Virtual Library

Background:
Anti-PD immunotherapy has provided a new therapeutic opportunity for lung cancer. However, overall objective response rates are relatively low in all NSCLC patients who receive anti-PD therapy. We hypothesized that the barrier to the success of anti-PD therapy in most NSCLC patients can be overcome by stimulating the inflammatory response at cancer sites through adenovirus-mediated gene therapy.

Method:
We determined combination effects of anti-PD immunotherapy and oncolytic adenoviral vector-mediated tumor necrosis factor-α-related apoptosis-inducing ligand (TRAIL) gene therapy (Ad/E1-TRAIL) or adenoviral-mediated TP53 (Ad/CMV-TP53) gene therapy in syngeneic mice bearing subcutaneous tumors derived from M109 lung cancer cells.

Result:
Both anti–PD-1 and anti–PD-L1 antibodies failed to elicit obvious therapeutic effects in the M109 tumors. Intratumoral administration of Ad/E1-TRAIL or Ad/CMV-TP53 alone suppressed tumor growth in animals preexposed to an adenovector and bearing subcutaneous tumors derived from M109 cells. However, combining either anti–PD-1 or anti–PD-L1 antibody with these two adenoviral vectors elicited the strongest anticancer activity in mice preexposed to adenoviral vectors. .Figure 1Figure 2





Conclusion:
Our results showed that the mouse lung adenocarcinoma M109 cell line is resistant to anti–PD-1 and anti–PD-L1 antibody treatment, and this resistance can be overcome by adenovirus-mediated gene therapy.

Background:
Lung adenocarcinoma (LAC) accounts for approximately 40% of all lung cancers, the leading cause of cancer death worldwide. Oncogenic Kras mutations are a common feature of LAC, although the identity of signaling networks which engage Kras to promote LAC remains ill-defined. Moreover, LAC is characterised by dysregulated inflammatory responses, which contribute to tumor promotion and progression. In that regard, we have identified a requirement for interleukin-6 (IL-6) in the molecular pathogenesis of Kras-driven LAC. Specifically, this was dependent on the soluble IL-6 receptor (sIL-6R), which is produced by proteolytic cleavage of the membrane-bound IL-6R by a disintegrin and metalloproteinase 17 (ADAM17), also known as the TNFα-converting enzyme (TACE). Although clinical studies indicate that ADAM17 (mRNA and protein) is upregulated in lung cancer and correlate with poor prognosis, the role of ADAM17 in promoting Kras-driven LAC remains unknown. Here, we sought to investigate the role of ADAM17 in the pathogenesis of Kras-induced LAC.

Method:
We coupled the Kras[G12D] LAC mouse model with Adam17[ex/ex] mice, which are homozygous for a hypomorphic Adam17 allele resulting in a dramatic reduction in ADAM17 protein expression. Oncogenic Kras[G12D] was activated using intranasal inhalation of Adenovirus Cre recombinase. Mice were culled 6 weeks following inhalation and LAC was evaluated using histopathology (H & E staining). Moreover, immunohistochemical analyses were carried out to assess markers for LAC (TTF-1), proliferation (PCNA) and inflammation (CD45). Serum sIL-6R levels were measured using ELISA. Quantitative PCR was also performed to assess the expression of IL-6 target genes.

Result:
Following Kras activation, Adam17[ex/ex] mice showed significant reduction in the area of lung parenchyma affected by tumor lesions. This was associated with reduced TTF-1 levels and cellular proliferation. Furthermore, reduced ADAM17 expression mitigates the inflammatory response associated with LAC. Serum levels of sIL-6R were significantly reduced in Adam17[ex/ex] mice, with significant down-regulation in IL-6 target genes.

Conclusion:
In conclusion, our data suggests that blocking of ADAM17 may represent an attractive therapeutic target for tackling LAC.

Background:
Because dendritic cells (DCs) play a key role in immune reactions to activate T cells against cancer cells by cancer antigen presentation at cellular membrane, DCs have been used in clinical trials as cellular mediators for therapeutic vaccination. It has reported that the exosomes released from vaccinated DCs are responsible for the persistence of antigen presentation. Cancer cells derived exosomes play an immunosuppressive. We considered that whether DCs-derived exosomes could induce suppress cancer cells and more effective response of immune system against cancer with control for the cancer cells-derived exosomes. Because dendritic cells (DCs) play a key role in immune reactions to activate T cells against cancer cells by cancer antigen presentation at cellular membrane, DCs have been used in clinical trials as cellular mediators for therapeutic vaccination. It has reported that the exosomes released from vaccinated DCs are responsible for the persistence of antigen presentation. Cancer cells derived exosomes play an immunosuppressive. We considered that whether DCs-derived exosomes could induce suppress cancer cells and more effective response of immune system against cancer with control for the cancer cells-derived exosomes.

Method:
DCs were generated from bone marrow cells in C57BL/6J by stimulation with GM-CSF and IL-4 mice for 6 days. Murine lung cancer cell line (3LL) was cultured in RPMI1640 medium containing 10%FCS. 3LL cells-derived exosomes and DCs-derived ones were isolated by ultracentrifugation methods and exosomes purification kit (Qiagen). 3LL cells were injected to C57BL/6J mice by intraperitoneal administration. DCs, DCs-exosomes or 3LL-exosmes were weekly administrated to cancer bearing mice. Tumor growth inhibition by exosomes was evaluated measurement of luciferase activity by in vivo image analyzing system.

Result:
DCs and DCs-derived exosomes inhibited lung cancer cell growth, on the other hand, lung cancer derived-exosomes increased in compared with DCs, DCs-exosomes and non-treated.

Conclusion:
For cancer immunotherapy, DC-exosomes and cancer-exosomes play important roles in cancer immune reactions. Further examination, we are going on analyze immunosuppressive molecules possessing cancer cell-derived exosomes, and immune activation molecules in DCs-exosomes.

Background:
Cytotoxic T lymphocytes (CTLs) play a critical role in protection against intracellular pathogens and tumor. To induce target cell death, CTL mainly use two major contact-dependent cytotoxic pathways that are dependent on Fas ligand (FasL) and lytic granules. CTLs eliminate malignantly transformed cells principally by releasing the contents of cytotoxic granules into the immune synapse formed with their target cell. The granule serine proteases, known as granzymes (Gzms), induce apoptosis after they are delivered into the target cell cytoplasm by the pore-forming granule protein perforin. Therefore, we hypothesized that other pore-forming protein, especially those can form pores from within mammalian cells, may be implicated in the target cell killing process of CTL. Since GSDMD is a recently discovered pore-forming protein whose N-terminal domain can insert the inner leaflet of the cell membrane and form extensive pores, we speculate that GSDMD may participate in the CTL attack. GSDMD is a recently discovered pyroptosis executioner in monocyte, whose N-terminal domain can insert the inner leaflet of the cell membrane and form extensive pores. Although the role of GSDMD in the pyroptosis has been clear, the function of GSDMD in other biological system remains elusive. In the present study, we investigated the role of GSDMD during CTL responses to NSCLC cancer cells.

Method:
3LL and H1299 cells were cultured in RPMI-1640 (HyClone, USA) supplemented with 10% fetal bovine serum, Ovalbumin-expressing 3LL cells (3LL-OVA) were generated by transfection with a lentiviral plasmids harbouring cytosolic chicken ovalbumin. C57BL/6 mice and TCR-transgenic OT-1 mice. Mouse CD8[+] T cell isolation and stimulation, Human CD8[+] T cell isolation and stimulation, Real-time PCR analysis, Western blot analysis, Immunofluorescence cell staining, Immunohistochemistry, Lentiviral vectors transduction, In vitro cytotoxicity assays, Bioinformatics analysis,

Result:
We showed that GSDMD expression was consistently correlated with CD8[+] T cell markers in TCGA cohorts. The expression of GSDMD protein could be detected in the tumor infiltrating lymphocyte. GSDMD cleavage increased both in the OT-1 CTLs and the human activated CD8[+] T cells. Moreover, Colocalization of GSDMD with granzymeB was observed in proximity of immune synapse. GSDMD deficiency reduced the cytolytic capacity of human CD8[+] T cells.

Conclusion:
These results identified a previously unknown role of GSDMD in CTL and demonstrated that GSDMD is required for an optimal CTL response to lung cancer cell.

Background:
Toll-like receptors (TLR) have been implicated in tumor progression by affecting the immune response in the tumor microenvironment. The role of these receptors in the growth and proliferation of human lung cancer cells is not known. We analyzed human lung cancer cells for the presence of TLR-2, their proliferation response to a TLR-2 agonist and the role of NFkB in TLR-2 activation.

Method:
Human non-small cell lung cancer (NSCLC) cell lines A549 and 1650 (adenocarcinoma), H1299 metastatic NSCLC and H125 adenosquamous were cultured using standard techniques. Standard Western blotting techniques determined baseline TLR-2 protein levels. Cells were treated with Pam3CSK4, a specific agonist of TLR-2, at doses of 0ug/ml, 5ug/ml, and 10ug/ml for 72 hours, and then the MTS assay was used for proliferation assessment. All cell lines were treated with 10 ug/ml Pam3CSK4 for 48 hours and Western blot analysis determined the level of increase in NFkB phosphorylation. Cells were treated with NFkB inhibitor, Bay11-7082, at doses of 1 uM, 5 uM and 25 uM with concomitant treatment of 10 ug/ml Pam3CSK4 over 5 hours. NFkB inhibition was evaluated by Western blot analysis.

Result:
Protein analysis demonstrated consistently detectable levels of TLR-2 in each cell line (Fig 1a). Proliferation was significantly promoted after Pam3CSK4 treatment in human lung adenocarcinoma cell lines (p=.03), but not in the other cell lines (p<0.05) (Fig 1b). NFkB phosphorylation was increased with TLR2-agonist treatment in adenocarcinoma, decreased in non-adenocarcinoma cells and decreased with specific inhibition of NFkB subunit p65 (Fig1c). Figure 1



Conclusion:
TLR-2 is consistently present and detectable on human lung adenocarcinoma cells. TLR-2 activation results in increased proliferation in human lung adenocarcinoma cells and this effect appears to be specific to adenocarcinoma cells. These effects are dependent on the NFkB signaling pathway. These findings may suggest TLR-2 to be a possible therapeutic target in human lung cancer.

Background:
Pemetrexed is a well-known folate pathway inhibitor that is used in the treatment of non-small cell lung cancer (NSCLC) and mesothelioma. Folate pathway is also known to play a critical role during T cell activation. However, the role of pemetrexed in modulating antitumor T cell-mediated immune response is largely unknown. Recent clinical data for cohorts C and G in the KEYNOTE-021 trial revealed compelling activity of pemetrexed-based chemotherapy in combination with PD-1 antibody (pembrolizumab) in NSCLC patients suggesting a potential positive interaction between these two therapeutic modalities. The objective of the present study was to understand the effects of pemetrexed on tumor immune microenvironment and evaluate its efficacy in combination with PD-1 pathway inhibition.

Method:
C57BL/6 mice bearing syngeneic MC38 tumors were treated with pemetrexed with or without platinum agents (cisplatin, carboplatin). Immune cell subsets and immune-related gene expression changes in MC38 tumor tissue were assessed by flow cytometry and Quantigene Plex assay, respectively. Pemetrexed-related effects on energy metabolism were evaluated by Agilent Seahorse XF analysis. Anti-mouse PD-L1 antibody 178G7 was used to evaluate effects of pemetrexed in combination with anti-PD-L1 on MC38 tumor growth.

Result:
Treatment with pemetrexed resulted in an increased frequency of intratumoral leukocytes and T cells accompanied by upregulation of immune-related genes indicative of enhanced antigen presentation and T cell infiltration and/or activation. Immune gene expression signature induced by pemetrexed was largely unaffected by cisplatin or carboplatin. The results of Seahorse XF analysis suggested changes in the bioenergetics of T cells exposed to pemetrexed. Combination of pemetrexed and anti-PD-L1 significantly delayed MC38 tumor growth whereas single agent treatments were largely ineffective.

Conclusion:
Pemetrexed exerts positive effects on the intratumor T cell-mediated immune response independently of platinum agents, and enhances effects of PD-L1 antibody in MC38 syngeneic mouse tumor model.

Background:
The complement system, a central part of innate immunity, is implicated in the maintenance of a favorable microenvironment for lung cancer progression. In particular, several studies have demonstrated a tumor-promoting role for the immune regulator C5a, but its direct impact on growth and dissemination of lung cancer cells is poorly understood. In this study we aimed to investigate the contribution of the C5a/C5aR1(CD88) axis to the malignant phenotype of NSCLC cells, particularly to skeletal colonization, a preferential lung metastasis site.

Method:
The association between C5aR1 expression and clinical outcome was assessed at both the mRNA and protein levels by in silico and immunohistochemistry analyses, respectively. The mRNA levels of C5aR1 were also determined in a panel of 45 cell lines representing the main lung cancer subtypes. The expression of the receptor was validated by flow cytometry. The functional significance of C5aR1 expression in NSCLC cells was evaluated using lentiviral gene silencing and drug inhibition in in vivo models of lung cancer bone metastasis. In vitro functional assays for signaling, migration, invasion, metalloprotease activity and osteoclastogenesis were also performed.

Result:
High levels of C5aR1 in primary human NSCLC tumors were significantly associated with shorter recurrence-free survival and overall survival both at the mRNA and protein levels. Many lung cancer cell lines expressed C5aR1 mRNA. C5aR1 was also detected by flow cytometry on the cell surface of representative lung cancer cell lines. Moreover, addition of C5a to cultured cells led to phosphorylation of p42/44 MAPK and translocation of NF-kB to the nucleus, demonstrating the functionality of the receptor. Silencing of C5aR1 in A549 and H460 lung cancer cells did not affect proliferation, but led to a substantial reduction in skeletal metastatic burden and osteolysis in in vivo models. C5aR1 pharmacological blockade also reduced the osseous metastatic activity of lung cancer cells in vivo. Moreover, metalloproteolytic, migratory and invasive tumor cell activities were modulated in vitro by C5aR1 stimulation or gene silencing. This effect was associated with decreased osteoclastogenic activity in vitro, which was rescued by exogenous addition of the chemokine CXCL16.

Conclusion:
Disruption of C5aR1 signaling in lung cancer cells abrogates osseous colonization through a CXCL16-mediated mechanism. This study reinforces the role played by the C5a/C5aR1 axis in lung cancer progression, and supports its potential use as a novel therapeutic target.

Background:
Allogeneic cancer cell lines might serve as a universal source of tumor antigens in the development of dendritic cell-based cancer vaccines. We showed that selected antigenic profile of lung cancer cell lines overlaps with antigenic profile of primary non/small cell lung cancer (NSCLC) tumors. However, it is unclear if T cells responses to all of these antigens can be detected in blood of NSCLC patients.

Method:
Peripheral blood mononuclear cells (PBMCs) of NSCL patients were stimulated and re-stimulated by commercially available mixes of antigenic peptides derived from these antigens over the course of 10 days. Tumor antigen-specific CD8[+] and CD4[+] T cells were characterized by IFN-γ production, granzyme B, perforin, an d CD137 or CD154 expression by flow cytometry. In addition, the expression of inhibitory molecules TIM3, CTLA-4, PD-1 and LAG-3 were evaluated on CD8[+] and CD4[+] T cells from PBMC of NSCLC patients. We further analysed 6 populations of myeloid-derived suppressor cells (MDCS) by a multicolor flow cytometry and their possible functional suppression by qPCR analysis of ARG1 and iNOS expression in PBMC and downregulation of CD3zξ in T cells from patient’s PBMCs compared to T cells from PBMCs of healthy donors.

Result:
We were able to detect tumor antigen-specific IFN-γ, Granzyme B and Perforin producing CD8[+] and CD4[+] T cells as well as expression of inhibitory molecules TIM3, CTLA-4, PD-1 and LAG-3. We were also able to detect populations of MDSCs in blood of NSCLC patients as well as healthy donors.

Conclusion:
This data will allow us to develop a protocol for immunomonitoring studies of the effectivity of dendritic cell-based lung cancer immunotherapy in ongoing phase I lung cancer clinical trial (NCT02470468).

Background:
Immune checkpoint inhibitors have changed the clinical practice for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) as the first line or second line therapies. Although PD-1/PD-L1 blockade has been demonstrated as a promising anti-tumor therapy with significant clinical benefits, the fact of acquired resistance after a response to PD-1/PD-L1 blockade has become a common concern. The mechanism underlying acquired resistance to immune checkpoint inhibitors have remained unclear.

Method:
FFPE samples from 127 Chinese NSCLC patients were collected, including 103 (81.1%) adenocarcinoma, 21 (16.5%) squamous cell carcinoma, 2 (1.6%) adenosquamous carcinoma and 1 (0.8%) large cell carcinoma. Comprehensive genomic profiling (CGP) assay with 450 genes whole exon region were performed for the analysis of genomic alterations including single base substitution, short and long insertions/deletions, copy number variations, gene rearrangement in selected genes and also tumor mutation burden (TMB) calculated as total somatic substitutions and indels per megabase. We considered high TMB as over 80% of the 500 patient TMB distrbutions from our inhouse cancer database across solid tumor types.

Result:
32 patients with higher TMB values were collected from 127 Chinese NSCLC patients. Interestingly, we identified the frequency of PI3K/mTOR pathway genes (AKT1, FBXW7, PIK3CA, PTEN, TSC1/2, STK11 and mTOR) was significantly higher in patients with high TMB value (28.1% vs 10.5%, p=0.033). Moreover, PI3K/mTOR pathway alterations existed in 3 patients who initially responded to PD-1/PD-L1 blockade and then were resistant to immune checkpoint inhibitors. Two patients with PIK3CA K111N and FBXW7 R465H have started to receive mTOR inhibitor everolimus mono therapy after 6 cycle nivolumab or pembrollizumab treatments. So far both showed stable disease or minor shrinkage on tumor. More investments are under way.

Conclusion:
In our study, PI3K/mTOR pathway alterations occurred more frequently in the NSCLC patients with higher TMB values. Several PD-1/PD-L1 blockade resistance patients harbored PI3K/mTOR mutations showed responses. The activation of PI3K/mTOR pathway might mediate the acquired resistance to immune checkpoint inhibitors. This finding suggested that mTOR inhibitors might be a potential strategy for those who harbored mutations in PI3K/mTOR pathway after the resistance of PD-1/PD-L1 blockade therapies.

Background:
T Helper 17 (Th17) cells play roles in several biological processes including malignancy. Most important Th17 related cytokines are interleukin-17 (IL-17) and IL-23. We reported previously that serum IL-23 levels are elevated in lung cancer patients and IL-17 and IL-23 values are correlated inflammatory markers (1). In this study, the prognostic effects of these cytokines have been evaluated with long follow-up data.

Method:
: Forty-six lung cancer patients are included to the study. Data of patients were achieved from clinic archive, hospital computed system, and previously study records (1). The median values of levels IL-17 and IL-23 were calculated, and the patients have been categorized as high (higher of median value) and low levels separately of IL-17 and IL-23. Survival analyses were analyzed with log rank test, survival curves were constructed with Kaplan Meier test.

Result:
The patients have been followed for a median time of 30.7 months (range: 2.0 to 194.4 months). Locally advanced, metastatic non-small cell lung cancer (NSCLC), limited stage, and extended stage small cell lung cancer (SCLC) patients have been analyzed separately. Because number of limited disease SCLC patients was little, they have not been evaluated. When high IL-17 group compare with low IL-17 group, overall survival times were not different in locally advanced NSCLC patients. Among metastatic NSCLC patients, low IL-17 group has numerically -but not significant- longer median overall survival time (MS: 36 (17.2 to 78.9) months vs 15.65 (3.2 to 76.9) months; p=0.4). The patients with extended stage SCLC and low IL-17 have been survived longer time compared those with high IL-17 (MS: 36.3 (14.0 to 41.3) months vs 9.8 (4.1 to 13.8) months; p=0.003). When high IL-23 group compare with low IL-23 group, overall survival times were not different in locally advanced, metastatic NSCLC and extended stage SCLC patients.

Conclusion:
Serum IL-17 levels may be prognostic factor in advanced stage lung cancer patients, particularly those with SCLC. In this situation, further studies are needed.

Background:
Many lung cancer patients developed malignant pleural effusion during the course of the disease. Previous studies revealed that the effusion associated lymphocytes (EAL) were in dysfunctional state which appeared to be immunosuppressed and unable to kill tumor cells. This study will evaluate the combined effects of IL-2, IL-12, αCD3 antibody (ab), and PD-1 ab on antitumor activity of lymphocytes. The underlying mechanism and relevant immune biomarkers will also be investigated.

Method:
We choose the malignant pleural effusion from lung cancer patients to analyze the association among lymphocytes, cancer cells, and cytokines in order to realize the lymphocyte immunity in the malignant pleural effusion of lung cancer patients. Flow cytometry was used to determined lymphocyte subpopulation. The Proliferation assay was performed to evaluate the effect of medication on lymphocytes. ELISA was used to evaluate cytokine level. Cell-mediated cytotoxicity assay was performed to evaluate the tumor-killing effect of EAL.

Result:
EAL were isolated from 21 malignant pleural effusions. Lymphocyte subpopulation was determied by flow cytometry, and total lymphocytes were composed of 8.9% exhausted T cells (CD3+/CD8+/ PD-1+), and 27.8% PD1+ NK cells. IL-2+αCD3 ab+pembrolizumab has demonstrated the trend toward to enhance the proliferation of EAL. IL-2+αCD3 ab or IL-2+IL-12+αCD3 ab or IL-2+IL-12+αCD3 ab+pembrolizumab demonstrated the trend for EAL to produce more IFN-γ. IL-2+αCD3 ab or IL-2+IL-12+αCD3 ab demonstred the trend for EAL to produce more IL-10. IL-2+αCD3+pembrolizumab did not demonstrated the trend for EAL to produce more IL-10. The addition of IL-2+αCD3 ab or IL-2+pembrolizumab showed the trend toward increased EAL cytolytic activity against autologous tumors (effector:target cells= 30:1). The addition of IL-2+αCD3 ab did not show the trend toward increased EAL cytolytic activity against autologous tumors in different conditions (effector:target cells= 10:1). The addition of IL-2+αCD3 ab or IL-12+αCD3 ab or IL-2+IL-12+αCD3 ab showed the trend toward increased EAL cytolytic activity against autologous tumors (effector:target cells= 3:1).

Conclusion:
The depressed cellular function of EAL may be potentially reversed with multiple signal stimulation, including IL-2 plus αCD3 ab, IL-2 plus pembrolizumab, IL-12 plus αCD3 ab or IL-2 plus IL-12 and αCD3 ab. Further studies are warranted in order to confirm the synergistic cytotoxicity effect of cytokines plus PD-1 inhibitors.

Background:
Patients with non-small cell lung cancer (NSCLC) who have metastasis to the liver have poor prognosis. The phase 3 trials CheckMate 017 and 057 demonstrated improved overall survival (OS) and a favorable safety profile with nivolumab, an anti-programmed death-1 antibody, versus docetaxel in patients with previously treated advanced squamous and non-squamous NSCLC, respectively. A prior subgroup analysis from these trials evaluated and demonstrated efficacy and safety with nivolumab in patients with asymptomatic central nervous system metastases (Goldman J. ASCO 2016). Here we report subgroup analyses from these trials of patients with baseline liver metastases.

Method:
In both trials, patients were randomized 1:1 to nivolumab 3 mg/kg every 2 weeks or docetaxel 75 mg/m[2] every 3 weeks until progression or discontinuation. The primary endpoint of each study was OS. Patients from CheckMate 017 and 057 with baseline liver metastases reported as either target or non-target lesions were identified and pooled across studies by treatment.

Result:
Baseline characteristics were generally similar between patients with liver metastases randomized to nivolumab (n=99) and docetaxel (n=94). In the nivolumab group, 26% of patients had squamous and 74% had non-squamous NSCLC; in the docetaxel group, 36% had squamous and 64% had non-squamous NSCLC. The minimum follow-up was 24.2 months (Feb 2016 database locks). Nivolumab resulted in improved OS compared with docetaxel in patients with liver metastases (hazard ratio [HR]=0.68; 95% confidence interval [CI]: 0.50, 0.91), similar to findings from the ITT group (HR=0.72; 95% CI: 0.62, 0.84). Median OS in patients with liver metastases was 6.83 months with nivolumab versus 5.93 months with docetaxel, both of which were lower than those observed in the overall pooled intent-to-treat (ITT) population (11.14 months vs 8.11 months). Two-year OS rates were 18% with nivolumab versus 6% with docetaxel in patients with liver metastases. Rates of grade 3−4 treatment-related adverse events in patients with liver metastases were lower with nivolumab compared with docetaxel (7% vs 53%), and similar to those in the ITT population (10% vs 55%).

Conclusion:
The lower median OS observed in this subgroup of patients with previously treated advanced NSCLC and baseline liver metastases corroborates previous findings that metastasis to the liver is an unfavorable prognostic factor. However, nivolumab demonstrated sustained OS benefit versus docetaxel in these patients, similar to the ITT population. The safety profile of nivolumab was favorable versus docetaxel in this subgroup, with no new safety concerns identified.

Background:
Non-small cell lung cancer (NSCLC) is a leading cause of cancer related death worldwide. Late diagnosis and poor prognosis of advanced cancer are considered to be the main causes for the high mortality rates in NSCLC. Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD1) demonstrated substantial improvements in overall survival (OS) compared with chemotherapy in previously treated patients with advanced NSCLC. However, the annual therapy costs are high (>EUR100,000 in Germany). The objectives of this study are to assess the cost-effectiveness of nivolumab and pembrolizumab in previously treated patients with advanced NSCLC from the perspective of the German statutory health insurance.

Method:
We developed a microsimulation model (discrete event simulation) to simulate the results of clinical trials and to extrapolate outcomes beyond the study duration. Clinical input parameters were gathered from published trial data (CheckMate017, CheckMate057, KEYNOTE-010). Kaplan-Meyer curves of progression free survival and OS were digitally reconstructed and survival analyses were conducted to inform model survival parameters. Utilities and cost data were extracted from published literature and German price databases. Cost-effectiveness analysis was performed for various PD-L1 expression levels. In each scenario, a Monte Carlo simulation with 10,000 iterations was performed to capture parameter uncertainty.

Result:
Additional cost per quality adjusted life year (QALY) gained of nivolumab vs. docetaxel in squamous-cell NSCLC, nivolumab vs. docetaxel in nonsquamous-cell NSCLC and pembrolizumab vs. docetaxel were EUR132,248 (EUR113,483 - EUR156,045), EUR197,187 (EUR171,718 - EUR228,407) and EUR208,652 (EUR182,492 - EUR237,161) respectively (table 1). Treating only patients with PD-L1-positive tumors substantially reduced additional costs per QALY gained for nivolumab in nonsquamous-cell NSCLC and for pembrolizumab but the incremental cost-effectiveness ratio still considerably exceeded EUR100,000 per QALY. Figure 1



Conclusion:
PD1-inhibitors nivolumab and pembrolizumab are likely not cost-effective in previously treated patients with advanced NSCLC, even in patients with substantial PD-L1 expression, at current price levels in Germany.

Background:
Currently available immune-checkpoint inhibitor therapies in NSCLC patients have different, approved PD-L1 expression assays. These assays have similarities, but also some differences. In our study, we estimated usefulness of two immunohistochemical (IHC) tests in patients with different pathological diagnosis of lung cancer and known most common genetic abnormalities.

Method:
The study included 48 NSCLC patients (median age: 65 years old) with known status of EGFR and ALK genes. PD-L1 expression examination was carried out using two IHC assays with SP142 (Ventana) and 22C3 (Dako) antibodies. The analysis was performed in histological (resected tissue) and cytological (cellblocks from bronchoscopy biopsies) material in a form of formalin-fixed paraffin-embedded blocks, on corresponding analysis platforms.

Result:
The expression of PD-L1 of ≥5% and ≥50% on tumour cells (TCs) was significantly (p<0.05) higher in assay with 22C3 (66.7% and 45.8%) than with SP142 antibody (39.6% and 22.9%). The median percentage of PD-L1-expressing TCs was significantly (p<0.0001) higher in test with 22C3 than with SP142 antibody. PD-L1 expression on TCs was observed significantly higher in squamous cell carcinoma (SCC) patients than in PD-L1-positive non-SCC patients (p=0,0224). We have observed low percentage of PD-L1-positive cases among patients with common EGFR mutations and ALK rearrangement.

Conclusion:
Our results support that the highest PD-L1 expression on TCs occurs in SCC patients and in adenocarcinoma patients without common, druggable genetic abnormalities. The obtained results were clearly visible in assays with 22C3 antibody, whereas the SP142 antibody showed more diverse results in the same cases.

Background:
Recently, progress in the treatment of NSCLC patients with PD-L1 expression has been heralded in the field of immune-oncology. Pembrolizumab and Nivolumab are anti-PD-1 (Programmed death) agents used in the treatment of NSCLC patients with PD-L1 expression, and the efficacy of these agents tremendously prolong the overall survival times (OS). Although, the data of concordance for staining each anti-body in clinical course is limited.

Method:
We reviewed all 81 patients who were diagnosed with, or suspected of having NSCLC and received a tissue biopsy between February 2017 and April 2017 in Matsusaka Municipal Hospital. A total of 81 NSCLC tumors were stained with four PD-L1 IHC assays (22C3 and 28-8) The aim of this study was to evaluate the clinical characteristics and to compare concordance between both groups, when divided into three groups as follows; no(negative), low(≧1-49%/1-5%),high(≧50%/≧5%), and to compare the concordance of PD-1 expression between old (stained after 6 months) and fresh (stained within 6months) samples.

Result:
The median age was 75 [range: 58-89], 59 were male, 22(27.1%) were never-smokers. 55(67.9%) and 21(25.9%) patients was diagnosed with adenocarcinoma and squamous cell carcinoma, respectively. Negative/low/high/unevaluable in PD-1 status were 38/21/16/6 and 39/19/18/5 in 22C3 and 22-8, respectively. In both group 22C3 and 22-8 PD-L1 staining group, no significant differences were seen in the characteristics of the results, whether positive or negative. The concordance rate between 22C3 and 28-8 staining was 75% in all stages, 87% in early stage, and 77 % in advance stage cases. The concordance rate of old samples against fresh ones was 75% versus 84%.

Conclusion:
The concordance between 22C3 and 28-8 was high value in clinical practice. This study also demonstrated the similar concordance of PD-1 expression between fresh and old samples, or between early stage and advanced stage.

Background:
Tumor Treating Fields (TTFields) are low intensity, alternating electric fields in the intermediate frequency range. TTFields disrupt mitosis, and are FDA approved for the treatment of glioblastoma. A study testing the efficacy of TTFields in combination with chemotherapy for the treatment of mesothelioma [NCT02397928] is ongoing , and a pivotal study testing the efficacy of TTFields in treating NSCLC was recently launched [ NCT02973789]. TTFields are delivered through two pairs of transducer arrays placed on the patient's skin. Preclinical research shows that treatment efficacy increases with the intensity of the field. Therefore, optimizing treatment requires a deep understanding of how TTFields distribute within the body. . Here we present a computational simulations-based study investigating the field distribution in male and female realistic computational phantoms when arrays are placed on the thorax

Method:
Simulations were performed using the Sim4Life software package realistic computational phantoms of a male, female and obese male (ZMT, Zurich, Switzerland). Arrays with a geometry similar to that used to deliver TTFields to the thorax with the NovoTTF-100L were placed on the chests of the models, and delivery of TTFields was applied by imposing boundary conditions simulating a 4 ampere peak to peak current at 150 kHz. The field intensities within the lungs of the models were then evaluated.

Result:
The highest field intensities within the lungs were obtained when the arrays were axially-aligned with the parenchyma as much as anatomically possible. Under these conditions, field intensities throughout the lungs exceeded the therapeutic threshold of 1 V/cm in all models. Array layouts in pairs delivered electric fields from the anterolateral to the posterior-contralateral aspect of the patient and from the antero-contralateral to the posterolateral aspect of the patient, respectively, resulted in high intensity relatively uniform field intensities through the lungs. These types of layouts could be used on male subjects. However, due to body contours, these cross-body layouts may not adhere well to females, potentially hampering the efficient delivery of TTFields. For the female phantom, a layout in which one pair of arrays is placed on the lateral and contralateral aspects , and the second set of arrays placed on the anterior and posterior aspects may be the preferred layout.

Conclusion:
This study provides insights into how transducer array layouts influence TTFields distribution in the lungs. These results should be accounted for when treating lung cancer with TTFields.

Background:
Tumor treating fields (TTFields) exert directional forces on microtubules and dielectrophoretic forces on charged molecules leading to abnormal spindle formation. As a result, Cells may die in mitotic arrest or divide into abnormal daughter cells which can die during the following interphase or proliferate to be re-exposed to TTFields. Studies have shown cancer cell type specific frequency dependence for TTFields effects, and that some of the outcomes of abnormal mitosis under TTFields may trigger different forms of cell death. In this study we determined the optimal frequency of TTFields in NSCLC cell lines, and evaluated whether cell death induced by TTFields is potentially immunogenic. Finally, we explored the combination of TTFields with anti-PD1 therapy in-vivo.

Method:
We investigated the effect of TTFields in-vitro using four human NSCLC cell lines and two murine cell lines. Inhibition of tumor cell growth was analyzed by cell count. Survival fractions were calculated relative to control. We also evaluated the induction of immunogenic cell death by TTFields in vitro. Lewis lung carcinoma (LLC) were treated with TTFields. Levels of calreticulin on the surface of treated cells and intracellular ATP levels were evaluated using flow cytometry. High mobility group box 1 (HMGB1) secretion was measured using an ELISA assay. The effect of TTFields and anti-PD1 was tested on mice orthotopically implanted with LLC cells and treated with TTFields, anti-PD1, or the combination. Tumor volume was monitored; flow cytometry analysis was performed for phenotypic characterization of infiltrating immune cells.

Result:
TTFields therapy was found to induce a frequency-dependent reduction in viability in all six cell lines, with a common peak effective frequency at 150 kHz. TTFields induced elevated cell surface expression of calreticulin, decreased intracellular ATP levels, and promoted HMGB1 secretion. The combined treatment of tumor-bearing mice with TTFields plus anti-PD1 led to a significant decrease in tumor volume compared to anti-PD1 alone or to the control group. Significant increases in CD45+ tumor infiltrating cells were observed in the TTFields plus anti-PD1 group. These infiltrating cells demonstrated a significant up-regulation of surface PD-L1 expression. Specifically, both F4/80+CD11b+ cells, and CD11c+ cells exhibited higher tumor infiltration and elevated PD-L1 expression versus infiltrating immune cells in the control group.

Conclusion:
The inhibitory effects of TTFields were maximal at 150 kHz for all NSCLC cell lines tested. TTFields treatment potentiates immunogenic cell death in cancer cells. Combining TTFields with anti-PD1 may enhance antitumor immunity and result in increased tumor control.

Background:
Concurrent chemoradio­therapy (CCRT) is standard treatment modality for patients with unresectable stage III NSCLC dis­ease. TIn this study, we aimed to investigate the efficacy and toxicity of CCRT with carboplatin (AUC 2) and paclitaxel (80 mg/m2) during radiotherapy.

Method:
Medical records of 41 patients with inoperable stage III NSCLC treated with concurrent chemoradiotherapy with carboplatin-paclitaxel were retrospectively analyzed. Carboplatin (AUC 2) and Paclitaxel (80 mg/m2) from periph­eral route were administered weekly during radiotherapy

Result:
41 consecutive unresect­able stage IIIA-B NSCLC patients treated with CCRT were included into this study. Median age was 62 years old (range 40–77), and 37 (90.2%) of the patients were men. ECOG per­formance score was 0 in 23 patients (56.1%). Adenocarcinoma, the most common histology, was diagnosed in 18 pa­tients (43.9%). There were 11 (26,8%) stage IIIA patients and 26 (63.4%) stage IIIB patients. Median follow-up time was 22.5 months. Median PFS and OS were 22.5 and 53.5 months. Hematological and non-hematological grade 3–4 toxicities were seen in 8 (19,5%) and 5 (12.2%) patients, respectively. Figure 1Figure 2





Conclusion:
This study showed that carboplatin-paclitaxel provides results similar to that in the literature survival parameters and it may be an option with lower toxicities for CCRT in patients with unresectable stage III NSCLC.

Background:
Numerous studies about small-sized lung cancer have been published recently. On the other hand, few studies have considered large-sized tumors. In this study we analyzed the prognostic factors for tumors that measured 5 cm or more.

Method:
Of the 547 patients who underwent resection of the lung due to primary lung cancer in our institution between 2002 and 2011, 90 had tumors that measured 5 cm or more. Among these 90 patients, 43 were adenocarcinomas, 32 were squamous cell carcinomas, 68 were male, and 14/26/1 cases were pathological N1/2/3, respectively. The average age was 70.1±8.9 years, and the average tumor diameter was 6.7±1.9 cm. Age at operation, gender, tumor location, operative method, tumor size, nodal status, lymphatic permeation, vascular invasion, pleural invasion (pl), preoperative pulmonary function status, serum carcinoembryonic antigen level, smoking status, and Charlson comorbidity index were analyzed using a Cox proportional hazards model to identify the postoperative prognostic factors.

Result:
In a univariate analysis, tumor size of 7 cm or more (p = 0.03), pathological N status of N2 or more (N0 vs. N2/3: p = 0.03), pl3 (pl0 vs. pl3: p=0.02), and < 80 (p=0.04) were found to be associated with a poor postoperative overall survival (OS). Lymphatic permeation (p = 0.66), and vascular invasion (p=0.10) were not significantly associated with OS. A multivariate analysis was performed using the 4 factors that were associated with a poor OS in the univariate analysis. As a result, tumor size of 7 cm or more (p < 0.01), pathological N status of N2 or more (N0 vs. N2/3: p < 0.01), and pl3 (pl0 vs. pl3: p=0.01) were independently associated with a poor OS.

Conclusion:
For large-sized lung cancer, tumor size, nodal status and pleural invasion were related to OS, whereas lymphovascular invasion was not.

Background:
A multimodal treatment is frequently performed in many initially inoperable stage III N2 non-small cell lung cancer. However, selection of the best treatment for these patients is controversial issue. This study was conducted to explore the benefit of neoadjuvant chemotherapy and adjuvant therapy in these patients.

Method:
Between Jan. 2008 and Dec. 2015, patients with stage III N2 NSCLC enrolled. All of them were treated with induction chemotherapy and surgical resection. Some of them who had high risk factors for disease recurrence underwent adjuvant treatment including chemothearpy, radiothearpy or concurrent chemoradiotherapy.We reviewed medical record including clinicopathologic characteristics and the survival outcome.

Result:
The median age was 65 (range 43-77), and male was more common (M:F, 3.8:1). Median follow-up period was 23.6 months (Range: 3.0-23.6 months). 32 patients (59.%) presented with squamous cell cancer (SqCC), and 20 patients (37.0%) were presented as adenocarcinoma. Docetaxel/cisplatin in 52 patients (96.3%) and gemcitabine/cisplatin in 2 patients (3.7%) were selected as neoadjuvant chemotherapy regimen. The overall clinical response rate to induction chemotherapy was 70.4%. After surgical resection, 27 patients (50.0%) underwent adjuvant chemotherapy alone and 20 patients (37.0%) underwent adjuvant radiotherapy with or without chemotherapy. Median OS was 56.4 months (range 33.5-79.3 months) and median PFS was 24.4 months (ranage 26.6-43.0 months). In multivariable analysis, the adjuvant treatment group showed better survival than the no adjuvant treatment group. Among them, median OS was not reached in adjuvant radiotherapy with or without chemotherapy group and 53.9 months in the adjuvnat chemotherapy alone group (p=0.016).

Conclusion:
Neoadjuvant chemotherapy is active in patients with stage III N2 NSCLC and adjuvant multimodal therapy including chemotherapy or radiotherapy demonstrated favorable survival outcomes. Based on our data, active multimodal neoadjuvant and postadjuvant treatment should be considered for the initially unoperable stage III N2 NSCLC patients.

Background:
To determine the overall survival of Nab-Paclitaxel (Nab) or Paclitaxel (P) plus Carboplatin (C) with concurrent radiation therapy (RT) followed by consolidative chemotherapy (CT) with Nab-C or PC for patients (pts) with Stage IIIA/B Non-small cell lung cancer (NSCLC) when compared to historical controls and to assess for the safety of each regimen to guide further investigation

Method:
This phase I/II trial randomized 98 pts (6 pts phase I; 92 pts phase II). 75 pts were eligible for analysis on the phase II portion. For the phase I portion, weekly 50mg/m[2] of Nab and C AUC 2 was administered with concurrent thoracic RT (60-66 Gy) followed by CT comprising 100mg/m[2] Nab on days 1,8,15 (of a 21 day cycle) and C AUC 6 on day 1 for 2 cycles. For the randomized phase II portion, patients received either arm A) weekly 50mg/m[2] P and C AUC 2 or arm B) weekly 40mg/m[2] of Nab and C AUC 2 with concurrent RT followed by consolidative 200mg/m[2] P and C AUC 6 every three weeks for 2 cycles or 100mg/m[2] Nab on days 1,8,15 (of a 21 day cycle) and C AUC 6 on day 1 for 2 cycles. The primary end point was 2-year overall survival of 50% or greater.

Result:
Median follow up was 14.3 months. 2 patients experienced dose-limiting toxicities on the phase I portion as defined per protocol (grade 3 febrile neutropenia and grade 4 thrombocytopenia) leading to a dose reduction of concurrent Nab from 50mg/m[2 ]to 40mg/m[2] for the phase II portion. On the Phase II portion, Grade 3+ esophagitis was 3 and 2 pts, Grade 3+ pneumonitis was 3 and 5 pts and Grade 4+ hematological adverse events was 3 and 8 pts on A and B arms respectively. The 1- and 2-year overall survival rates for arm A and B were 80.6% (95%CI 63.4-90.3) and 69.2% (51.2-81.7); and 72.5% (48.4-86.8) and 56.5% (33.7-74.1) respectively. The 1- and 2-year progression free survival were 57.5% (38.7-72.5) and 46.1% (29.2-61.5); and 45.5% (24.7-64.3) and 20.7% (6.5-40.3) for arm A and B respectively.

Conclusion:
For pts with locally advanced Stage IIIA/B NSCLC, both arms A and B provided 2-year overall survival rates greater than 50%. The addition of Nab to chemoradiation was overall well tolerated, prompting potential interest going forward. Further analyses of quality of life measurements are currently underway. This project was supported by Celgene. Clinical Trial information: NCT01757288

Background:
Here we report the case of a young, never-smoker Hispanic woman with a hereditary familial overlap syndrome (Li-Fraumeni plus CDHI) who develop synchronous multiple primary lung adenocarcinomas related to Intra-alveolar Tumor Spread (STAS) several years after the diagnosis of a locally advanced lower limb osteosarcoma.

Method:
Comprehensive genomic profiling by next generation sequencing (NGS) was performed on 90 cancer-related genes over each lung lesion (including two nodules of acinar adenocarcina, one lepidic spread tumor and in STAS area). In the same way, the broad genomic analysis was performed in archival tissue from the previous bone tumor.

Result:
Lung tumors were found to harbor PI3KCA (invasive lesions) and a rare in-frame insertion of 6 amino acids in exon 19 of EGFR (lepidic tumor), STAS area showed KRAS and BRAF mutations in two different segments, and osteosarcoma tested positive for well known PIK3CA, KRAS and CDH1 alterations.

Conclusion:
This unique case raises practical questions as to the challenges of molecular testing and highlights the potential association of germline p53 and CDH1 mutations with concurrent somatic alterations that elucidate the basis of tumor heterogeneity. Figure 1

Background:
Trimodal treatment incorporating neoadjuvant concurrent chemoradiotherapy (CCRT) and surgical resection is one of the treatment strategies for non-small cell lung cancer (NSCLC) patients with N2 disease. Although pathologic phenotypes as well as biological features might be different between adenocarcinoma (ADC) and squamous cell carcinoma (SqCC), histologic type has been rarely considered when selecting treatment strategy in patients with N2 disease. The aim of this study is to investigate if histologic type is associated with treatment response and survival outcomes in patients undergoing trimodal treatment for N2 disease.

Method:
A retrospective review of patients with N2 disease who underwent neoadjuvant CCRT followed by surgery at our institution was performed. Clinicopathologic features, response to CCRT, and survival outcomes were compared between ADC and SqCC.

Result:
From 2003 to 2013, 374 patients underwent curative-intent surgery after neoadjuvant CCRT for either ADC (n=233, 62.3%) or SqCC (n=141, 37.7%) with pathologically proven N2 disease. Sixty-nine patients (18.5%) had bulky and/or multi-stationed N2 diseases on pre-CCRT imaging tests. There were more male, more smokers, more advanced clinical T and N stages, and more bulky and/or multi-stationed N2 diseases in the SqCC group than in the ADC group. Conversely, the SqCC group had more radiologic responders, earlier pathologic T and N stages, more pathologic complete responders, and more frequent mediastinal downstaging than the ADC group. With a mean follow-up of 50.1 months, patients with SqCC showed significantly better 5-year recurrence-free survival than those with ADC (ADC, 22.8% vs. SqCC, 43%; p=0.001). However, there was no significant difference in the 5-year overall survival between the two groups (ADC, 57.5% vs. SqCC, 52.3%; p=0.366). This may be related to significantly better (p<0.001) post-recurrence survival in the ADC group (mean, 28 months) than in the SqCC group (mean, 14.5 months). In the ADC group, 164 patients developed recurrences and of those, 68 (41.5%) received targeted therapy. Patients who received targeted therapy for recurrences showed significant better 5-year overall survival than those who did not receive (61% vs. 45.6%, p=0.025).

Conclusion:
In this study, SqCC was associated with better treatment response and more favorable recurrence-free survival than ADC. Despite poor recurrence-free survival in ADC, its overall survival was improved by prolonged post-recurrence survival, which might be related to the use of targeted therapy for recurrence. Since treatment response and survival outcomes are different according to histologic type, individualized treatment strategy could be considered to improve outcomes of N2 disease.

Background:
Concurrent chemoradiotherapy (cCRT) has proven to increase survival in patients with inoperable, locally advanced non-small-cell lung cancer (ILA_NSCLC), however there is no consensus on the treatment of elderly population. Our aim was to determine the prognostic value and ability to predict toxicity of the comprehensive geriatric assessment (CGA) in this clinical setting.

Method:
Elderly patients (≥ 75 years) with LA-NSCLC underwent CGA (assessing comorbidity, polypharmacy, functional status, geriatric syndromes, mood, cognition and nutritional status), the Vulnerable Elders Survey (VES-13) screening tool and the Cancer and Aging Research Group (CARG) toxicity predictive tool. Patients were classified according to the CGA into fit and medium-fit who were deemed candidates for cCRT (platinum-based chemotherapy concurrent with thoracic radiation therapy) and unfit patients that were assigned to best supportive care.

Result:
85 elderly patients with LA-NSCLC were included. Based on CGA, 37%, 48% and 15% were classified in fit, medium-fit and unfit respectively, and 56% were considered vulnerable according VES-13 (≥ 3). Out of 72 fit and medium-fit patients initially considered candidates for cCRT, only 54 patients (75%) were actually treated. The reasons for not administering cCRTwere: non-suitable for radiotherapy (tumor extension or poor respiratory function) (n=8), specific contraindication to chemotherapy (n=8), and patient’s decision (n=2). According to CARG-risk, fit and medium-fit patients candidates to receive cCRT were classified as high 10%, medium 52% and low 38%. Forty-two (78%) patients completed the scheduled treatment without differences between both CGA groups. The major reasons for not completing cCRT were: toxicity (10%), cancer recurrence (4%), patient decision (4%) or aggravation of comorbidities (4%). Fit and medium-fit patients receiving cCRT (63.5%) had mOS of 21.1 m (95% CI 16.2 – 26.0). VES-13 ≥ 3 was associated with shorter mOS (16.33 vs. 24.3 m; p=0.027). The most common grade 3-4 adverse events were neutropenia (20%), febrile neutropenia (7.5%), asthenia/fatigue (11%), respiratory infection (13%) and radiation pneumonitis (13%). There were not differences between GGA groups related to grade 3-4 toxicity. Medium risk patients defined by CARG had a trend towards higher risk of developing grade 3-4 toxicity (p= 0.086).Vulnerable patients defined by VES-13 had significantly higher risk of grade 3-4 toxicity (OR=3.99, 95% CI 1.28-12.37, p=0.017).

Conclusion:
CGA is useful in selecting elderly patients with LA-NSCLC that might benefit from adapted cCRT. VES-13 showed independent prognostic value and, unlike CARG score, it was significantly associated with higher risk of G3-4 toxicity in this clinical setting.

Background:
Radiotherapy (RT) after surgery for locoregionally advanced mesothelioma is particularly challenging. Recent surgical advances with pleurectomy and decortication techniques are clinically promising, however, applying comprehensive ipsilateral pleural irradiation is technically difficult with two RT-sensitive, intact lungs. With state-of-the-art IMPT, we have successfully treated a 77-year-old woman who has now been disease-free and alive for 7 months after RT (and 18 months since diagnosis), with minimal therapy-related toxicities so far.

Method:
A woman was diagnosed with locally advanced mesothelioma of the right hemithorax, epithelioid type. She underwent appropriate metastatic workup which was negative. She received 4 cycles of carboplatin and pemetrexed, and underwent thoracotomy with parietal and visceral pleurectomies, decortication, and mediastinal nodal dissection. She was found to have ypT3, N0 disease postoperatively, and elected to undergo proton therapy. A 4D-CT simulation scan was performed, and negligible respiratory motions were found.

Result:
A 3-field, active beam scanning, multi-field optimization IMPT plan was made and passed quality assurance. She received 50.4 Gy in 28 fractions, and completed IMPT without any treatment interruption; the acute toxicities included mild pain, cough, and dyspnea which were all grade 1. She also developed subacute, RT-related grade 1 dermatitis. She has not had clinically significant RT-induced pneumonitis. In preparation for her proton therapy-based treatment, multiple dosimetric iterations and comparisons were made, for the best intensity modulated radiotherapy (photon-based, IMRT) vs. IMPT plans (see Figure). With IMPT, the contralateral (left) lung, heart, and also esophagus received significant amount of RT reduction in an otherwise historically morbid adjuvant treatment which were only reserved for the medically fittest. Figure 1



Conclusion:
Although promising, the clinical dosimetric levels of evidence are limited to this case report only. The paradigm of neoadjuvant platinum-based doublet therapy, pleurectomy/decortication, and adjuvant proton RT should be further explored and evaluated in the prospective settings in the future.

Background:
Standard treatment for mesothelioma (surgery+/-chemotherapy+/-radiotherapy) does not provide satisfactory oncologic results in view of the lack of evidence for a preferred treatment option in such a rare disease with little published evidence. We aim to assess the feasibility of delivering radical doses of radiotherapy in mesothelioma patients. We would also like to evaluate the dosimetric parameters to establish organs at risk and optimal dose potentially delivered if radiotherapy is a sole agent.

Method:
Patients with Mesothelioma were chosen from the SYSTEMS-1 and SYSTEMS-2 trial cohort. Treatment volumes and organs at risk were performed on the Eclipse planning system. The treatment volumes outlined were CTV Pleural cavity and GTV bulky disease. Doses were prescribed as follows: PTV pleural cavity (CTV + 0.8 cm) 45Gy/ 25# and PTV Bulky disease (GTV+5mm) 55Gy/25#. Physics planning was carried on the Eclipse 13.6.23 treatment planning system, by using VMAT technique with either 2 or 3 arcs, 6MV beams at a dose rate of 600MU/min. We calculated overlap volumes between PTV and Organs at Risk (OAR’s) in view of their proximity, prioritizing heart and liver dose constraints over PTV coverage.

Result:
5 patients with confirmed epitheliod mesothelioma. Ages ranged from 55 - 72 years, 4/5 patients were male. A Cisplatin or Carboplatin-Pemetrexed doublet was given to all the patients prior to the CT Scan. The table below shows the dosimetry data gathered from the plans done.

	Objectives	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5
TNM stage		T4N2M0	T3N2M0	T4N3M0	T4N2M0	T4N2M0
PTV Pleural cavity Volume (cc) D~99%~ (% of the prescribed dose) D~95%~ (% of the prescribed dose) V~105%~ (%) V~95%~ (%) Median Dose (Gy)	Dose prescribed 45Gy/25# - - >95% - >95%	1615 78.6 94.3 80.7 94.6 51	2276 77 108 96 97.6 53	1465 82.8 96 58.5 96.1 47.9	3701 58 91 87.1 93.2 53.4	1840 72 89 79.7 89 48.9
PTV Bulky disease Volume (cc) D~99%~ (% of the prescribed dose) D~95%~ (% of the prescribed dose) V~105%~ (%) V~95%~ (%) Median Dose (Gy)	Dose prescribed 55Gy/25# - - >95% - >95%	2905 72 89.3 15.7 90 55	3104 79 89.6 15.2 81.2 54.6	4924 56 87.7 10.7 75.9 53.6	764 83 89 4.5 74 54.3	3104 79 89.6 15 81 54.6
Contralateral lung Volume(cc) Overlap with PTV (cc) Mean lung dose (Gy) V~20Gy~ (%) V~5Gy~ (%)	- - ≤8-10 to 20 ≤4-10 to 35 ≤75	1637 0.1 12.2 11.3 98.6	1636 0 18.4 35.6 100	1247 0 13 18.3 92.6	2391 10.4 16.4 25.4 100	2082 0 17.5 31.3 100
Heart Volume(cc) Overlap with PTV (cc) Mean Heart Dose (Gy) V~35Gy~ (%)	- - <22-26 <35	776 44.4 33.5 33.6	619 94.9 25.5 30	790 150 27.8 28.8	681 111.7 31.1 34.7	822 65.8 32.9 34.7
Liver Volume(cc) Overlap with PTV (cc) Mean liver dose (Gy) V~30Gy~ (%)	- - 28-30 ≤40	1657 232 32.3 55.1	1544 0 17.3 4.0	1534 0 89.9 0.1	1931 485 32 57.2	1333 230 31.9 54.4
Oesophagus Volume (cc) Overlap with PTV (cc) Max dose (Gy) V~50Gy~ (%)	- - ≤50-55 <40	28 5.3 55.6 8.3	33.5 0 53.4 5.9	30.5 1 55.6 13.4	193 48.7 60.9 26.6	43 7.7 56.3 13
Spinal cord Volume(cc) Overlap with PTV (cc) Max dose (Gy)	- - <50	70.3 0 45.7	80.4 0 52.7	55.5 0 50.7	87.6 1.9 54.5	75 0 49.6
Contralateral Kidney Volume(cc) Overlap with PTV (cc) Max dose (Gy)	- - <5	279 0 17.4	115 0 20	116 0 4.4	177 0 30.1	163 0 21.9
Ipsilateral Kidney Volume(cc) Overlap with PTV (cc) V~30Gy~ (%) Mean Dose (Gy)	- - <50 ≤30	N/A N/A N/A N/A	118 0 29.6 17.4	89.8 0 0 2.1	134 2.8 23.3 18.9	239 20.5 44.6 29
Small Bowel Volume(cc) Overlap with PTV (cc) Max dose (Gy)	- - ≤45	183 0 18.3	348 0 27.9	307 0 10.7	672.5 0 33.2	309 0 23.4
Stomach Volume(cc) Overlap with PTV (cc) Max Dose (Gy)	- - ≤45	168 0.8 33.3	352 6.4 56.7	235 5.9 45.7	182.1 0 52.4	631 0 40.4

Conclusion:
Radical radiotherapy doses are achievable in mesothelioma by respecting organs at risk adequately, despite the challenging large volumes and complex disease anatomical pattern. VMAT is a promising technique allowing to potentially treat mesothelioma with radical doses of radiotherapy. Further trials are needed to assess the feasibility of radiotherapy as an upfront treatment for these patients.

Background:
The purpose of our study was to quantify the influence of heart dose on the early and late onset of dyspnea in a cohort of non-small cancer (NSCLC) and malignant pleural mesothelioma (MPM) patients having multimodality treatment including radiotherapy (RT).

Method:
In 121 patients with multimodality-treated NSCLC and MPM the maximal dyspnea score (CTCAE 4.0) before RT, at an early (<6 months) and a late (7-12 months) time point were obtained. Included patients needed to be clinically and radiologically progression-free 9 months after the end of RT. The difference (Δ) between the maximal dyspnea at <6 months and at 7-12 months with the pre-RT dyspnea was calculated.

Result:
Forty-four percent (50/113) of the patients developed an early worsening of at least 1 point in their dyspnea score (Δdyspnea >1) after the end of RT. Independent predictors of an early worsening were the mean heart dose (MHD) (for Δdyspnea >1: OR=1.03, p=0.04) and the dyspnea score before RT (for Δdyspnea >1: OR=0.40, p=0.0001; for Δdyspnea >2: OR=0.35, p=0.05). At the later time point, only the dyspnea score before RT (OR: 0.40, p=0.001) was identified as predictor of Δdyspnea >1.

Conclusion:
Our results, albeit exploratory, suggest that heart dose may play a role in the early worsening of the dyspnea in a heterogeneous cohort of patients having multimodality treatment including RT, whereas baseline dyspnea plays a major role for both early and later worsening.

Background:
Malignant pleural mesothelioma (MPM) is a rare cancer with a heterogeneous prognosis. We have previously described and validated a prognostic model using a classification and regression tree (CART) model to analyse the interaction of multiple variables with survival in a broad MPM population.(1) We aimed to test the performance of our model on a population with MPM who had surgical intervention.

Method:
Cases from Australia and Japan with confirmed MPM who underwent surgery were analysed with clinical variables available at the time of referral recorded. The model uses combinations of different variables (Table 1) to stratify participants into different risk groups (1-4) and the survival characteristics were compared using the Log Rank test. Figure 1



Result:
A total of 289 cases were included (205 from Australia and 84 from Japan) who had surgery between 1991-2016. Overall median survival was 34.6 (IQR 17.5-56.1) months; median age 63.0 (IQR 57.0-67.8) years, 240/289 (83.0%) were male. Epithelioid MPM was the most common subtype (80.9%), weight loss was present in 36.6%, dyspnoea in 54.4%, chest pain in 29.0% and 91.8% had an ECOG performance status of 0. EPP was the most common operation performed (56.7%), followed by pleurectomy/decortication in 30.4%. There were no clinically meaningful differences between the cohorts; 40 patients were alive at censure. Survival across the risk groups was significantly different (Log Rank test p<0.0001). The group with the longest survival (median 78.1, IQR 28.1-152.4 months) had no weight loss, Hb >153g/L and serum albumin >43g/L at the time of referral to specialist surgical centre.

Conclusion:
The combination and interaction of simple, clinical variables available early after diagnosis of MPM is able to stratify survival and discriminate higher and lower risk of death in high performance status patients

Background:
Our standard treatment strategy for operable malignant pleural mesothelioma (MPM) is trimodality therapy with extrapleural pneumonectomy (EPP) followed by radiation and chemotherapy. Our experience to treat MPM is reported.

Method:
45 consecutive EPP for MPM which were performed from June 2006 to February 2017 in our hospital were reviewed. We have instituted a trimodality therapy protocol consisting of EPP, adjuvant 45-50.4 Gy hemithoracic radiation, and adjuvant CDDP plus PEM chemotherapy. 36 patients have been treated with this protocol. However, 9 patients were given induction chemotherapy, and referred to us. They were scheduled to undergo EPP and adjuvant radiation. Overall survival was calculated using Kaplan-Meier method.

Result:
Median age at EPP was 61 years old (44-74). Female was 11, and male was 34. Right side was 25, and left side was 20. Epithelioid was 30, biphasic was 10, sarcomatoid was 2, and special variants was 3. Median EPP time was 7 hours 30 minutes (5 h 52 m-12 h 2 m). No blood transfusion during EPP was 17 cases (38%). Mortality was one patient (2.2%) who died due to acute aggravation of interstitial pneumonia. Atrial fibrillation was the most common morbidity, and developed in 16 patients (36%). IMIG pathological stage was stage IV in 3, stage III in 26, stage II in 8, and stage Ib in 8. Adjuvant 45-50.4 Gy radiation was completed for 38 patients (83%). 10 patients (22%) could not undergo chemotherapy. 31 patients (69%) underwent trimodality therapy. Postoperative median follow-up period was 5 years and 10 months. Five year survival, two year survival, and median survival of all 45 patients (graph) were 32%, 44%, and 17.4 months, and those of 30 epithelioid patients were 41%, 54%, and 30.4 months.Figure 1



Conclusion:
This trimodality treatment strategy with EPP, radiation, and chemotherapy for MPM is feasible, and the prognosis has been greatly improved.

Background:
Surgery for malignant pleural mesothelioma (MPM) is an invasive procedure associated with high morbidity. MPM often invades adjacent structures such as the chest wall, diaphragm, and mediastinum. Therefore, pulmonary functions and levels of physical fitness are reduced in advanced MPM. The aim of this study was to characterize preoperative exercise capacity and relate it to pulmonary functions, oxygenation, and postoperative outcomes in patients with MPM.

Method:
A retrospective study was conducted on 18 patients with MPM who were scheduled to undergo extrapleural pneumonectomy (EPP) or pleurectomy/decortication (P/D) followed by postoperative rehabilitation at Nagoya University Hospital from July 2012 to April 2016 (Institutional Review Board approval No. 2015-0413). To estimate preoperative exercise capacity, 6-min walk test (6MWT) and oxygen saturation of a peripheral artery (SpO~2~) during the 6MWT were assessed. Grades III and IV of the Clavien-Dindo classification were defined as major postoperative complications.

Result:
The age was 65.8 ± 6.4 years. Preoperative 6-min walk distance (6MWD) was 465.9±96.7 m. Minimum SpO~2~ ranged from 86% to 97%. The 6MWD significantly correlated with inspiratory capacity (r=0.507, P<0.05) and % of predicted value of diffusing capacity of the lung for carbon monoxide (%DL~CO~) (r=0.470, P<0.05). The minimum SpO~2~ during 6MWT significantly correlated with % of predicted values of vital capacity (r=0.619, P<0.01) and total lung capacity (r=0.493, P<0.05) and postoperative days of extubation (r=-0.495, P<0.05). The preoperative partial pressure of oxygen in arterial blood significantly correlated with %DL~CO~ (r=0.505, P<0.05). There was a total of 13 major postoperative complications (8 respiratory failure, 2 pneumonia, 1 empyema, 1 atrial fibrillation, and 1 prolonged air leak) in 6 patients. There was no in-hospital death or death within 30 days after surgery. The incidence of major complications was significantly associated with longer stays in intensive care unit (3.3±1.8 vs. 1.7±1.0 days, P<0.05) and hospital (54.2±31.2 vs. 12.3±3.2 days, P<0.05) but not with preoperative physical status or pulmonary functions. Stays in hospital after EPP (n=7) were significantly longer than those after P/D (n=11) (median 28 vs. 12 days, P=0.01) but there was no significant difference in incidence of major complications between the EPP and P/D groups.

Conclusion:
Our results indicate that the 6MWT is a convenient and useful field test to assess preoperative physical status in patients with MPM. Future studies with a larger cohort are required to elucidate risk factors for postoperative morbidity and mortality.

Background:
Staging for malignant pleural mesothelioma (MPM) remains a challenge due to poor prognostic utility. Other clinical factors may improve and refine the staging system. We investigate the impact thoracic asymmetry at time of initial presentation prior to therapy on survival in MPM patients treated with multimodal therapy.

Method:
We reviewed 93 consecutive treatment naïve MPM patients treated with Surgery for Mesothelioma after Radiation Therapy (SMART protocol) from Sep 2008 to Jul 2015. The right and left axial thoracic areas (defined as the product of the ant-post and med-lat extent of hemithoraces at the level of carina) were used to calculate the asymmetric thoracic ratio (ATR, where 1 is more symmetric, Figure 1). Significant factors were determined using univariate (log rank), multivariate (Cox proportional hazards) as well as recursive partition analysis (RPA). Continuous variables were discretized into binary categories split by its median value.

Result:
After a median follow-up of 15.6 months, 63 (68%) patients recurred, 56 (60%) died. The median ATR was 0.85, ranging from 0.52 to 1.00. On univariate analysis, histology (p=0.003 and 0.0002), gross tumour volume (GTV, p=0.004 and 0.001), and ATR (p=0.00001 and 0.0000002) all significantly impacted both overall and disease free survival, respectively, while mediastinal nodal involvement (p=0.03) was significantly associated with DFS only. On multivariate analysis, histology (p=0.01 and 0.005) and GTV (p=0.02 and 0.016) significantly impacted both overall and disease free survival, respectively. ATR significantly impacted disease free survival (p=0.02, HR=0.06 95% CI 0.02-0.20) and was suggestive of a trend for overall survival (p=0.07). On RPA, ATR<0.848 was significantly (p<0.001) associated with poorer DFS.

Conclusion:
A low asymmetric ratio (ATR<0.848) is significantly associated with poorer outcomes, specifically disease free survival, and is independent of histology and tumor volume. Further study is needed to validate this parameter.

Background:
The treatment of malignant pleural mesothelioma is challenging and multimodality treatment including surgery is recommended, although there are debates about the role of surgery. We analyzed the outcomes of surgery in MPM in the context of multimodality treatment focusing on extrapleural pneumonectomy (EPP).

Method:
Total 29 patients had pathologically proven malignant pleural mesothelioma from April 1998 to July 2015 were retrospectively reviewed. The overall survival rates of surgery group (any type of curative surgical treatment) and medical group (medical treatment only) were compared. Prognoses of EPP subgroup and medical group were also compared

Result:
Among 29 patients, 16 patients underwent surgery for curative intent, 12 patients underwent definitive chemotherapy, and one patient refused treatment. Epithelioid type (n=11, 68.8%) was the most common pathologic type in surgery group. Only 4 (33.3%) patients of medical group were epithelioid type. Half of surgery group patients were clinical stage I/II and there was no clinical stage I/II in medical group. Pulmonary functions of both group were not significantly different. In surgery group, 11 patients underwent EPP and one patient underwent pleurectomy/decortication. Four patients misdiagnosed as lung cancer preoperatively underwent lobectomy with chest wall resection. There were no postoperative 30-day nor in-hospital mortality. The median follow-up duration was 10.6 (1.0-78) months. The median survival time (MST) was 10.6 months, and the 3-year overall survival rate (3yr-OS) was 25 %. There was no statistical difference in overall survival between surgery and medical group (MST = 10.6 vs. 8.4 months, 3yr-OS = 31.1 % vs 16.7%, p=0.47) EPP subgroup (MST = 13.3 months, 3yr-OS = 45.5 %) also showed statistically similar survival with medical group (p=0.23). (Fig 1)Figure 1



Conclusion:
Multimodality treatment incorporating surgery was not superior compared with medical treatment in MPM. EPP with multimodality treatment also failed to show meaningful superior prognosis compared with non-surgical treatment in MPM.

Background:
We performed extrapleural pneumonectomy (EPP) as curative intent surgery for malignant pleural mesothelioma (MPM) from 2004 to 2012. We investigated that factors associated with long term survival in our current cases.

Method:
We retrospectively reviewed some factors concerning the patients underwent EPP from April 2004 to march 2017 and past more than 5 years after operation. We analyzed age, sex, epidemiology, side, clinical stage, measurements of pleural thickness, the value of SUV max of PET-CT, pathological stage, length from EPP to recurrence and end results.

Result:
A total of 54 patients were enrolled to this study. Six patients who had exploratory thoracotomy and three patients who had not macroscopic complete resection were excluded. Overall, 14 patients (31%) survived at least 5 years (Group S), and 31 patients (68%) survived less than 5 years (Group N). All patients had EPP. In Group S, 10 males (71%) and 4 females (29%); age when they had operation ranged from 37 to 69 years with a median age of 57.5 years. All of them, histological subtypes were epithelial type. By the comparison between Group S and Group N, there were significant differences among the value of SUV max of PET-CT validation of pre and post neoadjvant chemotherapy(＜3.0 vs ≧3.0, p=0.03), length from EPP to radiotherapy (＜60 days vs ≧60 days, p=0.02), length from EPP to recurrence (＜1 year vs ≧1 year, p=0.0001).

Conclusion:
More than 30% patients survived at least 5 years in this study. One patient survived more than 10 years. Another patient survived more than 8 years without recurrence. This case suggest that cancer of the patient possibly cured radically. In the future, we need comparison the prognosis, complication, quality of life (QOL) between the patients who underwent EPP and the patients who underwent pleurectomy/decortications (P/D).

Background:
Surgical resection of malignant pleural mesothelioma is discussed controversially. Using our data from nearly 2 decades of single center experience, and focusing on the shift from extrapleural pneumonectomy (EPP) to (extended) pleurectomy/decortication ((e)P/D) we compared the peri- and longterm outcomes of EPP and (e)P/D after induction chemotherapy.

Method:
In a retrospective analysis (September 1999 - June 2016) of our prospective database of mesothelioma patients 196 patients received mentioned multimodality therapy: 149 treated with EPP, 34 with eP/D and 13 with P/D. Major morbidity was defined as bleeding necessitating reoperation, patch failure, chylothorax, empyema, bronchopleural fistula (BPF), pulmonary embolism and acute respiratory distress syndrome (ARDS).

Result:
Both groups did not differ significantly in pT stage, hisotype, but in age and lymph node stadium. Overall 30-day and 90-day mortality were 4% and 8%, respectively. However, patients treated with (e)P/D the 30- and 90-day mortality was 0. Major morbidity was not significantly different between both groups with 37% (EPP) and 23% ((e)P/D), respectively. Patient’s characteristics, freedom from recurrence (FFR) and overall survival (OS) are demonstrated in figure 1.Figure 1



Conclusion:
Multimodality treatment with radical surgery is perfromed safely, (e)P/D known as the less invasive procedure than EPP, shows a longer OS whilst having a shorter FFR.

Background:
Despite significant efforts, there have been limited advances in the treatment of advanced pleural mesothelioma since the discovery of a survival benefit for first line chemotherapy with cisplatin and pemetrexed. Immunotherapy with checkpoint inhibitors has offered a new potential therapeutic strategy. In the phase 1b clinical trial KEYNOTE-28, pembrolizumab showed modest activity with a partial response rate of 20% (five out of 25 patients) in PD-L1+ mesothelioma, with responses being prolonged.

Method:
Section not applicable

Result:
A previously well 69 year old male with a history of industrial asbestos exposure presented with increasing dyspnoea over a period of several weeks. His ECOG PS was two. His CT scan showed significant pleural rind and nodularity together with a small pleural effusion. A core biopsy confirmed biphasic mesothelioma. After three cycles of cisplatin and pemetrexed the patient had achieve a partial response by modified RECIST and resolution of his symptoms. However, after a further two cycles the tumour had progressed. The patient then received two cycles of pembrolizumab at a dose of 2mg/kg (self-funded). Imaging showed minor radiologic progression after two cycles. In the face of symptomatic deterioration the patient elected to cease active anticancer therapy. The patient returned after a three month period with an improvement in symptoms and a reduction in disease burden on imaging. Palliative radiotherapy was instituted to a single large lesion, and pembrolizumab was recommenced. The patient has shown further interval reduction in disease over a four month period, seven months since the original treatment with pembrolizumab, with ongoing response maintained at ten months.

Conclusion:
Atypical response patterns to immunotherapy in solid tumours are described, but are uncommon. Our patient showed both radiographic progression and symptom deterioration and hence stopped treatment in view of the natural history of mesothelioma. However, he has achieved a late response which has been sustained. It is important for clinicians to monitor patients after presumed progression on immunotherapy due to this phenomenon. Pseudoprogression has not previously been reported with pembrolizumab in mesothelioma. It has been described in the Phase II NivoMes trial using nivolumab, with three patients out of 38 showing this response pattern. The availability of paired biopsy specimens from a number of patients in the NivoMes study may allow for this phenomenon to be explored further.

Background:
Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy. Multidisciplinary treatment including surgery, radiation therapy and adjuvant chemotherapy has been established as the cornerstone of management prolonging progression free survival (PFS). Although beneficial, this treatment strategy has morbidity and mortality. Therefore, selection of patients who benefit from this treatment strategy is crucial for maximizing clinical benefit.

Method:
A random forest tree model was build for the prediction of response to first line chemotherapy among Hispanic patients with MPM. Variables evaluated included sex, age, ECOG performance status, smoking history, exposure to asbestos and histology. Based on these characteristics, patients were classified by responders (partial or complete response) and non-responders (stable disease or disease progression). In order to validate the results, a random subset of 70% of the sample was used to construct the model and the remaining 30% was utilized as an independent validation cohort. Predictions were compared to each patient’s treatment response and operational characteristics for the validation cohort model and receiver operational curves were computed.

Result:
A total of 153 patients were included. Median age was 59 years old (r, 33-84), 60 (39%) were females, 127 (83%) had an ECOG performance score of 0-1 and 127 (83%) had an epithelioid histological subtype. In terms of expositional hazards, 107 (70%) were smokers (24% current/46% former), whereas 61 (40%) presented active exposure to asbestos. In terms of survival, median overall survival (OS) was 25 months (95%CI 23.4-29.4) and median PFS after first line chemotherapy was 6.97 months (95%CI 5.83-8.57). An objective response was observed in 74 patients (48%; complete response in 7/5%). In terms of operational characteristics, the validated model obtained a 0.992 AUC, a sensitivity of 100% and a specificity of 95% for detecting responders and non-responders to first line chemotherapy.

Conclusion:
Selection of responders to first line treatment based on clinical variables can accurately be achieved. These results could lead to better selection of Hispanic patients for aggressive and morbid treatments.

Background:
The aim of this study was to identify predictors of overall survival (OS) after pleural palliative procedures in patients with malignant pleural effusion (MPE).

Method:
Data was collected from our database between August 2013 and December of 2016 of patients with MPE. All patients were followed-up at least 30 days after the pleural procedure. Collected data included basic demographics, American Society of Anesthesiologists (ASA) physical status classification, performance status according to the Eastern Cooperative Oncology Group (ECOG) score, number of metastatic sites, hematological parameters, including white blood cells (WBC), number of neutrophils and lymphocytes, neutrophil/lymphocyte ratio (NLR), red blood cells (RBC) and platelets/lymphocyte ratio, in addition to body mass index (BMI) on the day before surgery. The influence of the primary tumor site was also assessed. During the period after the palliative procedure, we evaluated the volume of drained liquid, the type of palliative procedure performed, recurrence of pleural effusion, the presence of neoplastic cells in the pleural fluid, in addition to the biochemical profile including pleural fluid pH, levels of adenosine deaminase (ADA), total protein, albumin, glucose, lactate dehydrogenase (DHL) and the proportion of lymphocytes in pleural fluid. We also evaluated the presence of pleural thickening and pulmonary infiltrate through chest computed tomography. To analyze OS, patients were divided into two groups. Group I included OS greater than 30 days and Group II included OS shorter than 30 days. Prognostic factors for survival were identified by univariate analysis, using Fisher's exact and Student's T-Test. Subsequently, the significant variables were entered into a multivariate logistic regression analysis (p < 0.05).

Result:
A total of 208 patients were included in the analysis, 36,5% were male and the median age was 62 years. Median follow-up time for overall surviving was 127 days. The primary tumors were lung 39,9%, breast 29,3%, gastrointestinal 13%, gynecological 8,7% and others 9,1%. Factors affecting OS in univariate analysis were: procedure, ECOG, pulmonary infiltrate, albumin, protein, neutrophil, hematocrit and hemoglobin in peripheral blood. At the multivariate analysis, albumin (p=0.03), ECOG 3 e 4, hematocrit and pulmonary infiltrate with p<0.001 were identified as independents predictors of OS.

Conclusion:
Patients with MPE who presented pulmonary infiltrate, albumin < 2,5, hematocrit < 35, ECOG 3 and 4 were significantly associated with shorter survival. The identification of those prognostic factors may assist the choice of the optimal palliative support.

Background:
The Institute of Medicine (IOM) 2013 report recommends that supportive oncology care start at cancer diagnosis; the Commission on Cancer (CoC) Standard 3.2 requires distress screening and indicated action. The Coleman Supportive Oncology Collaborative “Patient Screening Questions for Supportive Care” tool was used to investigate the relationships between demographic/diagnostic data and screening scores.

Method:
Lung cancer patients at the University of Illinois Cancer Center were screened using the following Coleman Foundation tool shown below: Figure 1 Data was collected on an Excel spreadsheet and statistically analyzed.



Result:
We performed initial screening on 138 lung cancer patients. Demographics are shown in table below: Figure 1 Statistically signifcant correlations were found with the following: --Gender and racial/ethnic minority status correlated with distress/concerns over diagnosis and treatment. --Type of medical insurance correlated with distress/concerns over nutrition (food insecurity) and physical activity.



Conclusion:
Introduction of distress screening tool facilitated identification of some care needs such as patient education and counseling, nutrition services, and physical therapy. Moreover certain demographic groups have especially high burdens in some specific patient concern areas. Our next step is to expand distress screening to determine longitudinal trends, expand supportive oncology services to meet our patients’ needs, and to assess impact on unplanned ED visits and patient outcomes.

Background:
The National Lung Screening Trial showed that annual screening with low-dose computed tomography (LDCT) in high-risk patients reduced lung cancer mortality by 20%. The United States Preventative Services Task Force (USPSTF) now recommends lung cancer screening (LCS) for high-risk individuals. However only about 10% of eligible individuals are referred for LDCT possibly in part due to a lack of familiarity among primary care physicians with LCS guidelines. In this analysis, we sought to obtain a baseline acumen of providers’ knowledge and awareness about LCS and develop a series of interventions including embedding USPSTF criteria into electronic medical record (EMR) ordering to educate providers and facilitate more effective use of LCS for high-risk patients.

Method:
A Lung Cancer Screening Program was started in 2015 led by a nurse practitioner. Internal medicine residents at the University of Illinois – Chicago (UIC) General Medicine Clinic (GMC) were surveyed using paper questionnaires. The survey included 6 questions on USPSTF LCS guidelines. Next, educational efforts were addressed through a lecture, email reminders, and informational clinic flyers. Finally the EMR order set was updated to include USPSTF criteria directed ordering. The number of appropriately ordered screens through GMC was tracked monthly. A post-intervention survey was distributed to evaluate if providers’ knowledge was improved by these interventions.

Result:
Fifty-three IM residents were surveyed regarding LCS guidelines appropriate for LDCT screening. Of the respondents, 87% knew the correct test for screening was LDCT, 66% knew only smokers with >30 pack year history were eligible, 45% knew the minimum age criteria (55 years-old), 28% knew the maximum age (80 years-old), 42% knew interval to re-order screening for a negative test (1 year), and 38% knew the maximum time since quitting (15 years). Following the initial interventions there was an increase in the rate of appropriately ordered LDCT screening tests ordered through GMC clinic (from 6.8 per month [May 2016 to September 2016] to 10.8 per month [Oct. 2016 to Apr. 2017]). Post-intervention knowledge assessment is underway and will be presented.

Conclusion:
Although LCS is recommended by USPSTF, there are gaps in knowledge about eligibility criteria among internal medicine residents. We present data that suggests using educational interventions and changes in EMR to increase awareness and knowledge is associated with an increase in appropriate usage of LDCTs for LCS. Ultimately, we plan to broaden these interventions to additional primary care clinics (eg., Family Medicine, Pulmonary) to improve proper use of LCS at our institution.

Background:
Globally, lung cancer is the second most common cancer diagnosis and the leading cause of cancer death (WHO, 2017). Over the last decade, many efforts have focused on lung cancer prevention, early diagnosis, and finding more effective treatments. In the last two years, the FDA approved of a new class of medications called checkpoint inhibitors or immunotherapy, with proven efficacy in treating advanced lung cancer and several other malignancies. These drugs incite the immune system, resulting in unique immune-related adverse events (irAEs) which are difficult to diagnose, challenging to manage, and potentially life threatening if not properly assessed and managed. Diagnosis of irAEs are typically made on exclusion. It is vital that the medical team and supportive services have current and accurate knowledge on these therapies when patients present for work up during flare-ups.

Method:
A needs assessment survey was given to St. Joseph Hospital Emergency Care Center (ECC) providers and Registered Nurses at a department staff meeting. A one page pre in-service survey was administered in English only, followed a brief in-service, and a post in-service survey immediately followed. The Pre and post survey was used to evaluate effectiveness of teaching. Sample size: 20 MD’s or PA’s and 65 NP’s or RN’s. Selected questions assisted in identifying knowledge deficits among St Joseph Hospital ECC physicians and registered nurses. We were able to evaluate the effectiveness of teaching, and obtained feedback on the value of implementing an immunotherapy patient identification card. Knowledge of immunotherapy side effect management was measured with an identical pre and post in-service survey. The survey contained 5 items that measured the individual’s current knowledge/comfort with managing immunotherapy side effects for oncology patients receiving immunotherapy who are evaluated in St. Joseph Hospital Emergency Department. The questions were developed in conjunction with our current and prior Thoracic Oncology Program Medical Directors.

Result:
Data was analyzed with the Wilcoxon Statistic Responses. We identified a significant knowledge gap by our ECC providers at our institution. These providers are often the first to assess irAEs when patients present to the hospital with significant medical issues. Teaching intervention was effective as evidenced by post test results.

Conclusion:
IrAEs is a vital and relevant topic for our patient populations. ECC providers and our multidisciplinary providers are supportive of introducing Immuno-Oncology patient wallet cards and further education on Immunotherapy. Future projects include implementation of ISLAC’s irAEs management guidelines.

Background:
Patient and public involvement helps us understand and improve healthcare and treatments. A national UK group incorporating patient and carers who have had experience of thoracic surgery was developed in 2016. Involving this group could enhance thoracic surgery research. The aim of this study was to determine from the patient and carer perspective what could be improved with the thoracic surgery pathway to increase satisfaction and care thus enhancing clinical outcomes.

Method:
15 patients and carers from the national Thoracic surgery PPI group were sent a questionnaire via post. This consisted of 10 open ended questions regarding the service, education and advice they received before and after their lung surgery. They were also asked to comment on their experience as an inpatient, at the point of discharge and provide any suggestions for improvement. The questions were semi structured which allowed flexibility to follow up responses. Each questionnaire was analysed using phenomenological approach in order to gather a deep understanding of the patients and carer’s experiences through an inductive method.

Result:
Three themes were gathered from this audit; ambiguity regarding information; continuous need for reassurance, reflection, interpretation, and finally psychological impact. Overwhelmingly patients felt they needed additional advice and information to cope with the physical and more importantly mental changes which affected their daily lives following thoracic surgery.

Conclusion:
It is evident that patient and public involvement in developing ideas for further research in thoracic surgery is invaluable. Their insight and experience can assist healthcare professionals make appropriate improvements to the service for the benefit of future patients. From this audit it is apparent that receiving sufficient information and advice is vital to patient to managing the surgical journey and enhance recovery, interventions to support patients mental health would be of benefit to the patients. In order to achieve further in depth and detailed understanding of patient experiences post thoracic surgery, qualitative methods such as focus groups or interviews should be conducted with a larger sample size.

Background:
Erlotinib can cause skin toxicity in non-small cell lung cancer patients. This open-labeled phase II, efficacy-finding study evaluated the efficiency and safety of Pistacia terebinthus soap in patients with non-small cell lung cancer who developed erlotinib induced skin toxicity.

Method:
Patients who received erlotinib and developed Grade 2 or 3 skin toxicity were treated twice daily with a soap made of oil extracted from Pistacia terebinthus. During treatment, no topical or oral antibiotics, corticosteroids or other moisturizers were used. Patients were examined 1 week later and their photographs were taken.

Result:
Fifteen non-small cell lung cancer patients who developed skin toxicity while receiving erlotinib were included into the study. Twelve patients were male and the median age was 55 (45-70). Forty percent of the patients (n:6) had Grade 3 skin toxicity. Complete response rates in patients with Grade 2 and Grade 3 skin toxicities were 100 and 33%, respectively. In the remaining patients with Grade 3 toxicity the skin toxicity regressed to Grade 1. The objective response rate was 100%, and no delay, dose reduction or discontinuation of erlotinib treatment due to skin toxicity was necessary. Skin toxicity reoccurred in all patients when patients stopped administering the soap and therefore they used it throughout the erlotinib treatment.

Conclusion:
Pistacia terebinthus soap seemed to be used safely and effectively in the treatment of skin toxicity induced by Erlotinib in non-small cell lung cancer patients.

Background:
We sometimes experience unexpected sudden death (USD) of in-hospital patients, including the patients with lung cancer. However, information of sudden death of the patients with cancer is limited. The aim of this study is to see the prevalence and the tendency of the patients with lung cancer who died unexpected sudden death.

Method:
This is a cross sectional study. Those who had lung cancer and died at our hospital from Jan 1st to Dec 31st in 2015 were enrolled. Clinical data, such as age, gender, type of lung cancer, department of chief physician (Palliative care physician or not), place of death (palliative care unit or not), duration between the last chemotherapy and death, symptom (dyspnea, appetite loss, and edema), and blood test (number of lymphocyte, Alb and CRP) were corrected. Unexpected sudden death was defined as the death of which symptom occurred within 1 day without expectance. Patients were divided into two groups, expected death (ED) group and USD group and compared with their background information.

Result:
78 subjects were reviewed and their average age at death was 72.9. 54 were male and 24 were female. The proportion of non-small cell carcinoma, small cell carcinoma, and undetermined subject were 71.8%, 6.4%, and 21.8%, respectively. 9.0% (7/78) of them died unexpectedly. Non-specialist of palliative care, dying in general ward, and good appetite were significantly associated with USD. There were no significant different between the two groups in other factors.

Conclusion:
Our results emphasize the difficulty of “expecting Unexpected SD” and we have to recognize the fact that almost 10% of the patients with lung cancer died unexpectedly.

Background:
Most of lung cancer patients diagnosed in advanced stage. The reasons for the delay of the diagnosis might be from patient and/or health care system. Currently, Indonesia, as a developing country in Asia, has National Health Insurance System (Jaminan Kesehatan Nasional) of which the patients is feasibly referred to the referral hospital without worrying the cost. In Persahabatan Hospital-the National Referral for Respiratory Diseases many cases have diagnostic delayed that might contribute to the prognosis. We had been conducting a study to evaluate diagnostic time and diagnostic cost to diagnose lung cancer.

Method:
We conducted an observational study in Persahabatan Hospital Jakarta of which newly diagnosed lung cancer patients were reviewed. We evaluated the time and cost needed from the first visit until definitive diagnosis by histopatology obtained. We also evaluated the factors that have correlated with time and cost of lung cancer diagnosis.

Result:
One hundred and ten subjects were enrolled in this study. Eighty four (76,36%) were male and 26 (23,64%) were female. The median age was 57 years old with range 26 to 86 years old. Data have shown that 53 (48,2%) subjects were diagnosed under target time ( less than 2 weeks) but 57 subjects (51,8%) had diagnostic time more than 2 weeks. The median time of diagnostic was 15 days with the range of 1 to 68 days. Diagnostic delay was correlated with: early stage of the diseases, good performance status, no financial resource. The median cost of diagnosis was 13.025.381 Rupiahs ( around 1000 US$) with range Rp. 1.083.000,- to Rp156.285.000,- ( <100US$ to 11.000 US$). Subject who came with advanced stage, poor performance status, had complication of lung cancer and reffered to private hospitals had higher diagnostic cost.

Conclusion:
Median diagnostic time of lung cancer in Persahabatan Hospital Jakarta Indonesia was 15 days ranging from 1 to 86 days. Diagnostic time correlated with stage at admission, performance status at admission and financial support. The median cost of diagnosis was Rp. 13.025.381,- ( around 1000 US$) with the range of Rp. 1.083.000,- to Rp156.285.000,- ( < 100US$ to 10.000 US$). Cost of lung cancer diagnosis correlated with stage at admission, performance status at admission, source of financial support and complication related to lung cancer.

Background:
Established in 2001, the Global Lung Cancer Coalition (GLCC) is the international 'voice' of lung cancer patients. Comprised of 35 non-government patient organizations in 24 countries and the UK, nearly half of member organizations are run by fewer than five staff or are completely volunteer-run. Several meet the criteria of developing countries under the United Nations definition. The option of immunotherapy treatment is still relatively new in lung cancer and smaller, under-resourced member organizations have neither the expertise nor capacity to create credible educational materials on such a complex subject. The goal of this project was to offer information on immunotherapies to educate the global lung cancer community.

Method:
Created by coalition member representatives and reviewed by medical experts, the Immunotherapy and Lung Cancer factsheet provides an overview of immunotherapies and how they work. It has been professionally translated into the 17 primary languages of GLCC organizations and is available on the GLCC website. Member and non-member organizations and individuals can download the factsheet to help patients all over the world understand this new treatment option for lung cancer.

Result:
In the first six months after the October 2016 re-launch of the GLCC website, the factsheet was downloaded 276 times. At the December 2016 annual in-person meeting of GLCC, the coalition voted to prioritize and expand the effort to produce and translate additional educational materials. GLCC members are currently working on lung cancer screening and smoking cessation materials that will also be translated.

Conclusion:
An international coalition can take the lead in providing not just members but the broader global lung cancer community access to resources otherwise unavailable to them. Available in Chinese, Japanese, Danish, Slovenian, Dutch, Bulgarian, Swedish, German, Spanish, Italian, French, Norwegian, Turkish, Hebrew and English, the Immunotherapy and Lung Cancer factsheet, as well as future materials, are available to individuals, cancer providers and organizations from anywhere in the world to download, print and distribute.

Background:
A lung cancer diagnosis is devastating and patients are often left in shock and seeking trusted resources. The Addario Lung Cancer Foundation (ALCF) provides patient education and support resources, including the patient education handbook. The handbook is a comprehensive resource on lung cancer presented in an easy-to-navigate format, written for the general public, produced in multiple languages and updated to keep pace with emerging advancements. Previous studies have shown that health literacy is correlated with patient engagement and outcomes. The handbook fills a void for patients by providing physician-vetted information on all aspects of lung cancer diagnosis and treatment options.

Method:
Two studies were conducted to assess the value of the handbook to patients and nurse navigators. The first study was a qualitative market research study that included a total of 26 patient interviews, conducted by an independent market research firm in a blinded format. The second study was the COE Impact Study which assessed the usage of ALCF resources by 15 Centers of Excellence (COE) members (a network of community hospitals) through an online survey format.

Result:
Overall, patients had positive ratings for all ALCF resources and rated the handbook highest on a 1-5 point scale system (4.4) among the resources. Patients commented that the handbook is a “one-stop-shop” for everything they need to know about a lung cancer diagnosis. Patients noted it would be most valuable to have at the time of diagnosis but that it can help at any point in their patient journey. It delivers information in a straightforward way, mapping out treatment options and next steps and empowering patients to help them manage side effects and related lifestyle issues. Nurse navigators also rated the handbook highest among ALCF patient resources and many make the handbook part of the diagnosis conversation with each patient.

Conclusion:
The patient education handbook is a valuable tool for patients and nurse navigators, especially at diagnosis when the need for trusted information is greatest. Opportunities exist to continuously improve the patient education handbook including, reformatting it to be modular, coaching patients on how to use the information to dialog with their physicians and training nurse navigators on how to use the book when they first become a COE. ALCF hopes to reach and empower as many lung cancer patients as possible with valuable and accessible information that will guide their treatment options.

Background:
Lung cancer (LC) is frequently associated with interstitial lung disease (ILD). However, there are few reports about the frequency or prognostic impact of LC in the ILD patients.

Method:
Patients diagnosed with ILD at Tosei general hospital, from January 2008 to August 2015 were retrospectively reviewed, and a total of 1070 patients with ILD had complete clinical and follow-up data.

Result:
Of the 1070 subjects, 65.8% were male, and the mean age was 68 years. Prevalence of histologically proven lung cancer was 5.6% (n=60). Of the 295 patients with idiopathic pulmonary fibrosis (IPF), 491 with Unclassifiable IIPs (UC-IP), 193 with collagen vascular disease IP (CVD-IP), 6.1% (n=18), 6.1% (n=36) and 2.6% (n=5) were affected by lung cancer. The most frequently encountered histologic types of carcinomas were Adenocarcinomas (n=23, 38%), and squamous cell carcinomas (n=21, 35%). Small-cell lung cancer was encountered for eleven cases (18%). Survival in patients with ILD-LC was significantly worse than in patients with ILD without LC (median survival, 39 months vs 96 months; P<0.001). In patients with UC-IP and with CVD-IP, survival in patients with LC was significantly worse than in patients without LC. However, there was not a significant difference in survivals in patients with IPF (median survival, 42 months vs 54.6 months; P=0.35).

Conclusion:
Prevalence of histologically proven LC was 5.6%. The most frequently encountered histologic types of carcinomas were Adenocarcinomas and squamous cell carcinomas . Survival in patients with LC was worse than without LC. However, in IPF patients, there was not significant difference.

Background:
Pleurodesis is often used to prevent re-accumulation of malignant pleural effusions (MPE). Intrapleural urokinase (IPUK) therapy facilitates lung re-expansion for patients with loculated MPE or trapped lung and allows subsequent pleurodesis. The MPE management has been traditionally regarded as a symptomatic treatment with rare mention of its impact on survival. Our preliminary study involved 26 patients showed successful pleurodesis translates into a longer survival. (BMC Cancer 2016;16:463) The successfully induced inflammatory response by sclerosing agent is supposed to prohibit tumor invasion and metastasis.

Method:
Part I. Three hundred and eighty-nine consecutive patients with symptomatic MPE underwent minocycline pleurodesis with (n = 184) and without (n = 205) antecedent IPUK therapy between September 2005, and August 2015, were recruited for pleurodesis outcome and survival analysis. Part II. The pleural fluid pro-inflammatory (IL-6, TNF-α), or anti-inflammatory (IL-1β, IL-10, TGF-β) cytokines before and after pleurodesis in fifteen patients with MPE between September 2015 and April 2016 were measured using Bio-Plex® Multiplex assays and correlated with the pleurodesis outcome and patient survival.

Result:
Part I. Patients numbering 109 (59.2%) responded to the IPUK therapy. The success rate of the subsequent pleurodesis was similar to that of the simple pleurodesis group (70.5% vs 69.0%; p = 0.804). In both groups, the patients who succeeded pleurodesis had a longer survival rate than those that failed (median, 259 vs 102 days; p < 0.001 and 414 vs 100 days; p < 0.001 respectively). Multivariate analysis showed that successful pleurodesis was an independent prognosticator (hazard ratio, 0.374; p < 0.001 and 0.271; p < 0.001 respectively). The differences remained when lung and breast cancer patients were studied separately. Part II. After instillation of sclerosing agent, pleural fluid IL-1β and IL-10, with a lesser degree were elevated in the group of successful pleurodesis. There was no discrimination in the TGF-β1, and IL-6 level between those succeeded and failed pleurodesis. No consistent change of TNF-α was observed in either group.

Conclusion:
Successful pleurodesis translates into a better survival rate promotes performing pleurodesis on lung re-expansion. The selective elevation of anti-inflammatory cytokines following pleurodesis suggests an anti-tumor effect. The change of TGF-β1 correlated with its dual role in cancer. While chronic inflammation might promote tumor formation, therapy induced acute inflammation might well hamper the process, and is indeed used therapeutically to inhibit tumor. Further studies are warranted to clarify the mechanism and provide opportunities to develop novel therapeutic strategies.

Background:
Breathlessness is a common, debilitating symptom associated with both COPD and lung cancer. Opiates remain the mainstay of treatment for breathlessness in oncology.

Method:
Lung cancer patients were prospectively enrolled in this single-centre, open-label, randomised controlled trial. Eligible patients met British Thoracic Society diagnostic criteria for COPD, had a visual analogue score (VAS) dyspnoea ≥ 4 and had other reversible causes for breathlessness excluded. Patients were randomly assigned (1:1) between the intervention arm of salbutamol 100 mcg, 2 puffs QDS and tiotropium 18 mcg OD +/- salmeterol 50 mcg/fluticasone 500 mcg 1 puff BD (if FEV~1~ <50% predicted) in combination with best supportive care (BSC) or to BSC alone (control). Control arm patients could continue on any short-acting bronchodilators and BSC included oral morphine and/or benzodiazepines. Patients underwent spirometry, 6 minute walk test (6MWT), VAS dyspnoea and quality of life questionnaires (QOLQ) at baseline and after 2 and 4 weeks. The primary endpoint was the proportion of patients with ≥ 2 point improvement in VAS dyspnoea at 4 weeks.

Result:
Among the intention to treat population (n=63), 53 patients (84%) had NSCLC and 10 (16%) had SCLC. The median baseline VAS was 7.1 and the median baseline FEV~1~ was 1.5L (63% predicted). The primary endpoint response rate (RR) was higher in the intervention group n= 32 [RR: 53% (95%CI 35% to 71%)] than in the control group n= 31 [RR: 26% (95% CI 12% to 45%) p = 0.02]. Figure 1 There were no statistically significant differences between the groups for change in 6MWT or QOLQ between baseline and the 4 week assessments.



Conclusion:
For patients with co-existing COPD and lung cancers, VAS dyspnoea is significantly improved by the addition of inhaled therapies to best supportive care. This study highlights the importance of diagnosing and treating COPD in all lung cancer patients.

Background:
Radiation pneumonia is the most serious complications after radiotherapy of thoracic tumor. We use the Maidong extract as essential prescription, to assess its prevention and control effect of radiation pneumonia, and to explore its possible mechanism.

Method:
60 C57BL/6 mice were divided into:(1) blank control group, (2)merely irradiated group, (3)Chinese medicine (Maidong) group, and (4)western medicine (dexamethasone combine cefalexin)group, each group of 15 mice. Maidong extract was given 1 times per day to the mice of Chinese medicine group, dexamethasone and cefalexin were given 1 times per day to the mice of western medicine group by intragastric administration from 4 days prior to the irradiation day, last for 2 weeks; merely irradiated group and blank control group were given physiological saline instead. In addition to the blank control group, other groups were given chest a 6MV-X-ray single-wide irradiation of 18Gy.Each group randomly sacrificed 5 mice at 24 hours, 4 weeks, 12 weeks after irradiation. Took the blood, left lungs into homogenate and fixed right lungs in formaldehyde solution for research.

Result:
1, Compared to the merely irradiated group, the level of plasma IL-6(P<0.01), TNF-α(P<0.05)and TGF-β1(P<0.01), hydroxyproline(P<0.05) and MDA (P<0.01)content of the lung tissue in the Chinese medicine group mice were significantly reduced, SOD activity was significantly enhanced (P<0.01),and the expression of MMP-2(P<0.01) and TIMP-2(P<0.05) proteins were significantly reduced. 2, Compared to the western medicine group, the level of plasma IL-6, hydroxyproline content and SOD activity of the lung tissue, the expression of TIMP-2 protein didn’t show significant difference(p>0.05); because of the increase of the level of plasma TNF-α and TGF-β1(P<0.05), MDA (P<0.01)content of the lung tissue in western medicine group mice,the Chinese medicine group were significantly different at 12week; the expression of MMP-2(P<0.05) protein the Chinese medicine group were significantly higher than western medicine group at 4week, but didn’t show significant difference at 12week.

Conclusion:
Maidong has certain effect on the prevention and control of radiation pneumonia, the preventive effect may be achieved through the many kinds of approaches: Maidong is relatively more enduring than dexamethasone combine cefalexin, and Maidong had less side effects.

Background:
To demonstrate the possibility of diagnosing centrally located metastases of the lung cancer in the mediastinum by means of laser incision of right main bronchi followed by the cryo probe biopsy.

Method:
The 50-year–old patient had been admitted to the Thoracic Surgery Department due to mediastinal lymphadenopathy confirmed by computed tomography.He complained dysphagia. No tumors of the lungs were seen in the computed tomography.The standard diagnostic methods to determine the ethiology of the mediastinal mass failed.The primary mediastinal lymphoma was suspected, therefore, it was decided to collect a representative tissue samples of the mediastinal mass .The procedure was performed under general anesthesia. The patient was intubated with the rigid bronchoscope. EBUS confirmed mediastinal mass and transbronchial needle aspiration biopsy was performed to take a cytology sample and mark the place of the laser application in the bronchial tree. The laser incision of the right main bronchi wall was performed with using a flexible bronchoscope. The 1,9 mm cryo probe was introduced through the incision into the mediastinal mass and the representative tissue samples were collected.

Result:
The small cell lung cancer was confirmed in the EBUS cytology biopsy as well as mediastinal mass tissue saples collected by the cryo probe. The post bronchoscopy course was uneventful. The bronchoscopy performed 7 days after the first procedure revealed the laser incision of the right main bronchi wall healed well.

Conclusion:
The cryo biopsy of the mediastinal mass tissue is possible and it can be a valuable option to make a diagnosis of the mediastinal mass including lung cancer metastases or lymphomas.

Background:
Due to recent technical advances in bronchoscopy and improvement of molecular targeted therapy, physicians may perform diagnostic bronchoscopy (DB) even in lung cancer patients with poor general status. As for the safety in diagnostic bronchoscopy, there have been little evidence of perioperative mortality, especially in lung cancer patients. We aimed to evaluate the short-term all cause in-hospital mortality not only for adverse events of bronchoscopy, but also for any cause in lung cancer patients who underwent DB.

Method:
We retrospectively collected data of lung cancer patients who underwent bronchoscopy and who were hospitalized between July 2010 and 31 March 2014. Bronchoscopy without taking samples for histology nor cytology, bronchoscopy under mechanical ventilation and therapeutic bronchoscopy were excluded from DB in our study. The primary outcome of this study was all-cause in-hospital mortality within 7 days after DB. We accessed factors, including patients’ ADL (Barthel index) score, comorbidities at admission, and lung cancer staging.

Result:
A total of 77,755 adult lung cancer cases in 954 hospitals underwent DB in inpatient settings. Multivariable logistic regression analysis of factors associated with all-cause mortality within 7 days after DB showed that mortality was associated with sex (adjusted odds ratio (OR); 0.58, (95% CI; 0.44–0.76)), Barthel index score (5.70, 4.48–7.25), lung cancer stage III (3.65, 1.35-9.83)or IV (4.77, 1.89-11.99), Chronic heart failure (2.76, 1.92-1.34), and Interstitial pneumonia (2.58, 1.79-1.24).

Conclusion:
All-cause in-hospital mortality of lung cancer patients after DB were significantly associated with ADL score, lung cancer stage and comorbidities.

Background:
Characteristics of CT image, including tumor size and component were correlated to survival. However, most studies discuss the survival impact of image characteristics in early clinical stage populations. No articles were discussed the issue from the view of pathology stage, ie. actual disease presentations of non small cell lung cancer patients who presented as resectable disease. The aim of study was to analyze radiologic and pathologic findings of non small lung cancer patients who received curative resection in order to clarify he clinical correlation between image characteristics and survival impaction.

Method:
From 2010 January to 2014 May, 440 patients who underwent curative resection, ie. anatomic resection and mediastinal lymph node resection, were included and medical record were reviewed retrospectively. Chest CT characteristics, including tumor size and consolidation-tumor ratio, were re-evaluated and re-measured by radiologists. The correlation between image and pathology characteristics and its survival impaction were analyzed.

Result:
We identified tumor size presented in CT and pathologic measurement were highly coincidence. (p-value<0.001) The presentation of pure GGO and GGO predominant lesion were adenocarcinoma ( p< 0.001) Majority of these lesions ( 61/76, 80.2 %) were well differentiated. ( p<0.0001). In addition, pure GGO lesion has less risk for visceral pleura (p < 0.0001), angiolymphatic invasion (p < 0.002), and lower risk with N1 lymph node metastasis (p = 0.004) In addition, we found excellent disease free and disease free survival for patients who was identified GGO predominant lesion with size ≤ 2cm. (Figure 3) The difference of disease free (p= 0.0032, log rank test; Figure 3A) and overall survival (p= 0.0066, log rank test; Figure 3B) of these four subgroups was statistically significance. Figure 1



Conclusion:
Non small cell lung cancer patients who presented with ground glass opacity were corrected with well differentiated adenocarcinoma. In addition, less visceral pleura invasion, less angiolymphatic invasion, and less intrapulmonary lymph node metastases risk were also identified. Our results showed lung cancer patients who presented as GGO predominant lesions and size less than 2 cm may had excellent disease free and overall survival.

Background:
Perfusion CT parameters have showed promising results for evaluation of tumor response and follow-up. However, clinical implications in patients with lung cancer have been relatively limited due to the fact that perfusion CT is performed while the patient is breathing and high radiation dose. Therefore, the purpose of this study was to evaluate the effects of respiratory motion correction on perfusion assessment of lung cancer in a reduced dose perfusion CT using a 16-cm coverage scanner.

Method:
Eighty four patients with primary lung cancer who underwent a reduced dose perfusion CT (80 kVp, 80 mA) were enrolled in this study. Each perfusion CT study included 25 repeated dynamic CT scans obtained using the volume perfusion software and was reconstructed with hybrid iterative reconstruction at a strength level of 50%. Two observers measured blood flow (BF), blood volume (BV), and permeability of the entire tumor with and without the use of non-rigid registration algorithm. Single-measure intraclass correlation coefficients (ICC) were calculated and interobserver reproducibility for parameters obtained with two different manners were assessed through Bland-Altman analyses.

Result:
CTDIvol obtained with each of the dynamic perfusion CT in this study was 36.16 mGy and the estimated mean effective dose ranged from 2.02 mSv to 4.0 mSv. Using non-rigid registration, all ICC values for BF, BV, and permeability were increased (0.982~0.994 to 0.988~0.997) compared with those obtained before application of non-rigid registration. All ICC values of lower lung tumor (0.991~0.998) or tumor ≤ 3 cm (0.989~0.998) were higher than those of upper lung tumor (0.925~0.984) or tumor > 3 cm (0.975~0.996). Using non-rigid registration, all 95% limits of interobserver reproducibility were narrowed compared with those obtained before application of non-rigid registration, regardless of tumor location or tumor size, except those of BV for tumors located in upper lung and tumors > 3 cm.

Conclusion:
Perfusion assessment of lung cancer using a reduced dose perfusion CT scan is clinically feasible and application of respiratory motion correction using non-rigid registration can reduce measurement errors.

Background:
Outcomes in Non-Small Cell Lung Cancer (NSCLC) are poor but heterogeneous, even within TNM stage groups. To improve prognostic precision we aimed to develop and validate a simple model for the prediction of overall survival (OS) using patient and disease variables.

Method:
The study population included 1458 patients from three independent cohorts. Associations between baseline variables and OS were estimated in a derivation cohort from a prospective single-centre study (n=695) using Cox proportional hazards regression. Points were allocated to variables based on the strength of association to create the Lung Cancer Prognostic Index (LCPI). Model performance was assessed (by a c-statistic for discrimination and Cox-Snell residuals for calibration) in two independent validation cohorts (n=479 and n=284).

Result:
Three disease-related and six patient-related variables were found to predict OS: stage, histology, mutation status, performance status, weight loss, smoking history, respiratory comorbidity, sex and age. Patients were classified according to predicted LCPI score. Two-year OS rates according to LCPI in the derivation and two validation cohorts respectively were 84%, 77% and 68% (LCPI 1: score≤9); 61%, 61% and 42% (LCPI 2: score 10-13); 33%, 32% and 14% (LCPI 3: score 14-16); 7%, 16% and 5% (LCPI 4: score ≥15). Predictive performance (Harrell’s c-statistics) were 0·74 for the derivation cohort, 0·72 and 0·71 for the two validation cohorts.

Conclusion:
The LCPI contributes additional prognostic information which, in conjunction with other validated tools and evidence based management guidelines, may be applied to counsel patients, guide clinical trial eligibility, or standardise mortality risk for epidemiological analyses.

Background:
Lung cancer screening with low-dose computed tomography (CT) is better than chest X-rays but is non-specific. Accuracy is improved with positron emission tomography (PET), at a cost of additional radiation. We had previously reported on simulated low-dose PET imaging and demonstrated that 10x10[6] net true counts is sufficient to generate images with acceptable diagnostic quality. We now hypothesize that we can maintain image quality with a 92% reduction of fluorodeoxyglucose (FDG) tracer activity from 6 mCi to 0.5 mCi.

Method:
Nine patients have been scanned with two sequential PET/CT scans on the same day. The patient is first scanned with 0.5 mCi FDG and a low-dose CT protocol, followed by a routine PET/CT with 6 mCi FDG. PET data from the standard-dose scan were manipulated to emulate various noise (dose) levels, corresponding to nine pre-defined true count levels. Data were matched to the level of the low-dose scan, to compare noise statistics to a ground truth and to directly validate our methods. The data were reconstructed, with many independent noise realizations, and the images were reviewed. Ten lesions, in seven patients, were identified as having the size and uptake consistent with those found in early disease. For a given count level, the corresponding images were determined to be acceptable if lesion detectability was comparable to that found in the full-statistic image set. Detection performance was determined automatically by machine learning, namely, convolution neural networks trained by 4 previous observer responses.

Result:
Lesion detection accuracy was evaluated in 4458 total image sub-volumes. Regions containing both target lesions (2627 samples) and healthy lung background (1831 samples) were used to assess sensitivity and specificity for the task at all noise levels. The table shows data across the 4 observer models.

Mean Sensitivity & Specificity by True Count Groups

True count/ millions	<0.5	0.5-1	1-2	2-5	5-10	10-20	>20
Mean sensitivity/%	0.35	18.85	62.35	85.40	95.73	96.23	96.42
Mean Specificity/%	6.64	6.93	20.43	66.54	93.55	96.87	98.25

Conclusion:
Low-dose PET can provide good performance for lesion detection within the true count range 5-10×10[6].

Background:
The incidence of primary lung cancer in developing countries has increased and it constitutes the most common cause of cancer related mortality. Some radiological features can be predictive for different histologies and have prognostic utility. One of the features of imaging in the Fleischner Society guideline is common occurrence in the upper lobe with predilection for the right lung.

Method:
A retrospective audit was done to compare the characteristics of primary lung cancer in patients in our environment. Images and patient reports were obtained from our local database archives or from the hospital records. The location of the primary was defined as peripheral if located in the outer third of the lung parenchyma on axial CT or PET/CT images, and defined as central if located anywhere else. Lobe location was also recorded for each primary.

Result:
We reviewed 42 patients with histologically confirmed lung cancer that were referred for PET/CT imaging. The age range was 37- 80 years. Sixty nine percent (n=29) were males 31% (n=14) were females. The most common histologic subtype was adenocarcinoma (48%), followed by squamous cell lung cancer (40%), and small cell lung cancer (12%). Most of the primary pathology were in the right lung (60%, n= 25) as compared to the left lung (40%, n=17). The upper lobes were more commonly affected (64%, n=27), followed by the lower lobes (33%, n=14), and right middle lobe (3%, n=1). Sixty percent (n=25) of tumors were centrally located, of which 64% were of the histologic subtype squamous cell ca. Our findings also showed that 26% (n=11) of patients had metastases to ipsilateral lobes, and 24% (n=10) had metastases to the opposite lung. There were 22% (n=22) of patients that had only nodal metastases and 12% (n=5) had both nodal and visceral metastases. Nineteen percent of patients (n=8) had no evidence of nodal or visceral metastases.

Conclusion:
Our findings conform to those found in literature that primary lung cancer involves the right lung more often and involves the upper lobes more commonly. It also showed that squamous cell lung cancers are mostly central and most adenocarcinomas are peripheral in location.

Background:
Aim of the study was to correlate epidermal growth factor (EGFR) mutation status with computed chest tomography (CT) image patterns at the diagnosis in patients with lung adenocarcinoma.

Method:
Patients diagnosed between January 1, 2015 and March 3, 2017 with available CT and EGFR mutation status were analyzed. The maximal diameter of the nodules, shape (mix, solid) , presence of an air bronchogram and calcification, specula, incision, round shape, central necrosis, pleural connection, UH pre e post were evaluated.

Result:
87 patients (52 males, median age 66 years, range 43-87) were enrolled. 9, 36 and 42 patients had stage II, III and IV, respectively. EGFR mutations were found in 22 patients (25.3%; 1 exon 18, , 15 exon 19 deletions and 6 exon 21 mutations) and were more frequently among females (45.2% versus 18.6% males, p=0.020) and never smokers (77.8% vs 11.8% smokers, p<0.001). The median maximal diameter of the nodules was smaller in mutated patients (30.5, range 15-74 mm) than in wild-type patients (45.0, range 13-110 mm; p=0.010). Tumors with exon 21 mutations were smaller than wild type tumors (p=0.014). Mutations were statistically more frequent in solid pattern (30.6% vs 0 mixt, p=0.010). A higher number of mutations, not statistically significant, were also found in presence of tumors with regular margins (31.9% vs 17.5% spiculati, p=0.14), no incisions (30% vs 5.9% with incision, p=0.059), no central necrosis or calcification (26.3% vs 14.3% with central necrosis or calcification, p=0.67), no calcification (26.3% vs 14.3% with calcification, p=0.67). Median tumor density was 35 UH in wild type vs 40.0 UH in mutated tumors (p=0.29) and 70 UH in wild type vs 80 UH in mutated tumors (p=0.17), before and after contrast, respectively.

Conclusion:
Adenocarcinomas with EGFR mutations were associated with smaller tumors and with solid pattern.

Background:
There is no consensus on the best program for postoperative follow-up and surveillance after curative resection for non-small cell lung cancer (NSCLC) patients at this time. We reported that the diagnostic capability of [18]F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) was high in postoperative NSCLC patients without clinical and radiological evidence of recurrence (ICVTS 2012). However, there were some problems, such as radiation exposure and its cost. The aim of this study was to propose a more feasible follow-up and surveillance program using FDG-PET/CT for asymptomatic postoperative NSCLC patients.

Method:
Between January 2005 and December 2013, a total of 172 NSCLC patients (98 males and 74 females; mean age: 67.8 years) underwent potentially curative operations, and follow-up FDG-PET/CT was performed in patients without clinical or radiological evidence of recurrence for at least once a year in principle. A total of 481 FDG-PET/CT studies were entered and retrospectively reviewed.

Result:
The histological type was adenocarcinoma in 129 patients, squamous cell carcinoma in 36 and others in 7. The pathological stage was Stage 0 in 2 patients, IA in 106, IB in 28, IIA in 15, IIB in 7, and IIIA in 14 (UICC 7[th]. edition). Surgical procedures were pneumonectomy in 5 patients, lobectomy in 139, segmentectomy in 14, and partial resection with a sufficient margin in 14. The mean time interval between the initial surgery and latest follow-up was 49.1 months. During the follow-up period, the mean number of times that FDG-PET/CT was performed per patient was 2.8. FDG-PET/CT correctly diagnosed recurrence in 31 of 32 (96.9%) patients and 41 of 42 (97.1%) recurrent sites. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 96.9, 97.1, 88.6, 99.3, and 97.1%, respectively. In 6 (3.5%) patients, other diseases were detected and treated appropriately. On the other hand, FDG-PET/CT performed within 3 years after the operation detected significantly more FDG-positive lesions compared to after 4 years (10.0 vs. 2.0%, respectively, p=0.007). Additionally, in 147 patients with recurrence after curative operations between 2005 and 2013 in our institute, recurrence occurred in 123 patients (83.7%) within 3 years.

Conclusion:
FDG-PET/CT has a high capability to detect recurrence in asymptomatic NSCLC patients after a potentially curative operation. However, it might be sufficient to perform FDG-PET/CT up until 3 years after the operation. A large scale multi-institutional randomized control trial is warranted to ascertain the benefit of surveillance with FDG-PET/CT.

Background:
“Lung cancer associated with cystic airspaces” is a rare radiological entity that is becoming more frequently encountered on imaging studies and has been gaining more attention since the widespread use of CT for lung cancer screening. The goal of this retrospective study is to investigate and correlate clinical, imaging, histopathological and molecular findings in patients presenting with this type of lung cancer.

Method:
Between January 2014 and April 2017, 13 patients presented at the Multidisciplinary Thoracic Oncology Tumour Board with this rare entity. Clinical, histopathological and molecular data were collected and imaging studies were reviewed for the presence of emphysema, size, morphologic classification and findings on [18]F-FDG-PET.

Result:
Median age at the time of diagnosis was 69 years (53-86 years) with a male/female ratio of 8:5. Ten out of 13 patients were smokers. Eleven patients (11/13) had no previous oncological history. Two patients with previous oncological history both had a history of head-and-neck and stage IA lung cancer. Imaging findings showed emphysema in 7 cases. Four patients had type I, 1 patient type II, 4 type III and 4 type IV morphology. Median diameter for the type I, II, III and IV lesions was 20 mm (17-43), 20 mm, 60 mm (25-67) and 46 mm (37-77) respectively. Lesions were more frequent in the right upper (4/13) and lower lobe (4/13). FDG-PET-scan was available in 11 patients and showed high uptake in all patients who presented with a solid aspect of the associated tumour. Four patients (4/13) presented with stage IV at diagnosis. Other stages varied: IA (4/10), IB (1/10), IIA (1/10), IIIA (2/10) and IIIB (1/10). Adenocarcinoma was found in 11 patients (11/13) and squamous cell carcinoma in 2 (2/13). Molecular genotyping for EGFR, ALK and ROS-1 was available in 10 patients (10/13). None of the patients showed positivity for ALK-immunohistochemistry. A single patient showed an exon-18 mutation in the EGFR gene. One patient showed a translocation at the 6q22 breakpoint of the ROS-1 gene. In one patient, a p.Gly469Ala B-RAF mutation was present. Two patients showed a mutation in the exon 2 of the KRAS gene (exon2 c/35G>C;p.Gly 12Ala and c/35G>T;p.Gly 12Val).

Conclusion:
In this series, 5 out of 10 patients with a “lung cancer associated with cystic airspaces” showed a molecular alteration. This suggests that targeted molecular profiling is mandatory in this subgroup. Larger series are needed to confirm these findings.

Background:
Visualizing the spread of cancer cells in lung cancer surgery is sometimes difficult. γ-Glutamyl-transpeptidase (GGT) is a cell surface-associated enzyme that is overexpressed in various type of human cancers. γ-Glutamyl hydroxymethyl rhodamine green (gGlu-HMRG), an activatable fluorescent probe, is non-fluorescent under a neutral pH and normal cellular environment. However, it becomes highly fluorescent upon reaction with GGT. We evaluated ex vivo fluorescent imaging of lung cancers using the GGT-activatable fluorescent probe.

Method:
Between April 2011 to November 2014, 116 resected cancer cells (91 primary lung cancers, 21 pulmonary metastases, and 4 pleural disseminations) were prospectively included in this study. Each tumor was analyzed by first taking a baseline image before gGlu-HMRG was sprayed onto the freshly resected specimen (termed N0; fluorescent intensity of normal lung, T0; that of lung cancer), and then by taking fluorescent images 30 min after spraying (N30 and T30) with the Maestro In-vivo imaging system (PerkinElmer Inc.). Positive fluorescent activity was defined as follows: in cases where fluorescence was observed only in tumor tissues, ΔN(=N30-N0) < 0 and ΔT(=T30-T0) < 0, in cases where fluorescence was observed in both normal and tumor tissues, ΔN > 0 and ΔT/ΔN > 1.

Result:
Figure 1In primary lung cancer, 61 of 91 (67%) cases rapidly developed fluorescent activity. In cases with pulmonary metastases, 15 of 21 (71.4%) cases showed positive fluorescent activity. Four disseminated pleural nodules all showed positive fluorescent activity (100%). Age, gender, tumor size, tumor marker, histology (adenocarcinoma (Ad) vs. non-Ad, squamous cell carcinoma (Sq) vs. non-Sq), pleural invasion, and angio-lymphatic invasion were not significant factors influencing fluorescent intensity.



Conclusion:
Fluorescence imaging with gGlu-HMRG may become one of the most powerful tools for accurate staging by rapidly detecting cancer cells and thus become highly useful for cancer resection.

Background:
We analysed the correlation between the new pathologic classification of lung adenocarcinoma and radiologic findings of early invasive pulmonary adenocarcinomas versus preinvasive lesions appearing as PGGN on HRCT, and evaluated the values in the diagnosis of pathologic classification of lung adenocarcinoma with PGGN on HRCT.

Method:
Retrospective analysis of 123 lesions (16AAH, 35AIS, 35MIA, 37IA) with PGGN on HRCT with T1N0M0 lung adenocarcinoma or AAH from January 2014 to June 2014 in shanghai chest hospital. There were 93 females and 30 males, with a median age of 58 years old. Statistical relationship between the 2015 World Health Organization Classification of the lung adenocarcinoma and radiologic findings of PGGN were analyzed, then sceened out the best predictors, created a modal and verified it.

Result:
The Pearson correlation coefficient( P<0.05) between pathological types and all CT scan morphologic features showed a significant correlation. The logarithm linear correlation cient showed the CT feathures(lobulation, spiculation, pleural indentation, aterial gathering, bubbles/air bronchogram, shape,margin,internal uniformity) had a positive correlation with pathological types excluding tumor-lung interface. These scale variables as maximum lesion area on CT scan, lesion size in cranial-caudal direction, average density of lesion and the corresponding lung’s average background density were significant correlation with pathological types. Multinomial logistic regression analysis showed that the best predictors were spiculation, internal uniformity, lesion size in cranial-caudal direction,average density of lesion, gender in turn. Then the multinomial logistic regression model was built, a likelihood ratio test showed that 70.7% of the cases were classified correctly overall, and the predicted value of AAH was up to 92.9%. Figure 1



Conclusion:
The HRCT characteristics of PGGN were significant correlated with the new pathologic classification of lung adenocarcinoma. The pathologic types of PGGN should be evaluated by HRCT, and the best predictors were speculation, internal uniformity, lesion size in cranial-caudal direction, average density of lesion and gender.

Background:
Indeterminate lung nodules detected during lung cancer screening with low dose computed tomography (CT) present a challenge in distinguishing between malignant and benign disease. Our aim for this study is to compare the sensitivity and specificity of flour-deoxy-glucose positron emission tomography (FDG-PET), volume doubling time (VDT) and a combination of both in the diagnostic workup of indeterminate lung nodules in lung cancer screening.

Method:
The Danish Lung Cancer Screening Trial (DLCST) is a randomized controlled trial with heavy smokers between 50-70 years of age. The screening group underwent 5 annual rounds with low dose CT scan of the thorax. When a lung nodule was detected, participants could either be referred to diagnostic workup, 3-month follow-up or continue with the screening program. We included participants who had a 3-month follow-up scan. Before the follow-up scan was conducted, the participants received a FDG-PET scan. Nodules that were resected or stable for at least 2 years were included. FDG-uptake was categorized from most likely benign (uptake less than background uptake in the mediastinum) to most likely malignant (uptake as mediastinum or higher). VDT was calculated from nodule volume measurements from two time points closest to the FDG-PET scan date. We used a commercially available and validated semi-automated nodule evaluation software. Based on VDT the nodules were divided into three groups. Regressing nodules (VDT<0), slow growing nodules (VDT > 365 days - less likely malignant) and fast-growing nodules (VDT < 365 days – most likely malignant). Finally, we divided combined outcome into three groups: 1. Both tests suggest benignancy, 2. One of the tests suggest malignancy and 3. Both tests suggest malignancy. We used receiver operating characteristic (ROC) curves to compare sensitivity and specificity for the ability to predict a malignant or benign nodule.

Result:
A total of 87 lung nodules in 76 individuals were included. 68/87 (78%) were solid nodules. 41.5% were malignant. Nodule size ranged between 5 mm – 20 mm in largest diameter. The sensitivity and specificity of VDT alone were 61% and 90% respectively. For FDG-PET the sensitivity was 62% and specificity was 90%. Combined use of both tests showed an improvement in test sensitivity to 82% and a specificity of 79%.

Conclusion:
Combined use of FDG-PET and VDT is recommended in the diagnostic workup of indeterminate lung nodules in lung cancer screening.

Background:
Primary lung cancers show more complicated outline on computed tomography (CT) images of the chest than metastatic lung tumors or benign inflammatory lung disease. This feature is proving to be useful for clarifying the diagnosis of pulmonary nodules. The degree of complexity of pulmonary nodules seen on chest CT images is usually described subjectively by such designations as spiculated, irregular, and so on. Up to now there have been no established methods for evaluating a tumor outline numerically. In this study, we applied fast Fourier transform (FFT) analysis to pulmonary nodules on CT images to evaluate variations in the outlines of primary versus metastatic lesions or benign inflammatory lesions.

Method:
Sequential cases of 72 histologically proven primary lung cancers (group PL), 54 metastatic lung tumors (group MT), and benign inflammatory nodule (group BN) were included in the study. The average ± SD diameters of tumors in groups PL, MT, and BN were 18.9±7.4 mm, 12.2±6.1 mm, and 18.0±5.3 mm, respectively. For the measurements, the outline of each tumor on chest CT images was described using polar coordinates. The data were converted to rectangular coordinates, yielding wave data of the tumor outline. The FFT was then used to analyze the wave data. The complexity index (Cxi) and high frequency percent (HF%) were determined for each tumor. The Cxi was defined as the sum of the amplitude of all harmonics over a fundamental frequency. The HF% was defined as the percent of the high frequency components against Cxi.

Result:
The Cxi was 10.3±6.7 mm, 3.2±2.4 mm, and 8.0±3.8 mm, in groups PL, MT, and BN, respectively. The Cxi was significantly smaller in group MT than group PL (p<0.0001) and group BN (p=0.0003). Cxi was significantly correlated with tumor diameter in each group. Discriminant analysis showed a significant difference (P<0.0001) in Cxi between groups PL and MT with regard to tumor diameter. “Cutoff=0.127*DT+2.23” provided the cutoff value that yielded the highest diagnostic accuracy for distinguishing primary lung cancers from metastatic lung tumors. Use of this cutoff line resulted in a sensitivity of 95.8%, specificity of 81.5%, and accuracy of 89.7%. The HF% was 1.82±2.23%, 3.78±3.93%, and 5.29±1.28, in groups PL, MT, and BN, respectively. The HF% was significantly (p<0.0001) smaller in group PL than group BN.

Conclusion:
Fast Fourier transform analysis of tumor outlines appears useful for distinguishing primary lung cancer from the other diseases.

Background:
Visceral pleural invasion (VPI) is an important prognostic factor for patients with peripheral lung cancer, but its accurate preoperative evaluation with CT is difficult. Pleural tags, which are defined as one or more linear strands that extend from the tumor surface to the pleura, are sometimes seen in peripheral lung cancer that does not abut the pleura. However, studies evaluating the correlation of pleural tags with VPI are limited. The aim of this study was to evaluate the association of pleural tags with VPI of peripheral lung cancer, especially focusing on the type of pleural tags.

Method:
A total of 183 patients were retrospectively analyzed. They underwent pulmonary resection in our hospital between January 2009 and December 2015 for peripheral lung cancer ≦2 cm in solid tumor diameter and dose not abut the pleura. Forms of pleural tag were classified as follows; linear tag, linear tag with soft tissue component at the pleural end, and soft tissue cord-like tag. The relationships between VPI and clinical factors including the forms of pleural tag were analyzed using chi-square for independence tests, and then multivariate logistic regression models were applied.

Result:
Histologically, 23 (12.6%) patients were proven to have VPI. Overlap and multiple forms of pleural tags were frequently seen. Multivariate analysis revealed that tumors with linear tag with soft tissue component at the pleural end had significant association with VPI (p = 0.008). Sensitivity and specificity were 47.8% and 83.8%, respectively, in the prediction of VPI with this type of pleural tag. Presence of multiple linear tags also was associated with VPI (p = 0.036).

Conclusion:
Specific forms of pleural tag can predict VPI of peripheral lung cancer ≦2 cm in solid tumor diameter and dose not abut the pleura.

Background:
Erlotinib treatment is offered to NSCLC patients in a palliative setting also in EGFR wildtype (EGFR-wt) patients because we know that some of these patients will benefit, However, in order to evaluate the effect of treatment, we wait for 8-12 weeks before performing a CT scan, since the effect is rather subtle especially in EGFR-wt patients. The purpose of this study was to evaluate which method for evaluating change in 18F-FDG uptake is the best predictor for survival.

Method:
18F-FDG-PET/CT scans from 56 NSCLC patients (48 EGFR-wt and 8 EGFR mutated) performed before and after 7-10 days of erlotinib treatment were analysed with four different methods for response to treatment including visual evaluation, and three semi quantitative methods measuring % change in SULpeak, SULmax and TLG, with a range of cut-off levels determining response, stable disease and progression. A direct comparison of the semi-quantitative parameters was performed using univariate cox regression, linear regression and ROC analysis for progression free survival (PFS) and overall survival (OS) < the median. Kaplan-Meier analysis was used to estimate PFS and OS for the response categories.

Result:
Both %SULpeak, % SULmax and %TLG were correlated to PFS and OS. The strongest linear correlation was found for %TLG (R=0.51, p< 0.001). The ROC analysis showed the highest AUC for predicting OS for %TLG (0.70 (0.56-0.85) with a sensitivity of 0.68 and a specificity of 079. All the semi-quantitative methods showed a statistical overall difference in PFS for the three response categories at some cut-off levels for %SULmax both at 15 and 25%, for %SULpeak at 20 and 25% and for %TLG at 45/75, 50, 30, 25 and 20% cut-off. Visual evaluation failed to differentiate between response categories. For OS %TLG at 4 different cut-off levels and SULpeak at the three lowest cut-off levels showed a statistical overall difference in OS, both visual and %SULmax did not.

Conclusion:
The choice of method for analysis is not clear-cut, but %TLG as suggested by the PERCIST 1.0 is not inferior to other methods, and visual evaluation seems to be the least sensitive at this very early time-point. A lower cut-off level for discriminating between response categories seems to be relevant, we find that 20-25% change for both response and progression is optimal.

Background:
The use of 18F-FDG-PET/CT is increasing for radiotherapy planning. We wanted to investigate whether 18F-FDG-PET/CT scans at this time-point can be a tool for selecting patients with locally advanced NSCLC who are likely not to benefit from radical chemo-radiotherapy in order to avoid the potentially harmful side effects in patients undergoing futile treatment, by predicting progression free survival (PFS) and overall survival.

Method:
18F-FDG-PET/CT scans before and after 2 cycles of induction chemotherapy (carboplatin/vinorelbine) from 91 patients enrolled in a Danish randomized controlled multicenter study (the NARLAL study) was retrospectively evaluated using visual evaluation. Following the induction chemotherapy patients received radical radiotherapy (66 or 66 Gy) with concomitant vinorelbine treatment as according to the NARLAL protocol. Estimates of median OS and PFS was calculated with Kaplan-Meier analysis for the response categories resulting from the visual evaluation, both considering all four response categories and separate analyses for the SMD and PMR groups. Statistical significance was tested using the log rank test, and a significance level of 0.05 was applied.

Result:
The median OS was 25.3 months (95% CI: 21.0-29.6 months), median PFS was 8.6 months (95% CI: 7.9-9.4 months). Overall survival did not differ for PFS or OS when considering all four response categories (p = 0.424 for PFS and p= 0.245 for OS). Considering only partial metabolic response (PMR) and stable metabolic disease (SMD) no difference for PFS, but we found a median OS of 22.6 (95% CI: 18.9-26.3) months for PMR and 32.4 (28.4-36.3) months for SMD (p=0.036). Stratified by histology, the effect was seen in the adenocarcinomas only.

Conclusion:
The median overall survival in patients with a partial response by 18F-FDG-PET/CT evaluation is shorter than for patients with stable disease, in adenocarcinomas. This is surprising and may suggest a differentiation of the treatment for patients with locally advanced NSCLC.

Background:
In patients with inoperable, locally advanced NSCLC, radical chemo-radiotherapy is the preferred treatment, and 18F-FDG-PET/CT is increasingly used for radiotherapy planning. Despite the introduction of the PERCIST criteria for evaluation of response with 18F-FDG-PET/CT, various methods are being used making comparisons of studies a difficult task. The aim of this study was to investigate which method for analyses of 18F-FDG-PET/CT provided the best prediction of survival.

Method:
18F-FDG-PET/CT scans before and after 2 cycles of chemotherapy from 91 patients enrolled in a Danish randomized controlled multicenter study was retrospectively evaluated using four different methods. The change in 18F-FDG-uptake was measured in a single lesion a) SULpeak (according to PERCIST) and b) SULmax (according to the EORTC criteria), c) total disease evaluation qualitatively (visual), and d) total lesion glycolysis measured in all involved measurable lesions with a 45% decrease as cut-off for response and 75% increase as cut-off for progression as according to PERCIST (%TLG). Univariate cox regression was used to evaluate a direct correlation between 18F-FDG uptake at baseline, follow-up and %change and survival (PFS and OS). Estimates of median OS and PFS was calculated with Kaplan-Meier analysis for the response categories from all four methods and, a log rank test performed for evaluation of the statistical significance. A Bonferroni correction for comparison of four methods was applied rendering a p < 0.013 the considered level for statistical significance.

Result:
There was no clear correlation between survival (neither PFS nor OS) and % change in FDG-uptake (independent of analysis method), but TLG at baseline showed the strongest correlation to both PFS (p= 0.02) and OS (p= 0.03). %TLG was the only method to show a statistically significant difference in OS, (p=0.004). Visual evaluation and change in SULpeak both succeeded in discriminating between the two largest response groups, PMR and SMD, with median OS for visual evaluation: PMR: 22.6 (95% CI: 18.9-26.3) months versus 32.4 (95% CI: 28.4-36.3) months for SMD; SULpeak: PMR: 20.6 (95% CI: 18.0-23.2) months versus 29.7 (95% CI: 24.2-35.1) months for SMD. Change in SUL max and TLG showed no difference.

Conclusion:
There was no clear correlation between PFS or OS and percentage change in FDG-uptake. The response categories for SULpeak and TLG (PERCIST criteria for cut-off), and visual evaluation predicts OS at various levels. SULmax categories as according to the EORTC criteria did not successfully predict OS. None of the methods predicts PFS.

Background:
The incidence of lung cancer is dramatically increased. To review the clinical and imaging pattern of lung cancer, diagnosed and treated with breast cancer within 15 years. To evaluate clinical/pathologic stages, doubling time, and lung RADs categories, related with hormone receptor of breast cancers.

Method:
Retrospectively reviewed medical record of breast cancer patients, since 2007. 17 female patients(19 breast cancers)were included. 19 lung lesions were detected. Age range was from 43 to 78 years old(mean 63.8). We reviewed TNM stage, lung RADS, tumor doubling time and the status of hormone receptor. One patient had bilateral breast cancers, mucinous carcinoma (left), and invasive ductal carcinoma(right). Two nodules were shown, invasive ductal carcinoma and one is DCIS.

Result:
The pathology of breast cancer was invasive ductal carcinoma(15), DCIS(2) mucinous ca(1), papillary ca(1). The T stage of breast cancers was T1(17), T2(2) . The subtype of lung cancers was adenocarcinoma, mostly. T stage of lung cancer is T1(16), one is AIS, T3(1), T4(2). The node metastases were not shown and 2/17 showed distant metastases. The primary tumor dimension was from 8mm to 29 mm. The interval between two tumors from 11 days to 14 years. Lung RADs categories were 4A/B(14), 3(2), 2(3) and final category were increased in 5 (from 2 to 4A or B(4 cases), 3 to 4A/B(2 cases)). In 7 interval growing, the tumor doubling time was from70 to 2016 days (mean 712 days).Figure 1



Conclusion:
The receptor (-) breast cancer were higher T stage of lung cancer and lymph nodes metastases were more common. The growth rate of lung nodules are slow as matched with lung RADS category. Volume doubling time of lung cancers ranging from 70 to 2016 days, and exceptionally short in one of them. RADS up scaling in 7 cases are all T1 stage lung cancers, favorable response for the treatment.

Background:
Widespread CT scan availability generates the challenge of managing small pulmonary lesions generally undetected on chest radiographs. Preoperative nodule localization is critical for adequate diagnosis and an accurate resection. Metallic hook wire localization under CT is a widely used method but can be associated with pneumothorax, hook related discomfort, and dislodgement. CT-guided percutaneous barium marking (CT-GPBM) can be simpler, low cost procedure, without risk of dislodgement, and radiopaque on fluoroscopy, increasing resection accuracy. Barium marking through bronchoscopy has been previously reported. This study describes our experience with CT-GPBM in the diagnosis and management of ground glass abnormalities and small pulmonary nodules.

Method:
Between January 2013 and May 2017, 36 patients underwent preoperative CT-GPBM and VATS resections at our institution, and were retrospectively reviewed. All cases were discussed in multidisciplinary rounds. After CT localization and local anesthesia, a 21-gauge Chiba needle was utilized, under CT guidance, to inject 0,2 mL of 140% barium sulfate suspension. A control CT confirms the marking and verifies possible complications. CT-GPBM and VATS resection are performed in the same day. VATS resection is performed under fluoroscopy guidance. Finally, the specimen is submitted to fluoroscopy to confirm a complete resection.

Result:
Thirty-six different cases were analyzed (41.7% male / 58.3% female). Median age was 65 (ranging from 32 to 91). 18/36 were never smokers. Most lesions were identified on routine follow-up CT (21/36 - 58.3%). Many had previous history of cancer (24/36 - 66.7%). 31/36 (86.1%) were single nodules - median size of 14mm (ranging from 5 to 47). Solid lesion was the most common radiologic finding (21/36 - 61,8%), while the others were semi-solid or ground glass abnormalities. Pathological findings confirmed primary lung cancer in 41,6% of cases (15/36). Adenocarcinoma was the most common histology. Nine patients had benign diseases. Metastatic lesions represented 33,3% (12/36), most derived from colorectal cancer. No patient had reported complications.

Conclusion:
This analysis shows that CT-GPBM is an effective, easy and safe pre-operative (VATS) localization procedure, allowing accurate diagnosis and resection of small or faint pulmonary nodules, avoiding thoracotomies in benign diseases and metastatic tumors. Data will be updated for presentation.

Background:
Percutaneous transthoracic needle biopsy (NB) has been widely used for the preoperative diagnosis of lung nodules. It has been proposed that the risk of pleural recurrence is high following lung resection in patients who underwent preoperative NB for sub-pleural nodules (Kashiwabara, et al. Cancer Invest 2016; Wang, et al. Sci Rep 2017). The aim of this study is to investigate the prognostic impact of preoperative NB for pleural recurrence in patients with early-stage lung adenocarcinoma (ADC).

Method:
Patients who underwent lung resection for pathologic stage I (≤3cm) lung ADC were included in the analysis (1995-2014, n=992; NB group 626 patients and no-NB group 366 patients). We compared the clinicopathologic characteristics and recurrence free probability (RFP, separately analyzed for any, locoregional, pleural, and distant recurrence) between NB and no-NB groups. The risk of pleural recurrence was evaluated in tumors both with and without visceral pleural invasion (VPI).

Result:
The NB cohort was associated with older age and larger tumor size compared to the no-NB cohort (p<0.05). There was no statistical difference in the incidence of VPI (VPI in NB, 12% vs. VPI in non-NB, 15%, p=0.2). In RFP analysis by Kaplan-Meier method with log-rank test, there was no statistical difference between NB and no-NB groups (NB vs. non-NB: 5-year RFP for any recurrence, 86% vs. 86%, p=0.8; locoregional recurrence, 93% vs. 94%, p=0.7; pleural recurrence, 98% vs. 96%, p=0.14; and distant recurrence 94% vs. 93%, p=1). In tumors both with and without VPI (n=128 and n=864, respectively), the risk of pleural recurrence was not higher after NB (Figure; 5-year RFP for pleural recurrence [NB vs. no-NB]: VPI positive, 93% vs. 83%, p=0.3; VPI negative, 98% vs. 97%, p=0.4). Figure 1



Conclusion:
Preoperative needle biopsy was not associated with an increased risk of pleural recurrence following lung resection.

Background:
The EarlyCDT-Lung test detects autoantibodies to abnormal cell surface proteins in lung cancer patients. It has been studied in UK[1] and USA[2] in diagnosing lung cancer patients and has a sensitivity of up to 47%, specificity up to 90% and positive predictive value of 16%. It is a potential diagnostic test and when combines with radiological (Computed Tomography) test, the positive predictive value can be enhanced up to 72%[3]. We want to study the performance of the test in a predominantly Asian ethnic city. 1. Caroline J. Chapman
 et al. EarlyCDT®-Lung test: improved clinical utility through additional autoantibody assays. Tumor Biol. 2012; 33:1319–1326 2. JR Jett et al. Audit of the autoantibody test, EarlyCDT®-Lung, in 1600 patients: An evaluation of its performance in routine clinical practice. Lung Cancer 2014; 83:51–55 . 3. P Massion et al. Autoantibody Signature Enhances the Positive Predictive Power of Computed Tomography and Nodule-Based Risk Models for Detection of Lung Cancer Journal of Thoracic Oncology 2017; 12:578-584

Method:
Patients who had been referred to our clinic for follow up for lung nodules from March 1st to May 30th, 2017 were included. EarlyCDT-Lung test was performed for those with size greater than 0.8cm or size less than 0.8cm with smoking pack-year more than 30 years. EarlyCDT-Lung test sensitivity and specificity were evaluated. Confirmed lung cancer patients were retrospectively compared with non-lung-cancer patients.

Result:
10 patients (Chinese: Caucasian=9:1) were included during the study period (Mean age=51.5; male gender=9 (90%); Smoker=2 (20%). 5 patients were diagnosed lung cancer (Mean tumor size=2.9cm; 1 with Stage IA; 1 with stage IB; 1 with stage IIIA, 2 with stage IV; with adenocarcinoma 5/5, EGFR+ve 2/5, ALK+ve 1/5. Mean age=54.8; male gender=4 (80%); Smoker=0 (0%). 5 patients were diagnosed non-lung-cancer (Mean tumor size=0.8cm. Mean age=48.2; male gender=5 (100%); Smoker=2 (40%). EarlyCDT-Lung test was positive in 1/5 lung cancer patients, while 0/5 in non-lung-cancer patients, giving rise sensitivity 20% (1/5), while specificity 100% (5/5).

Conclusion:
This pilot study gives the initial experience of EarlyCDT-Lung test for Asian with high specificity in limited number of subjects. A larger study is warrant for a more accurate result.

Background:
Non-small cell lung cancer (NSCLC) is the common type of histology among all cases of lung cancer. Studies have shown that PET/CT is more accurate than CT for the detection of nodal status due to the increased FDG uptake in very small nodes. In fact, tumor-node-metastasis staging of the mediastinum is currently one the most common indications of PET/CT in lung cancer. The aim of this pilot retrospective review was to assess the role PET/CT as a non-invasive procedure for the visualised lymph nodes in lung cancer.

Method:
Twenty-nine patients [NSCLC (86%), NET (10%), SCL (4%)] underwent PET/CT imaging and were followed for a period of at least 3 years. There were 15 females (51.72%) and 14 males (48.28%) aged between 38-78 years (mean +/- SD= 61.24+/- 9.86) and were referred for staging (86%), restaging (10%) and response to therapy (4%). All patients underwent 18F-FDG PET/CT with a mean time of 71.2 minutes after tracer injection. Tumor and lymph node uptake were evaluated with both visual and quantitative assessment.

Result:
Seven patients (24%) died at 12 months despite treatment induction and by the end of two years follow-up, just a little more than half (51.72%) of the patients died. The majority of those who died were males (r=-0.38; p=0.041). Active lymph nodes were seen in one nodal station in 19 patients. They were also seen in two nodal stations in 12 patients and in three nodal stations in 5 patients. The common stations were as follows: Hilar (33.3%), right lower Para tracheal (22.2%) and subcarinal (19.4%). While no significant association was seen between the primary location of tumor and the occurrence of lymph nodes, patients with positive nodes on PET/CT staging tend to have a reduced survival than those without visualized lymph nodes [odd ratio= 2.33, 95% CI 1.60-9.02; p=0.08]. However, when the analysis was only done for the NSCLC group, a significant reduction of survival was noted in patients who had positive lymph nodes (p<0.01).

Conclusion:
This small cohort confirmed the predominance of NSCLC as described in the literature. While this histological predominance could result from a referral bias, it clearly showed that the male gender was associated with a reduced survival. However, a larger cohort must be studied in a prospective analysis to confirm the significantly reduced survival among NSCLC patients with positive lymph nodes during staging, for PET/CT imaging to become a robust predictor of survival.

Background:
In this study, we built three 3-dimensional convolutional neural networks (CNN) for recognition of epidermal growth factor receptor (EGFR) mutation status in Chinese patients with lung adenocarcinomas based on non-enhanced computed tomography (CT) images.

Method:
From October 2008 to December 2015, 405 patients with lung adenocarcinomas were included in this retrospective study. Their pathological phenotypes and EGFR mutation status were gained from surgical resections. Their CT images used in this study were taken before any invasive operation. Tumors with a diameter smaller than 8 mm or have ground glass component were excluded. Region of interest that includes tumors were segmented manually by clinicians and preprocessed to have uniform size and grey-level range before applied to CNNs. The three CNNs have 4 convolutional and 1 full connection layers between input and output layers. The inputs size of three CNNs are 21×21×21, 31×31×31, and 41×41×41, respectively. The outputs of the CNN are the probabilities of mutant and wild status. The CNN classifier’s performance was then validated using an independent set and evaluated using area under curve (AUC) values of the receiver operating characteristic.

Result:
405 patients diagnosed with lung adenocarcinoma staging I to IV were included in this study (195 male, 210 female; 61 smokers, 344 non-smokers). The patients received surgery based treatment and their tumor stage was based on pathological reports. EGFR mutations (mainly 19del and 21L858R) were found in 198/320(61.9%) and 56/85(65.9%) patients in training and validation sets, respectively. The CNN showed an AUC of 0.767 (95% confidence interval: 0.668-0.866, p<0.001) in the validation set. The sensitivity and specificity are 62.5% and 89.7% at best diagnostic decision point. These results were highest among published results of only using images to recognize EGFR.

Conclusion:
The CNN showed potential ability to recognize EGFR mutation status in patients with lung adenocarcinomas and could be improved in the future works to help make clinical decisions.

Background:
There were many reports and evidences for part-solid nodules with ground-glass opacity (GGO) in small-sized lung adenocarcinoma, and the component of GGO has been known to be a factor of malignant potency of the tumor, although the relation between radiological appearance of >2cm or >3cm lung adenocarcinoma and clinicopathological features were less noted.

Method:
A total of 136 patients with >2cm lung adenocarcinoma with >0.75 of consolidation to tumor ratio (C/T ratio) who underwent lung resection at Shinshu University Hospital from February 2003 through December 2010 were assessed. Among these patients, 83 with pure solid appearance in preoperative thin section computed tomography (C/T ratio = 1.0) were placed into Solid group, and 53 with small GGO surrounding the solid type tumor (0.75 < C/T ratio < 1.0) were placed into Subsolid group in this study. We retrospectively analyzed the clinicopathological features and prognosis after surgery in each groups.

Result:
The maximum standardized uptake value (SUVmax) of the tumor in preoperative radiological assessment using [18F] fluoro-2-deoxyglucose positron emission tomography (FDG-PET) were significantly higher (p=0.0048) in Solid group (7.65±4.36) than Subsolid group (4.82±3.32). The presence rate of vascular invasion (Ly or V) was 54.2% in solid group and 39.6% in Subsolid group. The numbers of node positive patients were 19 with N1, 27 with N2 in solid group, and 8 with N1, 7 with N2 in Subsolid group respectively, and the rate was significantly higher in Solid group (p=0.0019). The prognostic analysis of pathological stage 1 patients (29 patients in Solid group and 37 in Subsolid group) revealed that the overall survival and recurrence-free survival was significantly poorer (p=0.044 and p=0.019 respectively) in Solid group than in Subsolid group.

Conclusion:
The small GGO surrounding the solid type adenocarcinoma as C/T ratio >0.75 indicated lower malignant potency and better prognosis than pure solid tumor without GGO component. Even small GGO component was a clinical factor of favorable oncologic outcomes, it may contribute to regarding the decision making for surgical strategy in preoperative assessment.

Background:
In this study we aim to investigate predictivity of alveolar spread in primary lung cancer by using preoperatively scanning methods

Method:
In order to re-evaluate alveolar spread, pathology preparations of 45 patients had operated for primary lung cancer diagnosis and scanned preoperatively with PET CT all in our hospital which interpreted by same nuclear medicine specialists implicated in this study. As using the patients pet CT findings, CTV (computerized tomography volume), MTV (metabolic tumor volume), TLG(total lesion glycolysis), SUDmax, SUDort values and their relation with alveolar spread analyzed

Result:
Preoperatively PET-CT scanned all in our hospital 45 patients has included and cause of couldn't reach their pathological preparations, 6 of them exluded from the study. 21 of 39 patients were men (53.8%) , 18 of them were women (46.2%) and mean age was 66.67/+-7.88 (42-80). We didn't detect any relation between CTV, MTV, TLG, SUDmax, SUDort values and alveolar spread (p>0.05). However when the CTV/ MTV ratio analyzed, alveolar spread was statistically more common in the group of patients had ratio lower than 1. (62.9% versus 0% , p:0.01)

Conclusion:
High local recurrence risk in sublober rejected patients with alveolar spread has indicated in various studies. Regarding this matter, we recommend re-evaluation of the patients for sublober rejections whose CTV/MTV ratio is lower than 1.

Background:
Spinal cord compression is one of the most disabling complications in lung cancer. It may be caused either by the tumor itself or by metastatic involvement of the spine and meninges. The goal of this work is to appreciate characteristic of spinal cord compression in lung cancer.

Method:
Retrospective review of the MRI data of patients with lung cancer presenting with neurological symptoms caused by medullary or cauda equine compression. Only patients with abnormal findings were retained. All exams were performed by a 1.5 T machine.

Result:
From January 2014 to December 2016, only 24 patients (23 males and 1 female) were referred to the imaging department of our institution for medullary compression exploration. Their average age was 57 years. Seventeen patients had adenocarcinoma. Three patients were classed stage IIIB and 18 were classed stage IV. Medullary compression was caused by direct compression (12 cases) of the tumor or by a spine metastases (12 cases). One spine region was involved in 18 patients with dorsal location in 13 patients. In three cases, the compression concerned the cauda equina. Myelopathy was noted in 15 of the 21 patients with spinal cord compression.

Conclusion:
Spinal compression is not frequent in lung cancer. It is mainly observed in advanced stages. It may occur by direct tumor invasion or by vertebral metastatic extension.

Background:
Lung cancer has a poor prognosis unless patients are operated. However, few patients may undergo surgery. Recurrences are not rare and they increase the mortality. The objective of this study is to appreciate the frequency of recurrences after surgery in non-small lung cancer (NSCLC) in our institution and to correlate them to TNM classification and histological subtypes.

Method:
Retrospective review of 127 patients (106 men and 21 women) aged between 19 and 80 years with NSCLC that were operated. All patients had chest, abdomen and brain computed tomography (CT) in their follow up. We precised for each patient the histological type of the lung cancer, the c and p TNM stages, the resection type and the other treatments prescribed, the recurrence site and the delay between the surgery and the recurrence.

Result:
Recurrences were observed in 35 patients (27.5%). They had either a lobectomy (n=30), a pneumonectomy (n=4) or a wedge (n=1). Recurrences were located to the chest in 36 cases (half of them occurred in the operated lung) and in extra-thoracic organs in 13 cases; the brain was the mostly involved. The delay between surgery and recurrence ranged between 1 month and 7 years. Fourteen patients had a recurrence within the first year after surgical removal of their tumor. Recurrences were mostly observed in patients with T4 stage (23%), N3 stage (66.6%), stage III cancer (49%), and with adenocarcinoma. An under-estimation of the cT and cN stages was observed in 5.6% and 27.5% of patients, respectively.

Conclusion:
Recurrences in patients with surgically removed lung cancer are not rare. They depend on its histological type and on the cT and cN stages.

Background:
PET scans are used during diagnosis and staging of lung cancer. The role of PET scan in guiding therapy for advanced stage non-small cell lung cancer (NSCLC) is not proven, but it continues to be used during the treatment course at many centers. We studied the Surveillance, Epidemiology, and End Results (SEER) Program database and Medicare claims data to evaluate the use of PET scan in advance stage NSCLC patients in the United States and the impact on patient outcome.

Method:
The SEER-Medicare database was queried to capture patients with stage IV non-small cell lung cancer diagnosed between the years 2000-2011. The cohort of patients that received PET scan after diagnosis were analyzed and compared with the cohort that did not receive PET. The univariate (UV) association between covariates and overall survival (OS) were compared by log-rank tests. Time dependent Cox Model was used in multivariable (MV) analysis, with time from diagnosis to first PET scan as time-dependent variable, while the other covariates as time-independent. All analyses were performed using SAS Version 9.4.

Result:
A total of 52,712 eligible patients with stage IV NSCLC were identified between 2000-2011, out of which 13,873 (26.3%) had received PET scan. Characteristics of PET cohort: median age 74 years, 53% male, 87% white and 82% from metro locations. 87% of the patients that received PET were diagnosed between 2006-2011. In the first year after diagnosis, 70% of the patients had 1 PET, 16% had 2 PETs and 14% had 3 or more PETs. About 64% of the patients had received their first PET scan within 2 months of diagnosis and 19% had it between 2 to 6 months. The average Medicare cost associated with patients that received PET was significantly higher than that of patients that did not receive PET scan ($60,417 vs. $34,287; p<0.001). Chemotherapy and radiation were given in a higher proportion of patients that received PET versus those that did not receive it (56% and 45% versus 26% and 36% respectively; p<0.001). Though univariate analysis revealed that a PET scan within a year of diagnosis was associated with better 1-year survival (HR 0.87, P<0.001), this did not translate into overall survival advantage on multivariable analysis (HR 0.99, P=0.56).

Conclusion:
The utilization of PET scan in stage IV NSCLC patients was associated with higher cost, but without a tangible improvement in survival compared to those that did not have a PET scan.

Background:
Questions have been raised about the appropriate treatment of lung cancers manifesting as subsolid nodules (nonsolid nodules (NSNs) and part-solid nodules (PSNs)), as these have very high reported survival rates and have been observed in up to 10% of screening participants. Our goal in this report is to summarize the publications on survival of patients with resected lung cancers manifesting as PSNs and to further the development of consensus definitions of the CT appearance and the workup of such nodules.

Method:
PubMed/MEDLINE and EMBASE databases were searched for all studies/ clinical trials on CT-detected lung cancer in English before Dec 21, 2015 to identify surgically-resected lung cancers manifesting as PSNs. Outcome measures were lung cancer-specific survival (LCS), overall survival (OS), or disease free survival (DFS). All PSNs were classified by the percentage of solid component to the entire nodule diameter into: Category PSNs < 80% or Category PSNs ≥ 80%.

Result:
Twenty studies reported on PSNs < 80%: 7 reported DFS and 2 OS of 100%, 6 DFS 96.3-98.7%, and 11 OS 94.7-98.9% (median DFS 100% and OS 97.5%). Twenty-seven studies reported on PSNs ≥ 80%: 1 DFS and 2 OS of 100%, 19 DFS 48.0%-98.0% (median 82.6%), and 16 reported OS 43.0%-98.0% (median DFS 82.6%, OS 85.5%). Both DFS and OS were always higher for PSNs<80%.

Conclusion:
A clear definition of the upper limit of solid component of a PSN is needed to avoid misclassification because cell-types and outcomes are different for PSN and solid nodules. The workup should be based on the size of the solid component.

Background:
Poor adherence to the recommended guidelines in diagnosing and staging patients with non-small cell lung cancer (NSCLC), with negative downstream effects has been previously shown. In addition, studies have demonstrated benefits of staging with PET, including a reduction in number of non-curative resections performed and a higher rate of identifying M1b disease. Staging with brain MRI has demonstrated a yield up to 10% for detecting metastasis in patients with negative clinical examinations. We aimed to assess the adherence to imaging guidelines for PET and brain MRI in the staging of NSCLC patients prior to treatment within our healthcare system.

Method:
We reviewed patients who underwent initial work-up for primary NSCLC during 6/2013–6/2015, in a hospital network of 7 institutions. Clinical stage II-IV patients were stratified by imaging performed prior to the initiation of treatment. Evidence-based clinical practice guidelines referenced include the American College of Chest Physicians (ACCP) 3[rd] edition and the National Comprehensive Cancer Network (NCCN) 7[th] version. Both ACCP and NCCN recommend a PET scan for suspected cIb-III; while ACCP recommends a brain MRI for suspected cIII-IV, and NCCN for suspected cIb-IV.

Result:
The figure demonstrates compliance rates for the 283 included patients. Of cII patients, 7% (2/30) did not receive a PET scan and 43% (13/30) did not receive a brain MRI; while, 11% (6/56) of cIII did not receive a PET scan and 20% (11/56) did not receive a brain MRI. Figure 1



Conclusion:
Variable compliance with imaging guidelines for the use of PET and brain MRI imaging for the staging of our NSCLC patients was seen. Lack of appropriate imaging for NSCLC staging may lead to inappropriate management decisions resulting from incomplete staging information. Quality initiatives are necessary to ensure guideline compliance.

Background:
Fluorodeoxyglucose Positron emission tomography (FDG PET) is a main tool in diagnosis and staging in patients with non small cell lung cancer (NSCLC). Metabolic parameters as standardized uptake value (SUV) and total lesion glycolysis (TLG) were reported to have independent prognostic and predictive value in different stages of disease and were shown to correlate with tumor activity and tumor burden. However, little is known regarding the correlation of these parameters with histologic subtypes of NSCLC. In this study we aimed to explore associations of FDG PET metabolic parameters in patients diagnosed with NSCLC and histologic subtypes of NSCLC.

Method:
We retrospectively evaluated 87 consecutive patients who underwent FDG PET scans in the workup of pulmonary nodules highly suspicious for malignancy. At total of 62 of them were found to have NSCLC; 44 with adenocarcinoma (ADC) and 18 with squamous cell carcinoma (SQCC). Measurements of hounsfield units (HU), region of interest (ROI), SUVmax, SUVmean, volume of interest (VOI) and TLG were obtained. Follow up for final staging at diagnosis and overall survival (OS) were obtained from electronic medical records. Statistical analysis was made with T-test and Mann-whitney u test.

Result:
In patients with SQCC, the mean ±standard deviation (SD) SUVmax and TLG (±SD) were found to be significantly higher than in patients with ADC (Table 1). Differences in OS showed a trend favoring SqCC but no significance was found (complete results from 16 more patients are pending). Figure 1



Conclusion:
FDG PET Metabolic characteristics such as SUVmax and TLG significantly differ between histological subtypes in NSCLC. This report joins others on the utility of functional imaging studies in NSCLC in assessing not just disease burden but also prognosis and function. Further analyses of the PET parameters prognostic impact according to histology subtype is ongoing and would be presented at the meeting.

Background:
In part-solid nodule of lung adenocarcinoma, the diameter of the solid part in computed tomography(CT) scan correlates with the diameter of the pathological invasive part. However, there are some cases revealing dissociation between them. We analyzed clinical factors predicting the dissociation of the diameter between radiographical solid part and pathological invasive part in adenocarcinoma less than 3 cm.

Method:
Among 291 cases with a lung adenocarcinoma smaller than 3 cm, we identified 91 cases whose solid part in preoperative thin-slice CT scan was less than 5 mm. Based on pathological diagnosis of invasive part, we divided these cases into Adenocarcinoma in situ/Minimally Invasive Adenocarcinoma(AIS/MIA) group (less than 5 mm) and Massive invasion group (5mm or larger), and retrospectively analyzed the clinicopathological factors. We also performed logistic regression analysis to detect the factors predicting the dissociation between radiographical and pathological findings.

Result:
Of 91 cases, 67 cases were in AIS/MIA group (AIS: 57, MIA: 10) and 24 cases were in Massive invasion group. In univariative analysis, cases of Massive invasion group were significantly higher in Brinkman index, CEA, age, and total tumor size than those of AIS/MIA group (p = 0.02, 0.01, 0.04, 0.03 respectively). With these detected four factors, we performed logistic regression analysis after determining threshold by ROC curve, which resulted in Brinkman index equal or larger than 400, and age equal or elder than 67 as significant predictive factors for Massive invasion group (p < 0.01, p = 0.05 respectively). Among 11 cases positive for these two factors, 7 cases (63.6 %) were in Massive invasion group.

Conclusion:
In the cases of radiographical AIS/MIA, the diameter of pathological invasive part tends to exceed 5 mm if Brinkman index equal or larger than 400, and age equal or elder than 67.

Background:
Pulmonary emphysema is known to be related to an increased incidence of lung cancer. The risk factors of emphysema and lung cancer are smoking history and envirolmental pollution. Low-dose chest CT is useful method for imaging both: emphysema and solitary pulmonary nodules (SPN).

Method:
We have enrolled a total of 602 healthy volunteers to the Pilot Silesian Study of Early Lung Cancer Detection with LDCT. Retrospectively we analyzed the baseline round of LDCT scans. One person was excluded due to presence of lung cancer symptoms. Gradual accrual period lasted for two years, from 2010 to 2012. The positive result was defined as a presence of solid or part-solid nodule equal to or larger than 5 mm or non-solid equal to or larger than 8 mm. Participants were stratified by exposure to tobacco smoke into five groups: A) current smokers with a history of at least 40 years of smoking - chronic smokers; B) current smokers with a history of smoking at least 40 cigarettes per day - intensive smokers; C) former smokers who quit smoking fewer than 5 years ago; D) former smokers who quit smoking at least 10 years ago; E) exposed to a second-hand tobacco smoke. With the statistical methods we analized corelations between this five groups depending on tobacco exposure and demographic features.

Result:
We identified 1016 lung nodules in 265 individuals. A total of 410 nodules coexisted with emphysema in 99 individuals. In group with emphysema we diagnosed 3 early lung cancers, unlike to the group without emphysema, in which we diagnosed 4 cancers (HR=0.7 95% CI 0.16-1.02). Subsolid morphology and diameter of a nodule larger than 5 mm were associated with higher risk of malignancy. Emphysema and lung nodules were more often found in the group of chronic smokers (>40 years) - 8.1% (A), in comparison to the group of intensive smokers – 0.8% (B). There were no statistically significant differences in both subcohorts of former smokers (for group C and D, 2.1% and 2.3%, respectively).

Conclusion:
In the subgroup of chronic smokers emphysema and lung nodules were more likely to occur. Additional risk factors for the presence of lung nodules and emphysema were: age (above 65 years) and occupational exposure (especially coal miners and welders).

Background:
Lung Cancer (LC) is the leading cause of cancer-related death worldwide. The Lung Cancer Screening Trial screened 26,723 patients via Low-Dose chest CT-scan. Screening results were positive in 24.2%, however 96.4% were false positive. Therefore, a biomarker helping to discriminate false positive from true positive screening results will limit unnecessary interventions. The aim of this study was to analyze the feasibility of the DNA methylation markers prostaglandin E receptor 4 gene (PTGER4) and short stature homeobox 2 gene (SHOX2) as potential biomarkers in liquid biopsies additional to CT-scan findings suspicious for LC.

Method:
A total of 73 patients with a chest CT-scan suspicious for stage I-IIIA LC were included in this study. LC was histologically confirmed in 50 patients. In the remaining 23 patients benign diagnoses were established. Circulating cell-free DNA was extracted, bisulfite converted and purified from 3.5 ml plasma, using a commercially available kit. Triplicates of bisulfited DNA were assayed with a 45-cycle rtPCR assay detecting methylated DNA of SHOX2, PTGER4 and ACTB as reference assay. Assay result was called positive for PTGER4 if at least two out of three PCR results had cycle threshold (Ct) values below 45; for SHOX2 if the Ct value was below 35.

Result:
PCR-results were valid in 18 (4 organising pneumonias, 5 pneumonias, 3 post-pneumonic residues, 3 hamartochondroma, 1 mycosis, 1 coal-workers pneumoconiosis, 1 aspergilloma) of 23 benign samples (control), and in 43 of 50 LC samples. PTGER4 results were negative in all controls and positive for 18 of 43 LC. These results translate into a specificity of 100 % and a sensitivity of 41.86% for LC detection via PTGER4. The SHOX2 assay was negative in all controls and positive in 9 LC patients, resulting in a specificity of 100 % and a sensitivity of 20.93% for SHOX2. Overall 21 of 43 LC samples were positive in either PTGER4 or SHOX2 and all controls were negative for both measurements. In combination both markers showed a specificity of 100% and a sensitivity of 48.84%. This specificity would imply a positive predictive value of 100%, further validation in a larger cohort is required.

Conclusion:
DNA methylation of PTGER4 and SHOX2 was highly specific for patients with chest CT-scan findings suspicious for LC. This could help to identify high-risk patients, who should be directly transferred to tissue-based diagnostics, surgery or stereotactic radiation. In the other cases the next diagnostic step should be decided clinically.

Background:
In conventional cytology discrimination of the reactive mesothelium cells and malignant cells is the most important diagnostic problem. Cell block (CB) technique is helpful in discriminating cytological abnormalities or well differentiated adenocarcinoma.

Method:
95 consecutive patients (52% male, mean age 67±12yrs) with malignant pleural effusion in lung cancer were enrolled. 44% of patients had Eastern Cooperative Oncology Group performance score 0-1 and 66% ≥2. In all patients pleural fluid smears were sent for conventional cytological and CB immunocytochemical examination.

Result:
In 69 (73%) cases malignant pleural effusion was the first sign of lung cancer and in 26 (27%) cases developed in disease progression. First pleural fluid immunocytochemistry examination confirmed malignancy in 80 (84%) cases: adenocarcinoma – 70 (88%), small cell carcinoma – 7 (9%) and non small cell carcinoma – 3 (3%). First cytological examination was positive in 81 (85%) smears. Adenocarcinoma cells were identified in 51 (63%) cases although of them CB technique confirmed adenocarcinoma in 49 (96%) smears and reactive mesothelium cells in 2 (4%) smears. Out of 30 (37%) specimens that showed malignant cells in cytological examination, CB method confirmed: adenocarcinoma 15 (50%), small cell carcinoma 6 (20%), non small cell carcinoma 3 (10%) and reactive mesothelium cells 6 (20%). Whether first cytological smear was negative, second smear was positive in 4 (27%) cases and identified 1 (25%) adenocarcinoma and 3 (75%) malignant cells in cytological examination, notably out of them CB examination showed reactive mesothelium in 2 (50%) samples, small cell carcinoma in 1 (25%) sample and adenocarcinoma in 1 (25%) sample.

Conclusion:
Our study aims that pleural fluid cell block immunocytochemistry is more accurate method identifying lung cancer and should be considered as the initial diagnostic approach for malignant pleural effusion in primary investigation in lung cancer, especially in patients with worse performance status.

Background:
There has been increasing recognition that lung nodule measurement on CT scans is imprecise and that an understanding of the extent of this imprecision is necessary when trying to determine whether actual change in volume has occurred. The various factors that influence this are numerous with two of the most prominent being the overall quality of the CT scan (including all of the adjustable parameters) and the size of the nodule.

Method:
We have developed an automated system whereby a calibration device is scanned on a given scanner with a given protocol and then the system can automatically predict the extent of measurement error for a given size solid nodule. We compared this approach to empirically derived results obtained from a database of 117 screen-detected stable nodule ranging in size from 2.2 to 18.7 mm that were scanned twice on the same CT scanner using the same protocol. Automated volumetric analysis was performed using commercial software. This allowed us to determine the relationship between standard deviation of the measurements versus nodule size. We then scanned our calibration device using the same scanning protocol as was used on those nodules to automatically calculate the size and standard deviation relationship.

Result:
Predicted solid nodule volume standard deviation compared with empirically derived values across a range of nodule sizes was within 20% (see figure)Figure 1



Conclusion:
Results from our automated approach were highly correlated with results obtained from scans obtained in actual clinical practice. The ability to predict extent of error specific to a given scanner and scanning protocol is an essential step in understanding whether change has occurred and has implications for both diagnosis and therapy assessment, including predicting when a follow up scan should be obtained. This type of information will ultimately become a necessary component of all quantitative imaging programs.

Background:
Lung cancer mimicking organizing pneumonia (LCOP) is a novel radiological entity of lung adenocarcinoma that could be misdiagnosed as inflammatory lesions.. However, the characteristic biological and genetic features of LCOP are not fully clarified.

Method:
We used thin-section CT images to select cases of (LCOP) among surgically resected lung adenocarcinoma patients. We compared the clinicopathological characteristics and the immunophenotypes of LCOP (n = 44) and other lepidic-predominant adenocarcinomas (non-LCOP, n = 56). We also analyzed the genomic mutation features of LCOP (n = 4) by whole-exome sequencing (WES).

Result:
All LCOP lesions were lepidic-predominant invasive adenocarcinoma. Patients with LCOP had significantly superior recurrence-free survival, compared to non-LCOP patients (95.5% and 74.4%; P = 0.006, respectively). Vascular invasion and lymph node metastasis were less frequent in LCOP than in non-LCOP patients (P = 0.001 and P = 0.03, respectively). The cancer cell expression levels of aggressiveness-related molecules, including ezrin, ALDH-1, laminin-5 were similar between LCOP and non-LCOP. On the contrary, the number of tumor promoting stromal cells, i.e., podoplanin-positive cancer-associated fibroblasts and CD204-positive tumor associated macrophages, was significantly lower in LOCP (P = 0.021 and P = 0.037, respectively). WES revealed that ABCB1, DNAH3, MSI2, and SLITRK2 were specifically mutated in LCOP.

Conclusion:
Our results indicate that LCOP is characterized by fewer tumor-promoting stromal cells, which may contribute to the better prognosis of LCOP patients. Moreover, recognition of specific somatic mutations of LCOP patients may provide information regarding the development and progression of this type of lung cancer.

Background:
Ever since its first success in large scale image recognition problem, deep convolutional neural networks (DCNNs) have shown their capabilities in solving many challenging visual perceptual tasks, such as image classification, segmentation, object detection. In some cases, DCNNs have already achieved near-human performance. In medical image analysis, DCNNs have also been successfully applied to lesion detection, segmentation, and diagnosis. The power of DCNN lies in its ability to learn a hierarchical representation of raw input data, without hand-crafted features.

Method:
The focus of this study was to improve the performance of DCNN in automatic detection of pulmonary nodule on CT scan. In particular, nodules whose size is less than 4mm were considered. A total of 171 scans were collected at Zhongshan Hospital Fudan University, which was first process by the proposed DCNN system (12Sigma). The detection results were then carefully reviewed by an experienced physician, all false positives and missed nodules were manually labeled. To refine the system, all false positives and true nodules of sizes 4mm and under were selected.

Result:
The data set was randomly split into training and test sets, where the training set consists of 90% (154 scans) and the test set consists of 10% of data (17 scans). Figure 1 shows the FROC curves on the test set before and after re-training. Overall, the detection sensitivity were improved at all false positive levels, but the improvement was most significant at low FP rate region. For example, when FP is 0.5 per scan, the detection sensitivity increased from 0.36 to 0.49. Figure 1



Conclusion:
This improvement suggests that, even with limited data, the deep neural network can learn from its mistakes and be easily tuned to be more sensitive to small nodules. We believe that when more data is colllected, more significant improve in high FP rate region will be observed.

Background:
Pathways to lung cancer diagnosis are complex. General Practitioners (GPs) play a vital role in ensuring that people diagnosed with lung cancer receive timely access to appropriate specialist care. Australian guidelines recommend that the first specialist appointment should take place within two weeks of the initial GP referral. However, local data indicate that up to 60% of patients are not referred within two weeks, while state-based data shows that 11% of patients in New South Wales (NSW), Australia, do not see a lung cancer specialist at all; these patients may be missing out on curative and palliative treatments. We designed a primary care intervention to address these gaps and conducted a feasibility study in three sites across NSW. The RoaDmaP pilot study aimed to develop, implement and evaluate the Referral Decision Prompt (RDP), an intervention that supports GPs to refer patients with a suspicious lung lesion on CT scan for specialist care. Specific objectives were to evaluate feasibility and acceptability with GPs, radiologists and radiology practice staff.

Method:
The RDP intervention was developed with key stakeholder input and was tailored for three participating radiology practices. Eligibility criteria included any patient aged over 18 attending for a chest CT scan. Recruitment and consent procedures were tested to enable collection of patient’s medical data from GPs and hospitals to confirm lung cancer diagnoses. The RDP template was integrated into CT scan reports for patients with a suspicious lung lesion. A process evaluation with GPs, radiologists and radiology staff was undertaken through brief surveys and qualitative focus groups.

Result:
Over seven months, 445 patients had a GP-referred chest CT scan; 400 were given study documents; 293 consented (73%). Twelve patients had a suspicious lesion, eight of whom received a confirmed lung cancer diagnosis. Sixty-six percent had a specialist appointment within two weeks. The intervention was rated as highly acceptable by radiologists, radiographers and practice staff; four GPs participated in the evaluation, three recalled the RDP and two used it to change their referral practices.

Conclusion:
The RoaDmaP study presents an innovative approach to identifying lung cancer patients prior to diagnosis and has the potential to improve timely and appropriate specialist referral. The process evaluation findings indicate that this simple, low-cost intervention is feasible and can be easily integrated into radiology reporting practices. It is highly acceptable to radiologists and practice staff, and may positively influence GP referral practices.

Background:
Lung cancer is the first cancer responsible for metastases. They can be either intra-or extra-thoracic. Their diagnosis when the cancer is locally non-advanced modifies completely the treatment. The aim of this work is to find out variables influencing metastases occurrence in T1-T2 classed lung cancer.

Method:
Retrospective review of data of 63 patients (60 males and 3 females) with confirmed lung cancer, which were classed T1 or T2 according to the TNM 7 in the work up of their disease and who were explored in the imaging department of our institution between January 2011 and December 2016. Patients were subdivided into two groups: with or without metastases. The variables tested to find out a relationship with metastases occurrence were age, T1 or T2 status, N status and histological type of the cancer. A significant statistical relationship was retained when p was ≤0.05.

Result:
The mean age of the included patients was 61 years (ranging between 43 and 73 years). Adenocarcinoma was the most common histological type (71%). Twenty seven patients (43%) had metastases; 21 of them (77%) had extra-thoracic ones. Comparing patients with and without metastases, no significant relationship was found between the T1 or T2 stage (p= 0.147), the age (p=0.745) and metastases occurrence. In the opposite, they were statistically related to N2-N3 lymph nodes stage (p=0.032) and to adenocarcinoma (p=0.006).

Conclusion:
Metastases are quite frequent in T1-T2 classed lung cancer. Their occurrence was related to the N stage and to the adenocarcinoma.

Background:
Brain metastases frequently occur in patients with small-cell lung cancer. Therefore, prophylactic cranial irradiation (PCI) is recommended for good responders of initial treatment. The purpose of this study was to investigate influence of PCI on pattern of brain metastases as a first recurrence site (BMFR) after radical treatment for limited disease small-cell lung cancer (LD-SCLC).

Method:
This retrospective study included LD-SCLC patients treated with thoracic radiotherapy and concurrent chemotherapy between January 2006 and December 2014. Induction chemotherapy was permitted. Thoracic radiotherapy was performed with accelerated hyper-fractionated radiotherapy (twice daily, 45 Gy in 30 fractions over 3 weeks) or conventional-fractionated radiotherapy (once daily, 50 Gy in 25 fractions over 5 weeks). Regimen of chemotherapy consisted of intravenous platinum-etoposide.

Result:
One hundred and sixty-two patients were included in this study. The median follow-up duration for surviving patients was 38 months (range, 6-105 months). Among 123 patients (76%) who died, 104 patients died due to disease progression, 11 died due to unknown cause and 8 died due to other cause. Ninety-three patients (57%) underwent PCI, and the 3-year disease specific survival (DSS) rates were 20%(12-35) in patients without PCI and 43%(33-55) in those with PCI (p<0.001). Concerning the recurrence pattern, the frequency of BMFR was significantly higher in patients who did not underwent PCI compared with those who did (49% vs 25%, p=0.008) although no significant difference in frequency of all site of recurrence was observed between patients without PCI and those with PCI (83% vs 73%, p=0.109). Regarding the impact of BMFR on prognosis, patients with BMFR exhibited significant shorter DSS than those whose first recurrence sites was other than brain metastases (3yr-DSS 6% vs 22%, p=0.007), and patients who developed BMFR without PCI exhibited significant lower DSS compared with those who developed BMFR with PCI (3yr-DSS 0% vs 17%, p=0.005). In addition, 68% of patients who did not underwent PCI exhibited multiple BMFR lesions with 5 or more while 12% of patients who did (p<0.001).

Conclusion:
The results of this study indicated that BMFR exhibited significant negative impact on prognosis after radical treatment for LD-SCLC and the difference in the number of metastatic lesions in BMFR between patients with PCI and those without PCI might affect clinical outcomes.

Background:
Tri-modality management using chemoradiotherapy followed by surgical resection is the current standard of care for patients with pancoast tumors. Surgical resection is considered the key element to improve patient outcomes, however it involves a lengthy operative procedure with surgical/anesthetics related side effects, long period of rehabilitation, and significant additional cost. In the era of image-guided radiotherapy, we are able to paint the dose around the tumor, targeting it with a high dose of radiotherapy, while avoiding sensitive organs such as spinal cord and brachial plexus. Here we present our institutional experience treating advanced pancoast tumors with chemoradiotherapy.

Method:
Patients are usually staged with chest-abdomen CT scan, upper chest/brachial plexus MRI (if needed), brain MRI and a PET scan. Patients are treated in a supine position, using head and neck mask as the immobilization device; and cone beam image guidance. The radiation dose is 45-70 Gy in 25-35 fractions concurrent with at least 2 cycles of chemotherapy. Patients with resectable tumors have surgery done within 4-6 weeks upon completion of chemoradiotherapy. Patients are followed every 3-6 months with CT scan and/or upper chest MRI for 3 years, then yearly after.

Result:
Of 205 consecutive patients with stage 3-4 NSCLC treated with radical dose radiotherapy at Southlake regional cancer center, 9 patients with pancoast tumor were detected. Two patients (2/9) died; one from a heart attack before completion of his treatment, and the other one from tumor progression (6 months after completion of tri-modality management). All the other 7 patients are still alive and free of disease (table 1).

Patients	Gender	Age (year)	Tumor size (cm)	Tumor pathology	Tumor invasion	Sugery	RT (Dose/fraction)	Date of completion RT (D/M/Y)	Date of last FU
1	F	61	6.2	Squamous carcinoma	T2, vessels, bone marrow	No	66 Gy/33 fr	06/02/2010	13/10/2016
2	M	62	11.3	Adenocarcinoma	C6-T3 ribs	No	70 Gy/35 fr	05/10/2010	25/01/2017
3	M	72	9	Adenocarcinoma	rib, vessels, neck	No	70 Gy/35 fr	25/01/2011	29/06/2016
4	M	66	9	Squamous carcinoma	C7-T5 vessels	No	66 Gy/33 fr	26/01/2015	11/01/2017
5	F	58	5.6	Adeno carcinoma	ribs	Yes	45 Gy/25 fr	21/03/2016	25/04/2017
6	F	55	6.6	Squamous carcinoma	T2-T4 rib chest wall soft tissue	No	66 Gy/33 fr	04/04/2016	08/06/2017
7	F	74	4.3	Adenocarcinoma	T3-T4 rib	Yes	66 Gy/33 fr	26/05/2016	20/06/2017

Conclusion:
Selected patients with pancoast tumors treated with high dose radiotherapy, using image guidance, concurrent with chemotherapy may have long term disease free survival. A multi-institutional study is warranted to conclude the management recommendation for these rare tumors.

Background:
Evidence regarding optimal follow-up (FU) strategies for patients after curative radiotherapy for NSCLC is limited, resulting in variable FU practice. The aim of this study was to describe the patterns of FU care for patients undergoing curative radiotherapy +/- chemotherapy.

Method:
A retrospective study was conducted of patients with Stage I-III NSCLC, undergoing a course of curative radiotherapy (a minimum dose of 50Gy), between 1/1/2007-31/12/2011 at three institutions. Data was collected from oncology records, including patient demographics, tumour characteristics, treatment and follow-up. At each FU, the reason for FU (routine or symptomatic), specialist seen and imaging performed were recorded, until an event (recurrence or new primary) was diagnosed. The censor date was 31/12/2016. Analysis of FU included univariate chi-square tests for categorical variables, t-tests for continuous variables, multivariate logistic regression analyses, and Kaplan Meier survival curves.

Result:
Two-hundred-and-eighty-three patients (183 males, 100 females) were identified with a median age of 72(36-91) years. Eighty-four (29.7%) were Stage I, 47 (16.6%) were Stage II, and 152 (53.7%) were Stage III. Pathology was large cell in 91 patients (32.2%), squamous cell in 100 (35.3%), adenocarcinoma in 68 (24.0%), and NSCLC NOS in 24 (8.5%). One-hundred-and-sixty-five (56.5%) patients received radiotherapy alone and the remaining 123(43.5%) received chemoradiotherapy. The average frequency of FU visits per year was 5.12, median number of FU visits to first event was 6, and median time to first event was 11 months. 73.7% of FU were routine, while only 16.2% were symptomatic. 1641 imaging tests were performed, equating to an average of 5.8 scans per patient, with only 98 resulting in a diagnosis of an event. Overall, recurrences were diagnosed in 175 patients of whom 85 were symptomatic and 90 diagnosed on routine imaging. New primaries were diagnosed in 23 patients, 15 with symptoms and 8 on routine imaging. Subsequent treatment was curative in 25 (14.3%) patients with recurrent disease and 18 (85.7%) with new primaries. Univariate and multivariate analysis determined that the method of diagnosis of an event (symptomatic vs routine) had no statistically significant impact on the intent of further treatment (curative treatment 13.8% v 7.7%, p=0.089) or on overall survival (2y OS 49.5% vs 51.6%, p=0.772).

Conclusion:
Following curative radiotherapy, patients undergo frequent FU with regular imaging. Despite this only a minority of patients who develop recurrence are suitable for curative treatment. The use of routine imaging did not impact on further curative treatment or improve overall survival.

Background:
The microscopic extension, known as clinical target volume (CTV), of the primary tumor in locally advanced non-small cell lung cancer for chest radiotherapy planning has been well studied. However, the CTV of the primary tumor in limited-stage small cell lung cancer (SCLC) for thoracic radiotherapy planning has not been reported. In this study, we tried to quantify CTV of primary tumor in limited-stage SCLC with pathological approach.

Method:
Patients with stage T1-2N0-1M0 small cell lung cancer, treated with two cycles of etoposide plus cisplatin neoadjuvant chemotherapy or without neoadjuvant therapy were eligible for this study. Routine radical lobectomy and mediastinal lymph node dissection were performed for these patients. After operation, the intact lung lobe specimens were perfused with 10% neutral formalin and inflated as the natural state in the body. Specimens should be fixed for at least 12 hours. The fixed specimens were sectioned at 3mm thickness along the cross-sectional position of the body, and for each slice, the gross tumor and its surrounding 2cm lung tissue was embedded with paraffin and sliced with 4μm thickness. HE routine staining and CD56 immunohistochemical staining were applied. The slides were scanned by KFBIO reading software, and the pathologists confirmed the microscopic extension of the surrounding tumor. The minimal distances between microscopic nidus and the edge of gross tumor were measured.

Result:
Eight patients were enrolled, of whom 4 received 2 cycles of neoadjuvant chemotherapy and 4 received surgery without any neoadjuvant therapy. In patients who received neoadjuvant chemotherapy, one was diagnosed as squamous cell carcinoma after surgery and was excluded for further evaluation of CTV, while 1 patient achieved pathologically complete remission of tumor.The median range of CTV in patients received or did not receive neoadjuvant chemotherapy were 0.4mm (0.05mm-2.76mm) and 1.7mm (0.08mm-12.7mm) respectively, a margin of 1.4mm and 10.2mm could cover 95% of microscopic nidus (P=0.00).

Conclusion:
The preliminary results of this study indicated that to take into account 95% of the microscopic nidus, a 1.4mm and a 10.2mm margin should be need for CT-simulation based thoracic radiotherapy planning for limited-stage SCLC patients who were treated with or without induction chemotherapy. However, the sample size of this study was small and more cases are needed to justify the results.

Background:
The management of NSCLC-patients has evolved towards a more personalized care approach. Currently, the outcomes of concurrent chemoradiation (CCRT) in NSCLC patients are evaluated after the end of treatment, while individual treatment response during treatment is not taken into account. To pursue adaptive radiotherapy, it is important to distinguish responses during treatment and correlate this with outcome. Therefore, the aim was to identify subgroups that show a distinct treatment response during CCRT and correlate this with treatment outcome.

Method:
NSCLC-patients treated with CCRT between 2007-2013 were included. Treatment consisted of 66Gy/24 fractions with concurrent daily Cisplatin. Deformable image registration of the planning-CT to all Conebeam-CTs acquired during treatment was performed, and the gross tumor volumes on the ConeBeam-CTs were measured. Latent Class Growth Modeling was used to identify subgroups showing a distinct treatment response of the primary tumor during CCRT. Cox survival analysis was performed to assess the association of subgroup ‘membership’ with overall survival (OS) and progression free survival (PFS).

Result:
402 patients were included. Median follow-up was 63 months and median OS was 23 months (95%CI 20-26 months) and median PFS was 18 months (95%CI 15–21 month). Six different patterns of treatment response were identified (Figure1). Group 1&2 showed a relatively stable pattern during treatment. Group 5 showed tumor progression in the first week followed by sharp decrease in tumor volume. All other groups showed a decrease in tumor volume from start of treatment. Remarkably, the groups 1&5, that didn’t show a decrease in tumor volume from the beginning of treatment, had a significantly improved OS and PFS. Figure 1



Conclusion:
Six groups showing a distinct treatment response during CCRT were identified. This is an important finding to be able to pursue adaptive radiotherapy. First analyses revealed an association between tumor response during treatment and OS and PFS. In-depth analyses are warranted.

Background:
In Bangladesh lung cancer stands in the top 3 in both male & female patient. Most of the patients are diagnosed as advanced stage. Radiotherapy plays an important role in the management of lung cancer. Motion management is a big challenge in GTV & ITV delineation, RT planning and minimizing the dose to OAR (Organ at risk). In Bangladesh there are 18 LINAC (12 in private & 6 in Govt. centers) is available. But, only one centre has the facility to do 4DCT simulation (United Hospital Limited). So it is time to consider that slow CT (computerized tomography) simulation can help to delineate GTV more precisely than axial CT simulation in Radiation Center of a developing country like Bangladesh.

Method:
: In this study we included ten case of carcinoma of primary lung who have been treated using Radiotherapy. Most of the patients are in stage II or stage IIIA. All patients were treated with Radiotherapy In 3DCRT technique concurrently weekly cisplatin 30mg/m2. All the patients were underwent went 4 modes of CT scan Axial, Helical, Slow & 4D-CT using GE discovery 16 Slice PET-CT scanner. And KV-CBCT for the treatment verification was taken at regular interval. For standardization all the patients underwent different mode of scan using 2.5mm slice thickness and. Slow CT were performed using axial mode scan by increasing the CT tube rotation time as per the breathing period. In 4D-CT scan Respiratory cycle was divided in to 10 phases and scans were performed throughout the entire respiratory cycle. Maxmium Intensity Pixel (MIP), Minimum Intensity Pixel (MinIP) & Average Intensity Pixel (AvIP) were derived from the 10 Phases. GTV or ITV volumes were delineated for all the patients in all the scan modes (ITVAX - Axial, ITVSP - Spiral, ITVSl– Slow, ITVMIP - 4DCT) in the treatment planning system All the GTV or ITV volume were measured, documented and compared with the different modes of the CT scan. We have also done 4 modes of CT scan in moving phantom too. Phantom volume was delineated in all modes of scan (MIP, Slow, Axial and Helical) in treatment planning system and the difference in volume was compared.

Result:
The mean ± sd (range) for MIP, slow, axial, & helical were 36.5 ± 40.5 (2.29-87.0), 35.38 ±39.52 (2.1 – 82), 31.95 ± 37.29 (1.32 – 66.9) & 28.98 ± 33.36 (1.01 – 65.9. Overall underestimate of helical scan and axial scan compared to MIP is 21% and 12.5%. CBCT and slow CT volume has a good correlation with the MIP volume. Ratio of 4DCT and Slow CT scan is 0.97. While we compare volumes (Ratio) of moving phantom of different modes of CT scans, the findings were MIP 50.29cc (1.0), Slow CT 48.83cc (0.97), Axial 35.6 cc (0.71) and Helical 31.68 cc (0.63). Volume comparison in moving phantom also showed good correlation and match in both 4DCT and Slow CT scan. From this study we can draw inference that Slow CT volume has a very good correlation with the MIP volume, the ratio of the Slow CT vs MIP is 0.97 ± 0.12, where as The ratios of GTV(MIP) to GTV (Axial) and GTV(helical) were 0.87 ± 0.14 and 0.79 ± 0.12, respectively, which showed a marked difference in GTV volumes.

Conclusion:
Though, it was limited number of patients in this observational study. But, it showed a very crucial finding to improve the GTV or ITV delineation and to limit the dose to OAR. As slow CT Scan can be done in any CT simulator machine, where there is no facility to do 4DCT scan. Although, 4DCT scan is a gold standard for GTV delineation for the motion management of lung cancer, but, in the absence of 4DCT scan, slow CT can be used. We should need multiple centers, large number of patients’ data to validate this finding

Background:
The literature on dose-volume parameters and pneumonitis is extensive, whose results are inconsistent, both for the best predictive metrics and significant comorbid factors. To develop an improved functional equivalent uniform dose (fEUD) with perfusion factors of single photon emission computed tomography (SPECT) images as predictors of radiation peneumonitis (RP) in patients undergoing curative radiotherapy (RT).

Method:
Figure 1Functional lung imaging was performed using single photon emission computed tomography (SPECT) for perfusion imaging. Perfusion factors were defined as the mean percentile perfusion levels of the four areas of the top to 75%, 75% to 50%, 50% to 25%, 25% to 0%, respectively. fEUD were calculated from perfusion factors in computed tomography (CT) and SPECT fused images and standard dose-volume parameters were extracted from radiotherapy treatment planning. Total lung (TL) volumes minus GTV, V5 and V20 (the percentage of normal lung tissue receiving more than 5Gy and 20Gy), fEUD (equivalent to 2Gy/fx, α/β=3.3, a=1), and mean dose of TL were analyzed to evaluate correlations between RP, which was evaluated using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Statistical significance was defined as a P-values of <.05.



Result:
A total of 28 patients treated with intensity modulated RT or 3D conformable RT were analyzed, grades≥3 RP were observed in 6 patients. There was only a significant difference in fEUD between patients with RP and free (p=0.007). Insignificant tendency of difference was showed in the mean dose of TL (p = 0.052). V5 and V20 of whole lung were almost identical between the two groups (p=0.161 and 0.197), as the most values are below the recommended thresholds from published papers.

Conclusion:
SPECT-based equivalent uniform dose presented more significant to predict RP compared to standard dose–volume parameters and mean dose.

Background:
Early Stage lung cancer can be treated with surgical resection and SABR. In clinical practice, it may be important to find a characteristic matrix for precision radiotherapy. The characteristic matrix for a lung tumor should include: 1) a time factor that incorporates the motion pattern of the tumor, 2) spatial factor which is related to volumetric information including location and surrounding environment, and 3) intrinsic characteristics which are related to the biologic information and could be represented by imaging characteristics. In this investigation, the typical heterogeneous characteristics matrix of lung tumors treated with SABR were studied.

Method:
A total of 38 patients with 41 lung tumors were retrospectively reviewed. All targets were treated with SABR. 4-Dimensional Computed Tomography (4DCT) was used for simulation. The time factor parameter was defined by the breathing cycle signal recorded by an infrared reflector. The internal target volumes (ITV) were generated by the cine image set through phase binning method. The intrinsic characteristics of tumors were described by the image information inside the tumor, which was represented by the ITV. This target image information was described by the minimum Hounsfield Unit (HU), maximum HU, mean HU, and standard deviation.

Result:
For spatial location, there were 23 tumors in the right lung and 18 tumors in the left lung. For phase surrogate signal, the mean amplitude was 0.7 cm with standard deviation (SD) = 0.3 cm. Mean breathing cycle was 3.5 seconds (SD = 1.1). Mean prescription isodose volume (PIV) was 38.3 cc (SD = 37.7) and the mean corresponding diameter was 3.8cm (SD = 1.1cm). Mean ITV volume was 13.4 cc (SD = 20.4) and the corresponding diameter was 2.4 cm (SD = 1.2). With regard to imaging information, ITV minimum HU was -883.1 (SD = 120.3); ITV maximum HU was 222.3 (SD = 487.9); ITV mean HU was -224.9 (SD = 188.2). PTV minimum HU was -937.1 (SD = 62.2); PTV maximum HU was 437.1 (SD = 506.1); PTV mean HU was -482.3 (SD = 192.6).

Conclusion:
A characteristics matrix was computed for SABR treated lung tumors based on time, imaging, and spatial information. The matrix could be further expanded and assessed for intra-fractional and post treatment analysis. Other imaging modalities such as MRI and incorporation of immune system stimulation mechanisms can be combined with big data analysis methodologies for patient treatment options in precision medicine through similarity matching.

Background:
Despite wide adoption of intensity-modulated radiation therapy (IMRT), thoracic re-irradiation of lung cancer has been challenged by the tolerance doses of normal tissues such as lung and esophagus. We retrospectively analyzed the local control rate and the toxicity of thoracic re-irradiation using highly conformal radiotherapy.

Method:
Between September 2008 and November 2015, 50 patients received thoracic re-irradiation with 3D conformal therapy (n=6, 12%), linac-based IMRT (n=11, 22%), helical tomotherapy (n=31, 62%), and stereotactic body radiotherapy (n=2, 4%). Total lung mean dose (~Total~D~mean~) was calculated by the sum of lung D mean of initial radiotherapy (RT) and that of re-RT.

Result:
Twenty-two patients had distant metastasis at the time of re-RT. Median follow-up time was 14.0 months (range; 1.4 - 65 months) from re-RT. At the time of analysis, local progression after re-RT was observed in 40% (n=20) of patients. The 1-year and 2-year local progression-free survival (LPFS) were 60.3% and 47.1%, respectively. Median time to local progression was 8.5 months (range; 1.4 - 65 months) and median survival from re-RT was 13.9 months (range; 1.4 - 65 months). Median total dose was 70.3Gy (range; 33 - 131 Gy) with median fraction size of 2Gy (range; 1 - 10.9 Gy). Local control rate of 3D-conformal RT and that of IMRT was 50% and 61.4%, respectively. When we compared the LPFS of patients who received re-RT using IMRT, smaller PTV volume was associated with greater LPFS with marginal significance: the 1-year LRFR of PTV<57.5 cm[3 ]and PTV≥57.5cm[3]were 74.5% and 51.7%, respectively (p=0.054). Acute grade 1 and 2 radiation pneumonitis were observed in 16% (n=8) and 10% (n=5), respectively. No acute grade 3 or higher radiation pneumonitis occurred. ~Total~D~mean~of patients with and without acute radiation pneumonitis showed significant difference: 14.8Gy with acute radiation pneumonitis and 12.0Gy without acute radiation pneumonitis (p=0.048). Acute grade 2 esophagitis was observed in 6 patients (12%), and no grade 3 or higher esophagitis occurred. Chronic grade 2 radiation pneumonitis occured in 5 patients, and no chronic grade 3 or higher complications was observed

Conclusion:
The stratification of patients receiving thoracic re-RT is crucial in extending the indications and improving the efficacy of IMRT. Based on appropriate stratification, thoracic re-RT of lung cancer can be safely delivered using highly conformal radiotherapy with excellent local control and acceptable toxicity.

Background:
A potential benefit of integrating MR imaging in the radiotherapy planning and treatment process is the improved soft tissue contrast. However, this benefit may be obscured if there are substantial variations in the way that both target and organs at risk (OARs) are contoured, either at the time of initial simulation or at each fraction. The aim of this work is to develop standardised MR imaging sequences for target and OAR contouring in lung cancer patients for integration into the planning and treatment process for MR image-guided radiotherapy.

Method:
11 lung cancer patients were recruited across 3 European centres using a standardised MR protocol with various soft tissue contrasts as well as numerous respiratory management techniques. All MR images were acquired at 1.5 T with 3.5 mm slice thickness. 7 radiation oncologists and 3 radiologists reviewed the MR images alongside CT and FDG-PET-CT, rigidly registered to tumour area, to determine the most adequate sequences for OAR and tumour visualisation/delineation.

Result:
The most adequate MR sequences were found to be: Radial 3D T1, Turbo Spin Echo (TSE) fat-suppressed (fat-sat), DIXON TSE and T2 TSE (table 1). The sequences aided in visualisation of tumour, nodes and OARs including oesophagus, proximal bronchial tree, trachea, heart, lungs, spinal cord/canal and brachial plexus. The TSE (fat sat) and DIXON TSE gave strong signal from tumour, nodes and brachial plexus, aiding in their visualisation. The motion averaging characteristics ofthe Radial 3D T1 improve image consistency over slices, whereas the TSE sequences can include motion induced distortions.

Table 1. The most adequate sequences identified for tumour, node and OAR visualisation. These sequences have been acquired with varying contrast and different respiratory management techniques.

Sequence	Respiratory Management	Purpose	Coverage
Radial 3D T1 (fat sat)	Radial k-space sampling	Tumour, nodes, OARs, spatial reference	Ful thorax
TSE (fat sat)	Respiratory triggered	Tumour, nodes, OARs	Tumour (if tumour below aortic arch)
DIXON TSE	Multiple signal averages	Brachial plexus, tumour, nodes	Tumour and Brachial Plexus (if tumour above aortic arch)
T2 TSE	Respiratory triggered	Tumour, nodes, OARs	Full thorax

Conclusion:
A set of MR sequences suitable for lung cancer radiotherapy planning have been identified which provide adequate visualisation of tumour, nodes and OARs. The next step is to acquire these sequences in a set of patients and assess intra-/inter-clinician variability in target and OAR delineation, and develop an MR lung contouring atlas.

Background:
Early mortality after (chemo)radiotherapy can be caused by treatment-related toxicities and thus by delivered doses to normal lung and heart tissues. However, prediction models for mortality incorporating dosimetry are lacking. This study explores the prognostic value of common dosimetric features.

Method:
Two prospective cohorts containing 218 and 181 curatively treated stage I-III lung cancer patients from 2003-2007 and 2013-2016 periods, respectively, were studied. Prescribed dose was 66Gy/2Gy (concurrent chemotherapy), 66Gy/2.75Gy (sequential or no chemotherapy) or a similar schedule. Clinical (WHO performance status, age, T stage, N stage and primary gross tumor volume (GTV)) and dosimetric (mean lung dose (MLD) and mean heart dose (MHD)) covariates were analysed. Cox regression models of survival and a logistic regression model for the 12 month mortality endpoint were optimized using forward stepwise selection (p<0.05).

Result:
Median follow-up time was 80.2 and 20.2 months in dataset 1 and 2, respectively. MHD (HR=1.023, p=0.001) and WHO performance status (HR=1.25, p=0.03) were selected in the Cox model for dataset 1. Tumor volume (HR=1.0015, p=0.001), WHO performance status (HR=1.023, p=0.02) and MHD (HR=1.0030, p=0.03) were selected in dataset 2. Adding time-dependent covariates revealed a decreasing GTV HR over time in dataset 1 (p=0.02), while MHD risk did not significantly change with time. Worse survival observed in a high MHD subgroup indeed only starts after 8 months (Figure 1). 12 month survival modeling included the covariates MHD (optimal cut-off 22Gy) and GTV (AUC=0.71). In dataset 2, these covariates and cut-off resulted in a model with AUC=0.63. Figure 1



Conclusion:
Mean heart dose is an independent risk factor for early mortality in two cohorts with different treatment periods and techniques. The best classifier for 12 month mortality risk was obtained with the MHD<22Gy constraint, which could be used in model-based implementation of proton therapy.

Background:
A large proportion of patients with locally advanced/metastatic Non-Small Cell Lung Cancer (NSCLC) present disease progression despite aggressive treatments and will further receive immunotherapy. Pneumonitis is an uncommon but potentially fatal toxicity related to immunotherapy treatment. The association with the history of radiotherapy and the risk of developing pneumonitis have not been well described. We associated the history of radiotherapy with the development of pneumonitis in patients receiving immunotherapy.

Method:
Clinical information was retrospectively obtained from histologically confirmed advanced NSCLC patients treated from February 2013 to February 2017. Clinical and radiologic features of pneumonitis were collected from patients receiving immunotherapy. We sought associations between pneumonitis incidence and clinical characteristics.

Result:
Of 59 patients who received immunotherapy 61.7% were treated with nivolumab, 29.9% with pembrolizumab and 6.7% with the combination durvalumab plus tremelimumab. Immunotherapy treatment was administered in first line in 26.6% of patients, 28.3% received in second line and 36.7% in third or more line of treatment. Twenty-five of the 59 patients (41.7%) received previous radiotherapy, 16 of them (26.7%) to the lung and 9 (15%) to the thoracic spine. Fifteen (15/59) patients (25%) developed pneumonitis; this occurred irrespective of line of therapy in which immunotherapy was received (first line: 38.5%; second line: 33.5%; third line or more: 26.7%). No association was found between line of treatment and pneumonitis development. Median time from therapy initiation to pneumonitis was 4.5 months (range 18 days - 13.1 months). For any grade of pneumonitis, the percentage was of 25% (15 patients) of which 48% (12/25) had received radiotherapy, Grade >2 pneumonitis was seen in 10 patients (17%) and 32% (8/25) had history of radiation therapy. All Grade 3 pneumonitis events (n=4) presented in patients with previous lung radiotherapy. The incidence and severity of pneumonitis was higher in patients who had received radiotherapy (OR, 95% CI: 6.8 (1.6 – 28.5); p=0.009).

Conclusion:
The incidence of pneumonitis related to immunotherapy treatment could be underestimated. We observed an increase in the risk and severity of pneumonitis in patients with previous radiation therapy and subsequent treatment with immunotherapy, regardless of used drug or line of therapy. In these patients, we recommend close clinical and radiologic follow-up.

Background:
At our institution, we commonly treat brain metastases (BM) adjacent to critical structures with a smaller dose prescription (DP) to reduce the likelihood of toxicity. We sought to evaluate the impact of DP on LF and RN for small- to medium-sized BM (≤ 2 cm) from lung cancer.

Method:
A prospective registry of BM patients treated with gamma knife SRS between 2008 and 2016 was interrogated to determine per lesion rates of LF and RN. Each lesion was followed until LF or RN or at last MRI follow-up. Defined criteria were used to differentiate LF from RN. Whole brain irradiation (WBI) was a censoring event.

Result:
From 1,465 potential subjects, 345 small- to medium-sized BM from 151 lung cancer patients were evaluated. Median radiographic follow-up was 10.2 months. Median lesion volume and diameter were 0.17 cm[3], and 0.81 cm, respectively. The DP for 71 lesions (21%) was 15 Gy, and ≥ 20 Gy (median 21 Gy; 20-24Gy) for 274(79%). Most lesions were ≤ 1 cm (65%). Median number of SRS was 2 (1-4) and 36 patients received salvage WBI. Sixteen lesions (4%) developed LF and 12 (3%) developed RN. Freedom from local failure at 1 year (FFLF) for 15 Gy, and ≥ 20 Gy, was 80%, and 95%, respectively (p=0.02). FFLF for lesions ≤1cm, and >1 cm, was 95%, and 78%, respectively (p<0.01). Freedom from RN at 1-year (FFRN) for DP 15 Gy, and ≥ 20 Gy, was 98%, and 96%, respectively (p=0.3). FFRN for lesions ≤ 1cm, and > 1 cm, was 98%, and 93%, respectively (p=0.01). FFLF and FFRN for lesions ≤1 cm and >1 cm, according to DP, are shown in Table 1.

	Lesion size
	≤1 cm		P value	>1 cm		P value
	DP			DP
	15 Gy	≥20 Gy		15 Gy	≥20 Gy
FFLF	88.8%	96.4%	0.42	53.4%	88.2%	0.08
FFRN	100%	98%	--	98%	92%	0.43

Conclusion:
Our results suggest that, particularly for lesions >1 cm, DP ≥ 20 Gy correlates with improved FFLF, and similar FFRN rates, compared to DP 15 Gy.

Background:
Stereotactic body radiotherapy (SBRT) is the standard of care in patients with medically inoperable early stage NSCLC and an effective method of treatment of lung metastases (LM) in oligometastatic patient.We evaluated local control (LC), overall survival (OS), cause-specific survival (CSS), and related toxicity in the both group of patients treated in our center.

Method:
Between April 2012 and September 2016, 107 lung lesions were treated with SBRT; 62 early NSCLC(58%) and 45 LM(42%). Three risk-adapted fractionation schemes that ensure DBE>100Gy were considered: 3x18Gy, 5x11Gy and 8x7.5Gy. Kaplan-Meier(KM) curves were used to evaluate LC,OS and CSS. We analyzed toxicity and predictive factors.

Result:
The median follow-up was 16 months(range 6-44). For primary NSCLC: LC,CSS, and OS at 2 years were 100%,91% and 64%, respectively.19 patients died, 5 because of a lung cancer and 14 due to concurrent disease. Regional relapse was observed in five patients(7.6%).Six patients(9.2%) developed distant metastases. There was no statistically significant difference in OS and CSS when comparing peripheral-central tumors or T1-T2 tumors. However, T2 and central tumors showed lower survival rates. For lung metastatic lesions: LC,CSS, and OS at 2 years were 69%, 66% and 66%, respectively.The primary tumors were:colorectal 17(38%), lung 15(33%) and others 13(29%).There was no statistically signficant difference in survival among primary tumor or 1-3 metastatic lesions, but colorectal primary tumors and more than one lung metastases had lower survival.We compared LC and CSS in both group of patients. There was a statistically significant difference in local control(p=0.002) and CSS(p=0.027) among the primary tumors or lung metastases(Figure 1).According to RTOG,≤G2 lung and skin acute toxicity was 5% and 3% respectively.Lung late toxicity ≤G2 was 22.4%. No patients developed >G2 toxicities. Figure 1



Conclusion:
With a 2-year LC rate >95% with limited toxicity, SBRT confirms as state-of-the-art treatment for medically inoperable early stage NSCLC and effective options for oligometastatic patients.

Background:
The aim of this study was to perform a survival comparison between stereotactic body radiotherapy (SBRT) and sublobar resection (SLR) in patients with stage I non-small cell lung cancer (NSCLC) at high risk for lobectomy.

Method:
All patients who underwent SBRT or SLR because of medical comorbidities for clinical stage I NSCLC from January 2008 to December 2015 were reviewed retrospectively. Propensity score matching was performed to reduce selection bias between SBRT and SLR patients based on age, gender, performance status, tumour characteristics, pulmonary function. Overall survival (OS) and recurrence-free survival (RFS) were estimated with Kaplan–Meier method.

Result:
Forty-nine patients were matched into each group of SBRT and SLR (include 27 underwent segmentectomy, 22 underwent wedge resection). There were 32 and 30 men with median age of 67 and 69 years, respectively. Median follow-up was 25 months. In terms of treatment-related mortality, the 30- day mortality rates for the SBRT and SLR groups were 0 and 2.0 %, respectively. Patients treated by SBRT had a tendency to increase 3-year OS compared with SLR (94.0% versus 78.1%; P= 0.064).There was no difference between two groups in 3-year RFS (61.8% versus 65.7%; P=0.864). In a subanalysis, 3-year OS after SBRT was greatly better than wedge resection subgroup (94.0% versus 67.4%; P= 0.026), but there was no significant difference between SBRT and segmentectomy in 3-year OS (94.0% versus 88.0%; P= 0.212).

Conclusion:
SBRT had a tendency to increase OS compared with sublobar resection in patients who are not medically fit for lobectomy with clinical stage I NSCLC. However, OS after SBRT was better than wedge resection subgroup. SBRT can be an alternative treatment option to segmentectomy for patients who cannot tolerate lobectomy because of medical comorbidities. A randomized prospective study is necessary to determine survival in compromised SBRT and sublobar resection.

Background:
Radiotherapy is carried out five days in a week. Endostar is a target drug, its adminstration is d1-14 in three weeks. We changed endostar adminstration mode as the same of radiotherpy, five days in a week. Now we evaluate the efficacy and safety of different administration dose of endostar combined with concurrent chemoradiotherapy in ad vanced non-small cell lung cancer(NSCLC).

Method:
From September 2010 to December 2015，40 patients with local advanced NSCLC were recruited. All the patients received radiotherapy with 60Gy and two circles chemotherapy with docetaxel 75mg/m[2] d1 and cisplatin 75mg/m[2] d1～3，combined with two different administration dose of endostar(75mg/m[2] d1-14 in three weeks for two cycles and 75mg/m[2] d1-5 in one week for six cycles concurrent with radiotherapy. Tumor response were evaluated with RECIST1.1 criteria. Acute toxicities were evaluated with NCICTC3.0 and RTOG criteria.

Result:
In group one，2 patients achieved complete response，10 partial response，3 stable disease，5 progressive disease. Overall response rate was 60%. The 1-year progressive-free-survive rate was 40%. The 1-，2-year survival rates were 70% and 25%. The median overall survive is 19.9 month. In group two，overall response rate was 75%. The 1-year progressive-free-survive rate was 50%. The 1-，2-year survival rates were 80% and 45%. The median overall survive is 22.7 month. In group 2 there had a good survival and patient compliance, but there were no significant difference between two groups (P>0.05).

Conclusion:
Endostar combined with concurrent chemoradiotherapy is useful and well-tolerance. Administration mode of endostar combining with chemoradiotherapy, which is five day in a week for six weeks, had a better result and patient compliance.

Background:
To analyse the relation between clinical outcomes and dosimetric indices for SBRT lung treatments.

Method:
96 lung lesions were treated with SBRT(6MV photons 3DCRT). Planning CT included whole lung. 4DCT of tumor area was used to obtain a MIP-based ITV, with three risk-adapted fractionation schemes [3x18Gy, 5x11Gy, 8x7.5Gy(BED>100Gy)]. In treatment delivery the tumor was centered online using CBCT and its movement validated by fluoroscopy adjusting the gating limits to the breathing amplitude. Toxicity and dosimetric indices for PTV and OAR were evaluated and correlated with the clinical outcomes 6 months after radiotherapy

Result:
Table1 shows the dose constraints as well as the results of the dosimetric indices. It was found that 95%/75% of the patients developed G=0 acute/late toxicity, 3%/0% G=2 acute lung/skin toxicity, 3% G=2 late lung toxicity and no patients developed G>2 toxicities. Figure 1 displays the correlation between V~100~, V~90~, CI and the clinical outcomes after 6 months of radiotherapy. Only the CI was statistically significant(t-test p=0.017) as an indicator of the ratio between complete/partial responses(mean CI=1.1/1.05) Figure 1 Figure 2





Conclusion:
The lung SBRT technique is safe(no G> 2 toxicity has been reported) even for cases with OAR compromise. The CI has been statistically significant as a predictor of complete tumor remission at 6 months.

Background:
Continuation of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR TKI) in stage IV Non-small cell Lung cancer (NSCLC) patients harboring sensitive mutation (Exon 19 deletion /Exon 21 L858R mutation) upon first progression according to RECIST criteria were shown to be effective in ASPIRATION study and can prolong the use of EGFR TKI for 3 months till frank disease progression. Local ablative radiotherapy (LAR) on oligo-progression is increasingly advocated but the actual effect is to be determined.

Method:
Medical and radiotherapy records of patients given LAR from 2012-2017 were screened at a single centre. Patients with stage IV NSCLC harboring sensitive epidermal growth factor receptor (EGFR) activating mutations having extra-cranial oligo-progression and given LAR were included in the study. Patients’ demographics, site of oligo-progression, radiotherapy sites and dose/fractionation schedules were captured. Durations from starting of first line EGFR TKI to LAR was calculated (PFS1). Local progression free survival (L-PFS), overall progression free survival from LAR to further progression that led to stop of EGFR TKI (O-PFS) and overall survival (OS) were analyzed with Kaplan-Meier method.

Result:
There were 15 eligible patients with total 17 sites of oligo-progressive sites treated. There were 6 male and 9 female patients. The mean age was 59.6 years (36.5-82 years). All were treated with first-generation EGFR TKIs. The median duration PFS1 was 13.0 months (6.0-36.1 months). Treatment sites included 13 lung lesions and 4 bone lesions. The mean equivalent dose (2Gy) was 105Gy (64.5-122Gy). The median follow up time was 13.3 months. Ten out of 15 patients had CEA drop after treatment, with the median duration from treatment to first drop of CEA being 1.7 months. The median L-PFS and OS were not reached. The median PFS2 was 9.7 months (2.2-15.1 months). Eight out of 10 patients had second line/ third line treatment with either afatinib/ osimertinib chemotherapy or immunotherapy. Toxicities of radiotherapy were minimal and only grade 1 pneumonitis or pain flare documented. Duration of PFS1 was not found to affect duration of O-PFS.

Conclusion:
LAR appears to be a reasonable treatment approach in the event of oligo-progression in patients with advanced NSCLC harboring activating EGFR mutations. Longer follow-up and a larger cohort are underway to assess its impact on survival.

Background:
Small-cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers, and is characterized as being extremely aggressive, often displaying rapid tumor growth and multiple organ metastases. In addition, the clinical outcome of SCLC patients is poor due to early relapse and acquired resistance to standard chemotherapy treatments. Several molecular targeted therapies were evaluated in SCLC; however, they failed to improve the clinical outcome. The receptor tyrosine kinase MET is a receptor for hepatocyte growth factor (HGF). Although aberrant activation of HGF/MET signaling is known as one of the crucial mechanisms enabling cancer progression and invasion, the mechanisms in SCLC have not been elucidated clearly. The aim of the present study was to evaluate the effect of inhibiting the HGF/MET pathway on tumor progression in SCLC with multi-organ metastasis.

Method:
We used eight human SCLC cell lines to elucidate the effect of MET inhibition on tumor progression. MET inhibitors, crizotinib and golvatinib, were used in this study in vitro and in vivo.

Result:
We found that the HGF/MET signaling was aberrantly activated in chemo-resistant or chemo-relapsed SCLC cell lines (SBC-5, DMS273, and DMS273-G3H) by the secretion of HGF and/or MET copy number gain. HGF/MET inhibition, induced either by MET inhibitors (crizotinib and golvatinib), or by siRNA-mediated knockdown of HGF or MET, constrained growth of these SCLC cells via the inhibition of ERK and AKT signals. We also revealed that treatment with either crizotinib or golvatinib in vivo suppressed the systemic metastasis of SBC-5 cell tumors in NK cell-depleted SCID mice, predominantly via cell cycle arrest.

Conclusion:
These findings reveal that the therapeutic potential of targeting the HGF/MET pathway for inhibition, to constrain tumor progression of SCLC cells exhibiting aberrant activation of HGF/MET signaling. We suggest that it would be clinically valuable to further investigate HGF/MET-mediated signaling in SCLC cells.

Background:
Small Cell lung cancer (SCLC), which belongs to neuroendocrine tumor (NT), is known for its highly aggressive clinical features and poor prognosis. The molecular underpinnings that may prognosticate survival and could increase our understanding of tumor development and progression are still poor understood in its highly aggressive malignancies. We aimed to describe the proteomic characteristics and biomarker profiling of high-grade NT, SCLC versus low-grade NT, carcinoid tumor (CT) by the state-of-the-art proteomics techniques utilizing clinical specimens.

Method:
In order to obtain the molecular-based differences between SCLC and CT, we performed proteomic analyses for these histological types in lung NTs. Based on definite histological diagnosis, cancerous cells were collected by laser microdissection from FFPE tissues of 6 patients each with SCLC and CT. To elucidate their protein expression profiles, a mass spectrometry-based quantitative proteomic analysis was conducted. After the different profiles were identified using a hierarchical clustering, we applied protein-protein interaction (PPI) network and gene-set enrichment analyses to assess how significantly proteins are expressed and which molecular pathways are activated in SCLC and CT.

Result:
A total of 1,991 proteins were identified from cancerous cell in FFPE tissues throughout these NT subtypes. By hierarchical clustering of the protein expression profiles, 12 cases were clearly classified into two groups of 6 SCLC and 6 CT. We finally identified 11 for SCLC and 44 for CT as tumor-specific proteins, respectively. In brief, our curation-based analysis of PPI networks built from proteins expressed significantly in SCLC cells has revealed that the activations of both mismatch repair system, and its resulted cell cycle pathway but suggested a fatal failure in disruption of mismatched DNA sequences, which suggested an occurrence of carcinogenesis progression simultaneously with an activity trying to return to normal, and which might suggest a heterogeneity of SCLC cells. Proteins expressed significantly in CT cells were the molecules known representatively as the biomarkers of NTs such as neurosecretory protein VGF, chromogranin-A, secretogranin-1 and -2. Besides those, we have found that the certain key network modules controlling cellular proliferation and apoptosis, affecting a series of pathways, as well as regulating genomic instability and DNA damage and repair, which also promotes cell transformation and tumorigenesis.

Conclusion:
Our clinical proteomic profiling of both SCLC and CT revealed their corresponding nature of aggressiveness and extent of prognosis, and detailed curation of PPI networks of interestingly suggested candidates of their therapeutic targets, which might reflect their disease mechanisms.

Background:
SCLC has a high response rate to first line chemotherapy but this is often short lived. Patients who relapse six months after first line chemotherapy can be retreated with platinum +/- etoposide and patients that relapse early are treated with CAV (cyclophosphamide, doxorubicin and vincristine), Topotecan or best supportive care (BSC). There have been no clinical trials comparing oral Topotecan with iv CAV.

Method:
A retrospective case note review was undertaken of 296 SCLC patients who received second line chemotherapy for recurrent SCLC in the West of Scotland. Results were analysed using STATA version 14.

Result:
SCLC patients that relapsed after first line platinum-based chemotherapy received CAV (n=161), platinum +/-etoposide (n=61), oral topotecan (n=67) and 7 patients received other cytotoxic agents. Median survival for patients who received CAV was 5.1 months (CI 4.1 – 5.7), 6.3 months (CI 5.2-8.6) for platinum/etoposide and 3.0 months (CI 1.9-3.6) for Topotecan. As expected platinum +/- etoposide was superior to CAV (Log rank p = 0.016) and Topotecan (p <0.0001), as these patients had demonstrated platinum sensitivity. CAV appeared superior to Topotecan (p = 0.001) and was better tolerated. 79% of Topotecan patients required a dose reduction versus 29% of CAV patients. 16% of Topotecan, 8% of CAV and no platinum +/- etoposide patients died within 30 days of receiving chemotherapy. 39% of Topotecan and 19% of CAV patients experienced either neutropenic sepsis or myelosuppression requiring a dose reduction or dose delay. There was no difference in time to progression after first line chemotherapy in the CAV and Topotecan populations. Figure 1



Conclusion:
In this West of Scotland retrospective data collection, patients treated with oral Topotecan appear to have a lower median overall survival and experienced more toxicity than those receiving iv CAV.

Background:
Small-cell lung cancer (SCLC) is a devastating illness with a median five-year overall survival of 5%. Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase which regulates integrin and growth factor signaling pathways involved in cell proliferation, survival, migration, and invasion. FAK is overexpressed/activated in many cancers, including SCLC. We hypothesized that FAK overexpression/activation in SCLC contributes to its aggressive behavior and that FAK may represent a novel therapeutic target in SCLC.

Method:
Two SCLC cell lines, one growing in suspension (NCI-H82) and one adherent (NCI-H446), were treated with a FAK small-molecule inhibitor, PF-573,228 (PF-228) (1 to 5µM), or stably transfected with FAK shRNA and/or FAK-related non kinase (FRNK) domain (doxycycline-inducible) using lentivirus vector. Cell proliferation, cell cycle, apoptosis, motility, and invasion were studied by standard methodologies. FAK expression/activity was evaluated by WB. Active Rac1 expression was evaluated by WB after enrichment of cell lysates in active GTP-bound Rac using Rac pull down columns.

Result:
PF-228 decreased FAK activity by decreasing phospho-FAK (Tyr397) expression in both SCLC cell lines, without modifying total FAK expression. This induced significant inhibition of cell proliferation and DNA synthesis, cell cycle arrest in G2/M phases, and increase of apoptosis dose-dependently. PF-228 also decreased motility in the adherent cell line NCI-H446. Transfection of FAK shRNA decreased total and phospho-FAK expression but this did not affect cell proliferation, DNA synthesis, and cell cycle. We hypothesized that the absence of anti-proliferative effects was due to the loss of the FAK-targeting domain (FAT), normally attached to the focal adhesion complex where it inhibits other proteins supporting proliferation (such as Rac). To test this, we restored FAT function by transfecting FRNK, a physical repressor of FAK activity, into cells stably transfected with FAK shRNA and demonstrated inhibition of cell proliferation and DNA synthesis. Expression of FRNK in SCLC cell lines not previously transfected with FAK shRNA also significantly decreased cell proliferation and DNA synthesis. Moreover, FAK shRNA transfection increased active Rac1 levels, while FRNK re-expression in the cell lines previously transfected with FAK shRNA decreased it.

Conclusion:
This work demonstrates that FAK has a dual role in SCLC: 1/ it supports proliferation, migration, invasion, and inhibits apoptosis through the kinase domain, suggesting that inhibition of FAK kinase activity may represent a suitable therapeutic target for SCLC, and 2/ it inhibits SCLC proliferation through the non-kinase C-terminal domain FRNK, which keeps Rac inactive.

Background:
Scotland has one of the highest incidences of SCLC globally (cancerresearchuk.org). Lung cancer is the leading cause of cancer related deaths in the UK (cancerresearchuk.org), with SCLC having a worse prognosis than NSCLC and fewer treatment options. Initially, SCLC has a high response rate to first line chemotherapy but rapidly becomes resistant to chemotherapy. There is little evidence to support and guide third line chemotherapy regimens. A West of Scotland (WoS) retrospective database (2007 to 2013) has been developed to gain useful insights into this aggressive disease to improve patient outcomes.

Method:
A retrospective case note review was undertaken of 1325 SCLC patients from the WoS. 58 patients were identified as receiving third line chemotherapy. Information was collected regarding radiological staging, performance status (PS), treatment history, time to progression and survival. Results were analysed using STATA version 14.

Result:
17% of SCLC patients in this WoS database received no chemotherapy, 60% one line (n= 801), 22% (n= 296) two lines, 4% (n=58) three lines and 0.004% (n= 6) four lines of chemotherapy. Of the 58 patients that received third line chemotherapy 28 had Topotecan, 17 CAV, 7 platinum +/- etoposide and 6 included a variety of other cytotoxics. For all patients receiving third line chemotherapy the median survival was 4.7 months (CI 4.1-5.3) and progression free survival was 3.0 months (CI 2.5 – 3.6). Median survival was 3.5 months (CI 2.6- 5.6) for Topotecan, 4.1 months (CI 2.7-5.0) for CAV and 9.0 months (CI 1.8-12.2) for platinum +/ etoposide. 32 (55%) patients received 3 different regimens for each line of chemotherapy, 25 patients (43%) received a platinum-based chemotherapy regimen twice and 1 patient received a platinum based regimen all three lines of chemotherapy. Only 2 patients received a clinical trial novel treatment for their third line therapy.

Conclusion:
SCLC continues to have a poor prognosis with few patients receiving three lines of chemotherapy. The patients that maintain some sensitivity to platinum based chemotherapy tend to have a marginally better response to third line therapy. Clincial trial opportunities for this group of patients were limited. Patients should be enrolled in clinical trials wherever possible.

Background:
Metastasis are responsible for the death of 90% of patients with lung cancer (LC) indicating the necessity to know the multiple signaling pathways involved. Among them, high-grade neuroendocrine lung carcinomas (NELC) invade and metastasize rapidly. Therefore, biomarkers of aggressiveness in LC remain to be determined, especially in NELC. Epithelial to mesenchymal transition (EMT) genes profile emerge promise as indicator of invasion and metastasis. The aim was to investigate the expression of EMT markers and assessed their relationship with the clinicopathological features and prognosis.

Method:
Fresh frozen tissue from SCLC (n=15) and NSCLC (ADc n=23 and SqCC n=10) and matched normal tissue samples were collected for qRT-PCR analysis carried out on StepOnePlus™ Real-Time PCR with RT[2] Profiler PCR Array System for the EMT pathway with 84 target genes (Qiagen, Dusseldorf, Germany). Gene expression was correlated with clinicopathological variables in the SCLC and NSCLC groups. Survival curves were calculated using the Kaplan-Meier method and risk factors determined by multivariate Cox regression model. Differences were regarded as statistically significant at P<0.05.

Result:
Female patients presented significant higher expression of EGFR (p=0.03), ILK (p=0.05), JAG1 (p=0.01), MMP2 (p=0.04) and SNAI2 (p=0.04) genes. Tobacco history was associated with increased expression of EGFR (p<0.01), ITGAV (p=0.05), SPP1 (p<0.01) and WNT5A (p=0.02). NSCLC presented similar levels of EMT genes evaluated. Tumors from SCLC and NSCLC in advanced N and M stage expressed significant high levels of genes related to cellular membrane [EGFR (p=0.03), ILK (p<0.01), FR11 (p=0.05), ITGAV (p=0.02), ITGB1 (p<0.01), DSP (p=0.04)], extracellular matrix [COL5A2 (p=0.04), COL1A2 (p=0.04)], cytoplasm [GSK3B (p=0.01), VPS13A (p=0.02), MAP1B (p=0.01)] and nucleus SNAI2 (p=0.04). Interestingly, SCLC tumors expressed higher levels of FR11 (p=0.02), GSK3B (p=0.04), ILK (p<0.01), ITGB1 (p=0.01), JAG1 (p<0.01) and MAP1B (p=0.01) indicating more aggressiveness than NSCLC. A mathematical model controlled for N and M stage, histologic type and the gene expression showed that patients with SCLC expressing high levels of MMP2 and SPARC presented significant high risk of death (OR 5.41 and 4.94, respectively) compared to those with lower expression. Patients with NSCLC with low levels of ILK, SPP1, COL1A2, ITGB1 presented a low risk of death (OR -7.02, -0.4, -1.3 and -3.02, respectively).

Conclusion:
Different expression of EMT genes in SCLC and NSCLC, its relationship with histologic types, advanced stage, lymph node metastasis and death suggest a possible role of these markers in their malignancy, but more importantly provide a potential biomolecular marker to predict outcome.

Background:
SCLC accounts for 15%-20% of all lung cancer, and has poor prognosis. The aims of this study were to evaluate the patient characteristics and depict prognostic factors in a series of SCLC patients treated at Marmara University Hospital (MUH) Istanbul.

Method:
Among SCLC patients who were admitted to MUH since 01 January 2010, 154 had satisfactory data to analyse. Demographic data, pathology & radiology reports, lab investigations, information regarding local & systemic therapies were noted from written & electronic patient records. Patient and tumour characteristics were reported descriptively. OS difference between subgroups were analysed with Log-rank & factors that had independent effect on survival detected with Cox regression tests. OS data were calculated with Kaplan-Meier estimator. A p value <.05 was accepted as significant unless reported otherwise.

Result:
The median follow-up time was 17 (min-max; 3-84) months. Median survival time of all patients was 10 months; 1 year, 2 & 3 years survival rates were 41%, 22%, and 12%, respectively. Median survival of patients with limited stage and extension stage SCLC were; 22,6 Ms (9,9-35,3), and 9 Ms (7,2-10,8), respectively. On univariate analysis patient with low initial serum haemoglobin (<12 gr/dl), abnormal sodium or ALT (> 40 IU/l) levels, poor ECOG PS (2-3), advanced VA stage, having brain, liver, bone or adrenal mets, and having a paraneoplastic syndrome (PNS) had worse survival estimates. Whereas only ECOG PS (p=0.007, HR 2.2 [1.2-4]), and having a PNS (p=0.04, HR 1.66 [1.02-2.7]) maintained independent prognostic effect on survival in Cox analysis.

Conclusion:
Results of our small retrospective SCLC series showed that median survival of extensive stage SCLC patients is poor (< 1 year) which underlies the need of novel anticancer therapeutics for this group of patients. Our multivariate model pointed out well known prognostic factors but not the VA stage. This may be explained with the small population size of our study.

Background:
Inadequate drug delivered to target tumors contributes to ineffective treatment. However, the delivered drug concentration is difficult to assess in patients in a timely and clinically-relevant manner. To address this barrier to PARP inhibitor(PARPi) therapy, we evaluated a radiolabeled PARP inhibitor([F18]PARPi) as a pharmacodynamic biomarker. We hypothesized that [F18]PARPi PET imaging can measure PARP inhibitor concentration and activity intratumorally, thereby, predicting therapeutic efficacy. Here, we applied this approach to patient-derived xenografts(PDX) of small cell lung cancer(SCLC).

Method:
To study [F18]PARPi PET as a biomarker of talazoparib(TAL), SCRX-Lu149 PDXs were orally gavaged with different doses of TAL. Mice were injected with [F18]PARPi and imaged with PET, with the expectation that TAL would competitively block [F18]PARPi binding to PARP. Organ retrieval and gamma counting was performed for drug and radiotracer biodistribution. Ex vivo PARP enzymatic activity was measured by ELISA of PAR levels. Differences in PET uptake and the tumor volumetric endpoint (time to reach 1000 mm[3]) were analyzed by student t-test and the log-rank test, respectively.

Result:
In PK PET imaging with 0.2 mg/kg TAL, greatest blocking of the radiotracer was noted at 1 hour after gavage with less blocking as time from dosing was extended (avg of 3 mice: 4.5, 2.2, 2.7, 3.1, and 3.4% max injected dose per gram [ID/g] for untreated, 1, 3, 6, and 24 h after drug, respectively). [F18]PARPi PET differentiated between doses of 0.1 and 0.3 mg/kg TAL at 3 h after dosing (3.9 vs 2.1% ID/g or 13% vs 53% relative blocking, respectively; p=0.003). No differences were noted in heart, lung, esophagus, muscle, or bone. PET uptake correlated with ex vivo enzymatic inhibition/PAR levels (p=0.0009). PET measured differences in drug doses corresponded with improved outcomes for PDXs treated with 0.3 mg/kg in combination with radiotherapy(RT; median 84 days, p=0.04) but not 0.1 mg/kg + IR (66 days) compared to RT alone (52 days).

Conclusion:
[F18]PARPi PET can differentiate between multiple doses and timing of orally administered TAL and correlates with drug efficacy. This likely reflects differences in intratumoral drug level and demonstrates the potential of this PET radiotracer to assess differences in drug delivery and efficacy for patients treated with PARP inhibitors.

Background:
The impact of interstitial lung disease (ILD) on the clinical outcome in small cell lung cancer (SCLC) patients has not been fully understood. The purpose of this study is to investigate the impact of ILD on treatment and survival in SCLC.

Method:
From April 2006 to March 2016, 67 SCLC patients treated with chemotherapy at Kumamoto University hospital were evaluated. Therapeutic response, progression-free survival (PFS) and overall survival (OS) were compared between SCLC with ILD (n=16) and SCLC without ILD (n=51).

Result:
Patients’ characteristics including age, sex, smoking, serum LDH, stage (limited/ extensive disease) between two groups were similar, except for lower proportion of chemoradiotherapy in SCLC with ILD (7% vs. 57%, P= <0.001). SCLC with ILD had a significantly lower objective response rate than SCLC patients without ILD (50% vs. 84%, P= 0.005). SCLC patients with ILD had a significantly shorter PFS (median, 184 days vs. 290 days, P= 0.008) and OS (median, 241 days vs. 704 days, P= <0.001) than patients without ILD. In addition, multivariate analysis for PFS and OS revealed that the coexisting ILD was independent predictive factor for poor survival in SCLC patients treated with chemotherapy (PFS, hazard ratio [HR] 2.06, 95% confidence interval [CI], 1.01-4.18, P= 0.046, OS, HR 3.29, 95% CI 1.53-7.08, P= <0.002). Acute exacerbation of ILD was observed in 31% of SCLC patients with ILD.

Conclusion:
This study suggests that coexisting ILD is a predictive factor for poor PFS and OS in SCLC treated with chemotherapy.

Background:
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare, often benign pulmonary condition which is characterized by diffuse proliferation of neuroendocrine cells in respiratory epithelium. DIPNECH lesions are less than 5 mm in size and are limited to the basement membrane without any invasion. There is limited evidence regarding epidemiology, natural history of disease progression and management of this rare entity. We would like to present our single center experience.

Method:
Retrospective record based descriptive study of all DIPNECH patients managed at University of Kentucky Markey Cancer Center over past 5 years.

Result:
Our patient cohort had 8 females and one male with mean age of 64.5 years at the time of diagnosis. Dyspnea on exertion and dry cough were the commonest presenting symptoms. Three patients were under surveillance without treatment, two patients were treated with short acting somatostatin analog, another three were treated with long acting monthly somatostatin analogs and azithromycin combination, one patient got long acting somatostatin analog and everolimus combination. Two patients had concomitant well-differentiated neuroendocrine tumor of lung.

Conclusion:
DIPNECH is a rare pathology which can have profound effects on patient’s quality of life. Paroxysmal coughing spells can be difficult to treat. Our limited single center experience shows encouraging response to use of somatostatin analog, azithromycin and everolimus in the management of debilitating DIPNECH associated symptoms.

Background:
Despite rising incidence, there remains limited data guiding the prognostication and treatment of patients with bronchopulmonary carcinoid tumors, particularly atypical carcinoids. We report outcomes of a large, modern, single-institutional series of patients treated for localized or locally advanced atypical carcinoid of the lung.

Method:
We retrospectively analyzed the demographic, histologic and treatment histories of 69 patients (74% female) with median age of 65 at diagnosis (range 31-83) who were treated between 2004-2016. The Kaplan-Meier method was used for overall survival (OS) estimates and compared by log-rank. Cox proportional hazards models were used for univariate (UVA) and multivariate analyses (MVA).

Result:
Median follow-up time was 33.6 months. The majority (96%) of patients underwent surgical resection (86% R0, 9% R1, 3% R2) with common approaches being lobectomy (59%), wedge resection (13%) and pneumonectomy (9%). Three patients (4%) received definitive radiotherapy as their local treatment. Nearly half (49%) of patients had nodal involvement with a stage distribution of 39% stage I, 25% stage II and 36% stage III. Twenty-one patients received chemotherapy as part of their initial treatment, 81% of whom had stage III disease. Sixteen patients received radiotherapy (median 50.4 Gy, range 18-66 Gy) as part of their initial treatment, most of whom received postoperative radiation for N2 disease (63%). Five patients (31%) received postoperative radiotherapy due to concern of incompletely resected disease. Higher stage was significantly associated with poorer OS (p=0.04). 3-year OS for Stage I, II and III disease was 96%, 88% and 72%, respectively. Stage I disease also had a significantly lower risk of distant metastasis compared to Stage II/III disease (17% vs. 31% at 3 years p=0.04). On UVA, Stage III disease was significantly associated with poorer OS (HR 4.7, p=0.021) and risk of distant failure (HR 2.8, p=0.039). Multivariate modeling showed that older age (HR 1.05, p=0.03) and stage III status (HR 6.6, p=0.009) were predictive of poorer OS. For stage III patients treated surgically, receipt of adjuvant therapy (chemotherapy and/or radiotherapy) was not significantly associated with OS (p=0.36) or distant failure (p=0.69).

Conclusion:
This is one of the largest reported series of atypical pulmonary carcinoid patients treated with curative intent. We observed generally favorable prognosis in this cohort that was primarily treated with surgery. We did not observe a significant impact of adjuvant therapy on outcomes, but small patient numbers limit our ability to quantify their potential effect.

Background:
Chemo-radiation is considered to be the standard treatment for the management of limited disease of small cell lung cancer (SCLC). Even in this early stage, the role of surgery in SCLC is still controversial. We sought to examine the role of surgery; complete resection in terms of survival in SCLC.

Method:
A retrospective review was undertaken of patients who underwent surgery for SCLC between 2001 and 2015. Patients were staged according to the 7[th] edition of the Tumor, Node, Metastasis classification of lung cancer. Actuarial survival estimated with Kaplan Meier method and comparisons were undertaken using Cox regression hazard model. Clinicopathological factors and predictors of survival were analyzed.

Result:
We identified 49 patients who underwent complete resection. The mean follow up period was 1343 days. The mean age was 70.7 years. 40 patients were men and 9 were women. The number of patients of clinical stage was stage IA :21, IB: 15, IIA: 4, IIB: 6, IIIA:3. Operative procedure was lobectomy in 43, segmentectomy in 1, wedge resection in 5. The number of patients of pathological stage was stage IA :15, IB: 11, IIA: 14, IIB: 7, IIIA:2. Adjuvant chemotherapy was performed in 26 patients (53.1%). The 5-year overall survival (OS) rate in all patients was 58.8%. The 5-year OS was 61.3% in c-stage I, 54.5% in c-stage II, and 50% in c-stage III. The 5-year OS were 66.2% in p-stage I, 55.4% in p-stage II, and 50% in p-stage III. The 5-year OS of patients with adjuvant chemotherapy was significantly better than that of patients without adjuvant chemotherapy (77.8% vs. 39.8%, p=0.005). Multivariable Cox regression hazard model demonstrated that adjuvant chemotherapy was prognostic factor of overall survival (OS) (hazard ratio 0.255 (.095-.688), p=0.007)

Conclusion:
Surgical outcome for early stage SCLC was satisfied one. The role of surgery for this group seemed to be important. Adjuvant chemotherapy may improve prognosis and long-term survival will be expected.

Background:
The combination chemotherapy of etoposide and a platinum salt represents the standard therapy for almost 30 years in patients with ED-SCLC (extensive-disease small-cell lung cancer). While, the survival benefit of chemotherapy is not obvious. Antiangiogenic agents have been confirmed to have survival benefits for patients with NSCLC (non-small cell lung cancer). However, there is no established role for antiangiogenic therapy in SCLC

Method:
we conducted this meta-analysis to evaluate antiangiogenic agents plus chemotherapy in patients with ED-SCLC. Pub-med, EMBASE, Cochrane Library and ClinicalTrials.gov website were systematically searched for RCTs (randomized controlled trials) that compared antiangiogenic agents plus chemotherapy with chemotherapy alone in ED-SCLC.

Result:
We firstly found that antiangiogenic agents plus chemotherapy was well tolerated and could provide a statistically significant improvement in PFS (progression-free survival) for patients with ED-SCLC (HR = 0.76 [95% CI 0.65, 0.88], P = 0.0003). The results of ORR (objective response rate) (RR = 1.06 [95% CI 0.96, 1.18], P = 0.23) and OS (overall survival) (HR = 0.98 [95% CI 0.80, 1.21], P = 0.85) showed no benefit for antiangiogenic agents plus chemotherapy.

Conclusion:
Our study firstly shows that the addition of antiangiogenic agents to standard chemotherapy is well tolerated and can provide a statistically significant improvement in PFS for patients with ED-SCLC. Further, maintenance therapy with antiangiogenic agents is an effective treatment option for ED-SCLC patients who received four to six cycle of chemotherapy. Additionally, four-drug chemotherapy plus antiangiogenic agents may be better for ED-SCLC patients with PS of 1 to 2. However, whether antiangiogenic agents plus chemotherapy can influence OS for ED-SCLC needs further validation.

Background:
Patients with epidermal growth factor receptor (EGFR) mutant advanced non-small cell lung cancer (NSCLC) developed resistance to first- or second-generation EGFR-tyrosine kinase inhibitor (TKI) after 9-13 months and third-generation EGFR-TKI after 10 months, respectively. Small cell lung cancer (SCLC) transformation is a rare resistance mechanism in these patients.

Method:
Tissue re-biopsy was performed in 35 patients with EGFR mutant advanced NSCLC who failed first-line EGFR-TKI; and 4 patients with acquired T790M mutant advanced NSCLC who failed third-generation EGFR-TKI, to look for SCLC transformation

Result:
SCLC transformation was identified in 2 out of 35 (5.7%) patients who failed first-line EGFR-TKI and 1 out of 4 (25.0%) patients who failed third-generation EGFR-TKI. The first patient was a 70-year-old never-smoker male who was diagnosed with stage IV lung adenocarcinoma harboring exon 19 deletion mutation in April 2014. He had partial response (PR) to gefitinib 250 mg daily but developed symptomatic progressive disease (PD) after 26 months. Re-biopsy of his enlarging primary lung lesion showed SCLC transformation. The second patient was a 43-year-old never-smoker male who was diagnosed with stage IV lung adenocarcinoma harboring exon 19 deletion mutation in November 2015. He had PR to gefitinib 250 mg daily but developed symptomatic PD after 15 months. Re-biopsy of his rapidly enlarging primary lung lesion showed SCLC transformation. His plasma cell-free tumour DNA (cftDNA) was positive for T790M mutation. The third patient was a 62-year-old never-smoker female who was diagnosed with stage IV lung adenocarcinoma harboring exon 21 L858R mutation in November 2015. She had PR to gefitinib 250 mg daily but experienced symptomatic PD after 8 months’ of gefitinib therapy. Re-biopsy of her primary lung tumor revealed the presence of T790M mutation and her treatment was switched to osimertinib 80 mg daily. After an initial PR, she developed PR in the 12[th] month of osimertinib treatment. Biopsy from a metastatic inguinal lymph node showed SCLC. The first and second patients were given standard SCLC chemotherapy with carboplatin and etoposide but did not respond. The third patient sought treatment in another hospital.

Conclusion:
Re-biopsy is recommended in all patients with symptomatic PD while on EGFR-TKI treatment. SCLC transformation under the pressure of first, second and third-generation EGFR-TKI is an emerging challenge to the management of advanced NSCLC. Other than conventional carboplatin and etoposide chemotherapy, new treatment strategies should be explored to improve the outcome of patients who develop SCLC transformation.

Background:
Pulmonary large cell neuroendocrine carcinoma (LCNEC) represents a rare entity in lung cancer. Due to poor understanding of its biologic characters, optimal treatment strategy for patient with LCNEC remains undetermined. Recent data reveals that LCNEC can be divided into SCLC and NSCLC type based on distinct genomic signatures. It has been considered that SCLC is a central-type lung cancer and LCNEC usually locates in peripheral or midzone of lung. In the present study, we examined that whether there are significant differences between central tumors and peripheral tumors of LCNEC, in terms of clinicopathologic features, survival, and genomic profiles.

Method:
A total of 126 cases (113 cases with surgical samples) of pulmonary LCNEC were included in the present study. The tumors with invasion of the segmental and/or lobar bronchus were classified as central LCNEC and those without as peripheral LCNEC. EGFR mutations, ALK translocations, ROS1 translocations, Kras mutations, RET translocations and BRAF mutations were detected. Overall survival (OS) was determined from the date of operation until reported death or last follow-up visit. OS was analyzed by the Kaplan-Meier plots and the log-rank test was used to calculate the significance between groups. The prognostic factors for OS were analyzed using univariate and multivariate COX analyses.

Result:
Central tumors were associated with smoking history (p=0.047), higher T stage (p<0.001), N stage (p=0.001), TNM stage (p=0.014), and larger tumor size (p<0.001) compared with peripheral tumors. Although neuroendocrine marker expression of CD56, CGA, and SYN was not significantly different according tumor location, central tumors had higher expression of NSE (p=0.003). Moreover, peripheral tumors had higher incidence of EGFR mutations (18.8 vs. 0%, p=0.023) and similar incidence of Kras mutations (10.4 vs. 8.0%, p=1.000). Tumors harboring EGFR mutations were all pure LCNEC. No ALK translocations, ROS1 translocations, RET translocations and BRAF mutations were identified. The median OS was 3.71 years. TNM stage (p=0.039) and N stage (p=0.068) were associated with survival. Interestingly, central tumors had poorer survival compared with peripheral tumors, in terms of median OS (1.51 vs. 4.04 years), 1-year OS rate (54.0 vs. 83.9%), 2-year OS rate (37.0 vs. 75.9%), 3-year OS rate (31.7 vs. 59.9%). After multivariate analyses, tumor location was still an independent prognostic factor for OS (HR, 2.675, 95% CI, 1.384-5.171, p=0.003).

Conclusion:
Primary tumor location of LCNEC, divided into central and peripheral type, has distinct clinicopathologic feature, genomic characteristics and survival, which may help classify and manage patients with LCNEC.

Background:
Small cell lung cancer (SCLC) as the most aggressive tumor deserves a special attention. The aim of this research was to define the place of surgery of patients with SCLC in order to improve the results of treatment.

Method:
Clinical material for research consists of 49 patients in stage IA-IIIA with SCLC, which were radically operated in Ugra (region Russia) between 1999 and 2015. Among patients predominate males 41 (83,7%), versus females – eight (16,3%).

Result:
All patients underwent radical operations R0. All resection types were included (pneumonectomy, bilobectomy, and lobectomy). By 37 patients (75,5%) systematic nodal dissection (SND) was carried out, by 5 (10,2%) - mediastinal lymph node sampling (MLS) and by 7 patients mediastinal node dissection was not carried out. By SCLC combination treatment was used more often – 35 (71,4%). By that only in 11 cases additional adjuvant of thoracic radiotherapy was used. In 14 cases only surgical resection was used (28,6%). 5-year and 10-year overall survival (OS) rate was 47,6% and 37,2%. Median survival rate was 49 months. Five and ten-year OS rate by surgery combined with adjuvant chemotherapy was 53,8% and 39,5%, as compared to only surgical treatment – 35,6%. Median survival rate was 67 and 25 months, respectively. At I stage satisfactory results were achieved: 5-year and 10-year OS rate was 68,8% and 62,5% (р<0,05), – that corresponds with results of treatment of patients with non-small cell lung cancer with similar stage of process. Median survival rate was not achieved. At II stage 5-year and 10-year OS rate was 41,7 and 41,7%. Median survival rate was 36 months. At III stage unsatisfactory results were obtained. 5-year OS rate was 25,1%. Median survival rate was only 13 months.

Conclusion:
SCLC at I and II stages is the indication to radical treatment, mandatory including surgical resection with SND and adjuvant chemotherapy. The main method of treatment at III stage is chemotherapy or chemoradiotherapy.

Background:
The prognosis for patients with large-cell neuroendocrine carcinoma (LCNEC) of the lung is extremely poor, and optimal treatment strategies have not yet been established. To improve prognoses in patients with LCNEC, we analyzed immunohistochemical expression and gene mutations of several known molecular targets in LCNECs and compared the expression levels of these targets with those in lung adenocarcinomas.

Method:
Twenty-six patients with primary LCNEC and 40 patients with adenocarcinoma were analyzed. Topoisomerase II, epidermal growth factor receptor (EGFR)-L858R, and somatostatin receptor expression were evaluated by immunohistochemistry, and EGFR mutations were evaluated using direct DNA sequencing and the Scorpion-amplified refractory mutation system.

Result:
There was no significant difference between patients with LCNEC and adenocarcinoma in relation to age, gender, smoking status, pathological stage (8[th]), performance status, and pulmonary function. In patients with LCNEC and adenocarcinoma, positive rates of topoisomerase II, EGFR-L858R, and somatostatin were 65.4% and 15.0% (p < 0.0001), 0.0% and 20.0% (p = 0.0182), and 50.0% and 5.0% (p < 0.0001), respectively. The frequencies of EGFR mutations were 0.0% and 37.5% in LCNEC and adenocarcinoma (p = 0.0002), respectively.

Conclusion:
LCNEC showed overexpression of topoisomerase II, somatostatin, suggesting it was possible to have good response to treatment with etoposide and octreotide compared with adenocarcinoma. EGFR mutations were not observed in LCNEC. These results may indicate a favorable response to adjuvant treatments that are not typically prescribed for non-small cell lung cancer.

Background:
Pleural lavage cytology (PLC) is an independent prognostic factor for resected non-small cell lung cancer (NSCLC). However, there has been no standard method for the test and the optimal dose of saline is still unclear. We investigated the feasibility of 20 mL saline in this retrospective study.

Method:
From January 2001 to December 2011, 466 consecutive patients who underwent a curative resection for NSCLC and received both a pre- and post- PLC by using 20ml of saline were enrolled. The prognostic significance of each PLC status and other clinicopathological factors were investigated.

Result:
Patients with a positive pre-(n=24) or post-PLC(n=28) had significantly worse 5-year survival rates than those with negative results (pre-PLC positive/negative; 32.6%/69.9%, p=0.001, post-PLC positive/negative; 21.4%/71.1%, p<0.001, respectively). The post-PLC (p<0.001) was found to be an independent prognostic factor for the overall survival by a multivariate analysis, whereas the pre-PLC was not (p=0.95). In stage I disease, patients with a positive post-PLC had a significantly worse survival regardless of the pre-PLC status. These results were comparable to those of the past reports by using more saline of 50-1000mL.

Conclusion:
Using 20 mL of saline would be feasible for PLC and may be helpful to simplify the procedure.

Background:
Postoperative outcome for NSCLC patients with lymph node metastasis is unfavorable even after surgery with/without adjuvant chemotherapy. We sought to investigate postoperative prognostic factors in NSCLC patients with lymph node metastasis.

Method:
We retrospectively reviewed NSCLC patients with pathologically identified lymph node metastasis who underwent complete resection. Demographic, clinical, and pathologic factors (sex, age, smoking index, Performance Status, preoperative carcinoembryonic antigen [CEA], surgical procedure, lymphadenectomy extent, histology, tumor differentiation, tumor size, pT factor, metastatic node site, and adjuvant chemotherapy) were analyzed using the log-rank test as univariate analyses and a Cox proportional hazards regression model for multivariate analyses to identify independent predictors of favorable disease-specific survival (DSS).

Result:
Of the 146 eligible patients, 113 were male and 33 were female. The median age and preoperative CEA were 67 years and 5.3 ng/mL, respectively. Lobectomy or greater resection and segmentectomy were performed in 140 and 6 patients, respectively. Tumor histology was adenocarcinoma in 58 patients, squamous cell carcinoma in 70, and others in 18. Node metastasis was identified in hilum only in 85 patients and mediastinum in 61. Adjuvant chemotherapy was performed in 61 patients (platinum doublet in 56 and tegafur/uracil in 5, respectively) and was not performed in 85. The 5-year DSS was 58%. The CEA ≤5.3 ng/mL (HR: 0.368), without mediastinal node metastasis (HR: 0.436), and platinum doublet adjuvant chemotherapy (HR: 0.491) were identified as significant predictors of favorable DSS. The 5-year DSS in patients with CEA ≤5.3 and >5.3 ng/mL were 73% vs 41%, respectively (p<0.001). The 5-year DSS in patients who underwent platinum doublet chemotherapy or none/others were 67% vs 53%, respectively (p=0.047). Figure 1



Conclusion:
Even if NSCLC patients have lymph node metastasis, favorable postoperative prognosis may be expected in patients with low preoperative CEA. Platinum doublet adjuvant chemotherapy should be considered in patients with lymph node metastasis on pathological examination.

Background:
The world’s population is rapidly aging, and the age of patients with lung cancer will increase as well. The prognostic nutritional index (PNI), controlling nutritional status (CONUT), and the geriatric nutritional risk index (GNRI) are useful parameters for evaluating immune-nutritional status. We aimed to perform a multicenter retrospective study to investigate the correlations of these immune-nutritional parameters with postoperative comorbidities or surgical outcomes of elderly patients with non-small cell lung cancer (NSCLC).

Method:
We selected 272 consecutive patients with NSCLC aged >75 years treated from January 2005 to December 2012 and evaluate three preoperative immune-nutritional parameters as potential predictive factors of postoperative comorbidities or as prognostic factors for surgically resected elderly patients with NSCLC.

Result:
Both PNI and GNRI as well as sex and preoperative respiratory comorbidities, were significantly associated with postoperative comorbidities (P =0.0287, 0.0443, 0.0191 and 0.0177, respectively). Multivariate analyses showed that preoperative GNRI (P = 0.0161) as well as sex (P < 0.0001), preoperative serum carcino embryonic antigen levels (P = 0.0128), preoperative serum cytokeratin 19 fragment levels (P = 0.0125), pleural invasion (P = 0.0214) and lymphatic vessel invasion (P = 0.0165) significantly affected overall survival (OS). Abnormal GNRI was significantly associated with histology (P = 0.0419) and outcome (P =0.0077). In Kaplan–Meier analysis of OS by preoperative GNRI, the abnormal GNRI group had significantly shorter OS than the normal GNRI group (5-year OS, 45.15% vs. 64.10%, P = 0.0007, log-rank test). CONUT score did not have any correlation with postoperative comorbidities or surgical outcome.

Conclusion:
Preoperative GNRI is a novel preoperative predictor of postoperative comorbidities as well as a prognostic factor that may identify high-risk elderly patients with NSCLC.

Background:
Treatment of patients with lung cancer associated with interstitial pneumonia (IP) is difficult because of post-operative complications or treatment-related deaths. Indeed, post-operative acute exacerbation of IP in patients with lung cancer and IP is associated with a high mortality rate. In our institute, we have unified surgical methods and improved peri-operative management of such patients since 2013. In the current study, we retrospectively studied the clinical features, surgical methods, and peri-operative management, and analyzed the clinicopathologic features of patients with lung cancer associated with IP.

Method:
We selected patients with lung cancer associated with IP who underwent surgery from January 2004 to May 2017. A presumptive diagnosis of IP or an IP pattern on computed tomography (CT) was confirmed histologically by examination of resected specimens and/or the presence of the clinical diagnostic criteria. Acute exacerbation of IP was defined according to the guidelines of the Japanese Respiratory Society when the following criteria were fulfilled within 1 month: (1) increased respiratory distress; (2) fibrosis, newly developed ground glass opacity and infiltrative shadow on high-resolution computed tomography (HRCT); and (3) > 10 Torr decrease in PaO~2~ under the same oxygenation conditions. (4) no evidence of pulmonary infection, heart failure, pneumothorax, and pulmonary embolism. We studied the following clinicopathologic features in patients with lung cancer associated with IP: gender, age, surgical methods, pathologic stages, mortality rate, and post-operative complications, including acute exacerbation of IP.

Result:
Fifty-three patients underwent surgery. The mean age was 70.8 years (50 males and 3 females). Forty-three, 1, and 9 patients underwent lobectomies, a segmentectomy, and partial resections, respectively. Twenty-three, 17, and 13 patients were stage I, II, and III, respectively. Eight patients had post-operative acute exacerbations of IP and there were three in-hospital deaths caused by acute exacerbations. Of note, there have been no in-hospital deaths since 2013.

Conclusion:
It is possible to prevent severe post-operative complications in patients with lung cancer associated with IP with the aid of intra-operatively and optimal peri-operative management.

Background:
Introduction:Lung cancer is the most common form and cause of cancer death world-wide. Radical surgical resection, with or without adjuvant treatment, is still a prerequisite for cure.In European countries the proportion of patients who undergo surgery for this disease varies between 10 and 30% .Advances in operative and postoperative care have led to a decline in complications and mortality rates during the last two decades.In spite of different additional modes of treatment, survival is still poor.

Method:
The study comprised 388 consecutive patients referred to University Hospital of Lung Disease Tirane, from a defined population, during a 12-years period (2004-2017).There were in total 968 patients who underwent lung resection for bronchogenic carcinoma.There were 690 males and 278 females included 15-87 years with a mean age of 65.5 years.Postoperative events studied were divided into major and minor complications or death during the first 30 days after surgery.

Result:
Early mortality (within 30 days) after lung cancer surgery.During the study period an increasing number of women and of patients older than 70 years underwent surgery.The 30 day mortality rate was 3.4% (33 patients), 1.2% after single lobectomy(11 patients) and 3.1 % after pneumonectomy(22 patients).Major complications occurred in 48 patients (4.9%). Minor complications occurred in 75 patients (7.7%).Male gender, smoker, FEV1 70% of expected value, squamous cell carcinoma and pneumonectomy were risk factors predicting adverse outcome .

Conclusion:
Our results show low mortality and morbidity after lung cancer surgery.However, patients with reduced lung capacity and those undergoing pneumonectomy should be treated with great care, as they run a considerable risk of major complications or death during the first 30 days postoperatively.Older age (>70 years) does not appear to be a contraindication to lung cancer surgery, but patients in this group should undergo careful preoperative evaluation.

Background:
There is consensus for the treatment modalities of lung cancer. However, there were cases in which inadequate treatments were performed due to unavoidable reasons which could make different oncologic outcomes. So authors investigated factors affecting oncologic outcomes in patients with pathologic stage II and III lung cancer who underwent limited resection or omitted adjuvant therapy.

Method:
From January, 2010 to December, 2012, 231 patients underwent operation for non-small-cell lung cancer in our hospital. Of them, 63 patients who were diagnosed as pathologic stage II and III were enrolled in this research, and medical records of them were reviewed including demographic factors, treatment modalities, 5-year overall survival rate, 5-year recurrence and so on.

Result:
The mean age was 64.03±7.94 years old and preoperative performance status was good in all patients. The median follow-up duration was 58.7 [1.3, 88.4] months. Patients (group A) with resection more than lobectomy and adjuvant therapy were 50, patients (group B) with limited resection were 4, and patients with omitted adjuvant therapy were 13 (group C). 5-year overall survival rate of group A was 69.7% (stage IIA-84.4%, IIB-40.0%, IIIA-48.5%), but, all of group B were recurred and passed away. Of group C (stage IIA-9, IIB-1, IIIA-3), 5 were recurred and dead. Multi-variable analysis (Cox proportional hazard regression analysis) of prognostic factors for overall survival (OS) and recurrence (R) was performed, which showed limited resection (OS; hazard ratio 32.179, p=0.001 and R; hazard ratio 61.337, p=0.000) and pathologic stage (OS; hazard ratio 1.898, p=0.017 and R; hazard ratio 1.517, p=0.037) were presented as significant poor prognostic factors. And omitted adjuvant therapy didn’t significantly affect oncologic outcome, but had negative influence (OS; hazard ratio 8.102, p=0.074 and R; hazard ratio 5.528, p=0.13).

Conclusion:
This study has many weak points including small sample size, retrospective study and so on, but this study suggests that several factors affect prognosis in advanced stage non-small-cell lung cancer but, especially, the limited resection in advanced stage has been a significantly negative impact and should be considered carefully.

Background:
Positive margins after pulmonary resection for cancer is an uncommon and challenging occurrence, with no consensus currently available to guide best adjuvant treatments. Our objective was to determine the rate of positive parenchymal margins after non-pneumonectomy lung resection with an assessment of adjuvant treatment strategies and outcomes.

Method:
Ethics board approval was obtained for a retrospective analysis of prospectively collected data on all lung resections performed at the Ottawa Hospital during the period 2008-2014. Individual patient records were then examined to confirm margin status by a review of the final pathology report. Survival and disease-free intervals were analysed using log-rank statistics, with significance set at 5%.

Result:
Over the study period, 1428 patients underwent non-pneumonectomy lung resection. A total of 29 cases (2%) were identified with a positive lung parenchymal margin (PPM). A matched subset (n=662) of the remaining 1379 patients with negative parenchymal (NPM) were used as control group. Median followup for NPM was 36.7 [0-105.6] and for PPM was 29.1 [0.5-71.5]. Overall, lobectomy was the most common pulmonary resection performed; wedge resections represented the majority of the PPM (n=16, 55%) followed by lobectomy (n=9; 31%) and segmental resections (n=1; 3%). Overall survival (Figure) and disease-free survival (not shown) were significantly (p<0.0001) worse for the PPM (Hazard ratio 5.59, 95%CI [2.05-15.6]) with a median survival of 31.5 months; the control group had not reached median survival. Stage I and II NSCLC were predominant in both groups; however postive margins were more often associated with metastatic disease (24% in PPM; 0.9% in NPM). The majority of PPM went on to receive additional treatment (n=17; 68%) consisting of adjuvant chemotherapy (n=7; 28%), radiotherapy (n=4; 16%), chemoradiotherapy (n=5; 20%) and re-resection in one case. The remaining patients were observed. Recurrence was found at the staple line in 7 cases (24%); the remainder recurred at distant sites.

Conclusion:
The overall rate of PPM in this study is low (2%) as compared to reported rates of 5-15%. Wedge resection for metastases was associated with most cases of PPM; most patients received additional treatment and had distant sites of recurrence. Overall survival was significantly worse for PPM despite adjuvant therapy, which likely reflects the underlying disease.

Background:
Expression levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), and orotate phosphoribosyltransferase (OPRT) may predict the clinical efficacy of 5-fluorouracil (5-FU) -based chemotherapy in patients with cancer. We investigated the differences in mRNA expression levels of these enzymes in non-small-cell lung cancer (NSCLC) and evaluated them as prognostic factors for NSCLC treated by surgical resection.

Method:
Intratumoral mRNA levels of TS, DPD, OPRT, and TP were quantified in 71 patients following a complete resection in pathological stage I and II NSCLC (adenocarcinoma or squamous cell carcinoma) using the Danenberg tumor profile (DTP) method.

Result:
TP was the only significant prognostic factor for overall survival (OS) following complete resection of stage I and II NSCLC. Median values of TP mRNA expression significantly differed between the high and low mRNA expression groups for OS. OS at 5 years was significantly better in the low TP mRNA expression group than the high TP mRNA expression group (82.5% vs. 63.6%, p < 0.001). The Cox’s proportional hazard model indicated that the pathological stage, sex, and TP expression were independent prognostic factors for OS. Univariate analysis for disease free survival (DFS) indicated that the pathological stage was the only prognostic factor for DFS. However, DFS at 5 years tended to be better in low TP mRNA expression group than in high TP mRNA expression group (88.9% vs. 67.3%, p=0.083).

Conclusion:
TP mRNA expression presents an independent prognostic factor for OS in patients with stage I and II NSCLC following complete resection.

Background:
Postoperative hemorrhage after lung cancer surgery is a potentially fatal complication. This study aimed to investigate the indications and timing of reoperation for postoperative hemorrhage after lung cancer surgery.

Method:
We identified all patients who underwent lung resection and mediastinal lymph node dissection for lung cancer between October 2001 and September 2015 at Sichuan Cancer Hospital, identifying 57 who had undergone reoperation for hemostasis. The records of these 57 patients were reviewed and analyzed.

Result:
The most common postoperative hemorrhage site was the separation surface of the original pleural adhesions (29.8%). The median time interval between the initial operation and reoperation was 12 hours (range, 2-432 hours), and most patients (77.2%) underwent reoperation within 24 hours. The overall morbidity and mortality rates of reoperation were 50.9% and 5.3%, respectively. The morbidity rates of early reoperation group (≤ 24 hours) and late reoperation group were 43.2% and 77.0%, respectively, which were significantly different (P=0.033). The mortality rates of early reoperation group and late reoperation group were 0 and 23.1%, respectively, which were also significantly different (P=0.010).

Table 1 Origin of postoperative bleeding for reoperation

Origin of bleeding	Number of patients (n=57)	Percentage
Pulmonary resection surface	1	1.8
Pulmonary artery trunk	1	1.8
Pulmonary artery branch	2	3.5
Chest wall invasion resection surface	4	7.0
Intercostal blood vessel	4	7.0
Bronchial artery	6	10.5
Hemothorax-unknown origin	11	19.3
Lymph node dissection surface	11	19.3
Pleural adhesion separation surface	17	29.8

Figure 1



Conclusion:
Once indications of reoperation for postoperative hemorrhage after lung cancer surgery are identified, reoperation within 24 hours after the initial operation can get a better short-term outcome.

Background:
Postoperative pulmonary complications such as pneumonia are significant negative predictors of short- and long-term survival after thoracic surgery. A preoperative cardio-pulmonary function is known as a predictor for postoperative pulmonary complications in patients with lung cancer. However, little is known about the relationship between preoperative exercise capacity and complication of pneumonia after lung resection. The 6-min walk distance (6MWD) measured by the 6-min walk test (6MWT) is a simple, safe, and inexpensive field test that can be used to evaluate the functional exercise capacity. We examined the association between preoperative 6MWD and development of postoperative pneumonia.

Method:
A retrospective study was conducted on patients with malignant lung tumors who were scheduled to undergo lung resection at Nagoya University Hospital from January 2014 to December 2015 (Institutional Review Board approval No. 2015-0413). Preoperative pulmonary function tests and 6MWT were assessed. A logistic regression model and receiver operating characteristic (ROC) curves were used to analyze clinical variables and compare the performance on 6MWD and percentages of predicted values of forced expiratory volume in 1 s (%FEV~1~) and diffusion capacity of the lung for carbon monoxide (%DLco).

Result:
The data from a total 321 patients including 283 with primary lung cancer and 38 with metastatic lung tumors were analyzed. Preoperative 6MWD significantly correlated with age, FEV~1~, forced vital capacity (FVC), %DLco, and serum albumin level. Pneumonia developed in 13 patients (4.0%) and the 6MWD of patients with pneumonia was significantly lower than that of patients without (413.9±89.0 vs. 495.2±93.2 m, p=0.002). Incidences of smoking history and comorbidity of COPD and interstitial lung disease were significantly higher and %FEV~1~, FEV~1~/FVC, %DLco, and serum albumin level were significantly lower in patients with pneumonia than in those without. Length of hospital stay after surgery was significantly longer in patients with pneumonia than in those without (30.4±29.6 vs. 7.4±7.0 days, p<0.001). In ROC analysis, 6MWD ≤450 m was a threshold for predicting postoperative pneumonia with 69.2% sensitivity and 71.1% specificity. A 6MWD ≤450 m, %FEV~1~ <80%, %DLco <80%, serum albumin <3.5 g/dL, and blood loss during surgery >200 g were significantly associated with development of postoperative pneumonia in a logistic model adjusted by age, sex, and primary lung cancer.

Conclusion:
Preoperative 6MWD is associated with development of pneumonia after lung resection for malignancies. Preoperative 6MWT is a useful screening tool in patients with primary and metastatic lung tumors.

Background:
Arterial embolism including cerebral infarction is the major concern after surgery, because it can leave fatal or serious results. Recently, it is reported that pulmonary vein stump thrombosis is easy to occur after pulmonary resection, particular left upper lobectomy. However, it is unknown whether pulmonary vein thrombus is actually associated with cerebral infarction.

Method:
A totally 296 patients, underwent postoperative enhanced CT after left upper lobectomy in our hospital from September 2002 to December 2013, were retrospectively evaluated. We examined the association with pulmonary vein thrombus and cerebral infarction in both groups with thrombosis and without thrombosis formation. The relationship of patients’ background, clinical stage, pulmonary vein stump thrombus and postoperative cerebral infarction were analyzed.

Result:
Figure 121 patients (7.1 %) had a pulmonary vein thrombus, however all cases were asymptomatic and cerebral infarction was not developed. On the other hand, cerebral infarction developed in 15 patients of 275 patients without pulmonary vein thrombus formation. Only clinical stage was significantly relevant to cerebral infarction in univariate analysis. Table 1. Incidence of cerebral infarction according to a pulmonary vein stump thrombus



Conclusion:
Left upper lobectomy of the lung is well known to be a high risk of pulmonary vein stump thrombosis and cerebral infarction in all surgical procedures of the lung. However, pulmonary vein thrombus was not necessarily associated with the cerebral infarction after left upper lobectomy of the lung in this study.

Background:
Search of optimal diagnosis and treatment strategies for non-small cell lung cancer (LC) pa­tients (LCP) (T1-4N0-2M0) realized.

Method:
We analyzed data of 708 consecutive LCP (age=57.5±8.3 years; tumor size=4.3±2.4 cm) radically operated (R0) and monitored in 1985-2017 (m=613, f=95; lobectomies=461, pneumonectomies=247, mediastinal lymph node dissection=708; combined procedures with resection of trachea, carina, atrium, aorta, VCS, vena azygos, pericardium, liver, diaphragm, ribs, esophagus=192; only surgery-S=563, adjuvant chemoimmunoradiotherapy-AT=145: CAV/gemzar + cisplatin + thymalin/taktivin + radiotherapy 45-50Gy; T1=269, T2=251, T3=131, T4=57; N0=460, N1=130, N2=118, M0=708; G1=178, G2=216, G3=314; squamous=394, adenocarcinoma=266, large cell=48; early LC=164, invasive LC=544. Multivariate Cox modeling, clustering, SEPATH, Monte Carlo, bootstrap and neural networks computing were used to determine any significant dependence.

Result:
Overall life span (LS) was 2196.3±1764.1 days and cumulative 5-year survival (5YS) reached 71.1%, 10 years – 63%, 20 years – 43.4%. 451 LCP lived more than 5 years (LS=3125.7±1560.3 days), 128 LCP – more than 10 years (LS=5123.1±1547.9 days). 195 LCP died because of LC (LS=560±372.1 days). AT significantly improved 5YS (58.3% vs. 34.1%) (P=0.001 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, RH, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time, weight (P=0.000-0.030). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), healthy cells/CC (3), lymphocytes/CC (4), thrombocytes/CC (5), eosinophils/CC (6), erythrocytes/CC (7), segmented neutrophils/CC (8), glucose (9), monocytes/CC (10), stick neutrophils/CC (11), leucocytes/CC (12). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).

Conclusion:
5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic and cardiothoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.

Background:
Prognostic effect of EGFR gene mutation in disease progression which affecting recurrence pattern and recurrence dynamics after complete resection of lung adenocarcinoma has not been well established. We investigated the relationship between EGFR gene mutation and recurrence dynamics in completely resected lung adenocarcinoma.

Method:
We retrospectively review 527 patients who underwent curative surgery for lung adenocarcinoma from January 2006 to December 2009. Demographics, clinic-pathologic data, and prognosis data were obtained by review of medical records. The EGFR gene mutation was analyzed by nested polymerase chain reaction followed by bidirectional direct sequencing in case of recurrence. Adenocarcinoma patients who experienced recurrence and had data of EGFR mutation were included in the analysis. Pathologic stage IV were excluded. Patients were divided into M group (mutant EFGR gene) or W group (wild-type EGFR gene). Sites of recurrence and disease-free times (DFT) of two groups were compared.

Result:
Median follow-up duration was 72 months. Overall 5-year survival rate was 80.1%. Recurrence was detected in 153 patients and 5-year disease-free rate was 58.2%. EGFR gene sequencing was performed in 118 (77.1%) patients. There were 38 (32.2%) loco-regional recurrences and 80 (67.8%) distant metastases. Any mutation of EGFR gene was detected in 66 (59.9%) patients (M group) and 52 patients had wild-type EGFR gene (W group). Sites of recurrence in M group were loco-regional in 25 (37.9%) and distant metastasis in 41 (62.1%) patients. Site of recurrence in W group were loco-regional in 13 (25%) and distant metastasis in 39 (75%) patients. Sites of recurrence of both groups were not significantly different. (p=0.14) Median DFT of two groups were significantly different (M = 20.3 months vs W = 15.1 months, p=0.039). Visceral pleura invasion (p=0.045) and EGFR gene mutation (p=0.039) were prognostic factor for DFT in univariable analysis. In multivariable analysis, EGFR gene mutation was the only prognostic factor for DFT. (HR – 0.676, 95% CI – 0.371 ~ 0.986, p=0.042) No significant factor for DFT was identified in loco-regional recurrence. EGFR gene mutation, however, was the only significant prognostic factor for DFT of distant metastasis (HR – 0.561, 95% CI – 0.356 ~ 0.885, p=0.013) in univariable and multivariable analysis.

Conclusion:
In recurrent lung adenocarcinoma, EGFR gene mutation group showed longer DFT than wild-type EGFR group. EGFR gene mutation is a prognostic factor in lung adenocarcinoma and slow-growing nature of adenocarcinoma with EGFR gene mutation should be considered in surveillance after surgery.

Background:
The aim of this retrospective study was to review recurrence patterns of stage I non-small cell lung cancer (NSCLC) and identify prognostic factors for post-recurrence survival (PRS).

Method:
Among 940 patients with pathological stage I NSCLC who underwent curative resection between 2001 and 2009, 261 patients who had experienced a recurrence were included in this study. A total of 188 patients had adenocarcinoma (ADC), and 62 had squamous cell carcinoma (SCC). Oligo-recurrence was defined as one to three locoregional or distant recurrent lesions restricted to a single organ. Potentially curative local treatment (PCLT) included surgery, stereotactic radiotherapy (SRT), and photodynamic therapy.

Result:
The median follow-up duration was 65 months (range: 4–186 months), and the median disease-free interval (DFI) was 23 months (range: 2–95 months). The most common site of recurrence was the lung in 145 patients, followed by a mediastinal lymph node in 49 patients, pleura in 30 patients, and brain in 27 patients. Local treatment for recurrent tumors included surgery in 59 patients, SRT in 46 patients, photodynamic therapy (PDT) in 2 patients, and other radiotherapy in 41 patients. Seventy-eight patients received chemotherapy only, and thirty-five patients received conservative treatment. Among 125 patients who were evaluated for an epidermal growth factor receptor (EGFR) gene mutation study, positive results were detected in 63 patients, and 31 were treated with a EGFR-tyrosine kinase inhibitor (EGFR-TKI). The 3- and 5-year PRS rates were 49.1% and 33.8%, respectively. Age at recurrence, ADC cell-type, DFI, TKI, and PCLT were independent prognostic factors in a multivariate analysis.

Conclusion:
local treatment for recurrent tumors could be a good option for selected candidates. Local treatment seems to be a reasonable modality for treating oligo-recurrence, even an extrapulmonary recurrence. Use of an EGFR-TKI is applicable if an EGFR mutation has been detected. Further study is required to identify patients who are optimal candidates for local treatment.