolumab reported a PR rate of 15%, with stable disease rates of 35% and a median PFS of 3.6 months(5). Neither of these studies selected for PD-L1 expression. Finally, the JAVELIN study of Avelumab, a PD-L1 inhibitor, in patients with prior therapy reported a PR rate of 9.4% and DCR of 57%(6). There is no clarity on the importance of PD-L1 expression as a predictor of response. As with other cancers, pseudoprogression and subsequent response can be seen in some patients with the use of checkpoint blockade in mesothelioma. Whilst the results of single-agent therapies have been hailed as promising, only a minority of patients derive durable benefit, and as yet there is no clear predictive biomarker. The current generation of clinical trials are focusing on a. evaluating single agent checkpoint blockade in randomised trials; b. combining immunotherapies; and c. combining checkpoint blockade with existing therapies. The MAPS-2 study recently reported on combination ipilimumab and nivolumab as second or third line treatment(7). 125 participants were rapidly recruited to this phase IIb clinical trial, and were randomised to receive either nivolumab alone, or nivolumab with ipilimumab. In the intention to treat population, the disease control rate was 51.6% for the combination and 39.7% for nivolumab alone, with PR rates of 24.2% and 17.5% respectively. PFS was 5.6 months in the combination arm vs. 4.0 months in the nivolumab arm, and there was a promising survival signal in the combination arm. Nevertheless, as with this combination in other settings, toxicity was substantial (although manageable) and three treatment-related deaths were reported. Further maturity of these data is awaited. Ongoing clinical trials of single agent checkpoint blockade included the randomised phase III CONFIRM trial, comparing nivolumab with placebo in 336 previously treated patients (NCT03063450), and the randomised phase III PROMISE-Meso study, comparing pembrolizumab with chemotherapy in the second line (plus) setting in 142 patients (NCT02991482). These studies should be sufficient to confirm results of the previous single agent/single arm trials, with further single agent studies of PD1 blockade in the second/third line setting unlikely to move the field forward substantially unless they are focussed on biomarker questions. The successful rapid recruitment of MAPS-2 augurs well for rapid completion of other combination immunotherapy studies. The CA-209-743 (CheckMATE 743) trial is comparing platinum based chemotherapy to combination nivolumab and ipilimumab in 600 patients (NCT02899299). The INITIATE trial (NCT03048474) is testing nivolumab and ipilimumab in just 33 patients, but with a biomarker focus. The completed NIBIT-Meso 1 trial is a phase II study of tremelimumab and durvalumab for which results are likely to be available soon (NCT02588131), with a further phase II trial of the same agents and similar design open in the USA (NCT03075527). Finally, in combinations of checkpoint inhibitors with conventional therapies, the most mature concepts are combinations with chemotherapy in the first line setting. Two single arm phase II clinical trials of identical design are combining cisplatin and pemetrexed first line chemotherapy with durvalumab, one Australian (ACTRN 12616001170415) and one in the USA (NCT02899195). A randomised phase II study in Canada is comparing first line cisplatin/pemetrexed with either pembrolizumab or chemotherapy plus pembrolizumab (NCT02784171). The Australian ‘DREAM’ study has completed recruitment. All trials are incorporating biomarker studies, which may prove particularly challenging in the context of concurrent chemotherapy. No discussion on immunotherapy in mesothelioma would be complete without comment on anti-mesothelin strategies. The anti-mesothelin immunotoxin SS1P has undergone phase I testing, however neutralising antibody development mandated combination with immunosuppressive pre-treatment moving forward. Durable responses have been seen in small numbers of patients(8). The chimeric monoclonal mesothelin antagonist MORAb-009 (Amatuximab) has completed early phase testing and is now in phase III combined with cisplatin and pemetrexed (NCT02357147). Mesothelin is also being used as the target antigen in Chimeric Antigen Receptor (CAR) T cell therapy in pilot testing. Finally, anetumab ravtansine is an antibody drug conjugate linking a human anti-mesothelin monoclonal antibody to the spindle poison DM4(9). Results have recently been released suggesting no benefit over single agent vinorelbine in a second-line phase IIb study (NCT02610140). This abstract is not exhaustive, with other immunotherapies under investigation including dendritic cell therapy, CAR-T cell therapy, and allogeneic tumour cell vaccine therapies amongst others. It remains unclear which immunotherapies, in which combinations, and at which point in the disease trajectory will be permanently integrated into management. Biomarker studies to predict both toxicities and outcomes are likely to be critical to guide patient selection. REFERENCES 1. Calabro L, et al. (2013) Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol 14(11):1104-1111. 2. Calabro L, et al. (2015) Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study. Lancet Respir Med 3(4):301-309. 3. Alley EW, et al. (2017) Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial. Lancet Oncol 18(5):623-630. 4. Kindler H, et al. (2016) OA13.02 Phase II Trial of Pembrolizumab in Patients with Malignant Mesothelioma (MM): Interim Analysis. J Thorac Oncol 12(1):S293-294. 5. Quispel-Janssen J, et al. (2016) OA13.01 - A Phase II Study of Nivolumab in Malignant Pleural Mesothelioma (NivoMes): With Translational Research (TR) Biopies. J Thorac Oncol 12(1):S292-293. 6. Hassan R, et al. (2016) Avelumab (MSB0010718C; anti-PD-L1) in patients with advanced unresectable mesothelioma from the JAVELIN solid tumor phase Ib trial: Safety, clinical activity, and PD-L1 expression. J Clin Oncol 34:abstr 8503. 7. Scherpereel A, et al. (2017) Second- or third-line nivolumab (Nivo) versus nivo plus ipilimumab (Ipi) in malignant pleural mesothelioma (MPM) patients: Results of the IFCT-1501 MAPS2 randomized phase II trial. J Clin Oncol, p LBA8507. 8. Hassan R, et al. (2013) Major cancer regressions in mesothelioma after treatment with an anti-mesothelin immunotoxin and immune suppression. Sci Transl Med 5(208):208ra147. 9. Golfier S, et al. (2014) Anetumab ravtansine: a novel mesothelin-targeting antibody-drug conjugate cures tumors with heterogeneous target expression favored by bystander effect. Mol Cancer Ther 13(6):1537-1548.

Abstract:
Malignant mesothelioma (MM) is a mesodermally derived, primarily pleural or peritoneal tumor with aggressive behavior. The incidence of this once-rare tumor is increasing rapidly because of the widespread use of asbestos. In Japan, the annual number of MM-related deaths in 2015 was approximately 1,400, which is 3-fold higher than that observed 20 years ago. The median survival of patients with malignant pleural mesothelioma is 9 to 18 months after diagnosis, which necessitates urgent development of more effective new therapeutic modalities against this aggressive disease. Neurofibromatosis type 2 (NF2) is a tumor suppressor gene that is deleted or mutated in approximately 40% of MM tumors. The gene product of NF2, Merlin, suppresses MM cell proliferation, at least in part, by regulating the Hippo signaling pathway. Hippo signaling is a tumor-suppressive pathway, and alterations in the components of this pathway, including LATS2, SAV1, and AJUBA, have been detected in MM cells. Inactivation of the Hippo signaling pathway leads to the constitutive activation of YAP and TAZ, downstream transcription coactivators that are regulated by this pathway. We previously reported that inhibition of YAP in Merlin-deficient MM cells reduces cell proliferation and inhibits anchorage-independent growth, whereas expression of an active YAP mutant in immortalized mesothelial cells induces oncogenic transformation. While the oncogenic roles of YAP has been extensively studied in MM cells, the possible pro-oncogenic functions of TAZ, a homolog of YAP, is not well understood. Using a panel of MM cell lines, we observed that approximately 65% of these cell lines show activation (underphosphorylation) of TAZ. We knocked down TAZ with shRNA-TAZ in MM cells with high TAZ activation and detected strong inhibition of cell proliferation, anchorage independent growth, cell motility, and invasion in vitro. Meanwhile, immortalized mesothelial cells transduced with a constitutive activated form of TAZ (TAZ S89A mutant) showed enhancement of these in vitro phenotypes and tumorigenicity in nude mice. Using microarray analyses, we identified that while most upregulated genes were common between the TAZ and YAP activated cells, TAZ induced transcription of genes encoding cytokines and their receptors more than YAP. Among the upregulated cytokines, we observed that TAZ binds to the promoter region of the gene encoding IL1-beta along with TEAD transcription factors, which increased IL1-beta transcription and subsequently cell proliferation of immortalized mesothelial cells. In contrast, IL1-beta knockdown or an IL1 receptor antagonist inhibited cell proliferation of MM cells, suggesting that IL-beta signaling suppression may have stronger inhibitory effects on MM cells with TAZ activation. The mevalonate pathway has recently been reported to play a pivotal role in regulating the downstream events of the Hippo pathway. We identified antitumor effects of statin on MM cells with Hippo signaling pathway inactivation. Statin attenuated proliferation and migration of MM cells harboring a NF2 mutation by accelerating YAP phosphorylation/inactivation. Interestingly, not all MM cells with NF2-Hippo pathway inactivation exhibited statin sensitivity. All the statin high-sensitive MM cell lines had increased p-YAP/YAP ratios (inactivation) after statin exposure, whereas in statin low-sensitive cells, the p-YAP/YAP ratio was generally low or unchanged. Genetically, the statin high-sensitive MM cells harbored NF2 and/or LATS2 mutations without BAP1 mutation, whereas BAP1 mutations were frequently identified in statin low-sensitive cells. Indeed, the Y-MESO-25 cell line, carrying both NF2 and BAP1 mutations, regained moderate statin-sensitivity after transfection with a wild-type BAP1 plasmid, indicating that BAP1 mutations interfered with the anti-proliferative effects of statins on MM cells with Hippo pathway inactivation. However, the interactions between BAP1 and the Hippo pathway remain to be elucidated. In conclusion, YAP and TAZ activation via NF2-Hippo pathway inactivation is essential for MM cells to acquire more malignant phenotypes, and therefore, detailed understanding of the biology of this pathway is required to develop new therapeutic modalities against MM based on dysregulation of this pathway.

Abstract not provided

Abstract:
The UK has the highest incidence of Mesothelioma in the world with over 2700 cases diagnosed in 2014 (Cancer Research UK 2017). Data for 80% of these patients was submitted and analysed as part of the UK’s National Lung Cancer Audit Mesothelioma Report (NLCAMR) 2016 (Royal College of Physicians [RCP] 2016). The report confirmed that an increasing number of patients are receiving chemotherapy in the UK particularly patients with a good performance status; 53% compared to 41% in the audit’s 2014 report. The current audit does not identify the proportion of patients who receive their treatment as part of a clinical trial however the report recommends “All patients should be offered access to relevant clinical trials even if this requires referral outside of their network” (RCP 2016). With an increasing number of mesothelioma clinical trials now available in the UK, and more in development, facilitating seamless movement of patients from one specialist clinical team to another is essential. Mesothelioma UK, a national charity dedicated to improving outcomes for those affected by Mesothelioma, is establishing a comprehensive package of services and resources specifically to support this. The charity’s vision, for ensuring equitable access to treatment and trials is outlined in the charity’s 2016-2021 Strategy, The Next Five Years (Mesothelioma UK 2016). This presentation provides insight into readily transferable measures Mesothelioma UK has developed to support equitable access to treatment and care across the UK. References Cancer Research UK 2017 (Last viewed August 4th 2017).

Abstract:
The history of global tobacco control starts at the beginning of the twentieth century with early data linking the smoking of tobacco with the risk of lung cancer, a previously rare disease. The build up of scientific evidence for the link gained pace toward the middle of century when landmark publications brought more widespread recognition of the phenomenon[1][,][2]. The pivotal US Surgeon General Report from 1964 gave a clear message that tobacco smoking was unequivocally associated with an increased risk of developing lung cancer[3]. Over the following decades the paradigm of tobacco control recognizable today culminated in the development the first global public health treaty, the World Health Organization Framework Convention on Tobacco Control (WHO FCTC), which came into force in 2005 and currently lists 181 countries as Parties to the Convention[4]. In 2008, the FCTC launched the MPOWER measures (Table 1.), six steps proven to lead to reduction in tobacco use around the world[5] and that provide the ability to benchmark the effects of tobacco control strategies between countries[6]. In countries with robust implementation, these measures have achieved what may have once been unthinkable, the saving of millions of lives[6] and the reduction in smoking rates to historic post-WWII lows[6]. There have been enormous benefits, with a reduction in cigarette consumption, altered rates of disease and a reduction in smoking uptake. But the inconsistencies in regulation and in MPOWER implementation around the world have led to problems with the shifting of tobacco industry efforts to the developing world[7], the targeting of vulnerable groups for new market share[7] and the entrenchment, in some countries, of the tobacco industry in the halls of government. New threats to global tobacco control are starting to appear from the impacts of globalization of trade[7], newer products whether “low-harm” or otherwise and from focused, covert attacks by the tobacco industry itself. This presentation aims to review the development and impact of current tobacco control policy, to examine emerging threats to tobacco control, to focus on evasive manoeuvres of the globalizing tobacco industry and to discuss possible future tobacco control strategies that these developments will require. Over the last half century the tobacco industry in the developed world has become globalized. Four companies have come to dominate the global tobacco trade, Philip Morris International, British American Tobacco, Japan Tobacco International and Imperial Tobacco[8]. This has given companies such as PMI the economic clout to oppose, delay and threaten tobacco control strategies such as plain packaging and smoking bans[9]. The tobacco industry in Asia, a region of the world with very high smoking rates, is heading towards globalization. Companies such as Korean Tobacco and Ginseng (KT&G) and the China National Tobacco Corporation (CNTC) have developed foreign exports with government support[8] and have strengthened their domestic operations with consolidation and restructuring[8]. New global tobacco players have the potential to generate new competition, innovation and price reduction, all with detrimental impacts on public health[8]. The development of “low-harm” products such as electronic nicotine delivery systems (ENDS), including e-cigarettes, has opened new frontiers in regulatory control with concerns that such products may open new developed world markets for tobacco companies that otherwise continue to sell tobacco cigarettes in low and middle-income countries[7]. Tobacco companies use international trade relations to oppose the implementation of tobacco control measures; in the fight against plain packaging in Australia, the tobacco industry invoked trade treaties and the possibility of unfair trade restrictions. The tobacco industry holds to a culture of political sabotage that includes infiltration of government by lobbyists and open recognition of the value of political skills in undermining public health initiatives in tobacco control All of these developments call for a modernization of the tobacco control paradigm. This may include financial pressures such as disinvestment in the tobacco industry by pension funds[10], staunch regulatory approaches to ENDS and perhaps the development of finely honed political skills to match or surpass those of the tobacco industry. Even creative approaches to the dissemination of data, such as maps showing countries moving towards plain packaging or graphical presentation of the country-by-country distribution of tobacco factories may help inform the community and subvert the newer “low-harm” messages of the large tobacco companies. Many successes over many years can be attributed to traditional tobacco control, the emphasis on the science and the FCTC and MPOWER measures. However, the tobacco industry has very strong drive for survival with multiple strategies for evasion of control. The scientific arguments are irrefutable but are not enough to overcome an industry prepared to either deny the science, to ignore it while developing market share where regulations are weak or to espouse overt evasion techniques in company documents. MPOWER is no longer enough as the opposition does not play by the rules. Effective long-term global tobacco control will need to draw upon many resources including scientific evidence, economic pressure, the ability to avoid distractions and delaying tactics, resolute evaluation and regulation of ENDS and, ultimately, political dexterity in dealing with an industry prepared to do just about anything to maintain profit.

Table 1. MPOWER Measures

MPOWER Measures

Monitoring tobacco use and prevention policies Protecting people from tobacco smoke Offering help to quite tobacco use Warning about the dangers of tobacco Enforcing bans on tobacco advertising, promotion and sponsorship Raising tobacco taxes

References 1. Wynder EL, Graham EA. . Bull World Health Organ 2005;83(2):146–53. 2. Doll R, Hill AB. Bull World Health Organ 1999;77(1):84–93. 3. Health USSGAC on S and, General USPHSO of the S. Smoking and Health. http://profiles.nlm.nih.gov/NN/B/B/M/Q/ 4. United Nations Treaty Collection https://treaties.un.org/pages/ViewDetails.aspx?src=TREATY&mtdsg_no=IX-4&chapter=9&clang=_en 5. WHO | MPOWER [Internet]. WHO. [cited 2015 Jun 1];: http://www.who.int/tobacco/mpower/en/ 6. Levy DT, Yuan Z, Luo Y, Mays D. Tob Control 2016;tobaccocontrol-2016-053381. 7. Gilmore AB, Fooks G, Drope J, Bialous SA, Jackson RR. Lancet Lond Engl 2015;385(9972):1029–43. 8. Lee K, Eckhardt J. Glob Public Health 2017;12(3):367–79. 9. Peeters S, Costa H, Stuckler D, McKee M, Gilmore AB. Tob Control 2016;25(1):108–17. 10. Tobacco Free Portfolios http://www.tobaccofreeportfolios.org/

Abstract:
Tobacco use has been recognized by the World Health Organization as the number one preventable cause of premature death and disability. In the 21st Century, hundreds of millions of people will die because of tobacco use, with 70% of the toll occurring in low and middle-income countries. To magnify the horror of these projections, the tobacco epidemic, unlike other threats to global health, is a direct result of the activities of the most profitable industry in history. In recognition of this current and future epidemic, countries of the world negotiated and adopted in 2003 the WHO Framework Convention on Tobacco Control, the first-ever treaty of the WHO. The WHO FCTC has been ratified by 180 countries and the European Union, is an example of the promise of international health governance and highlights the central role of scientific evidence in tackling the global tobacco epidemic. A decision adopted by the FCTC Conference of the Parties at its 6th Session (Moscow, Nov 2014) called for an independent expert group to conduct an impact assessment of the treaty in its first decade. The expert group used three sources of evidence. The first source was a global evidence review of the scientific research on the impact of the FCTC across 17 of its articles; this review was conducted by the ITC Project. The second source was two reports prepared by global experts, of which one was prepared by the MacCabe Centre for Law and Cancer that reviewed the impact of the FCTC in legislative action taken by governments in tobacco control and in the use of the FCTC by governments in defense of legal challenges, and the second was prepared by Dr. Stella Bialous on the actions of the tobacco industry to weaken the FCTC. The third source was from evidence gathered by the expert group on country missions to 12 FCTC Parties, two from each of the six WHO Regions, and 3 from each of the four World Bank income levels. The main findings of the Impact Assessment Expert Group were the following: • FCTC has played an instrumental role as catalyst and framework for action— foundation for legislation and in defense against legal challenges. • FCTC has promoted tobacco control action in countries where little had been done, and has helped to strengthen action in countries where it was in place before ratification. • FCTC has broadened tobacco control across government and administration. And it has had impact on a range of international and global institutions and agendas. • FCTC has strengthened the role of civil society in tobacco control • FCTC has contributed to reductions in prevalence among Parties that have implemented FCTC policies at high levels, thus contributing to reductions in tobacco-related mortality and morbidity. • Tobacco industry continues to be the greatest threat to the implementation of the WHO FCTC. The expert group also cited the findings of a seminal study conducted by Gravely et al. on the impact of the FCTC on reductions in smoking prevalence. In an analysis of 126 countries, Gravely et al., found that over the first decade of the treaty, those countries that had implemented a greater number of key demand-reduction FCTC policies at the highest level (i.e., implementing those policies at sufficient strength to meet the standards of the FCTC Guidelines adopted for each of those policy domains: tax (Article 6), smoke-free (Article 8), labelling/warnings (Article 11), banning tobacco advertising, promotion, and sponsorship (Article 13), and cessation (Article 14)) experienced substantially greater decreases in smoking prevalence. On average, each additional policy implemented at the highest level was associated with a decrease in smoking prevalence of 1.57 percentage points (equivalent to a relative decrease of 7.09%). The Gravely et al. article, published in Lancet Public Health, demonstrates the power and potential of the FCTC to achieve its ultimate objectives. However, the article also presented findings on the current gap between the potential and the reality: that there have been very slow progress in the implementation of just these high-priority policies, consistent with the ITC Project’s global evidence review of the rate of implementation as well as the WHO’s assessment, which showed that by 2014, only 18% of the world’s population were living in countries with comprehensive smoke-free policies, and only 20% of the world’s population were living in countries with large pictorial warnings on tobacco product packaging. Why has implementation of the FCTC been so slow and in many cases at levels below the standards set by the FCTC Guidelines? All of the evidence gathered by the Expert Group points to one cause: the tobacco industry. Through their political influence, both explicit and covert, the tobacco industry has been quite effective in defeating efforts in many countries to implement the FCTC in accordance with their obligations under the treaty. It is necessary for all parties to engage in strong and vigilant implementation of Article 5.3, which forbids industry involvement in the process of formulating tobacco control policies, to advance the treaty and to more fully achieve its demonstrated potential to combat the global tobacco epidemic. The conclusions and take-home messages are: 1. FCTC Impact Assessment has demonstrated that the FCTC has great potential in reducing the number one preventable cause of death and cancer (esp. lung cancer) 2. BUT: FCTC implementation has been slow and in many cases is not at levels called for by the FCTC Article Guidelines. 3. Number of deaths and DALYs attributable to tobacco has increased since 1990. 4. Must SIGNIFICANTLY accelerate and strengthen FCTC implementation, especially in fully implementing Article 5.3. 5. Must expand implementation to other Articles (e.g., illicit trade, alternative livelihoods) 6. Research on evaluating FCTC implementation is essential for fighting industry attempts to weaken and slow the treaty.

Abstract:
WHO estimates that tobacco kills more than 7 million people each year. More than 6 million of these deaths are the result of direct tobacco use while around 890,000 deaths are the result of non-smokers being exposed to second-hand smoke. Around 60-70% of smokers want to quit smoking. However, the success rate for quitting smoking is quite low without a systematic approach. Counselling and medication can help increase the success rate. Only 24 countries provide national comprehensive cessation services with full or partial cost-coverage to assist tobacco users to quit. This represents merely 15% of the world's population. FCTC article 14 concerns the provision of support for reducing tobacco dependence and cessation, including counselling, psychological support, nicotine replacement, and education programs. Parties are required to develop and disseminate national guidelines on tobacco cessation and are encouraged to establish sustainable infrastructure for such services. Tobacco use treatment are not only clinically effective, but are cost-effective as well. Tobacco use treatments, ranging from clinician advice to medication to specialist-delivered intensive programs, are cost-effective in relation to other medical interventions such as treatment of hypertension, hyperlipidemia and to other preventive interventions such as periodic mammography. Even though a single application of any effective treatment for tobacco dependence may produce sustained abstinence in only a minority of smokers, tobacco use treatment remains highly cost effective. For example, Fiore and colleagues estimate the cost per life-year saved of tobacco dependence treatment to be $3,539. These estimates compare favorably with other health interventions in the U.S. like statins (which costs $50,000 per life-year saved), and diabetes treatment ($34,000 per life-year saved). Most effective way for more clinicians to intervene is to provide them with information regarding multiple effective treatment options and to ensure that they have ample institutional support to use these options. Clinicians, administrators, insurers, and purchasers can cooperate to encourage a culture in which intervention for smokers is an essential part of standard care. Korea is one such successful example. Eighty percent increase of price for a pack of cigarette since 1[st] of Jan, 2015 provided the momentum for other kinds of tobacco control activities. Even though only a small portion of increased tobacco tax was distributed to tobacco control activity, the tobacco control budget in 2015 has jumped by 13 times compared to previous year. 1. 246 Smoking Cessation Clinic in Health centers : All the health centers in Korea have smoking cessation clinic and gives counselling and NRTs for free. 2. Quitline : Nationwide quitline service is located in National Cancer Center. It gives counselling over the phone with proactive service for free. 3. Hospital based smoking cessation service : If a smoker visits hospital and gets counselling and medication(NRTs, bupropion, and varenicline) the fees for counselling and medication is actually free. National Health Insurance Foundation supports this program. 4. Community Smoking Cessation Center: There are 18 community smoking cessation centers in Korea. They provide three different services. 1) Residential 5 days smoking cessation program : intensive program which gives counselling, medication, etc. for free. 2) Residential 2 days smoking cessation program : short-term education program for free 3) Visiting program : Some underprivileged smokers, such as female smokers or adolescents who does not go to school, disabled smokers, or college students tend to not use smoking cessation programs due to various reasons. So community smoking cessation centers visit those special underprivileged populations. This service gives counselling and NRTs for free. References Fiore MC, Jaén CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. May 2008. Cromwell J, Bartosch WJ, Fiore MC, et al. Cost-effectiveness of the clinical practice recommendations in the AHCPR guideline for smoking cessation. Agency for Health Care Policy and Research. JAMA. 1997; 278: 1759-1766. Guerriero C, Cairns J, Roberts I, Rodgers A, Whittaker R, Free C. The cost-effectiveness of smoking cessation support delivered by mobile phone text messaging: Txt2stop. Eur J Health Econ. 2013; 14: 789-797. Krumholz HM, Weintraub WS, Bradford WD, Heidenreich PA, Mark DB, Paltiel AD. Task force #2--the cost of prevention: can we afford it? Can we afford not to do it? 33rd Bethesda Conference. J Am Coll Cardiol. 2002; 40(4): 603-615. Stapleton JA, Lowin A, Russell MAH. Prescription of transdermal nicotine patches for smoking cessation in general practice: evaluation of cost-effectiveness. Lancet. 1999; 354: 210-215. Tengs TO, Adams ME, Pliskin JS, Safran DG, Siegel JE, Weinstein MC, Graham JD. Five hundred life saving interventions and their cost effectiveness. Risk Analysis. 1995; 15: 369-390. Linda Bauld, Ph.D., Kathleen A. Boyd, MSc., Andrew H. Briggs, D.Phil., John Chesterman, Ph.D., Janet Ferguson, MPH., Ken Judge, Ph.D., Rosemary Hiscock, Ph.D.; One-Year Outcomes and a Cost-Effectiveness Analysis for Smokers Accessing Group-Based and Pharmacy-Led Cessation Services, Nicotine & Tobacco Research, Volume 13, Issue 2, 1 February 2011, Pages 135–145, Parrott S, Godfrey C, Raw M, et al. Guidance for commissioners on the cost-effectiveness of smoking cessation interventions. Thorax. 1998;53:S1-38.

Abstract:
Tobacco use is well known as a carcinogen linked to many malignacies and also linked to non-oncologic diseases such as cardiovascular disease, chronic lung disease, and respiratory infections. The majority of lung cancer patients do have a history of smoking; often many are actvely smoking at the time of diagnosis and many struggle with cessation during treatment and through survivorship. Patients may have a perception of futility and lack of perceived benefit regarding cessation, and some clinicians may view tobacco cessation with a pessimistic perspective in that "the damage is already done." One of the first steps toward cessation in lung cancer patients is to make patients, families, and physicians aware of the continued harms of smoking, the negative impact on efficacy of treatment, and for those who may be treated with curative intent, the potential for development of malignacy in the future. As the potential benefits range widely and may apply differently to different patients, the ability to individualize a message regarding relevant positive impacts of cessation is crucial. For cancer patients overall, there is survival advantage in those who are able to quit, compared to continued smoking. Nicotine and its metabolic products can promote tumor growth through increased proliferation, angiogenesis, and other pathways. Furthermore, nicotine can decrease the biologic effectiveness of conventional cancer treatments such as chemotherapy and radiotherapy. For patients undergoing surgery, smoother recovery and avoidance of perioperative complications such as respiratory infection, wound complications, and perioperative cardiovascular events is critical. For those treated with curative intent, continued smoking can clearly be a significant risk factor for metachronous lung cancer, or development of different primary tumors. Even in those with incurable disease, overall survival benefit of cessation has been demonstrated. In addition, many patients with lung cancer and a smoking history have significant burden of respiratory symptoms, including dyspnea, wheezing, exercise intolerance, cough, pneumonia, etc. From a palliative standpoint, cessation can ameliorate some of the respiratory symptoms, and improve quality of life. Physician advice is a powerful tool and should be part of every encounter. Ask-Advise-Refer is a simple standard strategy which can be integrated into even the busiest of workflows. This involves asking every patient about tobacco use, advising cessation and referral to a tobacco treatment resource. That resource may be a Certified Tobacco Treatment Specialist, a telephone counseling service (such as a 'quitline'), a group counseling setting or other specialist. A more indepth cessation strategy involves the "5 As": Ask, Advise, Assess, Assist, Arrange. In addition to asking every patient about use and advising them to stop, a physician should Assess their use, prior quit attempts, and willingness to make a quit attempt. Then a provider should Assist the patient with their quit attempt with counseling and pharmacotherapy. Motivational interviewing is a standard counseling strategy in which a process of questioning and interviewing which strengthens and engages intrinsic motivation within the patient in order to change behavior. Pharmacotherapy consists of nicotine replacement therapy, varenicline, and/or buproprion. Previous concerns regarding severe psychiatric side effects such as suicidal ideation with varenicline have made some patients and physicians wary to use it; however, a recent trial shows varenicline to be very safe with no higher incidence of psychiatric side effects than placebo. Nicotine replacement therapy (NRT) can be delivered in a slow continuous format via a nicotine patch, and/or via short acting NRT such as gum, lozenges, nasal spray, or prescription inhaler. Often times a long acting modality (nicotine patch) can be used in combination with a short acting NRT as combination therapy. Overall pharmacotherapy increases success of quit attempts, and should be integrated as a part of the patient's overall healthcare plan. Often times the choice of pharmacotherapy is guided by what has or has not worked for that patient in the past. Electronic Nicotine Delivery Systems (ENDS) or e-cigarettes have recently become widespread and commonly available in many countries. The nicotine content is widely variable, and other componenets of the vaporised liquid make comparison and quantification much more difficult than that for approved pharmacotherapy where dosing is consistent and predictable. It is true that ENDS may not contain the same level of carcinogens as cigarettes, but in reality many users of ENDS are not able to quit conventional cigarettes, but use ENDS when not able to smoke and then use conventional cigarettes when they can smoke. At current, data is lacking and does not support e-cigarettes above approved pharmacotherapy. For those patients who are using e-cigarettes, the primary goal to complete cessation of conventional cigarettes. Patients who are using e-cigarettes and unable to quit smoking should be steered toward approved pharmacotherapy. Multiple different strategies exist to support patients during cessation attempts. There is no universally applicable single way to approach cessation. Counseling and pharmacotherapy are mainstays of cessation support and best outcomes result from using them together. A concerted, consistent message combined with appropriate pharmacotherapy and counseling may help many patients with lung cancer to quit smoking and gain the benefits of cessation.

Abstract not provided

Abstract:
The 2016 FCTC Report of the Conference of Parties (COP 2016) alerts that tobacco is the only legal non-prescription product that can kill between 33% and 50% of consumers when used as recommended by the tobacco industry [[1]]. The tobacco industry is also the only industry that, due to the potential lethality of its products and their impact on public health, has elicited a legally-binding intergovernmental treaty for protecting public health policies from the interference by the industry and by those who act to protect their interests. Besides the heavy political lobbying for blocking, delaying or weakening public health policies on tobacco control, the industry frequently resorts to legal disputes on the basis of international free trade agreements and bilateral agreements to revert governmental policies1. During the 6th COP, in 2014, the FCTC adhering State Parties have declared that the tobacco industry interference in public health policy for tobacco control continues to represent the main hindrance for full implementation of FCTC articles [[2,3]]. According to the WHO’s global report on tobacco industry interference of 2012, the most common tactics used by the industry are [[4]]: • maneuvering to hijack the political and legislative process; • exaggerating the economic importance of the industry; • manipulating public opinion to gain the appearance of respectability; • fabricating support through front groups; • discrediting proven science; • intimidating governments with litigation or the threat of litigation. Despite the tobacco industry claiming otherwise, the Director-General of the World Trade Organization (WTO) has declared that there is no inherent conflict between FCTC implementation by the ratifying countries and the WTO rules [[5]]. He enlightens that there are two WTO principles that should be respected: the non-discrimination and the necessity principles. The first one implies that the implemented tobacco-control policy does not treat an imported product differently than its domestic equivalent; whereas the necessity principle states that such measure, law or provision “must be necessary for complying with the proposed health goal and that it should not be more restrictive than necessary on trade in order to achieve this goal”[[6]]. Furthermore, according to the WTO, a “Member States have the right to determine the level of health protection that they wish to promote…” and, “when considering the less restrictive alternatives, these must meet the regulatory goal and be reasonably available, as well as genuinely alternative and not complementary measures”[[6]]. As far as bilateral agreements are concerned, the industry has used them in some countries to revert or impede the FCTC provision on cigarette packaging and labeling, by claiming that it breaches bilateral trade provisions that protect trademark and property rights [[6]]. Therefore, legislators should consider four basic principles when implementing tobacco control regulations: 1), to make sure that the law “only restricts property rights to the extent of achieving a public health objective”; 2), to avoid raising expectations of tobacco-industry investors that they will not be subjected to the regulation in question; 3), to ensure legislation’s compliance with the principles of due process and natural justice; and 4), to make sure that the new regulation will not be discriminatory. The careful application of these principles in the legislation wording and form will not only reduce international litigation but also protect the FCTC-ratifying Party from having to pay the tobacco industry compensation for damages [[6]]. In 2014, the COP participants unanimously decided to accelerate the full implementation in all public administration sectors and diplomatic missions of Article 5.3 and its guidelines [[3]]. Article 5.3 of the Framework Convention for Tobacco Control (FCTC) offers essential guidelines that were unanimously approved by the FCTC-ratifying countries in 2008. Article 5.3 thereby obligates ratifying countries to protect their health policies from tobacco manufacturers’ interference and to recognize that the tobacco industry bears fundamental and irreconcilable conflict of interests with public health and the FCTC implementation. In fact, Article 5.3 guidelines are the backbone of the FCTC treaty and help to prevent and reduce litigations aiming at reversing or halting the implementation of further anti-tobacco policies [[1]]. According to Article 5.3, countries should refuse to treat tobacco companies as “collaborators” in public health policy making; should not invest in the tobacco industry; should not receive contributions or grants from the tobacco industry; should not partner with tobacco industry either for health or other purposes – including their so-called social responsibility programs; should not celebrate non-binding or non-enforceable agreements; nor admit tobacco industry representatives on FCTC delegations or on other tobacco-control administrative agencies. Another relevant provision of Article 5.3 concerns transparency[[7]] in the interactions between government agencies and the tobacco industry by promoting afore public notices and free public access to reports, records, and documents about such interactions, besides promoting public hearings about the meetings. Moreover, it recommends the disclosure or registration of tobacco-affiliated organizations, advocacy groups and lobbyists; legal penalties on tobacco business for disseminating false or misleading information or propaganda; disclosure of tobacco industry business, such as market share, revenues, production, manufacture, relationship with tobacco farmers, investments in marketing, analysis of tobacco products chemical contents, and “social responsibility” actions and related activities; obligatory disclosure of current or past work with tobacco industry by applicants to jobs in governmental bodies involved in health policy-making, policy execution or surveillance[[7]]. The 2016 PAHO Report for the Region of Americas alerts that there are more than one billion smokers in the world and that 11.4% of them live in the Region of the Americas, which represents a population of 127 million smokers in our continent [[1]]. Prevalence shows that 21.2% of adults or teenagers older than 15 are smokers [[1]], which poses a heavy burden on public health, especially because it is among the youth and the lower income segments that the prevalence is higher. However far we had already progressed in fighting smoking and the consumption of other tobacco products, we are still very far from eradicating this addiction that responds for the vast majority of lung cancer cases, not to mention Head & Neck tumors and cardiovascular diseases. The implementation by all ratifying Parties of the FCTC six provisions that comprise the MPOWER package may drastically reduce in the coming two decades the morbidity and mortality associated with tobacco consumption. Our struggle is just beginning. References Pan American Health Organization. WHO FCTC. Report on Tobacco Control for the Region of the Americas. Who Framework Convention on Tobacco Control: 10 Years Later. Washington DC: PAHO, 2016. World Health Organization. FCTC/COP6/16, Implementation of Art. 5.3 of the WHO Framework Convention on Tobacco Control: questions related to tobacco industry interference. Report of the Secretariat of the Convention. Conference of the Parties in the WHO Framework Convention on Tobacco Control, 6th Meeting; 13-18 October; Moscow, Russian Federation. Geneva: WHO; 2014. Available at: . Accessed on June 10, 2017.

Abstract not provided

Abstract not provided

Abstract:
Background The Evidence-Based Practice (EBP) or Evidence-based Healthcare (EBHC) movement has revolutionised health care in the last 20 years by promoting research appraisal, interpretation and implementation.[1] EBP has been the cornerstone of practice development and service improvement. The most common definition of EBP is “the conscientious, explicit and judicious use of current best evidence in making decisions about the care of the individual patient. It means integrating individual clinical expertise with the best available external clinical evidence from systematic research.”[2] This presentation will reflect on EBP relating to interpreting published research to enhance practice. In lung cancer this is an opportune time as evidence regarding new treatments, services and professional roles is growing. Some of the recent changes and challenges to EBP that influence how we interpret research will first be considered. Second, tools that can support lung cancer practitioners in interpreting published research will be discussed. Finally the presentation will reflect on the contribution of creative, methods of co-production to mobilize knowledge and published evidence to improve practice. The future application and contribution of these methods is considered Evidence-Based Practice: Changes and Challenges Much has changed since 1996 in terms of EBP and the environment in which it operates. Now EBP is considered to comprise 3 components, ‘Best Research Evidence’, ‘Clinical Expertise’ and ‘Patient Values, Experience and Preferences’.[3] Critically, the much quoted definition Sacket definition of EBP[1,2 ]misses the third vital element, which is, the integration of patient values, experiences and preferences. In addition, the initial emphasis in EBP was on medicine and applying evidence to practice regarding individual patients care and treatment. However, EBP has now evolved into Evidence-Based Healthcare (EBHC), where evidence is mobilized to change practice at a policy, organisation or service level. To address this change in emphasis a change to research methodologies is required, as well as a rethink regarding the hierarchy of evidence. The Randomised Controlled Trial is not always adequate. Mixed-methods approaches are more commonly employed and the value placed on qualitative, patient experience methods has increased. Whilst meta-analysis and randomised controlled trial methodologies remain the gold standard to generate evidence of effectiveness, EBH questions have become more complex and diverse. These questions require different research approaches and tools to generate answers. Finally, EBP is only as good as the evidence it’s based on.[4] We therefore need to be aware of the limitations of current evidence, for example, the influence of vested interest (e.g. industry and managers), not publishing negative trial results, cherry picking findings to report, over-inflation of claims from trials, the overwhelming volume of evidence, and the critical gaps in evidence.[4,5,6] In addition, policy across the globe demands more patient and public involvement in the identification of research priorities and the conduct of research. There have also been huge methodological developments in terms of applying research to practice for example, service improvement and quality improvement methodologies, such as Microsystems. More recently there has also been a growth in interest in knowledge mobilisation, co-production and co-design. These enable people working in health care to work in equal partnership with people receiving healthcare in order to generate, appraise and use research to develop creative solutions to current problems with health services, care and treatment.[7,8] Tools to support research interpretation and application A key task in EBP is to interpret published research. Over the years a proliferation of strategies, tools and resources have been developed to support clinicians, researchers and academics in appraising, interpreting and applying evidence to enhance practice.[3,5] Broadly a 5 stage EBP process is advocated, Ask, Acquire, Appraise, Apply, Assess, each with its own strategies and tools. The purpose of each of these stages will be explained and implications for interpreting research will be summarised. A brief summary of some of the current tools will be presented including online training courses, critical appraisal tools and quality assurance criteria. The role of co-production in interpreting and applying research The recent interest in co-production and knowledge mobilisation (KM) will potentially change how we interpret and use published research. Greater emphasis has been placed on creative approaches to knowledge generation through co-production, co-creation and co-design.[7] These approaches change the role of traditional published evidence in changing practice and service development. This change raises the importance of “blurring the boundaries between knowledge creation and knowledge use through integrating multiple stakeholders’ perspectives in research and implementation activity. It also supports the notion that such approaches should be iterative and incremental.”[8] Embracing a co-production approach to research generation, interpretation and application means rejecting a reliance on Mode 1 knowledge, where research knowledge is created by university-based scientists and then interpreted packaged and processed in a way that makes it accessible and usable to non-academics. In preference Mode 2 knowledge is espoused, where knowledge and research is collaboratively generated in its field of application with a range of stakeholders.[7] The co-production process in healthcare will be summarized with reference to key literature, examples [7-10 ]and evidence of impact.[10 ]Finally the relevance of this for research interpretation in lung cancer is considered. Conclusion There are limitations to published research to inform lung cancer treatment and practice. Published research is never going to tell you enough to support change. Need to incorporate patient and public view. Co-production in KM provides a way forward to think differently in interpreting evidence and developing services and care.

Abstract:
Background/Objective: Lung cancer clinical trials are critical to advancing our understanding of disease characteristics, diagnostic criteria and treatment options. With evolving molecular testing and immunotherapies, clinical trials are increasingly complex and challenging to conduct at the site level. This report highlights the role of the Lung Cancer Clinical Research Nurse (LC-CRN) as vital to supporting patient participation and physician involvement for lung cancer trials. We also review new challenges with immunotherapies, nuances of sending tissue for molecular testing and importance of managing patient and family expectations. Methods: The St. Joseph community hospital multidisciplinary Thoracic Oncology Program was established in 2004, averaging 150 lung cancer patients annually. Since 2013, we facilitated efforts to increase participation in research studies. Strategies included (1) streamlining practices within the internal program structure and catalyzing efforts to acquire novel trials, (2) training a specialized LC-CRN to efficiently screen patients to exclusion criteria, and (3) enhancing enrollment and retention practices. Results: To streamline our portfolio, we closed stagnant trials and prioritized non-competing trials with novel agents of interest to our providers that address particular needs of our community population. Since 2013, lung studies open to accrual have tripled and patient enrollment continues to increase in both clinical trials and donations to our tissue biorepository. Current lung trials include diverse standard-of-care options alongside immunotherapies, genomic profiling, tissue biorepository, a tumor device and liquid biopsy trial. Responsibilities of the LC-CRN are to engage physicians, identify and accrue patients, coordinate specimen requirements, ensure protocol and ethics compliance, and communicate readily with study team and sponsors. At our site, specialized LC-CRN training included NCCN guideline review, sponsor visits for protocol training, creating and utilizing simple recruitment and screening tools, flyers and worksheets. The LC-CRN provides routine education about available and upcoming trials at weekly thoracic tumor boards, using visual aids to simplify comparisons of patient entry criteria across multiple studies. In partnership with study investigators, LC-CRNs are uniquely skilled to simplify clinical trial summaries to patients and communicate study content and patient commitment. LC-CRNs must have a robust understanding of disease processes and standard oncology treatment guidelines, including mutation testing. The LC-CRN must also be well acquainted with lung research protocols to advise providers of required tests/procedures, treatment/dosing, and management of adverse reactions. During the consent review, study visits and follow-ups, the LC-CRN must address patient concerns and assess key areas for further education. Effective communication with study sponsors include proper charting and documentation, data entry and responses to queries, as well as record submissions for billing/insurance processes unique to the study or healthcare setting. We implemented recruitment and retention processes supported by literature to ensure a majority of new and recurrent lung cancer patients are considered for clinical trials. Patient cases are presented at multi-disciplinary tumor boards and lung program meetings for group discussions. A recent publication noted higher physician engagement at tumor boards correlated with increased patient accrual and satisfactory prognostic outcomes (Kehl et al., 2015). The LC-CRN also cross-collaborates with navigators, genetics counselors, infusion nurses, radiation staff and others to identify and manage study patients. Literature noted early and repeated presentation of trial information during patient visits boosted trial participation to over 50% of 309 patients with thoracic malignancies (Logan et al., 2017). The close relationship of the LC-CRN to patients and their care team may avoid patient dropout, which often occurs due to misinformation or non-compliance to complex oncology study protocols (McCarthy-Keith et al., 2010). Routine clinical guidance throughout treatment remains important for research engagement and addressing specialized needs of lung cancer patients (Islam et al., 2014; Mosher et al., 2017). Common challenges with immunotherapies include identifying immunotherapy adverse events (IrAEs), fulfilling tissue requirements for molecular testing, and managing patient/family expectations. Research teams ensure ongoing dialogue and education with patients to promptly address IrAEs. We conduct a protocol “dry run” with the clinic staff, pharmacist, hospital facilities director and safety manager to ensure compliance of agent preparation, delivery, spill preparedness and IrAE management. We also oversee tissue acquisition and processing, as it can be a significant barrier to enrollment and retention (Lim et al., 2016). Fresh tissue, via core or excisional biopsies, is often required over archived tissue at study entry, progression or change of treatment. Collaborations with our pathologist, interventional radiologist, finance team and technicians ensure timeliness and correct acquisition methods over multiple time points. With the emergence of personalized immunotherapies come high hopes, but also fears and misconceptions about drug capabilities and efficacy in treatment regimens. The LC-CRN can readily distinguish and manage family and patient expectations by conducting extensive and ongoing teaching about medical use, potential benefits and dangerous side effects. In one setting, 85% of 40 lung and esophageal cancer patients were satisfied with trial participation following a positive experience with a study navigator (Cartmell et al., 2016). Strategies utilizing dedicated staff members, such as a LC-CRN, are necessary in guiding and educating patients about research concerns and processes. Overall, the LC-CRN and thoracic oncology care team are intimately involved in addressing patient expectations and care management to maximize research participation and patient outcomes in oncology care. Conclusion: The landscape of lung cancer diagnosis and treatment is quickly shifting. A durable and flexible research infrastructure includes having an active multidisciplinary thoracic team with dedicated staff advocating for patient access to clinical trials. The role of the LC-CRN in supporting participation in lung cancer trials is vital. With proper education and training, the LC-CRN is best positioned to support patient participation, physician involvement and patient/sponsor expectations in lung cancer trials. REFERENCES Cartmell KB, Bonilha HS, Matson T, Bryant DC, Zapka JG, Bentz TA, Ford ME, Hughes-Halbert C, Simpson KN, Alberg AJ. Patient participation in cancer clinical trials: A pilot test of lay navigation. Contemp Clin Trials Commun. 2016 Aug 15;3:86-93. PMID: 27822566 Islam KM, Opoku ST, Apenteng BA, Fetrick A, Ryan J, Copur M, Tolentino A, Vaziri I, Ganti AK. Engaging patients and caregivers in patient-centered outcomes research on advanced stage lung cancer: insights from patients, caregivers, and providers. J Cancer Educ. 2014 Dec;29(4):796-801. doi: 10.1007/s13187-014-0657-3. PMID: 24744120 Kehl KL, Landrum MB, Kahn KL, Gray SW, Chen AB, Keating NL.Tumor board participation among physicians caring for patients with lung or colorectal cancer. J Oncol Pract. 2015 May;11(3):e267-78. doi: 10.1200/JOP.2015.003673. Epub 2015 Apr 28. PMID: 25922221 Lim C, Sung M, Shepherd FA, Nouriany N, Sawczak M, Paul T, Perera-Low N, Foster A, Zawisza D, Feld R, Liu G, Leighl NB. Patients with Advanced Non-Small Cell Lung Cancer: Are Research Biopsies a Barrier to Participation in Clinical Trials? J Thorac Oncol. 2016 Jan;11(1):79-84. doi: 10.1016/j.jtho.2015.09.006. PMID: 26762742 Logan JK, Tang C, Liao Z, Lee JJ, Heymach JV, Swisher SG, Welsh JW, Zhang J, Lin SH, Gomez DR. Analysis of Factors Affecting Successful Clinical Trial Enrollment in the Context of Three Prospective, Randomized, Controlled Trials. Int J Radiat Oncol Biol Phys. 2017 Mar 15;97(4):770-777. doi: 10.1016/j.ijrobp.2016.11.035. Epub 2016 Nov 27. PMID: 28244413 McCarthy-Keith D, Nurudeen S, Armstrong A, Levens E, Nieman, LK. Recruitment and Retention of Women for Clinical Leiomyoma Trials. Contemp Clin Trials. 2010 January; 31(1): 44. doi:10.1016/j.cct.2009.09.007. Mosher CE, Ott MA, Hanna N, Jalal SI, Champion VL. Development of a Symptom Management Intervention: Qualitative Feedback From Advanced Lung Cancer Patients and Their Family Caregivers. Cancer Nurs. 2017 Jan/Feb;40(1):66-75. PMID: 26925990

Abstract not provided

Abstract:
Immunotherapy: The Latest Immunotherapy agents are now a prominent drug class in the management of NSCLC. It is important for oncology nurses to understand the drugs that are approved as well as the management of the toxicities. There are currently 3 drugs approved for use in several scenarios for NSCLC, listed in table1.

DRUG	INDICATION	TYPE IMMUNOTHERAPY
Atezolizumab	2[nd] line NSCLC	PD-L1 inhibitor
Nivolumab	2[nd] line NSCLC	PD-1 inhibitor
Pembrolizumab	1[st] line NSCLC -single agent in PD-L1 > 50% -in combination with pemetrexed and carboplatin regardless of PD-L1 expression 2[nd] line NSCLC in patients with PD-L1 > 1%	PD-1 inhibitor

Table 1. Immunotherapy drugs still under investigation for NSCLC include durvalumab, another PD-L1 inhibitor. Also, anti-CTLA 4 drugs such as ipilumumab and tremelimumab are being studied in combination with PD-1 or PD-L1 inhibitors. Finally, early stage studies are beginning to look at the utility of CAR-T cell therapy in NSCLC. Follow up data from the Checkmate studies in NSCLC as well as the Keynote trials will give more up to date survival statistics for nivolumab and pembrolizumab, respectively. Toxicity management for these immunotherapy drugs has been at time challenging. The toxicities are very different from traditional chemotherapy used in NSCLC. When caught early, these toxicities can be managed and many times, treatment can be continued. However, if severe or identified late, toxicities from immunotherapy can be life-threatening. Immune-mediated toxicities reported in trials of NSCLC such as pneumonitis, colitis, endocrinopathies, nephritis, hepatitis are some of the toxicities that can become life-threatening if not managed properly. Other than the endocrinopathies, most of these toxicities must be managed with high dose corticosteroids and tapered slowly under close supervision. More common adverse events of the immunotherapies such as fatigue, rash, nausea, diarrhea, arthralgia can be expected and managed without using corticosteroids, instead, using more standard supportive care medications.

Background:
Experimental studies have shown different pathways of lymphatic drainage from particular pulmonary lobes. Especially important is lymphatic drainage from the left lower lobe to the contralateral mediastinal nodes. The aim of this study was to analyse the impact of bilateral mediastinal lymphadenectomy (BML) on survival in non small-cell lung cancer (NSCLC) patients.

Method:
Prospective, randomised trial including patients with proven or suspected NSCLC, stage cI-IIIA. Randomisation was performed in ratio 1:1. In the BML group, systematic lymph node dissection (SLND) was supplemented with contralateral mediastinal lymphadenectomy via additional cervical incision. In the SLND group, standard lung resection with SLND was performed.

Result:
102 patients were enrolled. 13 of them met the exclusion criteria, and data of 89 patients were analysed: 40 in the BML group and 49 in the SLND group. There were no significant differences between groups regarding age, sex, Thoracoscore, Revised Cardiac Risk Index, dyspnoea, lobar location of the tumour, histology and cTNM. Mean follow-up time was 66.5 months. In the whole group, the 4-year survival rate was significantly higher in the BML group than in the SLND group (72.5% vs 51%, p=0.039). Separate comparisons were performed for different lobar locations of the tumour. There was no significant difference in 4-year survival rates and mean survival time between both groups for tumours located in the right lung and those located in the left upper lobe. For the left lower lobe, the 4-year survival rate, and mean survival time was significantly higher in the BML group (90.9% vs 25%, p=0.003, and 1923 vs 1244 days, p=0.027, respectively). Also, analysis of the survival curves (Figure) has shown significant difference (p=0.018.).Figure 1



Conclusion:
For NSCLC located in the left lower lobe, removal of the contralateral mediastinal lymph nodes is associated with survival benefit. These results should be confirmed in larger studies.

Background:
Induction chemoradiation (ICR) for advanced non-small cell lung caner is often limited to 50Gy or less to avoid perioperative complications. Pulmonary resection following definitive chemoradiotherapy (DCR) has been an alternative approach for locally advanced lung cancer.

Method:
In this study, we compared pulmonary resection following ICR and DCR. From 1997 to 2016, we had 31 pulmonary resections following CR. There were 13 ICR and 18 DCR. Intercostal muscle flaps were used in 7 ICR and 2 DCR. Omental flaps were used in 12 DCR. Pericardial fat pad was used in 1 DCR．There was no mortality in any groups.

Result:
In comparison with ICR and HCR, operation time (min, interquartile range) were 344 (283-513) and 418 (563-572) (p = 0.057), estimated blood loss (ml) were 440 (225-575) and 525 (323-1313) (p =0,262), morbidity (%), 69 and 28 (p = 0.021). Bronchopleural fistula developed in one case of DCR who used intercostal muscle flap. Post operation hospital stay (days) was 21 (13.5-26.5) in ICR, 14.5 (13-20) in DCR (P = 0.221). Although operation time was longer and there were more blood loss in DCR, there was no significant increase of peri- and post-operative complications. 2- and 5-year over all survival rates (%) were 50 and 42 in ICR, and 68 and 51 in DCR (p=0.73, log-rank test).

Conclusion:
As a conclusion, high dose ICR may contribute to better local control and longer survival. Pulmonary resection after DCR is as safe as that following ICR.

Background:
To evaluate (1) the potential effect of primary tumor resection, an aggressive local consolidative therapy, for patients with oligometastatic NSCLC on 3 year overall survival; (2) the surgical outcomes in the treatment of patients with oligometastatic NSCLC; (3) the potential clinical factors predicting survival in order to better select patients for surgery.

Method:
According to the extent of pulmonary resection, the patients were divided into two subgroups. A. intent to cure (ITC: removal of total or primary pulmonary lesions); B. intent to biopsy (ITB: preservation of major lesions, only diagnostic biopsy via minimally invasive approach). M stage classified based on 8th UICC/AJCC TNM M categories.

Result:
From Jan 2002 through Dec 2015, a total of 115 consecutive metastatic NSCLC patients were enrolled from Peking University Cancer Hospital. The 3-year overall survival (OS) of ITC and ITB were 64.3% and 34.9% (log-rank p = 0.0009), respectively. Multivariate cox proportional regression analysis identified multiple station lymph nodes (LN) and bone involvement may be prognostic indicators. Figure 1Figure 2





Conclusion:
The current findings suggest that aggressive surgical therapy can extend the survival in selected stage IV NSCLC patients, and should be further explored in phase 3 trials as a standard treatment option in this clinical scenario.

Abstract not provided

Background:
The confirmation of an appropriate resection margin from the tumor is crucial for reducing the risk of local recurrence after lung segmentectomy for pulmonary malignancies. And the precise anatomical segmentectomy is also important for preserving pulmonary function. We evaluated intermediate results of tumor recurrence after anatomical ICG segmentectomy based on the virtual segmentectomy simulation.

Method:
From August 2014 to May 2017, forty-five patients underwent pulmonary segmentectomy under the guidance of ICG fluorescence. Before operation, several types of virtual segmentectomy were created by using Volume Analyzer Synapse VINCENT (Fujifilm co., Tokyo, Japan). We measured the shortest distance from the tumor to the resection margin in each simulated segmentectomy and selected the most appropriate area of sublobar resection based on the adequate resection margin of approximately 2 cm from the tumor. After this virtual segmentectomy, we performed segmentectomy by using an infrared thoracoscopy with transbronchial ICG instillation. Before operation, 10ml of 10-fold diluted ICG with autologous blood and 400ml of air were instilled into each associated subsegmental bronchus. Segmentectomy was performed under ICG visualization. We evaluated tumor recurrence and survival after the operation.

Result:
Thirty-seven patients were primary lung cancer and eight patients were metastatic lung tumor. Active limited resection was done in 28 patients, passive limited resection was in nine and metastatic lung tumor resection was in eight. Subsegmental resection was done in five, segmental resection in 22 and extended segmentectomy, which indicates resection of several segments with adjacent subsegment(s), was 18. The average shortest distance from the tumor to the resection margin in simulation and resected specimen were 22.5+/-11.7 mm and 24.1+/-7.3 mm, respectively (p=0.405). Postoperative complications were prolonged air leak longer than seven days in two cases and atrial fibrillation in one. In terms of the recurrence and survival after ICG segmentectomy, although the mean duration of follow-up was still short (530+/-349 days), no cancer recurrence in the ipsilateral lung was identified in lung cancer patients. In particular, no recurrence was found in the lung as well as lymph node in active segmentectomy patients.

Conclusion:
The combination of lung volume analyzer and ICG segmentectomy was an excellent tool for precise anatomical segmentectomy with an appropriate resection margin and excellent control of tumor recurrence.

Background:
A 1995 survey of Society of Thoracic Surgeons (STS) members revealed widespread variation in post resection lung cancer surveillance practices as well as pessimism regarding any survival benefit. We sought to compare contemporary practice patterns and attitudes toward post-resection surveillance among members of STS and of European Society of Thoracic Surgeons (ESTS).

Method:
A survey identical to one conducted in 1995 was administered via mail or electronically to surgeon members of the STS and ESTS requesting response from those treating NSCLC. Demographic information, type, frequency and duration of post-resection testing were collected. Goodness of fit tests were used to compare profiles of respondents and attitudes toward testing between groups. Analyses were performed using SAS 9.4 (SAS Institute, Cary, NC).

Result:
Between 8/2016-10/2016, 2978 STS members (response rate 7.8%, n=234) and 1450 ESTS members (response rate 8.4%, n=122) were surveyed. ESTS and STS respondents were similar in their frequent use of history and physical examination (75% vs 78%, p=0.26) and CT chest (71% vs 73%, p=0.61) although the timing of testing was widely variable. Compared to STS members, ESTS members reported more frequent use of testing not recommended by guidelines (for asymptomatic patients) including CXR (46% vs 34%, p=0.02) bronchoscopy (10% vs 1% p<0.01), bone scan (5% vs 0, p<0.01), brain CT (6% vs 0, p<0.01), and brain MRI (3% vs 0%, p=0.01). Compared to STS members, ESTS surgeons were more likely to “agree” or “strongly agree” that routine testing for NSCLC recurrence results in potentially curative treatment (86% vs 70%, p<0.01). Similarly, ESTS respondents were more likely to believe surveillance would identify a curable second primary NSCLC (94% vs 84%, p<0.01). More ESTS than STS respondents believed that current literature documents definitive survival benefits from routine follow-up testing (57% vs 30%, p<0.01), a misconception reported by only 26% STS respondents in the identical 1995 survey.

Conclusion:
Our survey suggests significant differences between ESTS and STS members regarding the method, frequency and attitudes regarding post-resection surveillance for NSCLC. European surgeons report a more optimistic belief in significant survival benefit from early detection of both recurrent and second primary NSCLC thus adopting more aggressive surveillance practices. This is in spite of a lack of definitive evidence-based literature underscoring the need for both better prospective studies and joint recommendations to standardize practice.

Background:
Tubeless technique, defined as non-intubated anesthesia and omitting chest tube after lung resection surgery, is a new concept to further minimize surgical trauma of thoracoscopic surgery. However, the feasibility and safety have been less investigated. Here we set up a protocol to prevent postoperative pneumothorax after tubeless single-port thoracoscopic surgery with the aid of digital chest drainage system (DCS).

Method:
From Nov. 2016 to Jun. 2017, 34 consecutive non-intubated single-port thoracoscopic surgery were performed in patients with pulmonary nodules. After excluding patients with nodule≧2 cm, intrapleural adhesion, and FEV1< 1.5 L/sec., 21 patients were selected to enter the tubeless protocol. At the end of the procedure, a single 16-Fr. catheter was placed into the pleural cavity and connected to a DCS which pressure was set at −15 cmH2O. Then the single incision was closed continuously. If the air flow reached zero after completion of wound closure, the catheter will be removed immediately; otherwise the catheter will be kept for drainage. The clinical characteristics and perioperative outcomes of patients were presented. Figure 1



Result:
Among tubeless protocol cases, 3 patients were detected to have minor air leak by DCS and were converted to have intrapleural drainage remained after closure of surgical wound. Among the remaining 18 patients, in whom the DCS showed no air leak, the intrapleural drainage catheter was not placed. Immediate postoperative chest roentgenogram showed full expansion in all protocol patients without pneumothorax. Only 5 (23.8%) patients developed minor subclinical pneumothorax on the first postoperative day. All patients were discharged uneventful without the need of intervention.

Conclusion:
Our tubeless protocol utilizes DCS to select patients for omitting intrapleural drainage after non-intubated single-port thoracoscopic surgery. With objective parameters by DCS, we believe that this is an effective way to reduce the rate of pneumothorax after tubeless single-port thoracoscopic surgery in selected patients after lung resection.

Background:
Lobe-specific lymph node dissection (L-SND) was proposed for clinical T1a-2b N0-1 non-small cell lung cancer (NSCLC), however, the benefit of this approach is still uncertain, especially for pathological nodal staging. In this study, we evaluated the percent detection of pN2 disease in L-SND and in systematic lymph node dissection (SLND).

Method:
From 2010 to 2016, 166 patients with cT1a-T2b N0-1 NSCLC underwent a lobectomy with SLND at Chiang Mai University Hospital. The pathologic results of the lymph nodes dissected in each station were extracted form medical records. Patients who underwent a SLND when then reclassified as L-SLN according to the site of the primary tumor; right upper lobe (station 2R-4R), left upper lobe (station 4L-6), and both lower lobes (station 7-9). Percent detection of pN2 disease was compared between L-SLN and SLND.

Result:
The rate of detection of pN2 in the SLND was higher than in the L-SLD, but the difference was not statistically significant (27.0 %versus 23.6%, p=0.474). The overall percent of cases upstaged to pN2 was only 4.4% after SLND; it was 4.4% in right upper lobe, 3.4 % in left lower lobe, 3.2 % in right lower lobe, and 1.9 % in left upper lobe (p=0.904). The pN2 disease detection agreement between L-SND and SLND was high (kappa=0.911 (95% CI; 0.784 - 0.957). Table 1 pathological N2 status in lobe-specific dissection and systematic lymph node dissection

Location of primary tumor	Clinical N0-1 status		Pathologic N2 status (lobe-specific dissection)		Pathologic N2 status (Systematic dissection)		% upstaged to N2 disease
	Negative	Positive	Negative	Positive	Negative	Positive
RUL (n=67)	57 (85.1)	10 (14.9)	52 (77.6)	15 (22.4)	49 (73.1)	18 (26.9)	4.5
RLL (n=31)	29 (93.65)	2 (6.5)	24 (77.4)	7 (22.6)	23 (74.2)	8 (25.8)	3.2
LUL (n=51)	43(84.3)	8 (15.7)	37 (72.5)	14 (27.5)	36 (70.6)	15 (29.4)	1.9
LLL (n=29)	24 (82.8)	5 (17.2)	23 (79.3)	6 (20.7)	22 (75.9)	7 (24.1)	3.4

Conclusion:
These results suggest that lobe-specific lymph node dissection is as adequate as SLND for pathological N2 staging in clinically early stage NSCLC surgery. However, systematic lymph node dissection achieved a higher detection of pN2 disease. Further studies with a larger sample size are warranted to confirm these results.

Abstract not provided

Background:
The ARCHER 1050 study (NCT01774721) demonstrated benefits of dacomitinib compared with gefitinib as first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) and EGFR-activating mutation. Here, we present the results of a prospective subgroup analysis by EGFR mutation subtype.

Method:
In this ongoing phase 3, open-label study, eligible patients with newly diagnosed stage IIIb/IV or recurrent NSCLC and EGFR-activating mutation (exon 19 deletion or L858R mutation ± T790M mutation) with an Eastern Cooperative Oncology Group performance status of 0–1 were randomized (1:1) to receive dacomitinib or gefitinib, stratified by race and EGFR mutation subtype. The primary endpoint was progression-free survival (PFS) by blinded independent radiologic central (IRC) review. Secondary endpoints included overall survival and objective response rate (ORR), as determined by IRC and investigators’ assessments.

Result:
A total of 452 patients were randomized (dacomitinib, n=227; gefitinib, n=225). Among the dacomitinib and gefitinib arms, respectively, 134 (59%) and 133 (59%) had exon 19 deletions and 93 (41%) and 92 (41%) had L858R mutations. The Table shows PFS, ORR, and duration of response by EGFR mutation per IRC. Results based on investigators’ assessments were consistent with those based on IRC review. Overall survival data are immature.

	Exon 19 Deletion		L858R Mutation
	Dacomitinib (n=134)	Gefitinib (n=133)	Dacomitinib (n=93)	Gefitinib(n=92)
PFS per IRC
Median, months (95% CI)	16.5 (11.3–18.4)	9.2 (9.1–11.0)	12.3 (9.2–16.0)	9.8 (7.6–11.1)
Hazard ratio (95% CI) 1-sided P value	0.551 (0.408–0.745) <0.0001		0.626 (0.444–0.883) 0.0034
ORR per IRC
CR, n (%)	7 (5.2)	3 (2.3)	5 (5.4)	1 (1.1)
PR, n (%)	95 (70.9)	90 (67.7)	63 (67.7)	67 (72.8)
ORR (CR + PR), n (%) (95% CI)	102 (76.1) (68.0–83.1)	93 (69.9) (61.4–77.6)	68 (73.1) (62.9–81.8)	68 (73.9) (63.7–82.5)
1-sided P value	0.1143		0.5395
DoR in responders per IRC
Median, months (95% CI)	15.6 (13.1–19.6)	8.3 (7.9–10.1)	13.7 (9.2–17.4)	7.5 (6.5–10.2)
Hazard ratio (95% CI) 1-sided P value	0.454 (0.319–0.645) <0.0001		0.403 (0.267–0.607) <0.0001
CI, confidence interval; CR, complete response; DoR, duration of response; PR, partial response.

Conclusion:
By IRC and investigators’ assessments, PFS with dacomitinib was superior to that with gefitinib in patients with either EGFR mutation. Despite a similar ORR among the treatment and EGFR mutation subgroups, duration of response was longer with dacomitinib for both mutations.

Background:
FLAURA (NCT02296125) is a Phase III, double-blind, randomized study assessing efficacy and safety of osimertinib vs standard of care (SoC) EGFR-TKI as first-line treatment for patients with EGFRm advanced NSCLC. Concordance between tissue and plasma testing for EGFRm (Ex19del/L858R), and progression-free survival (PFS) by baseline plasma EGFRm status were evaluated.

Method:
Eligible patients: ≥18 years (Japan ≥20 years); Ex19del/L858R mutation-positive lung adenocarcinoma; no prior systemic anti-cancer/EGFR-TKI therapy for advanced NSCLC. Randomization: 1:1 to osimertinib 80 mg once daily (qd) orally (po) or SoC (gefitinib 250 mg or erlotinib 150 mg, qd po). At baseline, patients provided tumor tissue samples for central analysis of EGFRm status (cobas EGFR Mutation Test) and blood samples for retrospective analysis of EGFRm status by plasma ctDNA (cobas EGFR Mutation Test v2). PFS by baseline plasma EGFRm status was assessed. Comparison of EGFRm status between baseline tumor tissue and evaluable ctDNA samples was an exploratory endpoint.

Result:
Globally, 556 patients were randomized: osimertinib, n=279; SoC, n=277. Good concordance was observed between central laboratory tissue and plasma testing for EGFRm in the screened population (see table). In plasma EGFRm-positive patients (n=359), osimertinib (n=183) reduced the risk of progression or death by 56% vs SoC (n=176), hazard ratio (HR) 0.44 (95% CI 0.34, 0.57). This was consistent with the overall PFS result observed with osimertinib vs SoC in the full analysis set (FAS; tumor tissue EGFRm-positive by local/central testing), HR 0.46 (95% CI 0.37, 0.57); p<0.0001 and in plasma EGFRm-negative patients (n=124: osimertinib, n=60; SoC, n=64), HR 0.48 (95% CI 0.28, 0.80).Figure 1



Conclusion:
In the subgroup of plasma EGFRm-positive patients, clinical benefit of osimertinib was superior to SoC, consistent with the overall FLAURA FAS. These results, and good concordance between tissue and plasma testing for EGFRm, support the utility of plasma EGFRm testing for selecting patients eligible for first-line osimertinib treatment.

Background:
Epidermal growth factor receptor (EGFR) activating mutations confer sensitivity to tyrosine kinase inhibitor (TKI) treatment for non-small cell lung cancer (NSCLC) and occur in ~50% of East Asian patients with NSCLC. While initial TKI treatment can be effective, acquired resistance inevitably develops with a secondary mutation (T790M). ASP8273 is a highly specific, irreversible, once-daily, oral, EGFR TKI which inhibits both activating (eg, exon 19 deletions, L858R) and resistance (eg T790M) mutations.

Method:
This dose-escalation/dose-expansion study (NCT02192697) was conducted in two phases. In Phase 1, adult Japanese patients (≥20 yr) with NSCLC previously treated with ≥1 EGFR TKI were enrolled and received escalating ASP8273 doses (25–600mg) to assess safety/tolerability as well as to determine maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). In phase 2, adult T790M-positive NSCLC patients in Japan, Korea, and Taiwan were enrolled to further define the ASP8273 safety/tolerability profile at RP2D and determine antitumor activity (assessed using RECIST v1.1). Antitumor activity in phase 2 was evaluated according to Simon’s 2-stage design (uninteresting response=0.3, desired response=0.5, α=0.05, β=0.1). If ≥9 of 24 ASP8273-treated patients achieved a desired response in the first stage, then 39 additional patients would be enrolled. If ≥ 25 of the 63 total patients achieved response, ASP8273 would be considered to have antitumor effects.

Result:
A total of 123 patients (n=47 phase 1; n=76 phase 2) were enrolled. In both phases, more women were enrolled. The median age was 65 years in phase 1 and 63 years in phase 2. Based on phase 1 findings, MTD and RP2D were 400mg and 300mg, respectively. As 27 of the 63 patients treated with ASP8273 300mg in the first and second stages combined achieved a clinical response (based on independent central review), ASP8273 was determined to have antitumor activity (ORR=42.9%; 95% CI: 30.5–56.0). The ORR at week 24 in all patients in the full analysis set was 42.1% (n=32/76; 95% CI: 30.9, 54.0). The median duration of PFS (central review) was 8.1 months (95%CI: 5.6,--). The most commonly reported treatment-emergent AEs (TEAE) in phase 2 were diarrhea (n=50/76), nausea (n=31/76), increased alanine aminotransferase (n=27/76), decreased appetite and vomiting (n=26/76 each), and hyponatremia (n=25/76). Drug-related TEAEs were reported in 93.4% (n=71/76) of patients, the most common of which was diarrhea (n=43/76).

Conclusion:
ASP8273 was generally well tolerated and demonstrated antitumor activity in Asian patients with both EGFR activating and T790M mutations.

Abstract not provided

Background:
Brigatinib, a next-generation ALK inhibitor, recently received accelerated approval in the United States for the treatment of patients with metastatic ALK+ NSCLC who have progressed on or are intolerant to crizotinib. We report updated data from the randomized phase 2 trial (ALTA; NCT02094573), which was designed to investigate the efficacy and safety of 2 brigatinib regimens in patients with crizotinib-refractory, advanced ALK+ NSCLC.

Method:
Patients were stratified by presence of brain metastases at baseline and best response to prior crizotinib and randomized 1:1 to receive brigatinib at 90 mg qd (arm A) or 180 mg qd with a 7-day lead-in at 90 mg (arm B). Investigator-assessed confirmed objective response rate (ORR) per RECIST v1.1 was the primary endpoint.

Result:
Among 222 patients (n=112/n=110, arm A/B), median age was 51/57 years; 71%/67% had brain metastases. As of February 21, 2017, 17 full months since the last patient enrolled, median follow-up was 16.8/18.6 months and 32%/41% of patients continued to receive brigatinib in A/B. The table shows brigatinib efficacy. Per independent review committee, confirmed ORR was 51%/55% and median PFS was 9.2/16.7 months in A/B. Among patients with measurable baseline brain metastases (n=26/n=18, A/B), confirmed intracranial ORR was 50%/67% as of January 24, 2017; median intracranial DoR was not reached/16.6 months. The most common treatment-emergent adverse events (TEAEs) were: nausea (38%/47%, A/B), diarrhea (28%/44%), cough (28%/40%), headache (30%/35%), and vomiting (36%/30%); the most common grade ≥3 TEAEs were: increased creatine phosphokinase (5%/13%), hypertension (6%/8%), pneumonia (4%/5%), and increased lipase (5%/4%). Dose reduction (9%/30%, A/B) or discontinuation (4%/11%) due to TEAEs was reported.

Conclusion:
In ALTA, brigatinib continues to show substantial efficacy and acceptable safety at both dose levels, with numerically longer PFS and higher intracranial ORR at the recommended dosing regimen of 180 mg qd (with lead-in) vs 90 mg qd.

	Investigator Assessment		Independent Review[a]
	Arm A (n=112)	Arm B (n=110)	Arm A (n=112)	Arm B (n=110)
Confirmed ORR, %	46 (35–57[b])	55 (44–66[b])	51 (41–61[c])	55 (45–64[c])
Median DoR in responders,[d] months	12.0 (9.2–17.7[c])	13.8 (10.2–17.5[c])	13.8 (7.4–NR[c])	14.8 (12.6–NR[c])
Median PFS,[d] months [% of events]	9.2 (7.4–11.1[c]) [65]	15.6 (11.1–19.4[c]) [50]	9.2 (7.4–12.8[c]) [54]	16.7 (11.6–NR[c]) [41]
Median OS,[d] months [% of events]	NR (20.2–NR[c]) [38]	27.6 (27.6–NR[c]) [29]	—	—
1-year OS probability,[d ]%	70 (61–78[c])	80 (71–87[c])	—	—
DoR, duration of response NR, not reached OS, overall survival PFS, progression-free survival [a]Last scan date: February 28, 2017 [b]97.5% CI for primary endpoint [c]95% CI [d]Kaplan-Meier estimate

Background:
Lorlatinib, a selective, potent, brain-penetrant ALK/ROS1 TKI, is active against most known ALK kinase domain mutations. In phase 1 of this ongoing study (NCT01970865), lorlatinib displayed robust clinical activity among patients with ALK[+]/ROS1[+] non-small-cell lung cancer (NSCLC), most of whom were heavily pretreated and had CNS metastases. Phase 2 evaluated efficacy (overall and intracranial), according to prior treatment, and safety at the recommended phase 2 dose (100 mg QD).

Method:
Patients with NSCLC ± asymptomatic CNS metastases enrolled in 6 cohorts (EXP1–5, ALK[+]; EXP6, ROS1[+]). The primary endpoint was objective response rate (ORR) and intracranial ORR by independent central review. Safety, patient-reported outcomes and molecular profiling were also assessed.

Result:
As of 15-March-2017, 227 ALK[+] patients were evaluated for ORR (Table), including 140 with CNS involvement who were evaluated for intracranial ORR.

	Confirmed ORR		Confirmed IC-ORR
	N	n (%)	N	n (%)
ALK[+] cohorts
EXP1 (treatment-naïve, no prior ALK-TKIs or CT)	30	27 (90)	8	6 (75)
EXP2 (prior crizotinib only)	27	20 (74)	17	10 (59)
EXP3 (1 prior ALK TKI ± CT)	59	30 (51)	32	20 (63)
EXP3A (prior crizotinib + CT)	32	21 (66)	20	15 (75)
EXP3B (any 1 other ALK TKI ± CT)	27	9 (33)	12	5 (42)
EXP4 (2 prior ALK TKIs ± CT)	65	27 (42)	45	25 (56)
EXP5 (3 prior ALK TKIs ± CT)	46	16 (35)	38	(15 (39)
CT, chemotherapy; IC, intracranial.

Of 219 ALK+ patients analyzed for ALK kinase domain mutations at baseline, 46/219 (21%) had ≥1 mutation detected in circulating free DNA; most derived treatment benefit with an ORR of (27/46) 59%. Across all cohorts (N=275), the most common treatment-related adverse events (AEs) and grade 3/4 treatment-related AEs were hypercholesterolemia (81%/16%) and hypertriglyceridemia (60%/16%); 30% and 22% of patients had treatment-related AEs associated with dose interruptions and reductions, respectively. No treatment-related deaths occurred; 7 patients (3%) had treatment-related AEs leading to treatment discontinuation. 157/275 (57%) patients remained on treatment at data cutoff. Most patients reported stable/improved global quality of life (40%/43%).

Conclusion:
Lorlatinib showed clinically meaningful activity, including substantial intracranial efficacy, among ALK[+]/ROS1[+] patients who were either treatment-naïve or failed ≥1 prior ALK TKI. Overall lorlatinib was well tolerated and when needed, AEs were managed by dose delay/reduction or standard medical therapy.

Background:
Ceritinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of patients with ALK+ non-small cell lung cancer (NSCLC) who are treatment-naive or have progressed on crizotinib at the recommended dose of 750 mg/day under fasted state. Gastrointestinal (GI) adverse events (AEs), eg, diarrhea, nausea, vomiting, are common with ceritinib 750 mg/day under fasting conditions. ASCEND‑8 study, (NCT02299505) evaluated alternative methods of ceritinib administration, utilizing potential benefit of dosing ceritinib with food to reduce GI toxicity, while maintaining the pharmacokinetic exposure at lower doses. Based on the primary pharmacokinetics analysis previously presented (n=137; WCLC 2016), ceritinib 450 mg with food had similar exposure and a more favorable GI safety profile vs ceritinib 750 mg fasted in patients with ALK+ NSCLC.

Method:
This is a multicenter, randomized, 3-arm (450 mg or 600 mg ceritinib taken with low-fat meal vs 750 mg ceritinib taken in fasted state), open-label, phase 1 study (ASCEND-8). Patients were eligible if they had stage IIIB or IV ALK+ advanced NSCLC, were aged 18 years or older, who were either previously treated with chemotherapy and/or crizotinib or treatment naive. We plan to report the updated safety (n=228) and preliminary efficacy for treatment-naïve patients (ALK+ by immunohistochemistry [IHC]) who were randomized at least 18 weeks before the cutoff date (March 28, 2017; n=79). Updated analysis is planned to be made available by August 2017 and the following data will be included at the time of final abstract submission: patient disposition; patient demographics; disease characteristics and prior therapies; overall response rate and duration of response by blinded independent review committee (BIRC; key secondary endpoints) in treatment-naïve patients (ALK+ by IHC) randomized at least 18 weeks prior to the cut-off date; progression-free survival per BIRC in treatment-naïve patients (ALK+ by IHC) randomized at least 18 weeks prior to the cut-off date; updated safety results with detailed information on GI (diarrhea, nausea, vomiting) and liver (alanine transaminase/aspartate transaminase) toxicities.

Result:
LBA shell - not applicable

Conclusion:
LBA shell - not applicable

Background:
Alectinib (ALC) is a selective, CNS-active ALK tyrosine kinase inhibitor. In two Phase 3 studies (J-ALEX and ALEX), ALC proved superior efficacy and tolerability compared to crizotinib (CRZ). Here we report the final efficacy and safety results of the 46 pts enrolled in the phase II part of study AF-001JP with a longer follow-up period than that observed in J-ALEX and ALEX studies.

Method:
ALC 300 mg b.i.d was given to ALK+ NSCLC pts who were ALK inhibitor-naive and had disease progression after at least one line of chemotherapy to investigate the efficacy and safety until the investigator confirmed no further clinical benefits.

Result:
This study was completed in December 2016. The median treatment duration was 46.1 months (range: 1-62). 20 of 46 pts were on treatment with alectinib at the study termination. Progressive disease (PD) was confirmed in 20 pts (43%). Median PFS was not reached and 4-year PFS rate was 52% (95% CI: 36-66). 14 of 46 pts had CNS metastasis at baseline. Median PFS was 38 months (95% CI: 9-NE) in pts with CNS metastases and was not reached in pts without CNS metastases. Four pts had CNS progression and the 4-year cumulative incidence rate of CNS progression was 9.5%. Median OS was not reached and the 4-year OS rate was 70% (95% CI: 54-81). Safety profile was similar to that reported previously and there were no treatment-related Grade 4 or 5 adverse events for this long administration period.

Conclusion:
Regardless of CNS metastases at baseline, ALC have demonstrated excellent efficacy in ALK+ NSCLC pts without prior ALK inhibitor treatment. ALC was well tolerated over a prolonged administration period.

Abstract not provided